Antimicrobial Agents General considerations Prof R K Dixit

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

Objectives…. – Important drug interactions related to antimicrobials

Important Drug Interactions of Antimicrobials Pharmaceutical • During manufacture, packaging, Storage • During drug administration • During Mixing and injecting drug • Mixing in oral solutions • Mixing in solvent, • In bottle, Pharmacokinetic • No drug in • Chlelation /(Antacids, Milk)- Tetracyclines • Blood, • Alteration of p. H/ Ionization of drug- Penicillins • Plasma and • Alteration with Enterohepatic recirculation- (OCP) • Electrolyte solutions • Inducer (Barbiturates, Rifampicin, Griseofulvin, Pharmacodynamic Carbamazepine) • Inhibitor (Cimetidine, Chlolramphenicol, Erythromycin, • Synergism/Addition/ Quinolones) • Antagonism • Protein biding displacement of drug (Important with high • Combinations of more than protein binding drugs)- Sulphonamides one antimicrobial • Combination of antimicrobial with other agents (ADME)

Important Drug Interactions of Antimicrobials Pharmaceutical • During Manufacture, Packaging, Storage • During drug administration • During Mixing and injecting drug (If Coagulate Reject) • Mixing in oral solutions (Not advisable) • Mixing in solvent (According to instructions) • No drug in • Blood, • Plasma and • Electrolyte solutions

Important Drug Interactions of Antimicrobials Pharmacodynamic • Synergism/Addition(Cidal + Cidal, Static + Static) • Antagonism (Cidal + Static) When more sensitive to Cidal • Combination of antimicrobial with other agents

Important Drug Interactions of Antimicrobials Pharmacokinetic (ADME) • Chelation /(Antacids, Milk) • Tetracyclines • Alteration of p. H/ Ionization of drug • Penicillin G (not absorbed orally) • Alteration with Enterohepatic recirculation • OCP with antimicrobials • Inducers- • Rifampicin, Griseofulvin, • Inhibitors- • Chlolramphenicol, Erythromycin, Quinolones (Grape fruit (Furanocoumarins) • Protein biding displacement of drug • Sulphonamides

List of Important Interactions Related to Antimicrobials Sulphonamides Oral hypoglycaemics (Especially Sulphonylureas) Increased hypoglycemia Oral anticoagulants Increased anticoagulation (Protein binding displacement) Methotrexate Increased methotrexate toxicity (Folate deficiency) (Inhibitor of Dihydrofolate Reducatase)

Fluoroquinolone Antacids (Al, Reduced absorption of Mg, Ca), Zinc, Fluoroquinolone Iron, Sucralfate, Milk Theophylline Increased concentration due to decreased metabolism. (Least with Lome, Levo, Spar) Warfarin (Oral anti-coagulant) Enhanced effect due to decreased metabolism (least with Levo, Spar) Quinidine, Procainamide, Amidarone, Erythromycin, Cisapride, Astemizole, Terfenadine, Enhance Q-T interval leading to dangerous arrhythmia

Ampicillin (Penicillin), Contraceptive pills (Cephalosporin) Failure of contraception (Inhibition of enterohepatic recirculation) Tetracycline, Antagonism of bactericidal action Chloramphenicol, (Cidal with Static) Erythromycin Aminoglycoside in same syringe Inactivation of both (Pharmaceutical) Hydrocortisone Inactivation of penicillin (Pharmaceutical) Allopurinol Increased incidence of non-urticarial maculo-papular rashes Probenecid Decreases tubular secretion of penicillin and increases action (Pk) Clavulanic acid, Sulbactam Inhibition of Betalactamase leading to better effect (Synergism)

Cephaloridine Furosemide Increased nephrotoxicity Rifampicin Warfarin and OCP Failure of anti-coagulation and contraception Griseofulvin Cefoperazone, Cefotetan, Cefamandole Metronidazole Alcohol Disulfiram like syndrome (Aldehyde Syndrome) (Good Chief Minister) Ethyl Alcohol – (Alcohol dehydrogenase or Acetaldehyde synthetase) Acetaldehyde(Acetaldehyde dehydrogenase) (Blocked by Disulfiram)- Accumulation of Acetaldehyde and precipitations of syndrome consisting of Headache, Vomiting, Flushing etc. Acetic Acid- Kreb’s cycle- ATP + CO 2+ H 2 O

Nalidixic acid Oral anticoagula nts Enhanced anticoagulation Nitrofurantoin Nalidixic acid Antagonises action of nalidixic acid Probenecid Reduced tubular secretion leading to decreased concentration in urine Digitalis Amphotericin induced hypokalemia increases digitalis toxicity Amphotericin-B

Erythromycin Linezolid Theophylline, Inhibition of metabolism Carbamazepine (Inhibit CYP 3 A 4) Statins, Warfarin, Terfenadine Q-T prolongation leading to life threatening ventricular arrhythmias MAO inhibitors Increased toxicity of MAO inhibitors (Linezolid is reversible inhibitor of MAO and may lead to cheese reaction with food containing tyramine and can precipitate Serotonin syndrome (confusion, hypertension, seizures, tachycardia and muscle rigidity)

Streptogramins (Pristinamycin) Calcium channel blockers, Cyclosporine, Statins, Diazepam, Warfarin, Terfenadine, Cisapride Reduce liver metabolism of these drugs

Aminoglycosides Tetracyclines Furosemide, Ethacrynic acid Increased Ototoxicity Skeletal muscle relaxants (curare like drugs) Enhanced and persistent neuromuscular blockade Contraceptive pills Failure of contraception Antacids, Iron Milk , Food Decreased absorption due to Chelation

Chloramphenicol Oral hypoglycemic Increased hypoglycemic effect (due to enzyme inhibition by Chloramphenicol) Oral anticoagulant Enhanced anticoagulant

Ketoconazole Griseofulvin Cisapride, Terfenadine, Astemizole, Quinidine, Warfarin, Cyclosporine Tacrolimus Statins Ketoconazole inhibits CYP 3 A 4 leading to decreased metabolism and accumulation of other drug (Least with Fluconazole) H 2 blockers, PPI, Antacids Decreased absorption of Ketoconazole due to decreased gastric acidity Amphotericin B Ketoconazole inhibits the synthesis of ergosterol and produces depletion of membrane ergosterol reducing the binding sites for Amphotericin B Other drug Inducer of microsomal

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