Mechanisms of antibiotic Mechanisms of antibiotic resistance in bacteriaresistance in bacteria

Misuse of Antibiotics: The Misuse of Antibiotics: The Worldwide Crisis of Worldwide Crisis of Resistant Bacterial Resistant Bacterial

InfectionsInfections

James A. Wilde MDJames A. Wilde MDMedical Director, GUARDMedical Director, GUARD

Associate Professor of Emergency Medicine and PediatricsAssociate Professor of Emergency Medicine and PediatricsMedical College of GeorgiaMedical College of Georgia

What Causes Infections?What Causes Infections?

Infections are caused by one of four life Infections are caused by one of four life forms:forms:

VirusVirus 75% or more of all infections75% or more of all infections BacteriaBacteria less than 25%less than 25% ParasitesParasites less than 1% in the USless than 1% in the US FungusFungus less than 1% in the USless than 1% in the US

Virus:Virus: Can live in the environment for yearsCan live in the environment for years Attack humans by invading cells of certain organs Attack humans by invading cells of certain organs

• Hepatitis virus: attacks the liver cellsHepatitis virus: attacks the liver cells• Encephalitis virus: attacks the brain cellsEncephalitis virus: attacks the brain cells• Cold virus: attacks the throat and breathing passagesCold virus: attacks the throat and breathing passages• Diarrhea virus: attacks the small intestineDiarrhea virus: attacks the small intestine

Cannot reproduce or grow unless inside a cellCannot reproduce or grow unless inside a cell ““Sucks” the energy from the cell, eventually kills itSucks” the energy from the cell, eventually kills it Too small to be seen with most microscopesToo small to be seen with most microscopes

BacteriaBacteria Easily visible with a microscopeEasily visible with a microscope Can live and grow wherever they find foodCan live and grow wherever they find food

• Mountain streamsMountain streams• Ocean waterOcean water• Rotting animal or plantRotting animal or plant• Sewer Sewer • TopsoilTopsoil• Blood/skin/throat/lungs/urinary bladder/intestineBlood/skin/throat/lungs/urinary bladder/intestine

Some divide and grow every 20 minutesSome divide and grow every 20 minutes Many produce poisonsMany produce poisons

Diseases Caused by Diseases Caused by Viruses and BacteriaViruses and Bacteria

VirusVirus Common coldCommon cold Diarrhea (99%)Diarrhea (99%) Acute BronchitisAcute Bronchitis Influenza (flu)Influenza (flu) MeaslesMeasles Chicken PoxChicken Pox AIDSAIDS RabiesRabies HepatitisHepatitis

BacteriaBacteria Urine infectionsUrine infections Strep ThroatStrep Throat Boils/abscessesBoils/abscesses GangreneGangrene Some pneumonia Some pneumonia Ear infections (half)Ear infections (half) Sinus infections (Sinus infections (< half)< half) Bubonic PlagueBubonic Plague TuberculosisTuberculosis

How Do We Cure These Infections?How Do We Cure These Infections?

Bacterial infectionsBacterial infectionsImmune system (white blood cells, etc)Immune system (white blood cells, etc)Antibiotics (Penicillin, etc.)Antibiotics (Penicillin, etc.)

VirusesVirusesImmune systemImmune systemAnti-viral medications: not much helpAnti-viral medications: not much helpAntibiotics do Antibiotics do NOTHINGNOTHING to harm a virus to harm a virus

FactFact

Bacteria Bacteria are the cause of the are the cause of the vast majority of deaths due to vast majority of deaths due to infection in the United States: infection in the United States: sepsis, meningitis, pneumoniasepsis, meningitis, pneumonia

FactFact

Most Most viralviral infections get better infections get better all by themselves in 1-3 weeks; all by themselves in 1-3 weeks; no medications are required: no medications are required: colds, flu, stomach viruscolds, flu, stomach virus

Resolution of Acute Resolution of Acute BronchitisBronchitis

0

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100

0 2 4 6 8 10 12 14 16 18

Days with cough

% P

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ts

No Antibiotic

(+) Antibiotic

Stott, BMJ 1976

Gonzales et al., Gonzales et al., JAMAJAMA, 1997, 1997

Examined rate of antibiotic use for common Examined rate of antibiotic use for common cold, bronchitis in private physicians officescold, bronchitis in private physicians offices Colds: 51% given antibioticsColds: 51% given antibiotics Upper respiratory infection: 52%Upper respiratory infection: 52% Bronchitis: 66%Bronchitis: 66%

These antibiotics are unnecessary!!!These antibiotics are unnecessary!!!

