Antibiotics ndash mechanism of resistance ndash

related history [MRSA VRE VISA ESBLS]

By DrRaghu prakash reddy

A statue of the Hindu God Brahma Hinduism believes in the divine origin of Ayurveda

1495 Europeans Mercury ------gt syphilis(Treponema pallidum)

1630 Europeans Quinine (bark of cinchona) -----gt malaria (Plasmodium spp)

A statue of the Hindu God Brahma Hinduism believes in the divine origin of Ayurveda

1495 Europeans Mercury ------gt syphilis(Treponema pallidum)

1630 Europeans Quinine (bark of cinchona) -----gt malaria (Plasmodium spp)

Ignaacutec Semmelweis (1818-1865)ndash assistant in midwifery ofAllgemeines Krankenhaus(Vienna) in 1846ndash noted that up to 15 women diedfrom childbed puerperal feverafter physician-assisted deliveryndash by contrast mortality was low indeliveries performed by midwives

History of infection control

bullIgnaacutec Semmelweisndash discovered that physician handwashing with carbolicacid prior to delivery dramatically reduced mortality

ndash he wrote a bunch of letters to the establishmentoutlining his discovery

ndash he was declared a lunatic and institutionalizedndash died from blood poisoning 10 d after receiving afinger cut while forced into a straightjacket

History of infection control

bull Joseph Lister (1827-1912)ndash English surgeonndash knew of Louis Pasteurs germ theoryndash reasoned that if airborne microbes could sour milk and rot meat they may also infect wounds

ndash in the 1860s he introduced disinfection of operating theatres using carbolic acid spray Listerian antisepsisldquo

ndash gloves were originally introduced toprevent dermatitis from antiseptics

History of Antibiotics

1877 Louis Pasteur Inhibition of some microbes by others anthrax

1908 Gelmo Synthesized sulfanilamide (1st sulfonamide)

1908-10 Paul Ehrlich Selective stains Synthesized arsenic compound arsphenamine (Nobel Prize) (606 Salvarsan) -----gt syphilis (T pallidum) Coined terms magic bullet chemotherapy chemical knife) Further progress delayed by physician hesitancy

1913 Eisenberg Studied bactericidal properties of azo dyes with sulfonamide grouping

Asepsis

bull Antisepsis vs asepsis

ndash aseptic techniques introduced in early 1900s

ndash focused on preventing microbes from getting to the patient rather than fumigating everything

ndash surgeons used gloves gowns masks filtered air etc in combination with disinfection

ndash asepsis continued as the primary means of infection control into the 1950s

Selman Waksman suggests the word antibiotic (coined in 1889 by P Vuillemin) after Dr J E Flynn the editor of Biological Abstracts asked him

to suggest a term for chemical substances including compounds and preparations that are produced by microbes and have antimicrobial

properties

Although there is no journal citation Waksman recalled the incident in his book The Antibiotic Era Because the word was accepted quickly and the

meaning became confused Waksman published a comprehensive definition in 1947

an antibiotic is a chemical substance produced by microbes that inhibits the growth of and even destroys other microbes (and is active in dilute

solutions) was added later

The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteurs pupil Paul Vuillemin which means a process by which life could be used to destroy life

Brief History of Antibiotics

bull 1928- Penicillin discovered by Fleming

bull 1932- Sulfonamide antimicrobial activity discovered Erlichbull

bull 1943- Drug companies begin mass production of penicillin

bull 1948- Cephalosporins precursor sent to Oxford for synthesis

bull 1952- Erythromycin derived from Streptomyces erythreus

bull 1956- Vancomycin introduced for penicillin resistant staphylococcus

bull 1962- Quinolone antibiotics first discovered

bull 1970s- Linezolide discovered but not pursued

bull 1980s- Fluorinated Quinolones introduced making then clinically useful

bull 2000- Linezolide introduced into clinical practice

Antibiotic natural source first description as anti-infective drug

discoverer

sulfanilamide (prontosil 1932

1941

GDomagk

penicillin Penicillium notatum AFleming Florey Chain

streptomycin Streptomyces griseus 1944 SAWaksman

cephalosporin Cephalosporium acremonium 1945 GBrotzu

bacitracin Bacillus subtilis 1945

BAJohnson

chloramphenicol Streptomyces venezuellae 1947 IEhrlich

polymyxin Bacillus polymyxa 1947 CGAinsworth

chlortetracyclin Streptomyces aureofaciens 1948 BMDuggar

neomycin Streptomyces fradiae 1949

SAWaksman

oxytetracyclin Streptomyces rimosus 1950 ACFinlay

The End of Infectious Disease

bullIn 1967 US Surgeon General William H Stewart told a White House gathering of health officers that ldquoit was time to close the book on infectious diseasesrdquoand shift all national attention (and dollars) to what he termed lsquothe New Dimensionsrsquoof health chronic diseasesrdquo

bullIn the US deaths from infectious disease dropped by 82 annually from 1938 to 1952 and by 23 annually thereafter until 1980

bullNew antibiotics were being discovered on a yearly basis to replace any that had lost effectiveness

The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually

bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001

bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion

bull37 new human pathogens have been identified in the last 30 years

bull12 of known human pathogens have been recognized as emerging or reemerging health threats

The End of Infectious Disease

bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)

