Antimicrobial Agents

1. Antimicrobial Agents

2. The Aminoglycosides Two or more amino sugars attached to a hexose nucleus Narrow spectrum of coverage (G- aerobes) Bactericidal protein synthesis inhibitor Resistance Enzymatic modification Impaired uptake Mutation in ribosome

3. The Aminoglycosides Given parenterally only Poor penetration Inside cells (no effect on intracellular bugs) CSF Eye Accumulates in perilymph and endolymph of the inner ear Excreted mostly through kidneys, a little through the liver

4. Streptomycin An anti-TB drug Against G - rods Also useful for: Bacterial endocarditis when combined with a beta-lactam Tularemia Plague Tuberculosis Plague

5. Gentamicin, Tobramycin, Amikacin, Netilmicin Gentamicin and tobramycin are good against P. aeruginosa amikacin and netilmicin are effective against gentamicin-resistant bugs

6. Therapeutic Uses(+ a beta-lactam) UTI Community acquired pneumonia Meningitis Dialysis associated peritonitis Bacterial endocarditis Sepsis Topical infections (keratitis)

7. Toxicity/Contraindications of the Aminoglycosides Ototoxic (common) Auditory dysfunction Vestibular dysfunction Nephrotoxic (common) Rare side effects Neuromuscular blockade hypersensitivity

8. The Tetracyclines Congeners of polycyclic napthacenecarboxamide Natural products of Streptomyces or semi-synthetic derivatives Broad spectrum but work better against G+ than G- Work against anaerobes, intracellular bacteria, and atypical bacteria Bacteristatic Resistance due to decreased influx or active efflux, production of protection protein, enzymatic inactivation

9. Pharmacology of the Tetracyclines Absorbance is incomplete Oral or parenteral Dairy products, antacids, etc interfere with absorption Wide distribution in tissues and fluids (including CSF)

10. Pharmacology of the Tetracyclines Crosses placenta and enters fetal circulation Found in breast milk Most are excreted by kidneys, others are concentrated into bile and excreted with the stool. Tetracyclines are secreted here…

11. Tetracycline, oxytetracycline, democycline Incompletely absorbed from stomach (60-80%) Primarily excreted through the kidneys Minocycline, doxycycline Completely absorbed from stomach (95-100%) Minocyclins is excreted through liver Doxycycline is excreted mainly through feces Pharmacology of the Tetracyclines

12. Tigecycline A glycylcycline antibiotic, a derivative of minocycline Truly broad spectrum Complicated intra-abdominal infections, soft tissue infections Toxicities and side effects similar to the tetracyclines

13. Therapeutic Uses of Tetracyclines Rickettsial infections RMSF All forms of typhus Q fever Mycoplasma infections Chlamydia infections Lymphogranuloma venereum Trachoma Non-specific urethritis RMSF LGV

14. Therapeutic Uses of Tetracyclines Syphilis Anthrax Bacillary infections Brucellosis Tularemia Cholera Infections with spirochetes Yaws Lyme disease Relapsing fever Vibrio cholerae Lyme Disease

15. Toxicity/Contraindications of Tetracyclines Gastrointestinal Nausea, vomiting, etc. Photosensitivity Hepatic toxicity Large doses Worse when pregnant Renal toxicity Fanconi syndrome Degraded drug Nausea, vomiting, etc.

16. Toxicity/Contraindications of Tetracyclines Because drug is deposited in tooth dentine and enamel, brown bands form Do not give to children or pregnant/nursing women Misc. side effects Thrombophlebitis Various WBC dystrophies Increased intracranial pressure in neonates Hypersensitivity reactions

17. Chloramphenicol A natural product (contains a nitrobenzene moiety) Broad spectrum Bacteristatic Resistance Acetylation Efflux Mutations in ribosome

18. Chloramphenicol Given orally or parenterally Wide distribution, including CSF Present in bile, milk, and placental fluid Rapidly excreted by kidneys Used to treat typhoid fever, bacterial meningitis, anaerobic infections, rickettsial disease (second choice drug)

