JAC Advance Access originally published online on June 23, 2006
Journal of Antimicrobial Chemotherapy 2006 58(2):479-480; doi:10.1093/jac/dkl255
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Correspondence |
Empirical antibiotic monotherapy for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials: authors’ response
1 Department of Medicine E, Rabin Medical Center Beilinson Campus, 49100 Petah-Tiqva, Israel 2 Sackler Faculty of Medicine, Tel-Aviv University Ramat-Aviv, Israel
*Correspondence address. Department of Medicine E, Rabin Medical Center, Beilinson Campus, 49100 Petah-Tiqva, Israel. Tel: +972-3-9376501; Fax: +972-3-9376512; E-mail: pil1pel{at}zahav.net.il
Keywords: neutropenic sepsis , antimicrobials , ß-lactams
Sir,
Drs Rolston and Bodey1 have raised several points regarding our study, which we would like to address.
We compared broad-spectrum ß-lactams currently recommended as first-line empirical monotherapy for febrile neutropenia in the latest Infectious Diseases Society of America (IDSA) guidelines, which include ceftazidime, cefepime, imipenem and meropenem.2 Indeed, our terminology (i.e. monotherapy) was inaccurate since we included studies that assessed combination therapy when vancomycin was added to both study arms.3 However, only 4 of the 33 included studies added vancomycin to all patients4–7 and 2 studies permitted the addition of vancomycin equally to both study arms when indicated.8,9 Exclusion of these studies does not change our results. Specifically, all-cause mortality with cefepime alone is significantly higher than the mortality with ceftazidime monotherapy (cefepime versus ceftazidime RR 1.74, 95% CI 1.02–2.98, 6 studies, values >1 favour ceftazidime). Mortality is similar with ceftazidime and carbapenem monotherapy (ceftazidime versus carbapenems RR 1.10, 95% CI 0.65–1.86, 8 studies). All-cause mortality with cefepime monotherapy remains significantly higher when compared with other monotherapies combined (cefepime versus others RR 1.52, 95% CI 1.07–2.14, 14 studies). Clinical failure results are identical to those presented in our publication. Our original objective was to guide clinicians in the selection of the type of the ß-lactam used for monotherapy, or in combination with vancomycin when indicated.
Local resistance patterns should be used to guide treatment. Obviously, antibiotics that are not active given local epidemiology should not be used. The (external) validity of any study to the local settings must be considered before applying its conclusions.10 Drs Rolston and Bodey focus the interpretation of our results in light of the epidemiology at their centre. However ceftazidime may be used for monotherapy in locations where antibiotic resistance patterns permit its use.
Drs Rolston and Bodey quote the results of a meta-analysis comparing ß-lactam monotherapies, showing ‘clear and statistically significant inferiority of ceftazidime’.11 This is not a systematic review, but a preliminary analysis of 25 randomized controlled trials ‘available in electronic databases’. This meta-analysis combined trials assessing ß-lactam monotherapy and ß-lactam-aminoglycoside combination therapy. The outcome reported by Glasmacher et al.11 is ‘response to the initial empirical antibiotic treatment without modification’ (opposite of treatment failure as defined in our study). Treatment failure in these trials is a composite endpoint driven mainly by modifications of the empirical treatment. Most of these trials were not blinded and treatment modifications were more common with ceftazidime when compared with a newer antibiotic. Comparability of study results is highly dependent on the definitions used in the study.12 The primary outcome on which our conclusions are based is all-cause mortality. This is also the main outcome for the patient. Other outcomes meaningful to patients include time to clinical response,13 need for invasive procedures, duration of hospital stay, but not treatment modification. Our study shows that cefepime was associated with significant higher all-cause mortality than comparators, despite its advantages in vitro. We cannot continue treating patients with an antibiotic that results in higher mortality unless the data, or our interpretation, are rebutted in a convincing way.
