Empirical antibiotic monotherapy for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES Early, empirical broad-spectrum antibiotic treatment is the established practice for febrile neutropenia. Several beta-lactams are accepted for monotherapy. We asked whether patients' outcomes are influenced by the chosen beta-lactam. METHODS Systematic review and meta-analysis of randomized controlled trials comparing anti-pseudomonal beta-lactams administered as empirical monotherapy for febrile neutropenia, with or without vancomycin. The search included The Cochrane Library, PubMed, Embase, Lilacs databases, bibliography, conference proceedings, trial registries and FDA new drug approvals. Two reviewers independently applied selection criteria, performed quality assessment and extracted the data. Trials assessing the same beta-lactam were pooled using the fixed effect model. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated. The primary outcome assessed was all-cause mortality. RESULTS Thirty-three trials fulfilled inclusion criteria. Cefepime was associated with higher all-cause mortality at 30 days than other beta-lactams (RR 1.44, 95% CI 1.06-1.94, 3123 participants). Carbapenems were associated with fewer treatment modifications, including addition of glycopeptides, than ceftazidime or other comparators. Adverse events were significantly more frequent with carbapenems, specifically pseudomembranous colitis (RR 1.94, 95% CI 1.24-3.04, 2025 participants). All-cause mortality was unaltered. Piperacillin/tazobactam was compared only with cefepime and carbapenems, in six trials. No significant differences were demonstrated with paucity of data for all-cause mortality. CONCLUSIONS The use of cefepime for febrile neutropenia is associated with increased mortality and should be carefully considered pending further analysis. Empirical use of carbapenems entails fewer treatment modifications, but an increased rate of pseudomembranous colitis. Ceftazidime, piperacillin/tazobactam, imipenem/cilastatin and meropenem appear to be suitable agents for monotherapy.

[1]  Douglas G. Altman,et al.  Systematic reviews in health care : meta-analysis in context , 2008 .

[2]  L. Leibovici,et al.  Single‐agent antibiotic therapy for the initial, empirical, treatment of febrile neutropenia: comparison of beta‐lactams , 2005 .

[3]  H. Döhner,et al.  Impact of fluoroquinolone prophylaxis on reduced infection-related mortality among patients with neutropenia and hematologic malignancies. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[4]  L. Leibovici,et al.  Empirical antibiotics against Gram-positive infections for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials. , 2005, The Journal of antimicrobial chemotherapy.

[5]  K. Rolston.  Challenges in the treatment of infections caused by gram-positive and gram-negative bacteria in patients with cancer and neutropenia. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[6]  B. Psaty,et al.  COX-2 inhibitors--lessons in drug safety. , 2005, The New England journal of medicine.

[7]  G. Jacoby,et al.  The new beta-lactamases. , 2005, The New England journal of medicine.

[8]  G. Jacoby,et al.  Mechanisms of disease: The new β-lactamases , 2005 .

[9]  M. Egger,et al.  Risk of cardiovascular events and rofecoxib: cumulative meta-analysis , 2004, The Lancet.

[10]  J. Mensa,et al.  Prospective evaluation of procalcitonin in adults with febrile neutropenia after haematopoietic stem cell transplantation , 2004, British journal of haematology.

[11]  P. Johansson,et al.  A prospective, randomized study comparing cefepime and imipenem-cilastatin in the empirical treatment of febrile neutropenia in patients treated for haematological malignancies , 2004, Scandinavian journal of infectious diseases.

[12]  G. Kanra,et al.  Cefepime vs. Meropenem as empirical therapy for neutropenic fever in children with lymphoma and solid tumours , 2004, Pediatric blood & cancer.

[13]  J. Tarrand,et al.  Current spectrum of bacterial infections in patients with cancer. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[14]  L. Leibovici,et al.  Considering resistance in systematic reviews of antibiotic treatment. , 2003, The Journal of antimicrobial chemotherapy.

[15]  Ronald N. Jones,et al.  Comparative activity and spectrum of broad-spectrum beta-lactams (cefepime, ceftazidime, ceftriaxone, piperacillin/tazobactam) tested against 12,295 staphylococci and streptococci: report from the SENTRY antimicrobial surveillance program (North America: 2001-2002). , 2003, Diagnostic microbiology and infectious disease.

