Infections caused by bacteria are a leading cause of preventable death. The mortality associated with severe infections necessitating hospitalization is about 30%. Antibiotic treatment improves survival.
There are several classes of antibiotics currently in use. The beta-lactam class is one of the most important class in use. Antibiotics belonging to it (penicillins, cephalosporins, and others) kill bacteria by disrupting their cell wall. Aminoglycosides (e.g. gentamicin) act though a different mechanism, inhibiting bacterial protein synthesis. Studies of bacteria in cell cultures have shown that combining a beta-lactam with an aminoglycoside results in bacterial killing superior to the simple additive activity of each of these antibiotics alone, a phenomenon termed 'synergism'.
In humans, combination therapy may have several drawbacks, such as an increased rate of adverse effects. We therefore decided to compile clinical studies that compared treatment with a beta-lactam to treatment with a beta-lactam plus an aminoglycoside. Our objective was to assess whether combination treatment results in better outcomes, mainly survival.
The review included 64 trials randomizing 7586 patients. Patients were hospitalized with urinary tract, intra-abdominal, skin and soft tissue infections, pneumonia, and infection of unknown origin. Antibiotics were administered intravenously.
Combination antibiotic treatment did not improve the clinical efficacy achieved with the beta-lactam antibiotic alone. One set of studies compared a new, broad-spectrum beta-lactam to an older, less potent beta-lactam combined with an aminoglycoside (44 studies). In these studies, mortality and failure were lower with single beta-lactam antibiotic treatment. Mortality was reduced by 15%, but the difference was not statistically significant. The other set of studies compared one beta-lactam to the same beta-lactam combined with an aminoglycoside (20 studies). In these trials, no differences between single and combination antibiotic treatment were seen. The relative risk for mortality was 1.01, denoting equivalence of the two regimens.
Adverse events rates did not differ between the study groups, overall, but renal damage was more frequent with combination therapy. Combination therapy did not prevent the development of secondary infections.
The reviewers conclude that beta-lactam-aminoglycoside combination therapy offers no advantage to beta-lactams alone. Furthermore, combination therapy is associated with an increased risk of renal damage. Paucity of trials comparing the same beta-lactam in both study arms and incompleteness of mortality reporting may limit these conclusions. These results may not apply to locations in which resistance rates to narrow-spectrum beta-lactams are very low, such as Scandinavian counties.