Antibiotics ppt
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Transcript of Antibiotics ppt
ANTIBIOTICS
Antibiotics
Topics- Antimicrobial Therapy- Selective Toxicity - Survey of Antimicrobial Drugs- Microbial Drug Resistance- Drug and Host Interaction
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Key WordsKey WordsSterilization/disinfection/antisepsis
Antibiotic
Selective toxicity
Bactericidal
Bacteriostatic
Minimal inhibitory concentration (MIC)
Susceptibility testing
Penicillin binding proteins
Penicillinase/beta lactamas
Resistance
Selective Toxicity
Drugs that specifically target microbial processes, and not the human host cellular processes.
Improved Patient Outcomes Associated With Proper Hand Hygiene
Semmelweis
Chlorinated lime hand antisepsis
Antibiotics
Naturally occurring antimicrobials– Metabolic products of bacteria and
fungi– Reduce competition for nutrients and
space Bacteria that produce them:
– Streptomyces, Bacillus, Molds
– Penicillium, Cephalosporium
History
Ancient remedies
Ehrlich
Domagk
Fleming
Neem Plant
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Neem Plant
Uses: Arthritis, blood purifier and detoxifier, convalescence after fever, cough, diabetes, eczema, fever (used with black pepper and gentian), inflammation of muscles and joints, jaundice, leukorrhea, malaria, mucus membrane ulcerations, nausea, obesity, parasites, rheumatism, skin diseases/inflammations, cleanses liver, syphilis, thirst, tissue excess, tumors, vomiting, worms, drowsiness, loss of appetite. Leaves—heal ulcers in urinary passage, emmenagogue, skin diseases. Fruit—skin diseases, bronchitis. Kernel powder —washing hair. Effective as a pesticide.
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Propolis
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Propolis
Propolis is plant resin compound, different fabric compositions, wax, essential oils, iron, microelements – copper, zinc, manganese, cobalt, plus pollen, flavonoids, salivary gland secretions of bees. Propolis is used as a bio-stimulator which enhances endurance and eliminate fatigue. Because its antiviral properties, antitoxic and anti-inflammatory propolis finds more and more uses. Recovery is a good stimulator of affected tissue injuries, cuts...
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Ehrlich’s Magic Bullets
Gerhard Domagk - Prontosil
Fleming and Penicillin
Selman Waksman
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Between 1962 and 2000, no major classes of antibiotics were introduced
Fischbach MA and Walsh CT Science 2009
A Changing Landscape forNumbers of Approved Antibacterial Agents
Bars represent number of new antimicrobial agents approved by the FDA during the period listed.
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Nu
mb
er o
f ag
ents
ap
pro
ved
1983-87 1988-92 1993-97 1998-02 2003-05 2008
Infectious Diseases Society of America. Bad Bugs, No Drugs. July 2004; Spellberg B et al. Clin Infect Dis. 2004;38:1279-1286;New antimicrobial agents. Antimicrob Agents Chemother. 2006;50:1912
Resistan
ce
Azamulin
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Daptomycin chemical structure.
Steenbergen J N et al. J. Antimicrob. Chemother. 2005;55:283-288
JAC vol.55 no.3 © The British Society for Antimicrobial Chemotherapy 2005; all rights reserved
Daptomycin mechanism of action.
Steenbergen J N et al. J. Antimicrob. Chemother. 2005;55:283-288
JAC vol.55 no.3 © The British Society for Antimicrobial Chemotherapy 2005; all rights reserved
Linezolid
Ideal Antimicrobial Attributes
Solubility
Selective toxicity
Stable toxicity level
Allergenicity
Tissue stability
Resistance Acquisition
Shelf Life
Cost
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ANTIBIOTICSANTIBIOTICS
• Selectively toxic for bacteriaSelectively toxic for bacteria– bactericidal (killing) bactericidal (killing) – bacteriostatic (growth inhibition)bacteriostatic (growth inhibition)
no harm to patientno harm to patient
Antibiotic/Antimicrobial
Antibiotic: Chemical produced by a microorganism that kills or inhibits the growth of another microorganism
Antimicrobial agent: Chemical that kills or inhibits the growth of microorganisms
Microbial Sources of Antibiotics
Administration of Antibiotics
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Spectrum of Activity
Determining Microbial Sensitivities
Disk Diffusion Method
Dilution Method
Serum Killing Power
Automated Methods
Drug Mechanisms of Action
Penicillin (over 50 compounds)– Share 4-sided ring ( lactam ring)
Natural penicillins• Narrow range of action• Susceptible to penicillinase ( lactamase)
Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis
Prokaryotic Cell Walls
Cell wall synthesis
Bactericidal– Penicillin and cephalosporins – binds
and blocks peptidases involved in cross-linking the glycan molecules
– Vancomycin – hinders peptidoglycan elongation
– Cycloserine – inhibits the formation of the basic peptidoglycan subunits
Antibiotics weaken the cell wall, and cause the cell to lyse.
