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Antimicrobial Medications

Antimicrobial Medications. Chapter 21. Preview. History of antimicrobials Wars between human and pathogens How antimicrobials kill--features and mechanism of antimicrobials Fighting back of pathogens -mechanism of resistance to antimicrobial drugs Human returns.

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Antimicrobial Medications

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  1. Antimicrobial Medications Chapter 21

  2. Preview • History of antimicrobials • Wars between human and pathogens • How antimicrobials kill--features and mechanism of antimicrobials • Fighting back of pathogens-mechanism of resistance to antimicrobial drugs • Human returns

  3. History and Development ofAntimicrobial Drugs • Discovery of antimicrobial drugs • Salvarsan • Discovered by Paul Erlich for treatment of syphilis (1910) • Basis for modern pharmaceutical research • Prontosil dye • effective against streptococcal infections by Dr. Domagk (1930’s) • No effect on Streptococcus growing in vitro • Enzymes in blood split prontosil into small sulfonamide molecules • Sulfonamide was the first sulfa drug • Acts as a competitive inhibitor to para-aminobenzoic acid

  4. Penicillium (mold) Discovery of Antibiotics Antimicrobial drugs naturally produced by microorganisms Alexander Fleming - discovered penicillin 1929 staphylococcus

  5. History and Development ofAntimicrobial Drugs • Discovery of antibiotics • Ernst Chain and Howard Florey successfully purified penicillin • Successfully treated patients with infection • Mass production of penicillin during WWII • Treatment of wounded soldiers and war workers • Selman Waksman isolated streptomycin from soil bacterium Streptomyces griseus

  6. Features of Antimicrobial Drugs • Most modern antibiotics come from organisms living in the soil • bacterial species Streptomyces and Bacillus • Fungus sepcies Penicillium and Cephalosporium • To commercially produce antibiotics • Antibiotic extensively purified from culture medium • In some cases drugs are chemically altered to impart new characteristics • Termed semi-synthetic

  7. History and Development ofAntimicrobial Drugs • Development of new generation of drugs • alteration of drug structure gave them new properties • Penicillin G altered to created ampicillin • Broadened spectrum of antimicrobial killing

  8. Features of Antimicrobial Drugs • Selective toxicity • Antibiotics cause greater harm to microorganisms than to human host • Generally by interfering with biological structures or biochemical processes common to bacteria but not to humans • Toxicity of drug is expressed as therapeutic index • Lowest dose toxic to patient divided by dose typically used for treatment

  9. Features of Antimicrobial Drugs • Antimicrobial action • Drugs may kill or inhibit bacterial growth • Inhibit = bacteriostatic • Kill = bacteriocidal • Bacteriostatic drugs rely on host immunity to eliminate pathogen • UTI drugs • Bacteriocidal drugs are useful in situations when host defenses cannot be relies upon to control pathogen

  10. Features of Antimicrobial Drugs • Spectrum of activity • Antimicrobials vary with respect to range of organisms controlled • Narrow spectrum • Work on narrow range of organisms • Gram-positive only OR-Gram negative only • Broad spectrum • Work on broad range of organisms • Gram-positive AND Gram-negative • Disadvantage of broad spectrum is disruption of normal flora

  11. Features of Antimicrobial Drugs • Tissue distribution, metabolism and excretion • Drugs differ in how they are distributed, metabolized and excreted • Important factor for consideration when prescribing • Rate of elimination of drug from body expressed in half-life • Time it takes for the body to eliminate one half the original dose in serum • Half-life dictates frequency of dosage • Patients with liver or kidney damage tend to excrete drugs more slowly

  12. Features of Antimicrobial Drugs • Effects of combinations of antimicrobial drugs • enhances each other’s effect--- synergistic • interferes with each other’s effect ---antagonistic • neither synergistic nor antagonistic effect -- additive

  13. Features of Antimicrobial Drugs • Adverse effects • Allergic reactions • Allergies to penicillin • Allergies often life threatening • Toxic effects • Aplastic anemia • Body cannot make RBC or WBC • Suppression of normal flora • Antibiotic associated colitis • Clostridium difficile given opportunity to establish themselves • Antimicrobial resistance • Microorganisms have innate or adaptive resistance to antibiotics

  14. Mechanism of Antimicrobial Drugs Action target

  15. Inhibition of cell wall synthesis - -lactam drugs Penicillin G Target - peptidoglycan synthesis • Transpeptidases • aka penicillin-binding proteins (PBPs) • High therapeutic index • (note: allergies) • Not effective against most Gram-negatives • Cell wall • PBP

  16. Fig. 3.34

  17. Sidechain Inhibition of cell wall synthesis - -lactam drugs Penicillin G Target - peptidoglycan synthesis; • Transpeptidases • aka penicillin-binding proteins (PBPs) • High therapeutic index • (note: allergies) • Not effective against most Gram-negatives • Acid-sensitive • Destroyed by penicillinase (a -lactamase)

  18. Family of penicillins • Natural penicillins • Penicillinase-resistant penicillins • Broad-spectrum penicillins • Penicillins + -lactamase inhibitor

  19. Mechanisms of Action of Antibacterial Drugs • Vancomycin • Inhibits formation of glycan chains • Does not cross lipid membrane of Gram - • Gram - organisms innately resistant • Important in treating infections caused by penicillin resistant Gram + organisms • Must be given intravenously due to poor absorption from intestinal tract • Acquired resistant most often due to alterations in side chain of NAM molecule • Prevents binding of vancomycin to NAM component of glycan

