ANTIMICROBIAL DRUG COMBINATIONS
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.
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
5. To obtain enhanced inhibition
or killing. This use of antimicro-bial combinations is discussed in the
paragraphs that follow.
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.
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.
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.
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.
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.
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
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