Chapter 20, part A

1. Chapter 20, part A Antimicrobial Drugs

2. Antimicrobial Drugs • Chemotherapy The use of drugs to treat a disease • Antimicrobial drugs Interfere with the growth of microbes within a host • Antibiotic Substance produced by a microbe that, in small amounts, inhibits another microbe • Synthetic produced in a lab, not from an organism • Selective toxicity A drug that kills harmful microbes without damaging the host

3. Chemotherapy • Ancient - potions, salves etc • Graviora quaedam sunt remedia periculus - “some remedies are worse than the disease” Using things like inorganic arsenic and mercury to treat syphilis • Koch and germ theory • Erlich with “magic bullet” idea • Fleming first Antibiotic - Penicillium notatum and penicillin with Staphylococcus spp. 1928

4. 1928 – Fleming discovered penicillin, produced by Penicillium. • 1940 – Howard Florey and Ernst Chain performed first clinical trials of penicillin. Figure 20.1

5. Sources of some noteworthy Antibiotics Table 20.1

6. Broad versus Narrow Spectrum Table 20.2

7. Criteria for Ideal Antibiotics • Selectively toxic to microbe but nontoxic to host • Soluble in body- tissue distribution - blood brain barrier • Remains in body long enough to be effective - resists excretion and breakdown • Shelf life • Doesn’t lead to resistance • Cost not excessive • Hypoallergenic • Concerns suppression of normal flora - antibiotic associated colitis with Clostridium difficile and it’s toxins or Candida albicans • Clostridium difficile causes approximately 20% of cases of diarrhea associated with antibiotics, including clindamycin and the second- and third-generation cephalosporins. Diarrhea is usually mild, but can be severe; extreme cases develop toxic megacolon

8. C. diff • Figure 1. Features of C difficile colitis: • A) Plain film of abdomen showing bowel wall thickening, loss of haustral markings (thin arrow) and dilation of the ascending and transverse colon (thick arrow); • B) Computed tomographic scan of abdomen showing colonic dilation (thin arrows) and bowel wall thickening with stranding (thick arrow); • C) Endoscopic view of classic C difficileassociated pseudomembranous colitis (arrows mark pseudomembranes). http://www.cfpc.ca/cfp/2004/Nov/vol50-nov-cme-1.asp

9. Mechanisms of Action Targets of antibacterial agents - many ways to attack • Cell Wall - peptidoglycan - Gram (+) vs (-) and forms “weak points” and are osmotically fragile easily lysed •  lactams like Penicillins and cephalosporin react with enzymes in formation of cross links • Cycloserine inhibits subunits of peptidoglycan • Vancomycin hinders the elongation of peptidoglycan • Bacitracin interferes with transport of precursors across plasma membrane • Nucleic acid synthesis • Inhibition of transcription and DNA replication • Sulfonamides - sulfa drugs block PABA to folic acid used to make nucleotides by competitive inhibition of enzyme trimethoprim and sulfamethoxazole SXT • Often toxic - allergic reactions

10. Mechanisms of Action - continued • Protein synthesis - different ribosomes 70s good site of attack • Aminoglycosides - (streptomycin, gentamicin) bind to 30s subunit blocks translation and misreading of mRNA • Tetracyclines - bind to 30s subunit and block attachment of tRNA • Chloramphenicol - binds to 50S subunits and prevents peptide bonds from being formed • Macrolides - bind to 50s subunits and prevents the continuation of protein synthesis - used in many G(+) and walking atypical pneumonia instead of penicillin • Plasma membrane attack • Polymyxin - binds with phospholipids in membrane - not as selectively toxic - topical • Inhibition of enzymatic activities • Like sulfa and PABA blocked to folic acid

11. The Action of Antimicrobial Drugs  Figure 20.2

12. The Action of Antimicrobial Drugs Figure 20.4

13. Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis • Penicillin • Natural penicillins • Natural from mold • Choice for Streptococcus spp and most Staphylococcus spp • Semisynthetic penicillins • More resistant to penicillinase • Methicillin-resistant Staphylococcus aureus (MRSA)

14. Penicillins Figure 20.6

15. Penicillinase Figure 20.8

16. Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis • Semi-Synthetic Penicillin • Penicilinase-resistant penicillins • Extended-spectrum penicillins • Penicillins + -lactamase inhibitors

17. Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis Cephalosporins • Different mold source • more effective against gram-negatives • More resistant penicillases Figure 20.9

18. Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis • Polypeptide antibiotics • Bacitracin - Margaret Tracey - 1945, 7 years old, hit by car, compound fracture contained B. subtilis that killed S. aureus • Topical application • Against gram-positives • Vancomycin • Glycopeptide • Important "last line" against antibiotic resistant S. aureus • vancomycin-resistant enterococci (VRE) • Enterococcus faecium and Enterococcus faecalis Anne Margaret Tracey born 15 February 1936

19. Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis • Antimycobacterium antibiotics • Isoniazid (INH) • Inhibits mycolic acid synthesis • Ethambutol • Inhibits incorporation of mycolic acid Multidrug-Resistant Tuberculosis Infection

20. Antibacterial Antibiotics Inhibitors of Protein Synthesis • Chloramphenicol • Broad spectrum • Binds 50S subunit, inhibits peptide bond formation • Aminoglycosides • Streptomycin, neomycin, gentamycin • Broad spectrum • Changes shape of 30S subunit

21. Antibacterial Antibiotics Inhibitors of Protein Synthesis • Tetracyclines • Broad spectrum • Interferes with tRNA attachment • Macrolides • Gram-positives • Binds 50S, prevents translocation • Common macrolides • ▪Azithromycin (Zithromax) • ▪Clarithromycin (Biaxin, Fromilid) • ▪Dirithromycin (Dynabac) • ▪Erythromycin • Gram-positives • Binds 50S, prevents translocation

22. Antibacterial Antibiotics Inhibitors of Protein Synthesis • Streptogramins • Gram-positives • Binds 50S subunit, inhibits translation • Synercid • Gram-positives • Binds 50S subunit, inhibits translation • Oxazolidinones • Linezolid • Gram-positives • Binds 50S subunit, prevents formation of 70S ribosome

23. Antibacterial Antibiotics Injury to the Plasma Membrane • Polymyxin B • Topical • Combined with bacitracin and neomycin in over-the-counter preparation

24. Antibacterial Antibiotics Inhibitors of Nucleic Acid Synthesis • Rifamycin • Inhibits RNA synthesis • Antituberculosis • Quinolones and fluoroquinolones • Ciprofloxacin • Inhibits DNA gyrase • Urinary tract infections

25. Antibacterial AntibioticsCompetitive and Noncompetitive Inhibitors • Sulfonamides (Sulfa drugs) • Inhibit folic acid synthesis • Broad spectrum Figure 5.7

26. Sulfa drugs as inhibitors Figure 20.13