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Find information on animal health topics, written for the veterinary professional.

Combination Therapy

By Dawn Merton Boothe, DVM, PhD, Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University

Treatment with antimicrobial combinations may be necessary in certain cases. The administration of two or more agents may be beneficial in the following situations: 1) to treat mixed bacterial infections in which the organisms are not susceptible to a common agent, 2) to achieve synergistic antimicrobial activity against particularly resistant strains (eg, Pseudomonas aeruginosa), or 3) to reduce the risk of or overcome bacterial resistance. In general, combination therapy is most appropriate with a mixed infection or when an empirical selection must be made in a life-threatening situation.

Additive or synergistic effects are seen when antibacterial agents are used in combination. Prime examples are the combination of clavulanic acid with amoxicillin or ticarcillin (or sulbactam with ampicillin), in which the first agent prevents β-lactamase destruction of the second agent, or the combination of a diaminopyrimidine such as trimethoprim or ormetoprim with a sulfonamide. Antibacterial antagonism may also emerge, sometimes with serious consequences. Generally, bacteriostatic agents act in an additive fashion with one another, whereas bactericidal agents are often synergistic when combined. However, the effects of several bactericidal antibiotics are substantially impaired by simultaneous use of drugs that impair microbial growth or “bacteriostatic” drugs (eg, most ribosomal inhibitors). This is a general guideline only; many exceptions are known, and confounding factors also play a role. Classification of antimicrobials as bactericidal or bacteriostatic can also be misleading, because “bactericidal” drugs can be rendered bacteriostatic if sufficient drug concentrations are not achieved at the site of infection. However, in general, the following common antimicrobials at MIC concentrations are likely to be bactericidal: penicillins, cephalosporins, aminoglycosides, trimethoprim/sulfonamides ("potentiated"), metronidazole, quinolones, rifampin, and glycopeptides. The following antimicrobials at usual concentrations are generally bacteriostatic: tetracyclines, the phenicols (eg, chloramphenicol, florfenicol), macrolides, lincosamides, spectinomycin, and the sulfonamides (nonpotentiated).

Ideally, antimicrobial selection should be based on different mechanisms of action and on complementary spectra of activity. β-Lactams are often selected, because their action may facilitate movement of other drugs through the damaged cell wall into the microbe. Examples of combination therapy for mixed infections include the use of clindamycin, metronidazole, or the semisynthetic penicillins for their anaerobic coverage in combination with aminoglycosides for their gram-negative efficacy. Synergism against certain bacterial pathogens frequently can be achieved with combinations of penicillins or cephalosporins and aminoglycosides. The combined use of trimethoprim with selected sulfonamides or clavulanic acid with other β-lactams are other examples of synergistic effects.