It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945

The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming

Howard Florey

Basic Classes of Antibiotics

bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets

ndashβ-lactams (penicillins) ndashcell wall biosynthesis

ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis

ndashAminoglycosides (gentamycin) ndashprotein synthesis

ndashMacrolides (erythromycin) ndashprotein synthesis

ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis

ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism

The four main mechanisms of antibacterial action

Lipid Carrier Cycle

Historical Aspects

bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection

Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported

Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-GenerationCephalosporins

1963

1965

TEM-1E coliS paratyphi

1970s

TEM-1Reported in28 Gram-NegativeSpecies

1980s1983

ESBLinUnitedStates

1987

ESBL inEurope

2000

gt120 ESBLsWorldwide

How Do Bacteria Develop Resistance

Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution

How Does it work

Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

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• Active efflux of antibiotics
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• Slide 63
• Slide 64

History of infection control

bullIgnaacutec Semmelweisndash discovered that physician handwashing with carbolicacid prior to delivery dramatically reduced mortality

ndash he wrote a bunch of letters to the establishmentoutlining his discovery

ndash he was declared a lunatic and institutionalizedndash died from blood poisoning 10 d after receiving afinger cut while forced into a straightjacket

History of infection control

bull Joseph Lister (1827-1912)ndash English surgeonndash knew of Louis Pasteurs germ theoryndash reasoned that if airborne microbes could sour milk and rot meat they may also infect wounds

ndash in the 1860s he introduced disinfection of operating theatres using carbolic acid spray Listerian antisepsisldquo

ndash gloves were originally introduced toprevent dermatitis from antiseptics

History of Antibiotics

1877 Louis Pasteur Inhibition of some microbes by others anthrax

1908 Gelmo Synthesized sulfanilamide (1st sulfonamide)

1908-10 Paul Ehrlich Selective stains Synthesized arsenic compound arsphenamine (Nobel Prize) (606 Salvarsan) -----gt syphilis (T pallidum) Coined terms magic bullet chemotherapy chemical knife) Further progress delayed by physician hesitancy

1913 Eisenberg Studied bactericidal properties of azo dyes with sulfonamide grouping

Asepsis

bull Antisepsis vs asepsis

ndash aseptic techniques introduced in early 1900s

ndash focused on preventing microbes from getting to the patient rather than fumigating everything

ndash surgeons used gloves gowns masks filtered air etc in combination with disinfection

ndash asepsis continued as the primary means of infection control into the 1950s

Selman Waksman suggests the word antibiotic (coined in 1889 by P Vuillemin) after Dr J E Flynn the editor of Biological Abstracts asked him

to suggest a term for chemical substances including compounds and preparations that are produced by microbes and have antimicrobial

properties

Although there is no journal citation Waksman recalled the incident in his book The Antibiotic Era Because the word was accepted quickly and the

meaning became confused Waksman published a comprehensive definition in 1947

an antibiotic is a chemical substance produced by microbes that inhibits the growth of and even destroys other microbes (and is active in dilute

solutions) was added later

The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteurs pupil Paul Vuillemin which means a process by which life could be used to destroy life

Brief History of Antibiotics

bull 1928- Penicillin discovered by Fleming

bull 1932- Sulfonamide antimicrobial activity discovered Erlichbull

bull 1943- Drug companies begin mass production of penicillin

bull 1948- Cephalosporins precursor sent to Oxford for synthesis

bull 1952- Erythromycin derived from Streptomyces erythreus

bull 1956- Vancomycin introduced for penicillin resistant staphylococcus

bull 1962- Quinolone antibiotics first discovered

bull 1970s- Linezolide discovered but not pursued

bull 1980s- Fluorinated Quinolones introduced making then clinically useful

bull 2000- Linezolide introduced into clinical practice

Antibiotic natural source first description as anti-infective drug

discoverer

sulfanilamide (prontosil 1932

1941

GDomagk

penicillin Penicillium notatum AFleming Florey Chain

streptomycin Streptomyces griseus 1944 SAWaksman

cephalosporin Cephalosporium acremonium 1945 GBrotzu

bacitracin Bacillus subtilis 1945

BAJohnson

chloramphenicol Streptomyces venezuellae 1947 IEhrlich

polymyxin Bacillus polymyxa 1947 CGAinsworth

chlortetracyclin Streptomyces aureofaciens 1948 BMDuggar

neomycin Streptomyces fradiae 1949

SAWaksman

oxytetracyclin Streptomyces rimosus 1950 ACFinlay

The End of Infectious Disease

bullIn 1967 US Surgeon General William H Stewart told a White House gathering of health officers that ldquoit was time to close the book on infectious diseasesrdquoand shift all national attention (and dollars) to what he termed lsquothe New Dimensionsrsquoof health chronic diseasesrdquo

bullIn the US deaths from infectious disease dropped by 82 annually from 1938 to 1952 and by 23 annually thereafter until 1980

bullNew antibiotics were being discovered on a yearly basis to replace any that had lost effectiveness

The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually

bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001

bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion

bull37 new human pathogens have been identified in the last 30 years

bull12 of known human pathogens have been recognized as emerging or reemerging health threats

The End of Infectious Disease

bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)

It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945

The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming

Howard Florey

Basic Classes of Antibiotics

bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets

ndashβ-lactams (penicillins) ndashcell wall biosynthesis

ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis

ndashAminoglycosides (gentamycin) ndashprotein synthesis

ndashMacrolides (erythromycin) ndashprotein synthesis

ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis

ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism

The four main mechanisms of antibacterial action

Lipid Carrier Cycle

Historical Aspects

bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection

Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported

Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-GenerationCephalosporins

1963

1965

TEM-1E coliS paratyphi

1970s

TEM-1Reported in28 Gram-NegativeSpecies

1980s1983

ESBLinUnitedStates

1987

ESBL inEurope

2000

gt120 ESBLsWorldwide

How Do Bacteria Develop Resistance

Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution

How Does it work

Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
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• Slide 7
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• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
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• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