[16]  D. Altman,et al.  Measuring inconsistency in meta-analyses , 2003, BMJ : British Medical Journal.

[17]  H. Kantarjian,et al.  Treatment of febrile neutropenic patients with cancer who require hospitalization , 2003, Cancer.

[18]  L. Leibovici,et al.  β lactam monotherapy versus β lactam-aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis , 2003, BMJ : British Medical Journal.

[19]  R. Wenzel,et al.  Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospitals in the United States. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[20]  G. Bodey,et al.  Ciprofloxacin versus Tobramycin for Neutropenic Fevers , 2003, Annals of Internal Medicine.

[21]  F. Goldstein.  Cephalosporinase induction and cephalosporin resistance: a longstanding misinterpretation. , 2002, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[22]  S. Hanada,et al.  Cefepime or carbapenem treatment for febrile neutropenia as a single agent is as effective as a combination of 4th‐generation cephalosporin + aminoglycosides: Comparative study , 2002, American journal of hematology.

[23]  T. Calandra,et al.  Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer , 2002 .

[24]  Chao‐Ping Yang,et al.  Cefepime versus ceftazidime as empiric monotherapy for fever and neutropenia in children with cancer , 2002, The Pediatric infectious disease journal.

[25]  F. Mandelli,et al.  A multicenter, double-blind, placebo-controlled trial comparing piperacillin-tazobactam with and without amikacin as empiric therapy for febrile neutropenia. , 2001, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[26]  A. Simon,et al.  Meropenem versus ceftazidime as empirical monotherapy in febrile neutropenia of paediatric patients with cancer. , 2001, The Journal of antimicrobial chemotherapy.

[27]  R. Kebudi,et al.  Randomized comparison of cefepime versus ceftazidime monotherapy for fever and neutropenia in children with solid tumors. , 2001, Medical and pediatric oncology.

[28]  M. Mustafa,et al.  Comparative study of cefepime versus ceftazidime in the empiric treatment of pediatric cancer patients with fever and neutropenia , 2001, The Pediatric infectious disease journal.

[29]  R. Ramphal,et al.  Randomized, double-blind, multicenter trial comparing clinafloxacin with imipenem as empirical monotherapy for febrile granulocytopenic patients. , 2001, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[30]  S. Cantor,et al.  Time to clinical response: an outcome of antibiotic therapy of febrile neutropenia with implications for quality and cost of care. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  A. Keating,et al.  Meropenem versus ceftazidime in the treatment of cancer patients with febrile neutropenia: a randomized, double-blind trial. , 2000, Journal of Clinical Oncology.

[32]  J. Sterne,et al.  Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. , 2000, Journal of clinical epidemiology.

[33]  P. Arnow,et al.  Cefepime versus Ceftazidime as Empiric Therapy for Fever in Neutropenic Patients with Cancer , 2000, The Annals of pharmacotherapy.

[34]  L. Elting,et al.  The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  Y. Humblet,et al.  Meropenem versus ceftazidime as empirical monotherapy for febrile neutropenic cancer patients , 2000, Annals of Hematology.

[36]  Fu-Der Wang,et al.  A Comparative Study of Cefepime versus Ceftazidime as Empiric Therapy of Febrile Episodes in Neutropenic Patients , 1999, Chemotherapy.

[37]  P. Biron,et al.  Cefepime versus imipenem-cilastatin as empirical monotherapy in 400 febrile patients with short duration neutropenia. CEMIC (Study Group of Infectious Diseases in Cancer). , 1998, The Journal of antimicrobial chemotherapy.

[38]  D. Cook,et al.  Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? , 1998, The Lancet.

[39]  D. Hoelzer,et al.  Piperacillin/tazobactam versus cefepime as initial empirical antimicrobial therapy in febrile neutropenic patients: a prospective randomized pilot study. , 1998, European journal of medical research.

[40]  H. Senn,et al.  Monotherapy with piperacillin/tazobactam versus combination therapy with ceftazidime plus amikacin as an empiric therapy for fever in neutropenic cancer patients , 1998, Supportive Care in Cancer.

