title: Empirical antibiotics targeting Gram-positive bacteria for the treatment of febrile neutropenic patients with cancer.
abstract: BACKGROUND
  The pattern of infections among neutropenic cancer patients 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.
  
  
  OBJECTIVE
  To assess the effectiveness of empirical antiGram-positive (antiGP) antibiotic treatment for febrile neutropenic cancer patients in terms of mortality and treatment failure. To assess the rate of resistance development, further infections and adverse events associated with additional antiGP treatment.
  
  
  METHODS
  We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 7), MEDLINE (1966 to 2013), EMBASE (1982 to 2013), LILACS (1982 to 2013), conference proceedings, and the references of the included studies. First authors of all included and potentially relevant trials were contacted.
  
  
  METHODS
  Randomised controlled trials (RCTs) comparing one antibiotic regimen to the same regimen with the addition of an antiGP antibiotic for the treatment of febrile neutropenic cancer patients.
  
  
  METHODS
  Two review authors independently assessed trial eligibility and risk of bias, and extracted all data. Risk ratios (RR) with 95% confidence intervals (CI) were calculated. A random-effects model was used for all comparisons showing substantial heterogeneity (I(2) > 50%). Outcomes were extracted by intention to treat and the analysis was patient-based whenever possible.
  
  
  RESULTS
  Thirteen trials and 2392 patients or episodes were included. Empirical antiGP antibiotics were tested at the onset of treatment in 11 studies, and for persistent fever in two studies. The antiGP treatment was a glycopeptide in nine trials. Seven studies were assessed in the overall mortality comparison and no significant difference was seen between the comparator arms, RR of 0.82 (95% CI 0.56 to 1.20, 852 patients). Ten trials assessed failure, including modifications as failures, while six assessed overall failure disregarding treatment modifications. Failure with modifications was significantly reduced, RR of 0.76 (95% CI 0.68 to 0.85, 1779 patients) while overall failure was the same, RR of 1.00 (95% CI 0.79 to 1.27, 943 patients). Sensitivity analysis for allocation concealment and incomplete outcome data did not change the results. Both mortality and failure did not differ significantly among patients with Gram-positive infections, but the number of studies in the comparisons was small. 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.
  
  
  CONCLUSIONS
  Current evidence shows that the empirical routine addition of antiGP treatment, namely glycopeptides, does not improve the outcomes of febrile neutropenic patients with cancer.
authors.affiliation: Unit of Infectious Diseases, Rambam Health Care Center, Haifa, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, 49100.
authors.forename: Mical
authors.initials: M
authors.lastname: Paul
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Dickstein
authors.forename: Sara
authors.initials: S
authors.lastname: Borok
authors.forename: Liat
authors.initials: L
authors.lastname: Vidal
authors.forename: Leonard
authors.initials: L
authors.lastname: Leibovici
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D064147:Febrile Neutropenia / Q000188:drug therapy*; D006020:Glycopeptides / Q000627:therapeutic use; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy*; D006801:Humans; D009369:Neoplasms / Q000150:complications*; D016032:Randomized Controlled Trials as Topic; D017211:Treatment Failure
chemical_list: D000900:Anti-Bacterial Agents; D006020:Glycopeptides