Treatment with antimicrobial combinations may be beneficial in certain cases, such as to treat mixed bacterial infections in which the organisms are not susceptible to a common agent, to achieve synergistic antimicrobial activity against particularly resistant strains (eg, Pseudomonas aeruginosa), or to decrease the risk of antimicrobial resistance (or overcome it). In general, antimicrobial combinations are most appropriate with a mixed infection or when an empirical selection must be made in a life-threatening situation.
The use of antimicrobial agents in combination results in additive or synergistic effects. Prime examples are the combination of clavulanic acid with amoxicillin or ticarcillin (or sulbactam with ampicillin), in which the first agent prevents beta-lactamase destruction of the second agent, or the combination of a diaminopyrimidine such as trimethoprim or ormetoprim with a sulfonamide. Antimicrobial 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 antimicrobials are substantially impaired by simultaneous administration of drugs that impair microbial growth (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 drugs that are normally bactericidal can be rendered merely bacteriostatic if sufficient drug concentrations are not achieved at the site of infection. In general, the following common antimicrobials are likely to be bactericidal at their respective MICs: penicillins, cephalosporins, aminoglycosides, trimethoprim-potentiated sulfonamides, metronidazole, quinolones, rifampin, and glycopeptides. The following antimicrobials are generally bacteriostatic at typical concentrations: tetracyclines, phenicols (eg, chloramphenicol and florfenicol), macrolides, lincosamides, spectinomycin, and nonpotentiated sulfonamides.
Ideally, antimicrobial selection should be based on different mechanisms of action and on complementary spectra of activity. Beta-lactams are often selected, because their action may facilitate the movement of other drugs through the damaged cell wall into the microbe. Examples of combination treatment 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 combinations of trimethoprim with selected sulfonamides or clavulanic acid with other beta-lactams are other examples of synergistic effects.
Macrolides combined with rifampin remain a mainstay of treatment for Rhodococcus equi pneumonia in foals, because of their synergistic effects on bacteria; however, drug-drug interactions may decrease overall treatment efficacy because of alterations of the in vivo pharmacokinetics of macrolides. Rifampin induces intestinal p-glycoprotein efflux pumps that affect the oral absorption and distribution of macrolides to the lungs. Coadministration of tulathromycin and rifampin in foals leads to decreased concentrations of tulathromycin in the lungs. Coadministration of gamithromycin and rifampin in foals leads to increased plasma exposure to gamithromycin due to rifampin's inhibition of hepatic elimination mechanisms. Coadministration of rifampin and clarithromycin decreases clarithromycin's bioavailability by up to 90%. However, because the bronchial and alveolar concentrations of clarithromycin exceed the MIC for R equi even in the face of coadministration of rifampin, the combination is still the treatment of choice and the most effective for R equi in foals. Additionally, consecutive dosing of clarithromycin if given 4 hours before rifampin has been found to significantly increase systemic exposure of clarithromycin in foals.
Irrational drug combinations include using drugs that compete for the same mechanism of action, and drugs that contain products that inactivate the other drugs. For example, chloramphenicol, macrolides, and lincosamides inhibit protein synthesis at the 50S ribosomal subunit, and therefore the mechanisms of action compete with the others when administered concurrently. In addition, the procaine in procaine penicillin G is metabolized to para-aminobenzoic acid, which may inactivate sulfonamide antimicrobials.