[41]  M. Territo,et al.  Randomized comparison of sulbactam/cefoperazone with imipenem as empirical monotherapy for febrile granulocytopenic patients. , 1998, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[42]  Ronald N. Jones,et al.  Inducible amp C beta-lactamase producing gram-negative bacilli from blood stream infections: frequency, antimicrobial susceptibility, and molecular epidemiology in a national surveillance program (SCOPE). , 1997, Diagnostic microbiology and infectious disease.

[43]  J. Aparicio,et al.  Randomised comparison of ceftazidime and imipenem as initial monotherapy for febrile episodes in neutropenic cancer patients. , 1996, European Journal of Cancer.

[44]  M. Boogaerts,et al.  Equivalent efficacies of meropenem and ceftazidime as empirical monotherapy of febrile neutropenic patients. The Meropenem Study Group of Leuven, London and Nijmegen. , 1995, The Journal of antimicrobial chemotherapy.

[45]  R. J. Hayes,et al.  Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. , 1995, JAMA.

[46]  C. Sanders.  Cefepime: the next generation? , 1993, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[47]  L. Young,et al.  Evaluation of new anti-infective drugs for the treatment of febrile episodes in neutropenic patients. Infectious Diseases Society of America and the Food and Drug Administration. , 1992, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[48]  E. Anaissie,et al.  A comparison of imipenem to ceftazidime with or without amikacin as empiric therapy in febrile neutropenic patients. , 1992, Archives of internal medicine.

[49]  T. Chan,et al.  Ceftazidime versus imipenem-cilastatin as initial monotherapy for febrile neutropenic patients , 1990, Antimicrobial Agents and Chemotherapy.

[50]  E. Anaissie,et al.  Randomized trial of beta-lactam regimens in febrile neutropenic cancer patients. , 1988, The American journal of medicine.

[51]  L. Elting,et al.  Escherichia coli bacteremia in cancer patients. , 1986, The American journal of medicine.

[52]  V. Melikian,et al.  Treatment of Febrile Episodes in Neutropenic Patients , 1976, Scottish medical journal.

[53]  G. Bodey,et al.  Comment on: empirical antibiotic monotherapy for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials. , 2006, Journal of Antimicrobial Chemotherapy.

[54]  R. Masterton,et al.  Trends in antimicrobial susceptibility in UK centres: the MYSTIC Programme (1997-2002). , 2006, International journal of antimicrobial agents.

[55]  A. Glasmacher,et al.  An evidence-based evaluation of important aspects of empirical antibiotic therapy in febrile neutropenic patients. , 2005, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[56]  G. Jacoby,et al.  The New b -Lactamases , 2005 .

[57]  G. Bodey,et al.  Imipenem or cefoperazone-sulbactam combined with vancomycin for therapy of presumed or proven infection in neutropenic cancer patients , 2005, European Journal of Clinical Microbiology and Infectious Diseases.

[58]  Ronald N. Jones,et al.  Sustained activity and spectrum of selected extended-spectrum beta-lactams (carbapenems and cefepime) against Enterobacter spp. and ESBL-producing Klebsiella spp.: report from the SENTRY antimicrobial surveillance program (USA, 1997-2000). , 2003, International journal of antimicrobial agents.

[59]  Á. Figuera,et al.  Initial empiric therapy of febrile neutropenia with antibiotic monotherapy. Piperacillin/tazobactam versus imipenem/cilastatin (1994-1996) , 2001 .

[60]  Douglas G. Altman,et al.  Systematic Reviews in Health Care , 2001 .

[61]  P. Johansson,et al.  Empiric monotherapy for febrile neutropenia--a randomized study comparing meropenem with ceftazidime. , 1998, Scandinavian journal of infectious diseases.

[62]  P. Biron.  Cefepime versus imipenem-cilastin as empirical monotherapy in 400 febrile patients with short duration neutropenia , 1998 .

[63]  Igor Sartori,et al.  Empirical Evidence of Bias. Dimensions of Methodological Quality Associated with Estimates of Treatment Effects in Controlled Trials , 1996 .

[64]  S. Steinberg,et al.  Monotherapy for fever and neutropenia in cancer patients: a randomized comparison of ceftazidime versus imipenem. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[65]  E. Anaissie,et al.  Beta-lactam regimens for the febrile neutropenic patient. , 1990, Cancer.

[66]  E. Anaissie,et al.  β‐Lactam regimens for the febrile neutropenic patient , 1990 .