History of infection control

bull Joseph Lister (1827-1912)ndash English surgeonndash knew of Louis Pasteurs germ theoryndash reasoned that if airborne microbes could sour milk and rot meat they may also infect wounds

ndash in the 1860s he introduced disinfection of operating theatres using carbolic acid spray Listerian antisepsisldquo

ndash gloves were originally introduced toprevent dermatitis from antiseptics

History of Antibiotics

1877 Louis Pasteur Inhibition of some microbes by others anthrax

1908 Gelmo Synthesized sulfanilamide (1st sulfonamide)

1908-10 Paul Ehrlich Selective stains Synthesized arsenic compound arsphenamine (Nobel Prize) (606 Salvarsan) -----gt syphilis (T pallidum) Coined terms magic bullet chemotherapy chemical knife) Further progress delayed by physician hesitancy

1913 Eisenberg Studied bactericidal properties of azo dyes with sulfonamide grouping

Asepsis

bull Antisepsis vs asepsis

ndash aseptic techniques introduced in early 1900s

ndash focused on preventing microbes from getting to the patient rather than fumigating everything

ndash surgeons used gloves gowns masks filtered air etc in combination with disinfection

ndash asepsis continued as the primary means of infection control into the 1950s

Selman Waksman suggests the word antibiotic (coined in 1889 by P Vuillemin) after Dr J E Flynn the editor of Biological Abstracts asked him

to suggest a term for chemical substances including compounds and preparations that are produced by microbes and have antimicrobial

properties

Although there is no journal citation Waksman recalled the incident in his book The Antibiotic Era Because the word was accepted quickly and the

meaning became confused Waksman published a comprehensive definition in 1947

an antibiotic is a chemical substance produced by microbes that inhibits the growth of and even destroys other microbes (and is active in dilute

solutions) was added later

The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteurs pupil Paul Vuillemin which means a process by which life could be used to destroy life

Brief History of Antibiotics

bull 1928- Penicillin discovered by Fleming

bull 1932- Sulfonamide antimicrobial activity discovered Erlichbull

bull 1943- Drug companies begin mass production of penicillin

bull 1948- Cephalosporins precursor sent to Oxford for synthesis

bull 1952- Erythromycin derived from Streptomyces erythreus

bull 1956- Vancomycin introduced for penicillin resistant staphylococcus

bull 1962- Quinolone antibiotics first discovered

bull 1970s- Linezolide discovered but not pursued

bull 1980s- Fluorinated Quinolones introduced making then clinically useful

bull 2000- Linezolide introduced into clinical practice

Antibiotic natural source first description as anti-infective drug

discoverer

sulfanilamide (prontosil 1932

1941

GDomagk

penicillin Penicillium notatum AFleming Florey Chain

streptomycin Streptomyces griseus 1944 SAWaksman

cephalosporin Cephalosporium acremonium 1945 GBrotzu

bacitracin Bacillus subtilis 1945

BAJohnson

chloramphenicol Streptomyces venezuellae 1947 IEhrlich

polymyxin Bacillus polymyxa 1947 CGAinsworth

chlortetracyclin Streptomyces aureofaciens 1948 BMDuggar

neomycin Streptomyces fradiae 1949

SAWaksman

oxytetracyclin Streptomyces rimosus 1950 ACFinlay

The End of Infectious Disease

bullIn 1967 US Surgeon General William H Stewart told a White House gathering of health officers that ldquoit was time to close the book on infectious diseasesrdquoand shift all national attention (and dollars) to what he termed lsquothe New Dimensionsrsquoof health chronic diseasesrdquo

bullIn the US deaths from infectious disease dropped by 82 annually from 1938 to 1952 and by 23 annually thereafter until 1980

bullNew antibiotics were being discovered on a yearly basis to replace any that had lost effectiveness

The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually

bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001

bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion

bull37 new human pathogens have been identified in the last 30 years

bull12 of known human pathogens have been recognized as emerging or reemerging health threats

The End of Infectious Disease

bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)

It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945

The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming

Howard Florey

Basic Classes of Antibiotics

bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets

ndashβ-lactams (penicillins) ndashcell wall biosynthesis

ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis

ndashAminoglycosides (gentamycin) ndashprotein synthesis

ndashMacrolides (erythromycin) ndashprotein synthesis

ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis

ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism

The four main mechanisms of antibacterial action

Lipid Carrier Cycle

Historical Aspects

bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection

Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported

Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-GenerationCephalosporins

1963

1965

TEM-1E coliS paratyphi

1970s

TEM-1Reported in28 Gram-NegativeSpecies

1980s1983

ESBLinUnitedStates

1987

ESBL inEurope

2000

gt120 ESBLsWorldwide

How Do Bacteria Develop Resistance

Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution

How Does it work

Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

History of Antibiotics

1877 Louis Pasteur Inhibition of some microbes by others anthrax

1908 Gelmo Synthesized sulfanilamide (1st sulfonamide)

1908-10 Paul Ehrlich Selective stains Synthesized arsenic compound arsphenamine (Nobel Prize) (606 Salvarsan) -----gt syphilis (T pallidum) Coined terms magic bullet chemotherapy chemical knife) Further progress delayed by physician hesitancy