So Why Do Doctors Give So Why Do Doctors Give Antibiotics For Viral Infections?Antibiotics For Viral Infections?

They think you want an antibioticThey think you want an antibiotic It’s easier than explaining why you don’t It’s easier than explaining why you don’t

need oneneed one Patients have been “trained” to expect themPatients have been “trained” to expect them Doctors think the antibiotics will prevent a Doctors think the antibiotics will prevent a

secondary bacterial infection secondary bacterial infection (they’re wrong)(they’re wrong)

They misdiagnose a viral infection for a They misdiagnose a viral infection for a bacterial infection: Sinusitis vs Coldbacterial infection: Sinusitis vs Cold

Problems With Improper Use of Problems With Improper Use of AntibioticsAntibiotics

They don’t help the patient at allThey don’t help the patient at all Expense: 75% of outpatient antibiotics are Expense: 75% of outpatient antibiotics are

used for respiratory infectionsused for respiratory infections Patient expectations: why no better?Patient expectations: why no better? Side effects: diarrhea, rash, allergySide effects: diarrhea, rash, allergy

Development ofDevelopment of resistanceresistance: the : the antibiotic won’t work when you really DO antibiotic won’t work when you really DO need it for a bacterial infectionneed it for a bacterial infection

HISTORICAL PERSPECTIVEHISTORICAL PERSPECTIVE Antibiotics introduced 60 years agoAntibiotics introduced 60 years ago Bacteria from pre-antibiotic era had Bacteria from pre-antibiotic era had

virtually no resistance genesvirtually no resistance genes Staph aureusStaph aureus was uniformly sensitive was uniformly sensitive

to Penicillin at the time of its release to Penicillin at the time of its release

How antibiotics workHow antibiotics work Inhibition of nucleic acid synthesisInhibition of nucleic acid synthesis

Rifampicin; ChloroquineRifampicin; Chloroquine

Inhibition of protein synthesisInhibition of protein synthesis Tetracyclines; ChloramphenicolTetracyclines; Chloramphenicol

Action on cell membrane Action on cell membrane Polyenes; PolymyxinPolyenes; Polymyxin

Interference with enzyme systemInterference with enzyme system

SulphamethoxazoleSulphamethoxazole

Action on cell wallAction on cell wall Penicillin; Vancomycin Penicillin; Vancomycin

• penicillin works by blocking the formation of peptide bonds in penicillin works by blocking the formation of peptide bonds in the bacterial cell wall and thereby weakens it, leaving the the bacterial cell wall and thereby weakens it, leaving the bacterium susceptible to osmotic lysis bacterium susceptible to osmotic lysis

How Antibiotic Resistance How Antibiotic Resistance HappensHappens

New Resistant Bacteria

Mutations

XX

Emergence of Antimicrobial Emergence of Antimicrobial ResistanceResistance

Susceptible Bacteria

Resistant Bacteria

Resistance Gene Transfer

Bacterial Resistance Bacterial Resistance MechanismsMechanisms

Mechanisms of Resistance

Enzymatic

degradation

Decreased entry

Efflux pumpAltered target site

Bypass pathway

Resistance Mechanisms Resistance Mechanisms Inside the Bacterial CellInside the Bacterial Cell

Mechanisms of antibiotic resistance

•Efflux Pumps•Hydrolysis•Reduced Uptake•Sequestering•Enzymatic Modification

The Science Creative Quarterly 2: Jan-March 2007.

