1. Microbiology B.E Pruitt & Jane J. Stein AN INTRODUCTION EIGHTH EDITION TORTORA FUNKE CASE Chapter 20, part A Antimicrobial Drugs

2. ChemotherapyThe use of drugs to treat a disease Antimicrobial drugsInterfere with the growth of microbes within a host AntibioticSubstance produced by a microbe that, in small amounts, inhibits another microbe Syntheticproduced in a lab, not from an organism Selective toxicityA 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. Table 20.1 Sources of some noteworthy Antibiotics

6. Table 20.2 Broad versus Narrow Spectrum

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 difficile associated pseudomembranous colitis (arrows mark pseudomembranes). http://www.cfpc.ca/cfp/2004/Nov/vol50-nov-cme-1.asp 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. 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 ) Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis

14. Penicillins Figure 20.6

15. Figure 20.8 Penicillinase

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

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

18. 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 Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis Anne Margaret Tracey born 15 February 1936

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

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

21. 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 Antibacterial Antibiotics Inhibitors of Protein Synthesis

22. 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 Antibacterial Antibiotics Inhibitors of Protein Synthesis

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

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

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

26. Figure 20.13 Sulfa drugs as inhibitors