1. Antimicrobial Agents (General considerations)
Prof. R. K. Dixit
Pharmacology and Therapeutics
K.G.M.U. Lucknow

2. Objectives….
Important drug interactions related to antimicrobials

3. 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

4. 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

5. 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

6. 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

7. 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)

8. 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

9. 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)

10. 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.

11. 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

12. 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)

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

14. 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

15. Chloramphenicol Oral hypoglycemic
Increased hypoglycemic effect (due to enzyme inhibition by Chloramphenicol)
Oral anti-coagulant
Enhanced anticoagulant

16. 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

17. Thanks