1913 Eisenberg Studied bactericidal properties of azo dyes with sulfonamide grouping

Asepsis

bull Antisepsis vs asepsis

ndash aseptic techniques introduced in early 1900s

ndash focused on preventing microbes from getting to the patient rather than fumigating everything

ndash surgeons used gloves gowns masks filtered air etc in combination with disinfection

ndash asepsis continued as the primary means of infection control into the 1950s

Selman Waksman suggests the word antibiotic (coined in 1889 by P Vuillemin) after Dr J E Flynn the editor of Biological Abstracts asked him

to suggest a term for chemical substances including compounds and preparations that are produced by microbes and have antimicrobial

properties

Although there is no journal citation Waksman recalled the incident in his book The Antibiotic Era Because the word was accepted quickly and the

meaning became confused Waksman published a comprehensive definition in 1947

an antibiotic is a chemical substance produced by microbes that inhibits the growth of and even destroys other microbes (and is active in dilute

solutions) was added later

The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteurs pupil Paul Vuillemin which means a process by which life could be used to destroy life

Brief History of Antibiotics

bull 1928- Penicillin discovered by Fleming

bull 1932- Sulfonamide antimicrobial activity discovered Erlichbull

bull 1943- Drug companies begin mass production of penicillin

bull 1948- Cephalosporins precursor sent to Oxford for synthesis

bull 1952- Erythromycin derived from Streptomyces erythreus

bull 1956- Vancomycin introduced for penicillin resistant staphylococcus

bull 1962- Quinolone antibiotics first discovered

bull 1970s- Linezolide discovered but not pursued

bull 1980s- Fluorinated Quinolones introduced making then clinically useful

bull 2000- Linezolide introduced into clinical practice

Antibiotic natural source first description as anti-infective drug

discoverer

sulfanilamide (prontosil 1932

1941

GDomagk

penicillin Penicillium notatum AFleming Florey Chain

streptomycin Streptomyces griseus 1944 SAWaksman

cephalosporin Cephalosporium acremonium 1945 GBrotzu

bacitracin Bacillus subtilis 1945

BAJohnson

chloramphenicol Streptomyces venezuellae 1947 IEhrlich

polymyxin Bacillus polymyxa 1947 CGAinsworth

chlortetracyclin Streptomyces aureofaciens 1948 BMDuggar

neomycin Streptomyces fradiae 1949

SAWaksman

oxytetracyclin Streptomyces rimosus 1950 ACFinlay

The End of Infectious Disease

bullIn 1967 US Surgeon General William H Stewart told a White House gathering of health officers that ldquoit was time to close the book on infectious diseasesrdquoand shift all national attention (and dollars) to what he termed lsquothe New Dimensionsrsquoof health chronic diseasesrdquo

bullIn the US deaths from infectious disease dropped by 82 annually from 1938 to 1952 and by 23 annually thereafter until 1980

bullNew antibiotics were being discovered on a yearly basis to replace any that had lost effectiveness

The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually

bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001

bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion

bull37 new human pathogens have been identified in the last 30 years

bull12 of known human pathogens have been recognized as emerging or reemerging health threats

The End of Infectious Disease

bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)

It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945

The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming

Howard Florey

Basic Classes of Antibiotics

bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets

ndashβ-lactams (penicillins) ndashcell wall biosynthesis

ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis

ndashAminoglycosides (gentamycin) ndashprotein synthesis

ndashMacrolides (erythromycin) ndashprotein synthesis

ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis

ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism

The four main mechanisms of antibacterial action

Lipid Carrier Cycle

Historical Aspects

bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection

Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported

Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-GenerationCephalosporins

1963

1965

TEM-1E coliS paratyphi

1970s

TEM-1Reported in28 Gram-NegativeSpecies

1980s1983

ESBLinUnitedStates

1987

ESBL inEurope

2000

gt120 ESBLsWorldwide

How Do Bacteria Develop Resistance

Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution

How Does it work

Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Asepsis

bull Antisepsis vs asepsis

ndash aseptic techniques introduced in early 1900s

ndash focused on preventing microbes from getting to the patient rather than fumigating everything

ndash surgeons used gloves gowns masks filtered air etc in combination with disinfection

ndash asepsis continued as the primary means of infection control into the 1950s

Selman Waksman suggests the word antibiotic (coined in 1889 by P Vuillemin) after Dr J E Flynn the editor of Biological Abstracts asked him

to suggest a term for chemical substances including compounds and preparations that are produced by microbes and have antimicrobial

properties

Although there is no journal citation Waksman recalled the incident in his book The Antibiotic Era Because the word was accepted quickly and the

meaning became confused Waksman published a comprehensive definition in 1947

an antibiotic is a chemical substance produced by microbes that inhibits the growth of and even destroys other microbes (and is active in dilute

solutions) was added later

The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteurs pupil Paul Vuillemin which means a process by which life could be used to destroy life

Brief History of Antibiotics

bull 1928- Penicillin discovered by Fleming

bull 1932- Sulfonamide antimicrobial activity discovered Erlichbull

bull 1943- Drug companies begin mass production of penicillin

bull 1948- Cephalosporins precursor sent to Oxford for synthesis

bull 1952- Erythromycin derived from Streptomyces erythreus

bull 1956- Vancomycin introduced for penicillin resistant staphylococcus

bull 1962- Quinolone antibiotics first discovered

bull 1970s- Linezolide discovered but not pursued

bull 1980s- Fluorinated Quinolones introduced making then clinically useful

bull 2000- Linezolide introduced into clinical practice

Antibiotic natural source first description as anti-infective drug

discoverer

sulfanilamide (prontosil 1932

1941

GDomagk

penicillin Penicillium notatum AFleming Florey Chain

streptomycin Streptomyces griseus 1944 SAWaksman

cephalosporin Cephalosporium acremonium 1945 GBrotzu

bacitracin Bacillus subtilis 1945

BAJohnson

chloramphenicol Streptomyces venezuellae 1947 IEhrlich

polymyxin Bacillus polymyxa 1947 CGAinsworth

chlortetracyclin Streptomyces aureofaciens 1948 BMDuggar

neomycin Streptomyces fradiae 1949

SAWaksman

oxytetracyclin Streptomyces rimosus 1950 ACFinlay

The End of Infectious Disease

bullIn 1967 US Surgeon General William H Stewart told a White House gathering of health officers that ldquoit was time to close the book on infectious diseasesrdquoand shift all national attention (and dollars) to what he termed lsquothe New Dimensionsrsquoof health chronic diseasesrdquo

bullIn the US deaths from infectious disease dropped by 82 annually from 1938 to 1952 and by 23 annually thereafter until 1980

bullNew antibiotics were being discovered on a yearly basis to replace any that had lost effectiveness

