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Drugs, Microbes, Host – The Elements of Chemotherapy

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1 Drugs, Microbes, Host – The Elements of Chemotherapy
Chapter 12 Drugs, Microbes, Host – The Elements of Chemotherapy

2 Introduction Terminology
Bacteriostatic (inhibits growth) vs. Bactericidal (kills organisms) Broad spectrum vs. Narrow spectrum Generic (chemical composition of drug) vs. Trade name (name given to a drug by a manufacture Sources of antimicrobial agents Antibiotics - growth products of organisms Chemosynthetic agents - synthesized in a laboratory Semi-synthetic agents - growth products of organisms that have been chemically altered in laboratory

3 Colony of Streptomyces, one of nature’s most prolific antibiotic producers

4 Major targets of drugs acting on bacterial cells

5 Mode of action of antimicrobial agents: competitive inhibition
Antibacterial drugs Involves inhibiting synthesis of a critical metabolite Bacteriostatic in activity Examples Sulfa - competition based on chemical similarity between sulfas and PABA which is needed for folic acid synthesis; folic acid critical in protein and NA synthesis; side effect = possible kidney damage from crystals

6 Mode of action of antimicrobial agents: inhibition of cell wall synthesis
Interfere with one of multiple steps in CW synthesis Greater effect demonstrated against G(+) than G(-) – most act against synthesis of peptidoglycan; many drugs cannot penetrate LPS Generally considered to be bactericidal - cause lysis

7 Mode of action of antimicrobial agents: inhibition of cell wall synthesis
Drugs with beta lactam ring - prevent cross-linking in last step of synthesis Penicillins Original penicillins effective only against G(+) - esp. staph & strep Semisynthetic penicillins developed to overcome penicillinase (beta lactamase) producing strains (i.e.methicillin, oxacillin & nafcillin) and broaden spectrum to G(-) (i.e. ampicillin & carbenicillin) Toxicity involves hypersensitivity

8 Mode of action of antimicrobial agents: inhibition of cell wall synthesis
Cephalosporins Broad spectrum antibiotics Used when individuals are allergic to penicillin Modifications to original drug increased spectrum (generations 1, 2, and 3) Moxalactams Other drugs - interfere at other steps Cycloserine Bacitracin - used primarily as topical (on the skin - not taken internally because of toxicity) Vancomycin

9 Mode of action of antimicrobial agents: Inhibition of protein synthesis
Inhibit one of many steps in protein synthesis Examples Aminoglycosides - includes streptomycin, kanamycin, tobramycin, gentamicin, neomycin, and amikacin; causes misreading of mRNA; bactericidal; synergistic with penicillins Tetracyclines - block binding to tRNA; bacteriostatic; broad spectrum Chloramphenicol - prevent peptide bond formation; bacteriostatic; excellent penetration of CNS (useful for treating meningitis); side effect = aplastic anemia Erythromycin - antimicrobial spectrum similar to penicillin; used especially in penicillin-allergic Lincomycin and clindamycin - bacteriostatic; clindamycin useful for anaerobes; may cause pseudomembranous colitis

10 Structure of aminoglycoside, tetracycline, chloramphenicol, and erythromycin

11 Effects of drugs on bacterial cell membrane
Act directly on cell membranes (do not need to enter cell to cause damage) Bactericidal - produce irreversible damage to membrane permeability Example = polymyxins and colistin Highly toxic to kidneys and nerves

12 Antifungal drugs Damage cell membranes
Bind or interfere with ergosterol (unique fungal sterol in membrane) Examples Polyenes - nystatin and amphotericin B Imidazoles - clotrimazole, miconazole (topical) and ketoconazole (systemic) Inhibition of nucleic acid synthesis Griseofulvin - interferes with mitosis; selectively binds to keratin in skin, hair & nails; used primarily with fungi classified as dermatophytic 5-fluorocytosine

13 Antiviral drugs Interference with uptake or uncoating of virus - amantadine (used to prevent influenza A) Inhibition of nucleic acid synthesis Ribavirin - effective in vitro against a wide range of viruses; highly toxic Acyclovir - Herpes-specific (genital herpes, cold sores, chickenpox) Azidothymidine (AZT) - treatment of HIV infections


15 Antibiotic resistance in bacteria
Sites of resistance Membrane transport - LPS layer of G(-) prevent entry of many drugs Targets of antimicrobial agents (e.g. ribosomes) Presence of antibiotic-destroying enzymes (e.g. beta lactamase)

16 Antibiotic resistance in bacteria
Mechanisms of changing resistance Mutations - permanent changes in chromosomes; not caused by antibiotics Acquisition of new genetic information - methods Transformation = naked DNA Transduction = via viruses Conjugation = via sex pili (sexual recombination) – most rapid method Selective pressures of antimicrobial therapy - use of antibiotics select for bacteria that are resistant - sensitive bacteria are destroyed

17 Antibiotic susceptibility testing
Susceptibility no longer predictable Variables affecting outcome of therapy Condition of host (immune status - underlying diseases) Site of infection (can drugs get to site?) Properties of antimicrobial agent Other drugs taken concurrently Susceptibility of organism to drug

18 The role of antimicrobials in disrupting microbial flora and causing superinfections

19 Broth dilution methods (Minimal Inhibitory Concentration) – Quantitative Method
Procedure Uses decreasing concentrations of antimicrobial agents prepared in 2-fold dilutions of broth that will support growth of test organism Standard inoculum is added to broth containing dilutions of antimicrobial agent, incubated overnight and then examined for growth (turbidity) Lowest concentration of agent that inhibits growth as detected by lack of visible turbidity = Minimal Inhibitory Concentration (MIC) Susceptibility and resistance determined by break point of drug (highest conc. of drug in the blood that can be achieved with maximal therapy); if MIC is lower than breakpoint, organism = susceptible; if MIC is higher than breakpoint, organism = resistant

20 Minimum Inhibitory Concentration

21 Disk diffusion (Kirby/Bauer) - Qualitative
Advantage - rapid testing of several antibiotics simultaneously Uses antimicrobial agents incorporated into filter paper disks placed on agar media causing drug to diffuse creating a concentration gradient (conc. highest closest to disk) Susceptibility/resistance determined by measuring diameter of zone of inhibition around disk and comparing to established zones for each antibiotic Standardization - Bauer, Kirby, Sherris & Turck (correlated with MIC’s using large numbers strains & regression analysis)

22 Techniques for preparation and interpretation of disc diffusion tests

23 Antimicrobial gradient strip method (E test)
Disk diffusion method that allows determination of MIC in agar Consists of plastic strip containing gradient of antimicrobial agent along with an interpretive scale Performed similar to disk diffusion Organisms grow in elliptical zone of inhibition around strip relative to concentration of antibiotic along its length MIC determined by reading scale at point where zone of inhibition intersects strip

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