Empirical antibiotics targeting gram‐positive bacteria for the treatment of febrile neutropenic patients with cancer
The pattern of infections among neutropenic patients with cancer has shifted in the last decades to a predominance of gram‐positive infections. Some of these gram‐positive bacteria are increasingly resistant to beta‐lactams and necessitate specific antibiotic treatment.
To assess the effectiveness of empirical anti‐gram‐positive (antiGP) antibiotic treatment for febrile neutropenic patients with cancer in terms of mortality and treatment failure. To assess the rate of resistance development, further infections and adverse events associated with additional antiGP treatment.
For the review update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 2), MEDLINE (May 2012 to 2017), Embase (May 2012 to 2017), LILACS (2012 to 2017), conference proceedings, ClinicalTrials.gov trial registry, and the references of the included studies. We contacted the first authors of all included and potentially relevant trials.
Randomised controlled trials (RCTs) comparing one antibiotic regimen versus the same regimen with the addition of an antiGP antibiotic for the treatment of febrile neutropenic patients with cancer.
Data collection and analysis
Two review authors independently assessed trial eligibility and risk of bias, and extracted all data. Risk ratios (RR) with 95% confidence intervals (CIs) were calculated. A random‐effects model was used for all comparisons showing substantial heterogeneity (I2 > 50%). Outcomes were extracted by intention‐to‐treat and the analysis was patient‐based whenever possible.
Fourteen trials and 2782 patients or episodes were included. Empirical antiGP antibiotics were tested at the onset of treatment in 12 studies, and for persistent fever in two studies. The antiGP treatment was a glycopeptide in nine trials. Eight studies were assessed in the overall mortality comparison and no significant difference was seen between the comparator arms, RR of 0.90 (95% CI 0.64 to 1.25; 8 studies, 1242 patients; moderate‐quality data). Eleven trials assessed failure, including modifications as failures, while seven assessed overall failure disregarding treatment modifications. Failure with modifications was reduced, RR of 0.72 (95% CI 0.65 to 0.79; 11 studies, 2169 patients; very low‐quality data), while overall failure was the same, RR of 1.00 (95% CI 0.79 to 1.27; 7 studies, 943 patients; low‐quality data). Sensitivity analysis for allocation concealment and incomplete outcome data did not change the results. Failure among patients with gram‐positive infections was reduced with antiGP treatment, RR of 0.56 (95% CI 0.38 to 0.84, 5 studies, 175 patients), although, mortality among these patients was not changed.
Data regarding other patient subgroups likely to benefit from antiGP treatment were not available. Glycopeptides did not increase fungal superinfection rates and were associated with a reduction in documented gram‐positive superinfections. Resistant colonisation was not documented in the studies.
Based on very low‐ or low‐quality evidence using the GRADE approach and overall low risk of bias, the current evidence shows that the empirical routine addition of antiGP treatment, namely glycopeptides, does not improve the outcomes of febrile neutropenic patients with cancer.
Ofrat Beyar‐Katz, Yaakov Dickstein, Sara Borok, Liat Vidal, Leonard Leibovici, Mical Paul
Plain language summary
Spectrum of the initial antibiotic treatment for cancer patients with fever and low leucocytes counts
Background: cancer patients develop neutropenia, a decrease in the subset of leucocytes responsible for protection against bacteria, as a result of chemotherapy or cancer. Neutropenia predisposes the patients to severe bacterial infections. Standard antibiotic regimens for cancer patients with neutropenia and fever are directed at most of the bacteria that can cause infections. However, a subset of resistant bacteria belonging to the gram‐positive group (Staphylococcus aureus and Streptococci) remain untreated unless specific antibiotics are added to the treatment.
Review question: we assessed whether the addition of specific anti gram‐positive antibiotics prior to identification of a causative bacteria improves survival and cure among cancer patients with fever and neutropenia.
Search dates: the evidence is current to February 2017.
Study characteristics: we included randomised controlled trials that compared a standard antibiotic regimen versus the same regimen with an antibiotic directed at gram‐positive bacteria. Overall, 14 randomised controlled trials were included with 2782 patients or episodes of infection. The antibiotics were given to cancer patients with neutropenia and fever as first‐line treatment (12 trials) or for recurrent fever (two trials).
Study funding sources: In 9/14 of the trials the trial received funding from the industry.
Key results: mortality did not differ between patients groups. Antibiotic treatment was more frequently modified among patients who did not initially receive specific antibiotics against gram‐positive bacteria, but overall treatment failures were not different. We attempted to examine the durations of fever and hospital stay, but these were not consistently reported. The addition of specific antibiotics against gram‐positive bacteria resulted in more adverse events, mainly rash. We conclude that antibiotic treatment directed against resistant gram‐positive bacteria can await identification of specific bacteria and need not be given routinely prior to bacterial identification.
Quality of the evidence: overall, the quality of the evidence was low to very low but was based on randomised controlled trials, most of which were at low risk of bias. A limitation of the results for mortality was that all‐cause mortality was not reported and could not be obtained in 6/14 of the studies. The trials did not examine specific circumstances that might mandate empirical use of antibiotics against gram‐positive bacteria and thus the evidence is relevant to cancer patients with fever, without low blood pressure, or a focus of infection that might be caused by gram‐positive bacteria.
Ofrat Beyar‐Katz, Yaakov Dickstein, Sara Borok, Liat Vidal, Leonard Leibovici, Mical Paul
Implications for practice
Our conclusions are in accordance with current practice guidelines (Freifeld 2011). Non‐selective empirical use of glycopeptides, initially or for persistent fever, is discouraged. Data from existing trials cannot aid in the selection of patient subgroups for whom an advantage does exist.
Implications for research
Further trials assessing empirical glycopeptide or other novel anti‐gram‐positive (antiGP) antibiotics may be justified only if the prevalence of resistant gram‐positive infections increases. Two trials (Cometta 2003; Erjavec 2000) tested the addition of a glycopeptide for fever persisting more than 48 hours showing no benefit to this intervention, in line with the clinical practice of a longer time period of persisting fever. Future trials should perhaps assess the value of empirical antiGPs for fever persisting for a longer duration (e.g. five to seven days).
Further research should focus on risk factors defining specific patient groups who will benefit from the addition of glycopeptides prior to microbiological documentation of these infections.
Our analysis highlights the pitfalls of assessing treatment failure in these and similar studies. Results are dependent on the definition of failure. In most studies, failure was defined as a change in the empirical antibiotic regimen, an outcome that is not necessarily associated with patient morbidity. Survival is the ultimate goal of chemotherapy in cancer patients. Usually not chosen as a primary outcome due to the sample size calculation considerations, all‐cause mortality should be reported in all trials assessing the management of febrile neutropenic patients. Other patient‐relevant outcomes include number of febrile days, hospital days for patients surviving the infectious episode and adherence to chemotherapy regimen.
We showed that the use of glycopeptides was associated with fewer gram‐positive superinfections. However, we do not rule out the possibility of resistance induced by their use by this as the trials did not assess the rates of colonisation with resistant microorganisms. Future studies must incorporate methods for surveillance of colonisation to correctly represent the effects of glycopeptide use on future infections and the environment.
All future studies should adhere to better methodological standards (Consort statement). Specifically, patients should be included in the study only once, data regarding overall mortality should be reported by ITT, and the number of exclusions after randomisation for all other outcomes should be reported per study arm.