The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually

bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001

bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion

bull37 new human pathogens have been identified in the last 30 years

bull12 of known human pathogens have been recognized as emerging or reemerging health threats

The End of Infectious Disease

bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)

It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945

The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming

Howard Florey

Basic Classes of Antibiotics

bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets

ndashβ-lactams (penicillins) ndashcell wall biosynthesis

ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis

ndashAminoglycosides (gentamycin) ndashprotein synthesis

ndashMacrolides (erythromycin) ndashprotein synthesis

ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis

ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism

The four main mechanisms of antibacterial action

Lipid Carrier Cycle

Historical Aspects

bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection

Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported

Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-GenerationCephalosporins

1963

1965

TEM-1E coliS paratyphi

1970s

TEM-1Reported in28 Gram-NegativeSpecies

1980s1983

ESBLinUnitedStates

1987

ESBL inEurope

2000

gt120 ESBLsWorldwide

How Do Bacteria Develop Resistance

Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution

How Does it work

Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Selman Waksman suggests the word antibiotic (coined in 1889 by P Vuillemin) after Dr J E Flynn the editor of Biological Abstracts asked him

to suggest a term for chemical substances including compounds and preparations that are produced by microbes and have antimicrobial

properties

Although there is no journal citation Waksman recalled the incident in his book The Antibiotic Era Because the word was accepted quickly and the

meaning became confused Waksman published a comprehensive definition in 1947

an antibiotic is a chemical substance produced by microbes that inhibits the growth of and even destroys other microbes (and is active in dilute

solutions) was added later

The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteurs pupil Paul Vuillemin which means a process by which life could be used to destroy life

Brief History of Antibiotics

bull 1928- Penicillin discovered by Fleming

bull 1932- Sulfonamide antimicrobial activity discovered Erlichbull

bull 1943- Drug companies begin mass production of penicillin

bull 1948- Cephalosporins precursor sent to Oxford for synthesis

bull 1952- Erythromycin derived from Streptomyces erythreus

bull 1956- Vancomycin introduced for penicillin resistant staphylococcus

bull 1962- Quinolone antibiotics first discovered

bull 1970s- Linezolide discovered but not pursued

bull 1980s- Fluorinated Quinolones introduced making then clinically useful

bull 2000- Linezolide introduced into clinical practice

Antibiotic natural source first description as anti-infective drug

discoverer

sulfanilamide (prontosil 1932

1941

GDomagk

penicillin Penicillium notatum AFleming Florey Chain

streptomycin Streptomyces griseus 1944 SAWaksman

cephalosporin Cephalosporium acremonium 1945 GBrotzu

bacitracin Bacillus subtilis 1945

BAJohnson

chloramphenicol Streptomyces venezuellae 1947 IEhrlich

polymyxin Bacillus polymyxa 1947 CGAinsworth

chlortetracyclin Streptomyces aureofaciens 1948 BMDuggar

neomycin Streptomyces fradiae 1949

SAWaksman

oxytetracyclin Streptomyces rimosus 1950 ACFinlay

The End of Infectious Disease

bullIn 1967 US Surgeon General William H Stewart told a White House gathering of health officers that ldquoit was time to close the book on infectious diseasesrdquoand shift all national attention (and dollars) to what he termed lsquothe New Dimensionsrsquoof health chronic diseasesrdquo

bullIn the US deaths from infectious disease dropped by 82 annually from 1938 to 1952 and by 23 annually thereafter until 1980

bullNew antibiotics were being discovered on a yearly basis to replace any that had lost effectiveness

The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually

bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001

bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion

bull37 new human pathogens have been identified in the last 30 years

bull12 of known human pathogens have been recognized as emerging or reemerging health threats

The End of Infectious Disease

bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)

It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945

The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming

Howard Florey

Basic Classes of Antibiotics

bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets

ndashβ-lactams (penicillins) ndashcell wall biosynthesis

ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis

ndashAminoglycosides (gentamycin) ndashprotein synthesis

ndashMacrolides (erythromycin) ndashprotein synthesis

ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis

ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism

The four main mechanisms of antibacterial action

Lipid Carrier Cycle

Historical Aspects

bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection

Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported

Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-GenerationCephalosporins

1963

1965

TEM-1E coliS paratyphi

1970s

TEM-1Reported in28 Gram-NegativeSpecies

1980s1983

ESBLinUnitedStates

1987

ESBL inEurope

2000

gt120 ESBLsWorldwide

How Do Bacteria Develop Resistance

Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution

How Does it work

Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Brief History of Antibiotics

