1. Antimicrobial Agents (General Considerations) Prof. R. K. Dixit Pharmacology and Therapeutics K.G.M.U. Lucknow dixitkumarrakesh@gmail.com

2. Objectives After this lecture you will be able to answer – General adverse effects of antimicrobials – Specific adverse effects of important antimicrobial groups

3. General-Adverse effects of antimicrobials Hypersensitivity reaction- Penicllins, Sulphonamides, Fluoroquinolones, Tetracyclines, Nitrofurantoin Skin rashes, Angioedema, Bronchospasm Anaphylaxis, Management with OASIS Oxygen, Adrenaline {Physiological antagonist of histamine} Antihistaminics Steroid, IV fluid Supportive,

4. Gastrointestinal symptoms- Nausea, Gastric irritation, Anorexia, Flatulence, indigestion, Altered GI motility, Mouth ulcers, Glossititis, Stomatitis, Chelitis Esophagitis, Mal-absorption syndrome Tetracyclines, Quinolones, Ampicilline, Metronidazole

5. Injectable Side effects- Pain, Abscess formation, Thrombo-phlebitis in case of IV Flushing, redness in case of rapid IV, Deficiency- V itamin B complex and Vitamin K, Deficiency of drugs which need entero-hepatic recirculation for their effect e.g. Oral contraceptives

6. Superinfections New infection Most common organisms Pseudomonas Candida Proteus Clostridium difficle- Pseudomembranous Colitis Due to removal of inhibitory mechanisms (Bacteriocins and competition for nutrition) – Common Clindamycin, Cotrimoxazole, Chloramphenicol, Ampicillin, Tetracyclines (CAT) Immunosuppressant, Diabetes mellitus Abdominal surgery Treated by Metronidazole, Vancomycin, Bacitracin

7. CNS- Headache, Irritability, Sedation, Tinnitus, Ataxia, Slurred speech, Blurring of vision,.

8. Masking of infections- eg. Tt Gonorrhea mask Syphilis Idiosyncratic and Intolerance- Drug Fever- Electrolyte imbalance- Teratogenic- No antimicrobial is absolutely safe during pregnancy No one is Category A. Category B, C and D can be given under special situation. Category X absolutely contraindicated to pregnant

9. FDA Categorization of Drugs in Pregnancy Category A (No antibiotic is under this) ◦ Controlled studies in women fail to demonstrate a risk Category B (Safe can be prescribed) ◦ Either animal-reproduction studies have not demonstrated or not confirmed in controlled studies in women Category C (Under special circumstance) ◦ Either studies in animals have revealed or studies in women and animals are not available. Category D (Under special circumstance with consent) ◦ There is positive evidence of human fetal risk, but the benefits may be acceptable despite the risk Category X (Not prescribed) ◦ Studies in animals or human beings have demonstrated fetal abnormalities and contraindicated

10. Antibiotics in Pregnancy FDA CategoryAntibiotics in Category A BPenicillins, Cephalosporins, Carbapenems (except Imipenem), Daptomycin, Vancomycin (oral), Clindamycin, Erythromycin, Azithromycin, Metronidazole (avoid first trimester), Nitrofurantoin, Acyclovir, Amphoterocin B, Ethambutol CQuinolones, Chloramphenicol, Clarithromycin, Imipenem, Linezolid, Trimethoprim/Sulfa (D if used near term), Vancomycin (IV), Rifampin, INH, PZA, PAS, Fluconazole, Caspofungin DTetracyclines (Doxy, Tige, Mino), Voriconazole, Aminoglycosides (some put gentamicin as a category C) XRibavarin

11. Specific Side effects of antimicrobials Bone marrow suppression- Chloramphenicol, Thrombocytopenia- Sulphonamides Cephalosporins, (Cefamandole, Cefoperazone, Cefotetam), Chloramphenicol Renal toxicity- Aminoglycosides, Tetracyclines except Doxycycline, Cephalothin, Talampicillin, Nitrofurantoin, Nalidixic acid, Amphotericin B, Vancomycin, Ethambutol, Flucytosine, Methacillin,

