Abstract: 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.

Plain-language summary: 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). In 9/14 of the trials the trial received funding from the industry. 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. 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.