bull 1928- Penicillin discovered by Fleming

bull 1932- Sulfonamide antimicrobial activity discovered Erlichbull

bull 1943- Drug companies begin mass production of penicillin

bull 1948- Cephalosporins precursor sent to Oxford for synthesis

bull 1952- Erythromycin derived from Streptomyces erythreus

bull 1956- Vancomycin introduced for penicillin resistant staphylococcus

bull 1962- Quinolone antibiotics first discovered

bull 1970s- Linezolide discovered but not pursued

bull 1980s- Fluorinated Quinolones introduced making then clinically useful

bull 2000- Linezolide introduced into clinical practice

Antibiotic natural source first description as anti-infective drug

discoverer

sulfanilamide (prontosil 1932

1941

GDomagk

penicillin Penicillium notatum AFleming Florey Chain

streptomycin Streptomyces griseus 1944 SAWaksman

cephalosporin Cephalosporium acremonium 1945 GBrotzu

bacitracin Bacillus subtilis 1945

BAJohnson

chloramphenicol Streptomyces venezuellae 1947 IEhrlich

polymyxin Bacillus polymyxa 1947 CGAinsworth

chlortetracyclin Streptomyces aureofaciens 1948 BMDuggar

neomycin Streptomyces fradiae 1949

SAWaksman

oxytetracyclin Streptomyces rimosus 1950 ACFinlay

The End of Infectious Disease

bullIn 1967 US Surgeon General William H Stewart told a White House gathering of health officers that ldquoit was time to close the book on infectious diseasesrdquoand shift all national attention (and dollars) to what he termed lsquothe New Dimensionsrsquoof health chronic diseasesrdquo

bullIn the US deaths from infectious disease dropped by 82 annually from 1938 to 1952 and by 23 annually thereafter until 1980

bullNew antibiotics were being discovered on a yearly basis to replace any that had lost effectiveness

The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually

bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001

bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion

bull37 new human pathogens have been identified in the last 30 years

bull12 of known human pathogens have been recognized as emerging or reemerging health threats

The End of Infectious Disease

bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)

It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945

The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming

Howard Florey

Basic Classes of Antibiotics

bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets

ndashβ-lactams (penicillins) ndashcell wall biosynthesis

ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis

ndashAminoglycosides (gentamycin) ndashprotein synthesis

ndashMacrolides (erythromycin) ndashprotein synthesis

ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis

ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism

The four main mechanisms of antibacterial action

Lipid Carrier Cycle

Historical Aspects

bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection

Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported

Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-GenerationCephalosporins

1963

1965

TEM-1E coliS paratyphi

1970s

TEM-1Reported in28 Gram-NegativeSpecies

1980s1983

ESBLinUnitedStates

1987

ESBL inEurope

2000

gt120 ESBLsWorldwide

How Do Bacteria Develop Resistance

Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution

How Does it work

Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Antibiotic natural source first description as anti-infective drug

discoverer

sulfanilamide (prontosil 1932

1941

GDomagk

penicillin Penicillium notatum AFleming Florey Chain

streptomycin Streptomyces griseus 1944 SAWaksman

cephalosporin Cephalosporium acremonium 1945 GBrotzu

bacitracin Bacillus subtilis 1945

BAJohnson

chloramphenicol Streptomyces venezuellae 1947 IEhrlich

polymyxin Bacillus polymyxa 1947 CGAinsworth

chlortetracyclin Streptomyces aureofaciens 1948 BMDuggar

neomycin Streptomyces fradiae 1949

SAWaksman

oxytetracyclin Streptomyces rimosus 1950 ACFinlay

The End of Infectious Disease

bullIn 1967 US Surgeon General William H Stewart told a White House gathering of health officers that ldquoit was time to close the book on infectious diseasesrdquoand shift all national attention (and dollars) to what he termed lsquothe New Dimensionsrsquoof health chronic diseasesrdquo

bullIn the US deaths from infectious disease dropped by 82 annually from 1938 to 1952 and by 23 annually thereafter until 1980

bullNew antibiotics were being discovered on a yearly basis to replace any that had lost effectiveness

The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually

bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001

bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion

bull37 new human pathogens have been identified in the last 30 years

bull12 of known human pathogens have been recognized as emerging or reemerging health threats

The End of Infectious Disease

bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)

It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945

The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming

Howard Florey

Basic Classes of Antibiotics

bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets

ndashβ-lactams (penicillins) ndashcell wall biosynthesis

ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis

ndashAminoglycosides (gentamycin) ndashprotein synthesis

ndashMacrolides (erythromycin) ndashprotein synthesis

ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis

ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism

The four main mechanisms of antibacterial action

Lipid Carrier Cycle

Historical Aspects

bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection

Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported

Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-GenerationCephalosporins

1963

1965

TEM-1E coliS paratyphi

1970s

TEM-1Reported in28 Gram-NegativeSpecies

1980s1983

ESBLinUnitedStates

1987

ESBL inEurope

2000

gt120 ESBLsWorldwide

How Do Bacteria Develop Resistance

Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution

How Does it work

Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
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• Slide 7
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• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
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• Slide 53
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• Slide 61
• Slide 62
• Slide 63
• Slide 64

The End of Infectious Disease

bullIn 1967 US Surgeon General William H Stewart told a White House gathering of health officers that ldquoit was time to close the book on infectious diseasesrdquoand shift all national attention (and dollars) to what he termed lsquothe New Dimensionsrsquoof health chronic diseasesrdquo

bullIn the US deaths from infectious disease dropped by 82 annually from 1938 to 1952 and by 23 annually thereafter until 1980

bullNew antibiotics were being discovered on a yearly basis to replace any that had lost effectiveness

The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually

bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001

bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion

bull37 new human pathogens have been identified in the last 30 years

bull12 of known human pathogens have been recognized as emerging or reemerging health threats

The End of Infectious Disease

bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)