Should evidence be discarded because epidemiology has changed? Randomized controlled trials have paved the path to evidence-based treatment of febrile neutropenia. Current treatment is based on the earliest trials conducted by Dr Bodey and colleagues. Clinicians debating the type of monotherapy most appropriate for their locale should look at the evidence available. Appropriately conducted meta-analyses originating from systematic reviews enable unbiased integration of the evidence and assessment of patients' safety. We believe that systematic reviews are a powerful tool to examine the evidence.14 The evidence should then be examined in the light of local patterns of pathogens and resistance at each medical centre. The applicability of results to specific settings should indeed be carefully considered.
Transparency declarations
We declare no conflict of interests.
Footnotes
Present address. Department of Social Medicine, University of Bristol, Bristol, UK 
References
1
Rolston KVI and Bodey GP. (2006) Comment on: Empirical antibiotic monotherapy for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother 58:478–9.
2 Hughes WT, Armstrong D, Bodey GP, et al. (2002) 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 34:730–51.[CrossRef][Web of Science][Medline]
3
Paul M, Yahav D, Fraser A, et al. (2006) Empirical antibiotic monotherapy for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother 57:176–89.
4 Anaissie EJ, Fainstein V, Bodey GP, et al. (1988) Randomized trial of ß-lactam regimens in febrile neutropenic cancer patients. Am J Med 84:581–9.[CrossRef][Web of Science][Medline]
5 Aoun M, Boogaerts MA, Bosly AJ, et al. A multicenter, randomized, prospective, comparative study of cefepime plus vancomycin versus ceftazidime plus vancomycin as empiric therapy in the treatment of febrile episodes in granulocytopenic patients with hematological malignancies. Joint clinical/statistical review of NDA 50,679/SE1-002. http://www.fda.gov/cder/foi/nda/97/050679s002.htm(18 September 2005, date last accessed).
6 Bodey GP, Fainstein V, Elting LS, et al. (1990) ß-Lactam regimens for the febrile neutropenic patient. Cancer 65:9–16.[CrossRef][Web of Science][Medline]
7 Bodey G, Abi-Said D, Rolston K, et al. (1996) Imipenem or cefoperazone-sulbactam combined with vancomycin for therapy of presumed or proven infection in neutropenic cancer patients. Eur J Clin Microbiol Infect Dis 15:625–34.[CrossRef][Web of Science][Medline]
8 Raad II, Escalante C, Hachem RY, et al. (2003) Treatment of febrile neutropenic patients with cancer who require hospitalization: a prospective randomized study comparing imipenem and cefepime. Cancer 98:1039–47.[CrossRef][Web of Science][Medline]
9 Glauser M, Dekker AW, Van Marwijkkooy M, et al. A multicenter comparative study of cefepime vs ceftazidime as empiric therapy in the treatment of febrile episodes in neutropenic patients. Joint clinical/statistical review of NDA 50,679/SE1-002. http://www.fda.gov/cder/foi/nda/97/050679s002.htm (18 September 2005, date last accessed).
10
Leibovici L, Soares-Weiser K, Paul M, et al. (2003) Considering resistance in systematic reviews of antibiotic treatment. J Antimicrob Chemother 52:564–71.
11 Glasmacher A, von Lilienfeld-Toal M, Schulte S, et al. (2005) An evidence-based evaluation of important aspects of empirical antibiotic therapy in febrile neutropenic patients. Clin Microbiol Infect 11:Suppl 5, 17–23.
12
Bodey GP, Rolston KV, Raad II. (2003) Ciprofloxacin versus tobramycin for neutropenic fevers. Ann Intern Med 138:435 author reply 436.
13
Elting LS, Rubenstein EB, Rolston K, et al. (2000) Time to clinical response: an outcome of antibiotic therapy of febrile neutropenia with implications for quality and cost of care. J Clin Oncol 18:3699–706.
14
Leibovici L and Reeves D. (2005) Systematic reviews and meta-analyses in the Journal of Antimicrobial Chemotherapy. J Antimicrob Chemother 56:803–4.
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