  20. Mechanisms of Action of Antibacterial Drugs • Inhibition of protein synthesis • Structure of prokaryotic ribosome acts as target for many antimicrobials of this class • Differences in prokaryotic and eukaryotic ribosomes responsible for selective toxicity • Drugs of this class include • Aminoglycosides • Tetracyclins • Macrolids • Chloramphenicol • Lincosamides • Oxazolidinones • Streptogramins

  21. Antibiotics protein synthesis

  22. Mechanisms of Action of Antibacterial Drugs • Tetracyclins • Reversibly bind 30S ribosomal subunit • Blocks attachment of tRNA to ribosome • Effective against certain Gram + and Gram - • Newer tetracyclines such as doxycycline have longer half-life • Allows for less frequent dosing • Resistance due to decreased accumulation by bacterial cells • Can cause discoloration of teeth if taken as young child

  23. Mechanisms of Action of Antibacterial Drugs • Inhibition of nucleic acid synthesis • These include • Fluoroquinolones • Rifamycins

  24. Mechanisms of Action of Antibacterial Drugs • Rifamycins • Block prokaryotic RNA polymerase • Block initiation of transcription • Rifampin most widely used rifamycins • Effective against many Gram + and some Gram - as well as members of genus Mycobacterium • Primarily used to treat tuberculosis and Hansen’s disease as well as preventing meningitis after exposure to N. meningitidis • Resistance due to mutation coding RNA polymerase • Resistance develops rapidly

  25. Mechanisms of Action of Antibacterial Drugs • Inhibition of metabolic pathways • Relatively few • Most useful are folate inhibitors • Mode of actions to inhibit the production of folic acid • Antimicrobials in this class include • Sulfonamides • Trimethoprim

  26. Sulfa Enzymes Enzyme inhibition • Competitive inhibition - Inhibitor/substrate act at the same site Ex.:  PABA   folic acid  coenzyme

  27. Antiviral Drugs Nucleic Acid synthesis • Virally-encoded enzymes as target for antiviral drugs • Reverse transcriptase, Error-prone ( mutations) ex. AZT - nucleotide analog. • Herpes simplex virus (HSV) has an enzyme convert acyclovir to a nucleotide analog. Viral uncoating--block influenza A viruses. Assembly and Release of viral particles- protease inhibitors

  28. Determining Susceptibility of Bacteria to Antimicrobial Drug • Determining MIC • MIC = Minimum Inhibitory Concentration • Quantitative test to determine lowest concentration of specific antimicrobial drug needed to prevent growth of specific organism • Determined by examining strain’s ability to growth in broth containing different concentrations of test drug

  29. Determining the susceptibility of a bacterial strain to an antimicrobial drug - Minimum Inhibitory Concen. (MIC)

  30. Determining the susceptibility of a bacterial strain to an antimicrobial drug - Minimum Inhibitory Concen. (MIC) Resistant vs intermediate vs susceptible

  31. Determining the susceptibility of a bacterial strain to an antimicrobial drug - Disk diffusion (Kirby-Bauer) test

  32. Determining the susceptibility of a bacterial strain to an antimicrobial drug - Disk diffusion (Kirby-Bauer) test

  33. Resistance to antimicrobial drugs

  34. Mechanisms of resistance

  35. Acquisition of resistance Spontaneous mutation Gene transfer Single-step S R Multi-step SS S S R

  36. Acquisition of Resistance • Spontaneous mutation • Occurs at low rate • have profound effect of resistance of bacterial population • Example of spontaneous mutation • Resistance to streptomycin is result a change in single base pair encoding protein to which antibiotic binds • Better drug development: target multiple proteins.

  37. Acquisition of resistance Gene transfer Resistance plasmids (R plasmids) Can encode resistance to multiple medications Don’t use antimicrobial medications except when necessary!!!!!

  38. Examples of drug resistant bugs • Staphylococcus aureus (Superbug) • Common cause of nosocomial infections • Becoming increasingly resistant • most strains acquired resistance to penicillin in past 50yrs. • Due to acquisition of penicillinase genes • treated with methicillin (penicillinase resistant penicillin) • MRSA  methicillin resistant Staphylococcus aureus • MRSA many of these strains still susceptible to vancomycin • Some hospitals identified VISA • VISA vancomycin intermediate Staphylococcus aureus

  39. Examples of drug resistant bugs • Streptococcus pneumoniae • Has remained sensitive to penicillin • Some strains have now gained resistance • Gain of gene coding for penicillin-binding proteins • Generally via DNA mediated transformation

  40. Examples of drug resistant bugs • Mycobacterium tuberculosis • First-line drugs incur spontaneous mutations readily • often develop resistant to one of the multiple drugs used to treat • Reason for multiple drug therapy required • multi-drug-resistant: resistant to rifampin and isoniazid.

  41. Solutions • Slowing emergence and spread of resistance • Responsibilities of physicians and healthcare workers • Increase efforts to prescribe antibiotics for specific organisms • Educate patients on proper use of antibiotics • Responsibilities of patients • Follow instructions carefully • Complete prescribed course of treatment • Misuse leads to resistance

  42. Solutions • Slowing emergence and spread of resistance • Importance of an educated public • educate public about appropriateness and limitations of antibiotics • Antibiotics have no effect on viral infections • Misuse selects antibiotic resistance in normal flora • Global impacts of the use of antimicrobial drugs • Organisms develop resistance in one country can be transported globally • Many antimicrobials are available as non-prescription basis • Use of antimicrobials drugs added to animal feed • Produce larger more economically productive animals • Also selects for antimicrobial resistant organisms

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