Antimicrobial Drug Combinations

ANTIMICROBIAL DRUG COMBINATIONS

RATIONALE FOR COMBINATION ANTIMICROBIAL THERAPY

Most infections should be treated with a single antimicrobial agent. Although indications for combination therapy exist, anti-microbial combinations are often overused in clinical practice. The unnecessary use of antimicrobial combinations increases tox-icity and costs and may occasionally result in reduced efficacy due to antagonism of one drug by another. Antimicrobial combina-tions should be selected for one or more of the following reasons:

1. To provide broad-spectrum empiric therapy in seriously ill patients.

2. To treat polymicrobial infections (such as intra-abdominal abscesses, which typically are due to a combination of anaero-bic 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 com-bination 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 demon-strated for tuberculosis.

4. To decrease dose-related toxicity by using reduced doses of one or more components of the drug regimen. The use of flucyto-sine 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 antimicro-bial combinations is discussed in the paragraphs that follow.

SYNERGISM & ANTAGONISM

When the inhibitory or killing effects of two or more antimicrobi-als 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 van-comycin 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 endocardi-tis. Some evidence exists that synergistic combinations of antimi-crobials may be of benefit in the treatment of gram-negative bacillary infections in febrile neutropenic cancer patients and in systemic infections caused by Pseudomonas aeruginosa.

Other synergistic antimicrobial combinations have been shown to be more effective than monotherapy with individual components. Trimethoprim-sulfamethoxazole has been successfully used for the treatment of bacterial infections and P jiroveci (carinii) pneumonia.^∗β-Lactamase inhibitors restore the activ-ity 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:

·    Blockade of sequential steps in a metabolic sequence: Trimethoprim-sulfamethoxazole is the best-known example of this mechanism of synergy . Blockade of the two sequential steps in the folic acid pathway by trimethoprim-sulfamethoxazole results in a much more complete inhibition of growth than achieved by either component alone.

·    Inhibition of enzymatic inactivation: Enzymatic inactivationof β-lactam antibiotics is a major mechanism of antibiotic resistance. Inhibition of β lactamase by β-lactamase inhibitor drugs (eg, sulbactam) results in synergism.

·    Enhancement of antimicrobial agent uptake: Penicillins andother cell wall-active agents can increase the uptake of amino-glycosides by a number of bacteria, including staphylococci, enterococci, streptococci, and P aeruginosa. Enterococci are thought to be intrinsically resistant to aminoglycosides because of permeability barriers. Similarly, amphotericin B is thought to enhance the uptake of flucytosine by fungi.

Mechanisms of Antagonistic Action

There are few clinically relevant examples of antimicrobial antago-nism. The most striking example was reported in a study of patients with pneumococcal meningitis. Patients who were treated with the combination of penicillin and chlortetracycline had a mortality rate of 79% compared with a mortality rate of 21% in patients who received penicillin monotherapy (illustrating the first mechanism set forth below).

The use of an antagonistic antimicrobial combination does not preclude other potential beneficial interactions. For example, rifampin may antagonize the action of anti-staphylococcal penicil-lins or vancomycin against staphylococci. However, the aforemen-tioned antimicrobials may prevent the emergence of resistance to rifampin.

Two major mechanisms of antimicrobial antagonism have been established:

1. Inhibition of cidal activity by static agents: Bacteriostaticagents such as tetracyclines and chloramphenicol can antago-nize the action of bactericidal cell wall-active agents because cell wall-active agents require that the bacteria be actively grow-ing and dividing.

2. Induction of enzymatic inactivation: Some gram-negative bacilli, including enterobacter species, P aeruginosa, Serratiamarcescens, and Citrobacter freundii, possess inducibleβlacta-mases. β-Lactam antibiotics such as imipenem, cefoxitin, and ampicillin are potent inducers of β-lactamase production. If an inducing agent is combined with an intrinsically active but hydrolyzable β lactam such as piperacillin, antagonism may result.