Beta‐lactam versus beta‐lactam‐aminoglycoside combination therapy in cancer patients with neutropenia Edited (no change to conclusions)

Abstract

Continued controversy surrounds the optimal empirical treatment for febrile neutropenia. New broad‐spectrum beta‐lactams have been introduced as single treatment, and classically, a combination of a beta‐lactam with an aminoglycoside has been used.

To compare beta‐lactam monotherapy versus beta‐lactam‐aminoglycoside combination therapy for cancer patients with fever and neutropenia.

The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 7, 2012), LILACS (August 2012), MEDLINE and EMBASE (August 2012) and the Database of Abstracts of Reviews of Effects (DARE) (Issue 3, 2012). We scanned references of all included studies and pertinent reviews and contacted the first author of each included trial, as well as the pharmaceutical companies.

Randomised controlled trials (RCTs) comparing any beta‐lactam antibiotic monotherapy with any combination of a beta‐lactam and an aminoglycoside antibiotic, for the initial empirical treatment of febrile neutropenic cancer patients. All cause mortality was the primary outcome assessed.

Data concerning all cause mortality, infection related mortality, treatment failure (including treatment modifications), super‐infections, adverse effects and study quality measures were extracted independently by two review authors. Risk ratios (RRs) with their 95% confidence intervals (CIs) were estimated. Outcomes were extracted by intention‐to‐treat (ITT) analysis whenever possible. Individual domains of risk of bias were examined through sensitivity analyses. Published data were complemented by correspondence with authors.

Seventy‐one trials published between 1983 and 2012 were included. All cause mortality was lower with monotherapy (RR 0.87, 95% CI 0.75 to 1.02, without statistical significance). Results were similar for trials comparing the same beta‐lactam in both trial arms (11 trials, 1718 episodes; RR 0.74, 95% CI 0.53 to 1.06) and for trials comparing different beta‐lactams-usually a broad‐spectrum beta‐lactam compared with a narrower‐spectrum beta‐lactam combined with an aminoglycoside (33 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 (16 trials, 2833 episodes; RR 1.11, 95% CI 1.02 to 1.20), and was significantly more frequent with combination therapy in trials comparing different beta‐lactams (55 trials, 7736 episodes; RR 0.92, 95% CI 0.88 to 0.97). Bacterial super‐infections occurred with equal frequency, and fungal super‐infections were more common with combination therapy. Adverse events were more frequent with combination therapy (numbers needed to harm 4; 95% CI 4 to 5). 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‐label. No correlation was noted between mortality and failure rates and these trials.

Beta‐lactam monotherapy is advantageous compared with beta‐lactam‐aminoglycoside combination therapy with regard to survival, adverse events and fungal super‐infections. Treatment failure should not be regarded as the primary outcome in open‐label trials, as it reflects mainly treatment modifications.

Author(s)

Mical Paul, Yaakov Dickstein, Agata Schlesinger, Simona Grozinsky‐Glasberg, Karla Soares‐Weiser, Leonard Leibovici

Abstract

Cancer patients with fever and suspected infection can be treated with a single 'new‐generation' beta‐lactam antibiotic 

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 is a decreased white blood cell count. 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 when single‐drug therapy is used, and side effects, mainly damage to the kidneys, are more frequent with combination therapy.

Author(s)

Mical Paul, Yaakov Dickstein, Agata Schlesinger, Simona Grozinsky‐Glasberg, Karla Soares‐Weiser, Leonard Leibovici

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

Monotherapy can be regarded as the standard of care for the empirical treatment of febrile neutropenic patients. The addition of an aminoglycoside does not improve survival. On the contrary, it is associated with significant morbidity incurred mainly through aminoglycoside‐associated nephrotoxicity.

The monotherapies assessed in recent years have included imipenem, meropenem, ceftazidime, piperacillin‐tazobactam and cefepime. These beta‐lactams have also been assessed in head‐to‐head trials comparing different monotherapies and have shown similar efficacies, but for cefepime this was associated with increased all cause mortality (Paul 2006). Thus, individual centres should select the best matching monotherapy according to local epidemiology and susceptibility patterns.

RCTs do not support an advantage of combination therapy for Pseudomonas aeruginosa infection and other more severely ill patient subgroups. However the paucity of data precludes firm conclusions regarding these patient subgroups.

Implications for research 

Assessment of new beta‐lactams for febrile neutropenia should not be performed by comparison with a narrower‐spectrum beta‐lactam combined with an aminoglycoside. The results of these trials are uniformly unfavourable for patients. Assessment of new beta‐lactam monotherapies should be performed by comparison with established monotherapies for febrile neutropenia. This design can and does show the advantages and disadvantages of specific beta‐lactams (Paul 2006).

The need for further trials assessing the addition of an aminoglycoside to the same beta‐lactam is doubtful given the results of our review, spanning more than two decades of clinical trials in febrile neutropenia and without a change in RRs throughout the years. We can foresee such a need if a reduction in aminoglycoside‐related adverse effects is expected, or if new data will point toward drug combinations with a marked synergistic effect-much greater than that observed in current studies. Trials targeting specific patient subgroups, such as those with severe sepsis and septic shock, documented Pseudomonas aeruginosa infection, etc. are warranted.

Future trials should report all cause mortality. The primary outcome used in these studies should be re‐defined because with current definitions, no correlation can be noted between failure and the ultimate outcome: survival. This outcome should be defined in a consensus statement and applied universally to permit comparisons and compilation of different studies. The unit of randomisation should be the patient-not the episode. If recurrent episodes are allowed, results for the first randomisation of each patient should be reported separately, or the analysis should be adjusted to the clustering effect of patient episodes. Length of follow‐up should be uniform and should be determined before the study is begun.

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