19. Toxicity/Contraindications of Chloramphenicol Hypersensitivity Hematological toxicity – anemia Gastrointestinal – nausea, vomiting, nasty taste, diarrhea Gray baby syndrome (2-9 days after dose) Within 24 hours, baby starts to vomit, stops eating, rapid and irregular respiration, abdominal distension, periods of cyanosis, and pooping loose green stool Baby then turns ashen gray and becomes flaccid and hypothermic Death in 40% of cases Prolongs half lives of warfarin, dicumerol, and anti-retroviral protease inhibitors

20. The Macrolides Erythromycin is natural product, clarithromycin and azithromycin are semi-synthetic derivatives 14 to 15 member lactone ring attached to one or more deoxy sugars Effective against G+ Effective against atypical mycobacteria and some intracellular bugs Bacteristatic, binds ribosomes much like chloramphenicol Resistance – efflux, ribosomal protection, esterases, mutate ribosome

21. Pharmacology of the Macrolides Administered orally Adsorbed in upper small intestine Gastric acid inactivates drug so pills are coated Food delays adsorption of erythromycin and azithromycin Readily diffuses in all intracellular fluids except CSF and brain Crosses placenta and enters fetal circulation Secreted in breast milk Excreted by kidney and liver (through bile)

22. Pharmacology of Selected Macrolides Clarithromycin More effective against staph and strep than erythromycin Can be given with food Azithromycin Slightly less effective against G+ but works better than other 2 against Haemophilus influenzae good against atypical mycobacteria Azithromycin

23. Therapeutic Uses of Macrolides Mycoplasma infections Legionairre’s Disease Chlamydia infections Diphtheria/pertussis Staph/strep GI infections Tetanus AIDs related infections pseudomembrane of diphtheria H. pylori

24. Toxicity/Contraindications of the Macrolides Epigastric distress with large doses Cholestatic hepatitis (rare) Potentiate the effects of Carbamazepine Corticosteroids Cyclosporine Digoxin Ergot alkaloids Theophylline Triazolam Valproate warfarin

25. The Streptogramins Two agents combined [Quinupristin-dalfopristin] (Synercid) Derived from pristinamycin antibiotic (derived from the bacterium Streptomyces pristina spiralis.) Covers G+ cocci Effect on bugs similar to macrolides Wide distribution Mostly hepatic excretion Only given IV in 5% dextrose in water

26. The Streptogramins Treatment of vancomycin-resistant enterococci MSSA strep infections Toxicity Infusion related pain and phlebitis Potentiates same drugs as macrolides

27. Clindamycin Similar to macrolides in many ways Good against anaeobes Given orally, parenterally, or topically Food does not interfere with absorption Wide distribution excluding CSF Crosses placenta Accumulates in PMN, alveolar macrophages, and pus Excreted by liver and kidneys

28. Clindamycin Good for anaerobic infections (except brain abscesses) Staph infections (including MRSA) Diarrhea is common side effect Pseudomembranous colitis to toxic megacolon Skin rash Rare side effects – SJS, anaphylaxis toxic megacolon

29. Linezolid Synthetic agent (an oxazolidinone) G+ coverage only, no anaerobes Prevents assembly of ribosome Oral or IV = 100% absorption Food does not interfere with absorption Distributed widely to well perfused tissues Excreted mostly by kidney Treat VR enterococci, MSSA, MRSA Well tolerated, minor gastrointestional complaints

30. Vancomycin Tricyclic Glycopeptide G+ coverage only Inhibits polymerization of peptidoglycan subunits given IV over an houror orally for pseudomembranous colitis Wide distribution Secreted by kidneys Treatment of MRSA Red-man syndrome: a complication of too rapid an infusion MRSA

31. Red-man syndrome

32. Teicoplanin (Targocid) • Glycopeptide • G+ coverage only • Its mechanism of action is to inhibit bacterial cell wall synthesis. • Wide distribution • Secreted by kidneys • MRSA and Enterococcus faecalis. • Oral teicoplanin: pseudomembranous colitis and Clostridium difficile-associated diarrhea • S/E: nausea, vomiting, diarrhea, rash, fever, bronchospasm, anaphylactic reactions, dizziness, headache, blood disorders, and mild hearing loss. • Should not be given to patients who are allergic to vancomycin

33. The End? Almost…