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, No drug in Blood, Plasma and Electrolyte solutions Synergism/Addition/ Antagonism Combinations of more than one antimicrobial Combination of antimicrobial with other agents Pharmacodynamic Pharmacokinetic (ADME) Chlelation /(Antacids, Milk)- Tetracyclines Alteration of pH/ Ionization of drug- Penicillins Alteration with Enterohepatic recirculation- (OCP) Inducer (Barbiturates, Rifampicin, Griseofulvin, Carbamazepine) Inhibitor (Cimetidine, Chlolramphenicol, Erythromycin, Quinolones) Protein biding displacement of drug (Important with high protein binding drugs)- Sulphonamides

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

Important Drug Interactions of Antimicrobials Pharmacokinetic (ADME) Chelation /(Antacids, Milk)- Tetracyclines Alteration of pH/ 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 (Inhibitor of Dihydrofolate Reducatase) Increased methotrexate toxicity (Folate deficiency)

Fluoroquinolone Antacids (Al, Mg, Ca), Zinc, Iron, Sucralfate, Milk Reduced absorption of Fluoroquinolone 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), (Cephalosporin) Contraceptive pills Failure of contraception (Inhibition of enterohepatic recirculation) Tetracycline, Chloramphenicol, Erythromycin Antagonism of bactericidal action (Cidal with Static) 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)

Ethyl Alcohol – Acetaldehyde- Acetic Acid- ATP + CO2+ H2O Cephaloridine Furosemide Increased nephrotoxicity Rifampicin Warfarin and OCP Failure of anti-coagulation and contraception Griseofulvin Cefoperazone, Cefotetan, Cefamandole Metronidazole (Good Chief Minister) Alcohol Disulfiram like syndrome (Aldehyde Syndrome) Ethyl Alcohol – (Alcohol dehydrogenase or Acetaldehyde synthetase) Acetaldehyde- (Acetaldehyde dehydrogenase) Acetic Acid- Kreb’s cycle- ATP + CO2+ H2O (Blocked by Disulfiram)- Accumulation of Acetaldehyde and precipitations of syndrome consisting of Headache, Vomiting, Flushing etc.

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

Erythromycin Theophylline, CarbamazepineStatins, Warfarin, Terfenadine, Inhibition of metabolism (Inhibit CYP3A4) Terfenadine Q-T prolongation leading to life threatening ventricular arrhythmias Linezolid 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 Tetracyclines 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 anti-coagulant Enhanced anticoagulant

Ketoconazole Griseofulvin Cisapride, Terfenadine, Astemizole, Quinidine, Warfarin, Cyclosporine Tacrolimus Statins Ketoconazole inhibits CYP3A4 leading to decreased metabolism and accumulation of other drug (Least with Fluconazole) H2 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 Griseofulvin Other drug Inducer of microsomal enzymes

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