12. Hepatotoxicity- Rifampicin, Isoniazide (in fast acetylators due to accumulation of Acetyl – isoniazide and acetyl – hydrazine) Pyrazinamide, Tetracycline, Erythromycin estolate, Talampicillin, Nalidixic acid, Trovafloxacin Oxacillin, Photoxicity- Tetracyclines (Demeclocycline, Doxycycline), Quinolones (Sparfloxacin)

13. Ototoxicty- Aminoglycosides, Vancomycin Diabetes insipidus- Demeclocycline Neuromuscular block- Amino-glycosides, Polymyxin- B, Colistin (May cause respiratory paralysis in patients of Myasthenia gravis, Gaping of wound)

14. Retinal damage- Chloroquine Neuropathy- Isoniazide- more in slow acetylators Due to increased excretion of pyridoxine in urine and Accumulated INH inhibits pyridoxine-kinase (Pyridoxine Kinase converts pyridoxine to active form pyridoxyl phosphate) Polypeptide antimicrobials, Amphotericin B, Nitrofurantoin, Carbenicillin

15. Haemolysis (G-6-PD deficiency), - X-Linked recessive. G-6-P-D is required for regeneration of NADPH. NADPH is required for reduction of oxidized glutathione Reduced glutathione protects –against oxidative injury In presence of pro-oxidants like Naphthalene, Methylene Blue, Beans (Favism) Drugs- Sulfa drugs, Primaquine, Isoniazide, Nitrofurantoin, Nalidixic acid, Dapsone, Furazolidione, Quinolones, Chloramphenicol, Chloroquine, Aspirin, Haemolysis occurs G-6-P-D Glutathion reductase GlutathioneGlutathione disulphide NADP NADPH SPIN Delivery

16. Discolouration of Teeth and bone damage- Tetracyclines Redman (Red neck) Syndrome- Vancomycin, Teicoplanin, Discolouration of secretions (saliva, sweat, urine)- Rifampicin, Clofazimine, Nitrofurantoin Kernicterus- Sulphonamides, Rifampicin Flu-like syndrome- Rifampicin Antitestosterone effect- Ketoconazole (reduces synthesis of testosterone and estradiol which leads to gynaecomastia)

17. Crystaluria- Sulphonamides Antianabolic effect- Tetracycllines Cholestatic jaundice- Erythromycin estolate, Nitrofurantoin, Fosfomycin, Optic neuritis- Ethambutol Tendon rupture- Fluroquinolones

18. Hyperuricemia- Pyrazinamide (Gout) Jarisch Herxheimer Reaction- Penicillin in syphilis Neuromuscular blockadage- Amino-glycosides Alopecia- All anti-cancer drugs Fanconi’s Syndrome- (Renal toxicity)- Expiry date tetracyclines- due to toxic metabolites epitetracycline Teratogenic- Aminoglycosides, Tetracyclines Pulmonary eosonophilic syndrome- Tetracylines

19. Pseudotumor cerebri- and bulging fontanelles- Tetracyclines Vestibular toxicity- Minocycline Disulfiram like reaction – (Good Chief Minister) Griseofulvin, Cefoperazone, Cefotetan, Cefamandole, Metronidazole,

20. Grey Baby Syndrome- (Ashen Grey Cyanosis)- Chloramphenicol Pulmonary Fibrosis- Bleomycin, Nitrofurantoin Special- Gatifloxacin Prolongs QT interval and arrhythmia Hypo or hyperglycemia in patients of diabetes. Aminoglcosides have NONE side effects- Neuromuscular block (more with Neomycin and Streptomycin), Ototoxicity (Vestibular by Streptomycin, Gentamicin while Cochlear by Neomycin, Amikacin), Nephrotoxicity least with Streptomycin, Etc. Teratogenic) High dose of Ceftriaxone Pseudo-lithiasis (Gall bladder sludge)

21. Mafenide Has carbonic anhydrase inhibitor activity- May alkalinize urine and cause acidosis Hyperventilation. 8-Hydroxy-quinoines (Iodochloro-hydroxyquinol,) SMON (Subacute myelo-optic neuropathy) Arrhythmia- Quinolones, Macrolides Antianabolic effect (reduce protein synthesis)- Tetracyclines

22. Thanks