Penicillin Penicillin chrysogenum A diverse group (1st, 2nd , 3rd generations)
– Natural (penicillin G and V)– Semisynthetic (Ampicillin, Carbenicillin)
Structure– Thiazolidine ring– Beta-lactam ring– Variable side chain (R group)
-4C – 28C - 38C water activity 0.98
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The R group is responsible for the activity of the drug, and cleavage of the beta-lactam ring will render the drug inactive.
Chemical structure of penicillins
Penicillins
Figure 20.6
Penicilinase-resistant penicillins• Carbapenems: very broad spectrum• Monobactam: Gram negative
Extended-spectrum penicillins Penicillins + -lactamase inhibitors
Semisynthetic Penicillins
Penicillinase ( Lactamase)
Cephalosporins– 2nd, 3rd, and 4th
generations more effective against gram-negatives
Other Inhibitors of Cell Wall Synthesis
Figure 20.9
Cephalosporin Cephalosporium acremonium (mold) Widely administered today
– Diverse group (natural and semisynthetic) Structure
– similar to penicillin except
• Main ring is different
• Two sites for R groups
The different R groups allow for versatility and improved effectiveness.
Other Inhibitors of Cell Wall Synthesis
Mycobacteria: interfere with mycolic acid synthesis or incorporation
– Isoniazid (INH)
– Ethambutol
Polypeptide antibiotics– Bacitracin
• Topical application• Against gram-positives
– Vancomycin• Glycopeptide• Important "last line" against antibiotic resistant S.
aureus
Other Inhibitors of Cell Wall Synthesis
Broad spectrum, toxicity problems Examples
– Aminoglycosides: Streptomycin, neomycin, gentamycin
– Tetracyclines
– Macrolides: Erythromycin
– Chloramphenicol
Inhibitors of Protein Synthesis
Aminoglycosides From Streptomyces Inhibit protein synthesis
Streptomyces synthesizes many different antibiotics such as aminoglycosides, tetracycline, chloramphenicol, and erythromycin.
Sites of inhibition on the procaryotic ribosome
Tetracycline
Inhibits proteins synthesis Broad spectrum and low cost Commonly used to treat sexually
transmitted diseases Minor side effect – gastrointestinal
disruption
Tetracyclines (bacteriostatic)tetracycline, minocycline and doxycycline
Mode of action - The tetracyclines reversibly bind to the 30S ribosome and inhibit binding of aminoacyl-t-RNA to the acceptor site on the 70S ribosome.
Spectrum of activity - Broad spectrum; Useful against intracellular bacteria
Resistance - Common
Adverse effects - Destruction of normal intestinal flora resulting in increased secondary infections; staining and impairment of the structure of bone and teeth. Not used in children.
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Spectinomycin (bacteriostatic)
Mode of action - Spectinomycin reversibly interferes with m-RNA interaction with the 30S ribosome. It is structurally similar to the aminoglycosides but does not cause misreading of mRNA. Does not destabilize membranes, and is therefore bacteriostatic
Spectrum of activity - Used in the treatment of penicillin-resistant Neisseria gonorrhoeae
Resistance - Rare in Neisseria gonorrhoeae
Erythromycin
Inhibits protein synthesis Broad-spectrum Commonly used as prophylactic drug
prior to surgery Side effects - low toxicity
Streptomycin - treat Plague
Chloramphenicol
Broad-spectrum Treat typhoid fever, brain abscesses Rarely used now due to side effects –
aplastic anemia
Chloramphenicol
UDP-glucuronyl transferase
Aminoglycoside
Polymyxin B (Gram negatives)– Topical– Combined with bacitracin and neomycin (broad
spectrum) in over-the-counter preparation
Injury to the Plasma Membrane
Polymyxin B (Gram negatives)
– Topical
– Combined with bacitracin and neomycin (broad spectrum) in over-the-counter preparation
Injury to the Plasma Membrane
Rifamycin
– Inhibits RNA synthesis
– Antituberculosis Quinolones and fluoroquinolones
– Ciprofloxacin
– Inhibits DNA gyrase
– Urinary tract infections
Inhibitors of Nucleic Acid Synthesis
Inhibition of Nucleic Acid Synthesis
Rifampin binds to DNA-dependent RNA polymerase and inhibits intiation of RNA synthesis
Antibacterials — Antimetabolites
Sulfonamides
Isoniazid
Ethambutol
Nitrofurans
Folic acid synthesis
Sulfonamides (sulfa drug) and trimethoprim
– Analogs
– Competitive inhibition of enzymes
– Prevents the metabolism of DNA, RNA, and amino acid
– Sulfonamides (Sulfa drugs)• Inhibit folic acid synthesis• Broad spectrum
Competitive Inhibitors
Figure 5.7
Sulfonamides compete with PABA for the active site on the enzyme.