To date, more than 100 resistance To date, more than 100 resistance genes have been identifiedgenes have been identified

These genes allow the bacteria to These genes allow the bacteria to shield themselves from the antibioticshield themselves from the antibiotic

Resistance genes can be transferred Resistance genes can be transferred from one bacterial species to another: from one bacterial species to another: spread of resistance is RAPIDspread of resistance is RAPID

Mechanisms of Antibiotic ResistanceMechanisms of Antibiotic ResistanceAntibiotic Method of resistance

Chloramphenicol reduced uptake into cell

Tetracycline active efflux from the cell

β-lactams, Erythromycin, Lincomycineliminates or reduces binding of antibiotic to target

β-lactams, Erythromycin hydrolysis

Aminoglycosides, Chloramphenicol, Fosfomycin, Lincomycin

inactivation of antibiotic by enzymatic modification

β-lactams, Fusidic Acidsequestering of the antibiotic by protein binding

Sulfonamides, Trimethoprimmetabolic bypass of inhibited reaction

Sulfonamides, Trimethoprimoverproduction of antibiotic target (titration)

Bleomycinbinding of specific immunity protein to antibiotic

Chronology of Development of Chronology of Development of Antibiotic ResistanceAntibiotic Resistance

AntibioticAntibiotic Year introducedYear introduced Resistance Resistance identifiedidentified

PenicillinPenicillin 19401940 19421942

StreptomycinStreptomycin 19471947 19471947

TetracyclineTetracycline 19521952 19561956

ErythromycinErythromycin 19551955 19561956

GentamicinGentamicin 19671967 19701970

VancomycinVancomycin 19561956 19871987

Resistance: Resistance: The World 2000The World 2000

In much of South-East Asia, resistance to penicillin has In much of South-East Asia, resistance to penicillin has been reported in been reported in up to up to 98% of gonorrhoea strains. 98% of gonorrhoea strains.

In Estonia, Latvia, and parts of Russia and China, over In Estonia, Latvia, and parts of Russia and China, over 10% of tuberculosis (TB) patients have strains resistant to 10% of tuberculosis (TB) patients have strains resistant to the two most the two most effective anti-effective anti-TB TB drugsdrugs. .

Thailand has completely lost the usThailand has completely lost the usee three of the most three of the most common anti-malaria drugscommon anti-malaria drugs because of resistance because of resistance. .

A small but growing number of patients are already A small but growing number of patients are already showing primary resistance to AZT and other new showing primary resistance to AZT and other new therapies for HIV-infected persons. therapies for HIV-infected persons.

The consequences of antibiotic The consequences of antibiotic resistanceresistance

Increased morbidity & mortalityIncreased morbidity & mortality ““best-guess” therapy may fail with the patient’s best-guess” therapy may fail with the patient’s

condition deteriorating before susceptibility results condition deteriorating before susceptibility results are availableare available

no antibiotics left to treat certain infectionsno antibiotics left to treat certain infections Greater health care costsGreater health care costs

more investigationsmore investigations more expensive, toxic antimicrobials requiredmore expensive, toxic antimicrobials required expensive barrier nursing, isolation, procedures, etc. expensive barrier nursing, isolation, procedures, etc.

Therapy priced out of the reach of Therapy priced out of the reach of some some third-world countriesthird-world countries

Clinical Significance of Antibiotic Clinical Significance of Antibiotic ResistanceResistance

Therapeutic failures and relapseTherapeutic failures and relapse Facilitates spread in the hospital under Facilitates spread in the hospital under

“antibiotic pressure”“antibiotic pressure” Need to use more costly and toxic agentsNeed to use more costly and toxic agents The emergence of untreatable pathogensThe emergence of untreatable pathogens

S. aureus

Penicillin

[1950s]

Penicillin-resistant

S. aureus

Evolution of Drug Resistance in Evolution of Drug Resistance in S. aureusS. aureus

Methicillin

[1970s]

Methicillin-resistant S. aureus (MRSA)

Vancomycin-resistant

enterococci (VRE)

Vancomycin

[1990s]

[1997]

Vancomycin

intermediate-resistantS. aureus (VISA)

[ 2002 ]Vancomycin

-

resistantS. aureus

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1989 1991 1993 1995 1997 1999 2001 2003

Year

Per

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Proportion of S. aureus Nosocomial Infections Resistant to Oxacillin (MRSA)

Among Intensive Care Unit Patients,1989-2003*

*Source: NNIS System, data for 2003 are incomplete

Emergence of Vancomycin Emergence of Vancomycin Resistant EnterococciResistant Enterococci

Source: NNIS Data

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1990

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1995

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1997

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2000

Per

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Non-Intensive Care Unit Patients

Intensive Care Unit Patients

Development of of Resistance in Development of of Resistance in Gram Positive PathogensGram Positive Pathogens

1Smith TL et al. N Engl J Med. 1999;340:493-501. 2Martone WJ. Infect Control Hosp Epidemiol. 1998;19:539-545. 3Hiramatsu K et al. J Antimicrob Chemother. 1997;40:135-136. 4CDC. MMWR Morb Mortal Wkly Rep. 2002;51:565-567.

