Whether combination antimicrobial therapy is more efficacious than monotherapy for infections with Gram-negative bacteria remains controversial, particularly for infections due to organisms more commonly acquired in hospital settings, such as Pseudomonas spp., Serratia spp., Acinetobacter spp., and Enterobacter spp. THE INTUITIVE APPEAL OF COMBINATION THERAPY This review primarily focuses on β-lactam and aminoglycoside or fluoroquinolone combination therapy compared with β-lactam monotherapy, but other combinations are briefly discussed. The major objective of this review is to evaluate clinical outcomes, comparing monotherapy versus combination antimicrobial therapy for infections with Gram-negative bacteria. With the availability of new broad-spectrum and highly bactericidal antibiotics, the need to combine β-lactams with a second agent for the treatment of infections with Gram-negative bacteria should be reassessed. The question of whether a combination of a β-lactam and an aminoglycoside or fluoroquinolone confers a benefit in patients beyond broadening the antimicrobial spectrum during the empiric treatment period before culture results are available is unsettled. Observational studies show that between 25 and 50% of patients with bacteremia, surgical site infections, or pneumonia and over 50% of patients with septic shock in the intensive care unit (ICU) are administered combination antibiotic therapy ( 20, 54, 100, 117, 134, 138, 152, 173, 228, 246). However, when identification and susceptibility testing results are known, an argument can be made that the antibiotic regimen for Gram-negative organisms can be “fine-tuned” and narrowed in many cases ( 20, 134). There is evidence supporting the initial use of combination therapy for severe infections with Gram-negative bacteria, such as sepsis or ventilator-associated pneumonia (VAP), in the existing environment of MDRGNs because of the broad empiric coverage provided by two antimicrobial agents with different spectra of activity ( 20, 33, 89, 116, 117, 134, 136, 153, 246). One area where the approach to antibiotic use needs to be readdressed is the use of combination antibiotic therapy, which generally consists of a β-lactam and an aminoglycoside or fluoroquinolone, for the treatment of infections with Gram-negative bacteria. Every effort needs to be made to carefully select antibiotics, balancing the need for a broad spectrum of empiric coverage of potential microorganisms with the need to preserve available antibiotics for when they are absolutely necessary. A reduction in inappropriate utilization of broad-spectrum antibiotics is clearly important to minimize the emergence of MDRGNs. The emergence and proliferation of these highly resistant Gram-negative organisms are particularly concerning given the limited number of antimicrobial agents that are currently available or in the drug development pipelines of the pharmaceutical industry to combat these organisms ( 35). ![]() A vicious cycle is created as MDRGN infections force us to rely on additional broad-spectrum antibiotics to treat these infections, leading to yet more resistance ( 208, 241). ![]() The abundant and often inappropriate use of broad-spectrum antibiotics contributes to the emergence of MDRGNs ( 208). Multidrug-resistant Gram-negative organisms (MDRGNs) have emerged as a major threat to hospitalized patients and have been associated with mortality rates ranging from 30 to 70% ( 30, 33, 89, 102, 153, 177, 203). In this review, we summarize the available data comparing monotherapy versus combination antimicrobial therapy for the treatment of infections with Gram-negative bacteria. ![]() ![]() The available evidence suggests that the greatest benefit of combination antibiotic therapy stems from the increased likelihood of choosing an effective agent during empiric therapy, rather than exploitation of in vitro synergy or the prevention of resistance during definitive treatment. The wisdom of continued combination therapy after an organism is isolated and antimicrobial susceptibility data are known, however, is more controversial. An argument can be made for empiric combination therapy, as we are witnessing a rise in infections caused by multidrug-resistant Gram-negative organisms. Summary: Combination antibiotic therapy for invasive infections with Gram-negative bacteria is employed in many health care facilities, especially for certain subgroups of patients, including those with neutropenia, those with infections caused by Pseudomonas aeruginosa, those with ventilator-associated pneumonia, and the severely ill.
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