The sulfonamide Sulfamethoxazole is commonly used in combination with trimethoprim
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Necrotizing Fasciitis
Group A hemolytic streptococci and Staphylococcus aureus, alone or in synergism, are frequently the initiating infecting bacteria. However, other aerobic and anaerobic pathogens may be present, including Bacteroides, Clostridium, Peptostreptococcus, Enterobacteriaceae, coliforms, Proteus, Pseudomonas, and Klebsiella.
Summary of Targets
Figure 20.20
Antibiotic Resistance
Antimicrobial Resistance
Relative or complete lack of effect of antimicrobial against a previously susceptible microbe
Increase in MIC
• Enzymatic destruction of drug
• Prevention of penetration of drug
• Alteration of drug's target site
• Rapid ejection of the drug
Mechanisms of Antibiotic Resistance
Antibiotic Selection for Resistant Bacteria
What Factors Promote Antimicrobial Resistance?
Exposure to sub-optimal levels of antimicrobial
Exposure to microbes carrying resistance genes
Inappropriate Antimicrobial Use
Prescription not taken correctlyAntibiotics for viral infectionsAntibiotics sold without medical
supervisionSpread of resistant microbes in
hospitals due to lack of hygiene
Inappropriate Antimicrobial Use
Lack of quality control in manufacture or outdated antimicrobial
Inadequate surveillance or defective susceptibility assays
Poverty or war Use of antibiotics in foods
Antibiotics in Foods
Antibiotics are used in animal feeds and sprayed on plants to prevent infection and promote growth
Multi drug-resistant Salmonella typhi has been found in 4 states in 18 people who ate beef fed antibiotics
Consequences of Antimicrobial Resistance
Infections resistant to available antibiotics
Increased cost of treatment
Multi-Drug Resistant TB
MRSA “mer-sah”
Methicillin-Resistant Staphylococcus aureus
Most frequent nosocomial (hospital-acquired) pathogen
Usually resistant to several other antibiotics
Proposals to Combat Antimicrobial Resistance
Speed development of new antibiotics
Track resistance data nationwide Restrict antimicrobial use Direct observed dosing (TB)
Proposals to Combat Antimicrobial Resistance
Use more narrow spectrum antibiotics
Use antimicrobial cocktails
Antimicrobial peptides
– Broad spectrum antibiotics from plants and animals
• Squalamine (sharks)
• Protegrin (pigs)
• Magainin (frogs)
The Future of Chemotherapeutic Agents
Side Effects
Resistance to Drugs
Chromosomal
Plasmid borne
Mechanisms of Drug Resistance
Mutations in Target molecules
Alterations in membrane permeability
Enzyme development
Mechanisms of Drug Resistance
Enzyme Activity Changes
Alterations in Anabolic Pathways
Generations of Drugs
First/Second/Third Line Drugs
Cross Resistance
Limiting Drug Resistance
Effective Drug Concentrations
Simultaneous Drug Administration
• Synergism
• Antagonism Restricting Drug Prescriptions
Antibiotic Resistance
Inactivation of the antibiotic by a microbial enzyme
Prevention of the antibiotic from reaching its target cell structure
Alteration of the target cell structure so that it is no longer affected by the antibiotic
Mechanisms of Resistance
Failure of the antibiotic to penetrate the outer membrane
Failure to bind to the target site (penicillin binding protein)
Hydrolysis of the antibiotic by beta lactamases
Drug Resistance
Intrinsic as well as acquired Intrinsic drug resistance exists naturally
and is not acquired through specific genetic changes
How does drug resistance develop?
The genetic events most often responsible for drug resistance are either chromosomal mutations or transfer of extrachromosomal DNA from a resistant species to a sensitive one.
