Beta‐lactam versus beta‐lactam‐aminoglycoside combination therapy in cancer patients with neutropenia
Abstract
Background
Continued controversy with regard to the optimal empirical treatment for febrile neutropaenia exists. New broad spectrum beta‐lactams have been introduced as single treatment, while classically, a combination of a beta‐lactam combined with an aminoglycoside has been used.
Objectives
To compare beta‐lactam monotherapy versus beta‐lactam‐aminoglycoside combination therapy for cancer patients with fever and neutroepaenia.
Search methods
The Cochrane Central Register of Controlled Trials (CENTRAL), (Cochrane Library Issue 3, 2007), LILACS (June 2007) and PubMed (June 2007) and several conference proceedings (up to 2006). We scanned references of all included studies, pertinent reviews, and contacted the first author of each included trial and the pharmaceutical companies.
Selection criteria
Randomised controlled trials (RCTs) comparing any beta‐lactam antibiotic monotherapy to any combination of a beta‐lactam and an aminoglycoside antibiotic, for the initial, empirical treatment of febrile neutropaenic cancer patients. All cause mortality was the primary outcome assessed.
Data collection and analysis
Data concerning all cause mortality, infection related mortality, treatment failure (including treatment modifications), superinfections, adverse effects and study quality measures were extracted independently by two review authors. Relative risks (RR) with their 95% confidence intervals (CI) were estimated. Outcomes were extracted by intention‐to‐treat (ITT) analysis whenever possible. Individual components of the methodological quality were examined through sensitivity analyses. Published data were complemented by correspondence with authors.
Main results
Sixty eight trials published between 1983 to 2007 were included. All cause mortality was lower with monotherapy, RR 0.87, 95% CI 0.75 to 1.02. Results were similar for trials comparing the same beta‐lactam in both trial arms (10 trials, 1646 episodes, RR 0.74 95% CI 0.53 to 1.06) and trials comparing different beta‐lactams, usually a broad spectrum beta‐lactam compared to a narrower spectrum beta‐lactam combined with an aminoglycoside (37 trials, 5468 episodes, RR 0.91, 95% CI 0.77 to 1.09). Infection related mortality was significantly lower with monotherapy (RR 0.80, 95% CI 0.64 to 0.99). Treatment failure was significantly more frequent with monotherapy in trials comparing the same beta‐lactam (15 trials, 2761 episodes, RR 1.11, 95% CI 1.02 to 1.21), and significantly more frequent with combination therapy in trials comparing different beta‐lactams (53 trials, 7524 episodes, RR 0.92, 95% CI 0.87 to 0.96). Bacterial superinfections occurred with equal frequency, while fungal superinfections were more common with combination therapy. Adverse events were more frequent with combination therapy, numbers needed to harm 4 (95% CI 4 to 5) patients. Specifically, the difference with regard to nephrotoxicity was highly significant. Adequate trial methods were associated with a larger effect estimate for mortality and smaller effect estimates for failure. Nearly all trials were open‐labeled. There was no correlation between mortality and failure rates and these trials.
Authors' conclusions
Beta‐lactam monotherapy is advantageous compared to beta‐lactam‐aminoglycoside combination therapy with regard to survival, adverse events and fungal superinfections. Treatment failure should not be regarded as the primary outcome in open‐label trials, as it reflects mainly treatment modifications.
PICOs
Plain language summary
Cancer patients with fever and suspected infections can be treated with a single 'new generation' beta‐lactam antibiotic and Single therapy is as efficacious as dual‐combination therapy and associated with fewer adverse events
Cancer chemotherapy or bone marrow transplantation disrupts the immune system, exposing patients to severe infection. The major sign of infection is fever, and the hallmark of damaged immune defences a decreased white blood cell count. Previously patients have usually been treated with a combination of two different classes of antibiotics. Evidence shows that treatment with a new single drug (monotherapy), belonging to the beta‐lactam class of antibiotics, is associated with better outcomes. Survival is improved using the single drug therapy, while side effects, mainly damage to the kidneys, is more frequent with combination therapy.