It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945

The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming

Howard Florey

Basic Classes of Antibiotics

bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets

ndashβ-lactams (penicillins) ndashcell wall biosynthesis

ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis

ndashAminoglycosides (gentamycin) ndashprotein synthesis

ndashMacrolides (erythromycin) ndashprotein synthesis

ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis

ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism

The four main mechanisms of antibacterial action

Lipid Carrier Cycle

Historical Aspects

bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection

Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported

Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-GenerationCephalosporins

1963

1965

TEM-1E coliS paratyphi

1970s

TEM-1Reported in28 Gram-NegativeSpecies

1980s1983

ESBLinUnitedStates

1987

ESBL inEurope

2000

gt120 ESBLsWorldwide

How Do Bacteria Develop Resistance

Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution

How Does it work

Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 16
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• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually

bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001

bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion

bull37 new human pathogens have been identified in the last 30 years

bull12 of known human pathogens have been recognized as emerging or reemerging health threats

The End of Infectious Disease

bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)

It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945

The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming

Howard Florey

Basic Classes of Antibiotics

bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets

ndashβ-lactams (penicillins) ndashcell wall biosynthesis

ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis

ndashAminoglycosides (gentamycin) ndashprotein synthesis

ndashMacrolides (erythromycin) ndashprotein synthesis

ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis

ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism

The four main mechanisms of antibacterial action

Lipid Carrier Cycle

Historical Aspects

bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection

Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported

Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-GenerationCephalosporins

1963

1965

TEM-1E coliS paratyphi

1970s

TEM-1Reported in28 Gram-NegativeSpecies

1980s1983

ESBLinUnitedStates

1987

ESBL inEurope

2000

gt120 ESBLsWorldwide

How Do Bacteria Develop Resistance

Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution

How Does it work

Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
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• Slide 19
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• Slide 23
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• Slide 29
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• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

The End of Infectious Disease

bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)

It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945

The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming

Howard Florey

Basic Classes of Antibiotics

bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets

ndashβ-lactams (penicillins) ndashcell wall biosynthesis

ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis

ndashAminoglycosides (gentamycin) ndashprotein synthesis

ndashMacrolides (erythromycin) ndashprotein synthesis

ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis

ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism

The four main mechanisms of antibacterial action

Lipid Carrier Cycle

Historical Aspects

bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection

Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported

Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-GenerationCephalosporins

1963

1965

TEM-1E coliS paratyphi

1970s

TEM-1Reported in28 Gram-NegativeSpecies

1980s1983

ESBLinUnitedStates

1987

ESBL inEurope

2000

gt120 ESBLsWorldwide

How Do Bacteria Develop Resistance

Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution

How Does it work

Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 13
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• Slide 16
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• Slide 19
• Slide 20
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• Slide 23
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• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
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• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945

The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming

Howard Florey

Basic Classes of Antibiotics

bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets

ndashβ-lactams (penicillins) ndashcell wall biosynthesis

ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis

ndashAminoglycosides (gentamycin) ndashprotein synthesis

ndashMacrolides (erythromycin) ndashprotein synthesis

ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis

ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism

The four main mechanisms of antibacterial action

Lipid Carrier Cycle

Historical Aspects

bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection

Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported

Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-GenerationCephalosporins

1963

1965

TEM-1E coliS paratyphi

1970s

TEM-1Reported in28 Gram-NegativeSpecies

1980s1983

ESBLinUnitedStates

1987

ESBL inEurope

2000

gt120 ESBLsWorldwide

How Do Bacteria Develop Resistance

Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution

How Does it work

Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 16
• Slide 17
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• Slide 19
• Slide 20
• Slide 21
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• Slide 23
• Slide 24
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• Slide 26
• Slide 27
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• Slide 29
• Slide 30
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• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming

Howard Florey

Basic Classes of Antibiotics

bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets

ndashβ-lactams (penicillins) ndashcell wall biosynthesis

ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis

ndashAminoglycosides (gentamycin) ndashprotein synthesis

ndashMacrolides (erythromycin) ndashprotein synthesis

ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis

ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism

The four main mechanisms of antibacterial action

Lipid Carrier Cycle

Historical Aspects

bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection

Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported

Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-GenerationCephalosporins

1963

1965

TEM-1E coliS paratyphi

1970s

TEM-1Reported in28 Gram-NegativeSpecies

1980s1983

ESBLinUnitedStates

1987

ESBL inEurope

2000

gt120 ESBLsWorldwide

How Do Bacteria Develop Resistance

Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution

How Does it work

Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 30
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• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Howard Florey

Basic Classes of Antibiotics

bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets

ndashβ-lactams (penicillins) ndashcell wall biosynthesis

ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis

ndashAminoglycosides (gentamycin) ndashprotein synthesis

ndashMacrolides (erythromycin) ndashprotein synthesis

ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis

ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism

The four main mechanisms of antibacterial action

Lipid Carrier Cycle

Historical Aspects

bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection

Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported

Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-GenerationCephalosporins

1963

1965

TEM-1E coliS paratyphi

1970s

TEM-1Reported in28 Gram-NegativeSpecies

1980s1983

ESBLinUnitedStates

1987

ESBL inEurope

2000

gt120 ESBLsWorldwide

How Do Bacteria Develop Resistance

Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution

How Does it work

Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
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• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Basic Classes of Antibiotics

bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets

ndashβ-lactams (penicillins) ndashcell wall biosynthesis

ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis

ndashAminoglycosides (gentamycin) ndashprotein synthesis

ndashMacrolides (erythromycin) ndashprotein synthesis

ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis

ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism

The four main mechanisms of antibacterial action

Lipid Carrier Cycle

Historical Aspects

bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection

Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported

Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-GenerationCephalosporins

1963

1965

TEM-1E coliS paratyphi

1970s

TEM-1Reported in28 Gram-NegativeSpecies

1980s1983

ESBLinUnitedStates

1987

ESBL inEurope

2000

gt120 ESBLsWorldwide

How Do Bacteria Develop Resistance

Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution

How Does it work

Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
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• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
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• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