Resistance Factors – R Factors
Transferred through conjugation, transformation or transduction
Many bacteria also maintain transposable drug resistance sequences – tansposons that are duplicated and inserted from one plasmid to another or from a plasmid to a chromosome
Conjugation – plasmids and chromosomal elements, conjugative transposons plasmids
Conjugative plasmid – plasmids that transfer themselves by conjugation must carry a number of genes encoding proteins needed for the conjugation process itself (tra genes)
Self-transmissable plasmids (STP) are usually at least 25kb
Mobilize plasmids – much smaller than STP because they need only 1 or 2 genes (mob genes)
Resistance Genes
Acquire sequential transposon insertions Integrons are probably responsible for
evolution of many of the plasmids that carry multiple resistance genes
Integrons
Integrons like transposons are linear DNA segments that insert into DNA
Unlike transposons, integrons integrate at a single site and do not encode a transposase
Conjugative transposons – located in the bacterial chromosome, also integrate into plasmids
Mechanism of Transfer
Excise themselves from the donor genome to form a covalently closed circle that does not replicate
The circular intermediate transfers similarly to a plasmid
In the recipient, the circular intermediate integrates in the chromosome by a mechanism that does not duplicate the target site
Origin of Antibiotic Resistant Genes
First it was assumed that antibiotic resistance genes appeared only after antibiotics began to be widely used in medicine
The genetic diversity within some classes of resistance makes it clear that these genes have been evolving for a much longer time
Origin of resistance
Hypothesis: resistance genes first evolved in the antibiotic-producing bacteria such as Streptomyces spp. As a mechanism for protecting them from the antibiotics they produce.
Genes for antibiotic production are frequently found in the same gene clusters with genes encoding resistance proteins
Specific mechanisms of drug resistance
Bacteria lose its sensitivity to a drug by expressing genes that stop the action of the drug.
Gene expression
Synthesis of enzymes that inactivate the drug
Decrease in cell permeability and uptake of the drug
Change in the number or affinity of the drug receptor sites, or
Modification of an essential metabolic pathway
Resistance
Some bacteria can become resistant indirectly by lapsing into dormancy, or, in the case of penicillin, by converting to a cell-wall-deficient form (L form) that penicillin cannot affect.
Drug Inactivation Mechanisms
Produce enzymes that permanently alter drug structure (beta lactamases)
Decreased Drug Permeability or Increased Drug Transport
Prevent drug from entering the cell and acting on the target
Gram negative – natural blockade for some of the penicillin drugs
Resistance to the tetracyclines can arise fro plasmid-encoded proteins that pump the drug out of the cell
Resistance
Resistance to the aminoglycoside antibiotics is a specific case in which microbial cells have lost the capacity to transport the drug intracellulary
Multidrug Resistant (MDR) Pumps
Actively transport drugs and other chemicals out of the cell
These pumps are proteins encoded by plasmids and chromosomes
They are located in the cell membrane and expel molecules by a protonmotive force similar to ATP synthesis
PUMPS
Because they lack selectivity, one type of pump can expel a broad array of antimicrobic drugs, detergents and other toxic substances.
Change of Drug Receptors
Alter nature of target site On bacteria resistant to rifampin and
streptomycin, the structure of key proteins has been altered so that these antibiotics can no longer bind.
Changes in Metabolic Patterns
Sulfonamide and trimethoprim resistance develops when microbes deviate from the usual patterns of folic acid synthesis
Natural selection and drug resistance
When a population of bacteria is exposed to a drug, sensitive cells are inhibited or destroyed and resistant forms survive and proliferate
In ecological terms, the environmental factor has put selection pressure on the population, allowing the more fit microbe to survive, and the population has evolved to a condition of drug resistance.
Antimicrobial Resistance: Key Prevention Strategies
Optimize Use
PreventTransmission
PreventInfection
EffectiveDiagnosisand Treatment
Antimicrobial-Resistant Pathogen
Antimicrobial Resistance
Antimicrobial Use
Infection
Susceptible Pathogen
12 Steps to Prevent Antimicrobial Resistance: Hospitalized Adults
12 Contain your contagion 11 Isolate the pathogen
10 Stop treatment when cured 9 Know when to say “no” to vanco 8 Treat infection, not colonization 7 Treat infection, not contamination
6 Use local data 5 Practice antimicrobial control
4 Access the experts3 Target the pathogen
2 Get the catheters out 1 Vaccinate
Prevent TransmissionUse Antimicrobials WiselyDiagnose and Treat EffectivelyPrevent Infection
Methicillin (oxacillin)-resistantStaphylococcus aureus
Vancomycin-resistantenterococci
Non-Intensive Care Unit Patients
Intensive Care Unit Patients
Antimicrobial Resistance Among Pathogens Causing Hospital-Acquired Infections
Source: National Nosocomial Infections Surveillance (NNIS) System
Prevalence of Isolates of Multidrug-Resistant Gram Negative Rods Recovered Within The First 48 h After
Admission to the Hospital
Pop-Vicas and D'Agata CID 2005;40:1792-8.
Conjugative transposons
Responsible for at least as much resistance gene transfer as plasmids, especially among G+, and they have a broad host range
G+ G+ ; G - G - ; G+ G -
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