1975 1995199019851980Path

ogen

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to A

ntib

iotic

s (%

)100

90

80

70

60

50

40

30

20

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19962000

MRSA = methicillin-resistant Staphylococcus aureusVRE = vancomycin-resistant enterococciGISA = glycopeptide-intermediate S aureusVRSA = vancomycin-resistant S aureus

MRSA1

VRE2

GISA3

Year 2002

VRSA4

Antibiotics in Animal FeedAntibiotics in Animal Feedrationalerationale

Promotes growthPromotes growth Decreases amount of feed neededDecreases amount of feed needed Prevents infectious diseasesPrevents infectious diseases Facilitates confinement housingFacilitates confinement housing Lowers costsLowers costs

48% of all antibiotics by weight is added to animal feeds to 48% of all antibiotics by weight is added to animal feeds to promote growth. Results in low, subtherapeutic levels which promote growth. Results in low, subtherapeutic levels which are thought to promote resistance.are thought to promote resistance.

Farm families who own chickens feed tetracycline have an Farm families who own chickens feed tetracycline have an increased incidence of tetracycline resistant fecal floraincreased incidence of tetracycline resistant fecal flora

Chickens at Spanish supermarkets have >90% of cultured Chickens at Spanish supermarkets have >90% of cultured campylobacter resistant to quinolonescampylobacter resistant to quinolones

39% of enterococci in the fecal flora of pigs from the 39% of enterococci in the fecal flora of pigs from the Netherlands is resistant to vancomycin vs 0% in Sweden. Netherlands is resistant to vancomycin vs 0% in Sweden. (Sweden bans antibiotic additives in animal feed)(Sweden bans antibiotic additives in animal feed)

ANTIMICROBIAL RESISTANCE:ANTIMICROBIAL RESISTANCE:The role of animal feed antibiotic additivesThe role of animal feed antibiotic additives

Cross-resistance Between Growth Cross-resistance Between Growth Promoters and Antibiotics for Human Promoters and Antibiotics for Human

UseUse

AvoparcinAvoparcin VancomycinVancomycin AvilamycinAvilamycin EverninomicinEverninomicin VirginiamycinVirginiamycin SynercidSynercid TylosinTylosin ErythromycinErythromycin

EID 1999; Vol 5

Decrease in VRE After Removing Decrease in VRE After Removing Avoparcin From Animal FeedAvoparcin From Animal Feed

US US –– New Antibacterial New Antibacterial AgentsAgentsYear No. Approved Agents

1991 20± Multiple agents

1992 3 Temafloxacin, lomefloxacin, cefpodoxime

1993 1 Piperacillin/Tazobactam

1994 0 Lowest number of new agents (22) since 1988

1995 2 Dirithromycin, ceftibutin

1996 4 Meropenem, levofloxacin, sparfloxacin, Cefepime

1997 2 Grepafloxacin, Trovafloxacin

1998 0 Rivaled 1994

1999 3 Dalfopristin/quinupristin, gatifloxacin, moxifloxacin

2000 1 Linezolid

2001 2 Ertapenem, ceftidoren

2002 0 89 drugs approved, no antibacterial agents

2003 2 Daptomycin, gemifloxacin

INDONESIAINDONESIA

AMRIN Study (The Antimicrobials AMRIN Study (The Antimicrobials Resistance in Indonesia ‘Prevalence and Resistance in Indonesia ‘Prevalence and Prevention’) : 2000 – 2005 Prevention’) : 2000 – 2005 The antimicrobial resistance has become a The antimicrobial resistance has become a

public health threat in Indonesiapublic health threat in Indonesia IARW (Indonesia Antimicrobials IARW (Indonesia Antimicrobials

Resistance Watch)Resistance Watch) Antibiotic Policy in hospitalsAntibiotic Policy in hospitals

Waiting Room Poster