To treat polymicrobial infections (such as intra-abdominal abscesses, which typically are due to a combination of anaerobic and aerobic Gram-negative organisms, and enterococci). The antimicrobial combination chosen should cover the most common known or suspected pathogens but need not cover all possible pathogens. The availability of antimicrobials with excellent polymicrobial coverage (eg, β-lactamase inhibitor combinations or carbapenems) may reduce the need for combination therapy in the setting of polymicrobial infections.
3.
To decrease the emergence of resistant strains. The value of combination therapy in this setting has been clearly demonstrated for tuberculosis.
4.
To decrease dose-related toxicity by using reduced doses of one or more components of the drug regimen. The use of flucytosine in combination with amphotericin B for the treatment of cryptococcal meningitis in non-HIV-infected patients allows for a reduction in amphotericin B dosage with decreased amphotericin B–induced nephrotoxicity.
5.
To obtain enhanced inhibition or killing. This use of antimicrobial combinations is discussed in the paragraphs that follow.
When the inhibitory or killing effects of two or more antimicrobials used together are significantly greater than expected from their effects when used individually, synergism is said to result. Synergism is marked by a fourfold or greater reduction in the MIC or MBC of each drug when used in combination versus when used alone. Antagonism occurs when the combined inhibitory or killing effects of two or more antimicrobial drugs are significantly less than observed when the drugs are used individually.
Mechanisms of Synergistic Action
The need for synergistic combinations of antimicrobials has been clearly established for the treatment of enterococcal endocarditis. Bactericidal activity is essential for the optimal management of bacterial endocarditis. Penicillin or ampicillin in combination with gentamicin or streptomycin is superior to monotherapy with a penicillin or vancomycin. When tested alone, penicillins and vancomycin are only bacteriostatic against susceptible enterococcal isolates. When these agents are combined with an aminoglycoside, however, bactericidal activity results. The addition of gentamicin or streptomycin to penicillin allows for a reduction in the duration of therapy for selected patients with viridans streptococcal endocarditis.
Other synergistic antimicrobial combinations have been shown to be more effective than monotherapy with individual components. Trimethoprim-sulfamethoxazole has been successfully used in the treatment of bacterial infections and P jiroveci (carinii) pneumonia. *β-Lactamase inhibitors restore the activity of intrinsically active but hydrolyzable β lactams against organisms such as Staphylococcus aureus and Bacteroides fragilis. Three major mechanisms of antimicrobial synergism have been established: 1.
Blockade of sequential steps in a metabolic sequence: Trimethoprim-sulfamethoxazole is the best-known example of this mechanism of synergy (see Chapter 46). Blockade of the two sequential steps in the folic acid pathway by trimethoprimsulfamethoxazole results in a much more complete inhibition of growth than achieved by either component alone.
2.
Inhibition of enzymatic inactivation: Enzymatic inactivation of β-lactam antibiotics is a major mechanism of antibiotic resistance. Inhibition of β lactamase by β-lactamase inhibitor drugs (eg, sulbactam) results in synergism.
3.