The four main mechanisms of antibacterial action

Lipid Carrier Cycle

Historical Aspects

bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection

Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported

Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-GenerationCephalosporins

1963

1965

TEM-1E coliS paratyphi

1970s

TEM-1Reported in28 Gram-NegativeSpecies

1980s1983

ESBLinUnitedStates

1987

ESBL inEurope

2000

gt120 ESBLsWorldwide

How Do Bacteria Develop Resistance

Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution

How Does it work

Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
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• Slide 10
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• Slide 30
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• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Lipid Carrier Cycle

Historical Aspects

bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection

Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported

Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-GenerationCephalosporins

1963

1965

TEM-1E coliS paratyphi

1970s

TEM-1Reported in28 Gram-NegativeSpecies

1980s1983

ESBLinUnitedStates

1987

ESBL inEurope

2000

gt120 ESBLsWorldwide

How Do Bacteria Develop Resistance

Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution

How Does it work

Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 13
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• Slide 16
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• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Historical Aspects

bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection

Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported

Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-GenerationCephalosporins

1963

1965

TEM-1E coliS paratyphi

1970s

TEM-1Reported in28 Gram-NegativeSpecies

1980s1983

ESBLinUnitedStates

1987

ESBL inEurope

2000

gt120 ESBLsWorldwide

How Do Bacteria Develop Resistance

Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution

How Does it work

Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
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• Slide 23
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• Slide 27
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• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported

Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-GenerationCephalosporins

1963

1965

TEM-1E coliS paratyphi

1970s

TEM-1Reported in28 Gram-NegativeSpecies

1980s1983

ESBLinUnitedStates

1987

ESBL inEurope

2000

gt120 ESBLsWorldwide

How Do Bacteria Develop Resistance

Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution

How Does it work

Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
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• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-GenerationCephalosporins

1963

1965

TEM-1E coliS paratyphi

1970s

TEM-1Reported in28 Gram-NegativeSpecies

1980s1983

ESBLinUnitedStates

1987

ESBL inEurope

2000

gt120 ESBLsWorldwide

How Do Bacteria Develop Resistance

Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution

How Does it work

Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

How Do Bacteria Develop Resistance

Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution

How Does it work

Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 17
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• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

What does not destroy me makes me strongermdashNietzsche 1899

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
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• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Whats MRSA And What Can Be Done About It

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
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• Slide 16
• Slide 17
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• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Mechanisms of Antibiotic Resistance

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Horizontal Gene Transfer

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 13
• Slide 14
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• Slide 16
• Slide 17
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• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Resistance to Antibiotics

bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed

bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)

bullThe basic resistance mechanisms are quite simple

1Modify the antibiotic

2Modify the target of the antibiotic

3Destroy the antibiotic

4Make it more difficult for the antibiotic to get into the cell

5Actively remove the antibiotic from the cell

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Active efflux of antibiotics

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Efflux pump is a less potentand less common cause ofresistance

Efflux pumpPmrA

Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Antibiotic Efflux Pumps

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Alteration of the Drug Target SiteVancomycin

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
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• Slide 61
• Slide 62
• Slide 63
• Slide 64

Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)

bull Mutationsbull Plasmidsbull Transposonsbull Integrons

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
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• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Beta Lactamases

bull Classified based on Prim structure

ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)

bull Class AampD - plasmid mediated

bull Class BampC - encoded by chromosomal genes

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Beta Lactamasesbull Major defence of GNB against B lactams

bull Hundreds have co-evolved with newer drugs

bull Spread from Staphylococci to H Influenzae and N gonorrhoeae

bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 13
• Slide 14
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• Slide 16
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• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases

New Beta lactamases

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 13
• Slide 14
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• Slide 16
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• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

Antibiotics in Agriculture Antibiotics in poultry

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
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• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Active efflux of antibiotics
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64

AntibioticsSubject Antimicrobial (Pounds)Human 3000000

Beef 3700000

Swine 1030000

Chicken 10500000

Total in animals 24500000

The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

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• Active efflux of antibiotics
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The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

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• Active efflux of antibiotics
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• Slide 64

The History of Medicine

2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
• Slide 2
• Slide 3
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• Active efflux of antibiotics
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• Slide 62
• Slide 63
• Slide 64

What Is Antimicrobial Stewardship

bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177

IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

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• Slide 2
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• Active efflux of antibiotics
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IDSA Guidelines ndash Definition ofAntimicrobial Stewardship

bull Antimicrobial stewardship is an activity that promotes

ndash The appropriate selection of antimicrobials

ndash The appropriate dosing of antimicrobials

ndash The appropriate route and duration of antimicrobial therapy

The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

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• Active efflux of antibiotics
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The Primary Goal ofAntimicrobial Stewardship

bull The primary goal of antimicrobial stewardship is to

ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

bull Unintended consequences include the followingndash Toxicity

ndash The selection of pathogenic organisms such as C difficile

ndash The emergence of resistant pathogens

Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

• Slide 1
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• Active efflux of antibiotics
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Antimicrobial StewardshipSuggested Starting Points

bull Obtain baseline informationndash Antimicrobial usage and expenditures

ndash Institutional susceptibilities

ndash Recurrent problems

bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)

ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results

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• Active efflux of antibiotics
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