Polypharmacy is increasingly common in the prevention and treatment of diseases in animals. Drug-drug interactions represent one common event associated with multidrug therapy that may interfere with optimal clinical outcome.
Polypharmacy is increasingly common in the prevention and treatment of diseases in animals. Drug-drug interactions represent one common event associated with multidrug therapy that may interfere with optimal clinical outcome. Mechanisms whereby drugs may interact during concurrent treatment are well established for many drug combinations. However, the incidence and clinical relevance of interactions are difficult to determine with accuracy because of the many factors involved and because there is very little clinical data to validate in vitro findings. Therefore, the need for clarification of the clinical relevance of potential interactions has become crucial, since clinicians are faced with the difficult task of evaluating both qualitatively and quantitatively the risk of drug interactions in their patients in order to make sound therapeutic decisions. An understanding of the role of pharmacokinetics, pharmacodynamics, and the factors that alter these processes are vital in the clinician's process of decision making.
Objectives of the presentation
Relevant therapeutic points
Key drug interactions in small animals
Interacting Drugs or
Mechanism and Effect
Chloramphenicol inhibits liver CYP2B1112. Decreased phenobarbital clearance, increased elimination half-life and increased plasma and tissue concentrations. Prolonged sedation and toxicity potential.
In vitro, In vivo PK and PD1-6
CYP2B11 inhibition by chloramphenicol. Decreased clearance and prolonged recovery time. Breed differences are possible.
In vitro, In vivo PK and PD13-14.
Some flouroquinolones inhibit liver CYP1A2. Decreased theophylline clearance and potential for increased toxicity. In vivo effect more evident with enrofloxacin than with marbofloxacin. In vitro effect observed with ofloxacin, orbifloxacin, and ciprofloxacin.
In vivo PK15-16
Dog, Buffalo, Sheep
Enrofloxacin and flunixin meglumine decrease each other clearance in dogs. Enrofloxacin decreases diclofenac clearance in sheep and increases Vd in buffalo. Unknown interactions between FQ and other NSAIDs.
In vivo PK18-20.
Induction of doxycycline metabolism by phenobarbital. Clearance of doxycycline doubled in patients undergoing long-term phenobarbital therapy. Decreased doxycycline efficacy is likely.
In vivo PK9.
Antacids/Fluoroquinolones, Tetracyclines, Azithromycin.
Dog, cat, horse, other
The systemic availability of many drugs is consistently decreased by their adsorption to concurrently administered antacids. The extent of this decrease is variable but usually significant.
In vivo PK21-23
Chloramphenicol, Erythromycin and to lesser extent Clarithromycin inhibit CYP3A4 resulting in increased cisapride concentrations in humans. In one study in dogs erythromycin did not modify cisapride cardiovascular pharmacodynamics.
In vivo PD24
Synergistic effect has been observed in vitro against Bacteroides fragilis.
Ceftazidime or cefepime plus a flouroquinolone (ciprofloxacin, levofloxacin, gatifloxacin, or moxifloxacin) resulted in additive effect when strains were susceptible to both agents in the combination (less than 10% of synergy) but showed synergy 92% of the cases when strains were resistant to one or both agents. No significant differences were found between the various combinations. Clinical relevance depends on PK.
Classical synergistic interaction described in vitro for many organisms, including strains of Staphylococcus aureus that are susceptible to each drug alone. One mechanism is enhanced bacterial penetration of the aminoglycoside by the beta-lactam in organisms such as streptococci. This synergism may carry to gram-negative organisms like Enterobacteriaceae, including Pseudomonas aeruginosa. Even though synergistic effect is expected when using this combination, it is often possible that the effect cannot be clinically achievable
In vitro29, In vivo30
Sanders JE, Yeary RA, Fenner WE, et.al. Interaction of phenytoin with chloramphenicol or phenobarbital in the dog. J Am Vet Med Assoc 1979;175(2):177-180.
Teske RH, Carter GG. Effect of chloramphenicol on pentobarbital-induced anesthesia in dogs. J Am Vet Med Assoc 1971;159(6):777-780.
Adams HR, Dixit BN. Prolongation of pentobarbital anesthesia by chloramphenicol in dogs and cats. J Am Vet Med Assoc 1970;156(7):902–905.
Houston DM, Chochrne SM, Conlon P. Phenobarbital toxicity in dogs concurrently treated with chloramphenicol. Can Vet J 1989;30:598.
Adams RH, Isaacson EL, Masters BS. Inhibition of hepatic microsomal enzymes by chloramphenicol. J Pharmacol Exp Therap 1977;203(2):388-396.
Campbell CL. Primidone intoxication associated with concurrent use of chloramphenicol. J Am Vet Med Assoc 1983;182(9):992-993.
Palmer DL, Despopoulos A, Rael ED. Induction of chloramphenicol metabolism by phenobarbital. Antimicr Ag Chemother 1972;1(2):112-115.
Graham RA, Downey A, Mudra D et al. In vivo and in vitro induction of cytochrome P450 enzymes in beagle dogs. Drug Metab Dispos 2002;30(11):1206–1213.
Neuvonen PJ, Penttilä. Interaction between doxycycline and barbiturates. Br Med J 1974;1:535-536.
Pillai SK, Moellering RC, Eliopoulos GM. Antimicrobial Combinations. In: Lorian V, ed. Antibiotics in Laboratory Medicine, 4th ed. 1996; Williams and Wilkins.
Huovinen P, Wolfson JS, Hooper DC. Synergism of trimethoprim and ciprofloxacin in vitro against clinical bacterial isolates. Eur J Clin Microb Infect Dis 1992;11:255-257.
Trepanier LA. Cytochrome P450 and its role in veterinary drug interactions. Vet Clin North Am Small Anim Pract 2006;36:975-985.
Mandsager RE, Clarke CR, Shawley RV, et.al. Effects of chloramphenicol on infusion pharmacokinetics of propofol in greyhounds. Am J Vet Res 1995;56(1):95–99.
Hay Kraus BL, Greenblatt DJ, Venkatakrishnan K, et.al. Evidence for propofol hydroxylation by cytochrome P4502B11 in canine liver microsomes: breed and gender differences. Xenobiotica 2000;30(6):575-588.
Hirt RA, Dederichs D, et.al. The effect of orally administered marbofloxacin on the pharmacokinetics of theophylline. J Vet Med A Physiol Pathol Clin Med 2003;50(5):246–250.
Intorre L, Mengozzi G, Maccheroni M, et.al. Enrofloxacin-theophylline interaction: influence of enrofloxacin on theophylline steady-state pharmacokinetics in the beagle dog. J Vet Pharmacol Ther 1995;18(5):352–356.
Regmi NL, Abd El-Aty AM, Kuroha M, et.al. Inhibitory effect of several fluoroquinolones on hepatic microsomal cytochrome P-450 1A activities in dogs. J Vet Pharmacol Ther 2005;28(6):553-557.
Ogino T, Mizuno Y, Ogata T, et.al. Pharmacokinetic interactions of flunixin meglumine and enrofloxacin in dogs. Am J Vet Res 2005;66(7):1209-1213.
Kumar N, Singh SD, Jayachandran C. Pharmacokinetics of enrofloxacin and its active metabolite ciprofloxacin and its interaction with diclofenac after intravenous administration in buffalo calves. Vet J 2003;165:302-306.
Rahal A, Kumar A, Ahmad AH, et.al. Pharmacokinetics of diclofenac and its interaction with enrofloxacin in sheep. Res Vet Sci 2008;84(3):452-456.
Lehto P,Kivistö. Effect of sucralfate on absorption of norfloxacin and ofloxacin. Antimicr Ag Chemother 1994;38:248–251.
Jaehde U, Sörgel F, Stephan U, et.al. Effect of an antacid containing magnesium and aluminum on absorption, metabolism, and mechanism of renal elimination of pefloxacin in humans. Antimicr Ag Chemother 1994;38(5):1129-1133.
Sadowski DC. Drug interactions with antacids. Mechanisms and clinical significance. Drug Safety 1994;11(6):395-407.
Al-Wabel NA, Strauch SM, Keene BW, et.al. Electrocardiographic and hemodynamic effects of cisapride alone and combined with erythromycin in anesthetized dogs. Cardio Toxicol 2002;2(3):195-208.
Busch DF, Sutter VL, Finegold SM. Activity of combinations of antimicrobial agents against Bacteroides fragilis. J Infect Dis 1976;133(3):321-328.
Fish DN, Choi MK, Jung R. Synergic activity of cephalosporins plus flouroquinolones against Pseudomonas aeruginosa with resistance to one or both drugs. J Antimicr Ther 2002;50:1045-1049.
Miranda-Novales G, Leaños-Miranda BE, Vilchis-Pérez M, et.al. In vitro activity effects of combinations of cephalothin, dicloxacillin, imipenem, vancomycin and amikacin against methicillin-resistant Staphylococcus spp. strains. Ann Clin Microb Antimicr 2006;5:25-29.
Paul M, Benuri-Silbiger I, Soares-Weiser K, et.al. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials. Br Med J 2004;328:668-672.
Snyder RJ, Wilkowske CJ, Washington JA 2nd. Bacetericidal activity of combinations of gentamicin with penicillin or clindamycin against Stretococcus mutans. Antimicr Ag Chemother 1975;7(3):333-335.
Klastersky J, Meunier-Carpentier F, Prevost JM. Significance of antimicrobial synergism for the outcome of gram negative sepsis. Am J Med Sci 1977 Mar-Apr;273(2):157-167.