JAC Advance Access originally published online on November 28, 2005
Journal of Antimicrobial Chemotherapy 2006 57(1):151-152; doi:10.1093/jac/dki415
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Correspondence |
Comment on: Evidence-based review of antifungal prophylaxis in neutropenic patients with haematological malignancies
1 Klinik I für Innere Medizin, Klinikum der Universität Köln, Köln, Germany; 2 Medizinische Klinik III, Johannes Gutenberg Universität, Mainz, Germany; 3 Medizinische Klinik II, Ev. Johannes-Krankenhaus, Bielefeld, Germany
* Corresponding author. E-mail: oliver.cornely{at}uni-koeln.de
Keywords: antifungals , prophylaxis , meta-analysis
Sir,
A recently published JAC review claims to have found ‘unambiguous evidence’ in the field of antifungal prophylaxis.1 In our view this topic is too complex to allow such a simple conclusion. This review by Glasmacher et al. shows several short comings that require further comment and some additional clarification.
In 2003, we collected evidence available from all published major clinical trials on antifungal prophylaxis and applied the standard evidence grading system of the Infectious Diseases Society of America.2 It is the decisive strength of this review that available data were listed in detail extensively for the first time, thus facilitating the reader's assessment of single trials.3
Glasmacher et al. claim that our review on this topic recommended no indication for the use of any kind of antifungal prophylaxis. Unfortunately, the authors failed to quote our conclusions adequately. We clearly recommend prophylaxis with fluconazole 400 mg once daily in patients undergoing allogenic stem cell transplantation. It is the only regimen based on ‘Good evidence to support a recommendation for use’ and ‘Evidence from 
1 properly randomized, controlled trial’ (category A I).2 Furthermore, we concluded—and still do so—that data advocating the prophylactic use of itraconazole are less conclusive (category B I). The evidence for the use of any antifungal agent in subjects receiving conventional chemotherapy is poor to support prophylaxis (category C I).3
We agree with the authors that most single trials do not achieve an adequate statistical power to detect a statistically significant difference between placebo and antifungal prophylaxis. However, we disagree that this problem can only be overcome by cumulative meta-analysis to answer the question of antifungal efficacy. This is mainly due to an enormous heterogeneity in patient population and their risk factors for fungal infections treated within different clinical trials. Meta-analysis has, in our opinion, a potential usefulness in the design of future trials when previous results are inconclusive, but cannot replace them. Obviously, this problem can only be overcome by adequately powered large clinical trials. The feasibility of such a trial was demonstrated by Slavin et al.4 We are convinced that future challenges lie in the design of adequately powered and risk-stratified trials.
Glasmacher et al. seem not to be aware of a recently published trial on antifungal prophylaxis. Their review on the prophylactic use of micafungin is imprecise; Glasmacher et al. overlooked an article by van Burik et al.5 that had previously been published in October of 2004.
Finally, it is difficult to identify new aspects relevant for the scientific community. Neither systematic reviews nor meta-analyses are superior to each other per se. They are two different scientific approaches to solve the same burning clinical question. We agree with Petticrew6 that both are not a substitute for high quality individual trials.
Transparency declarations
OAC has received research grants from, is an advisor to, or served on the speakers bureau of Astellas, Basilea, Gilead, Pfizer, Merck, Schering-Plaugh, Vicuron and Zeneus. AJU has received research grants from, is an advisor to, or served on the speakers bureau of Astellas, Basilea, Gilead, Pfizer, MSD and Schering-Plough. MK is an advisor to Gilead, Pfizer and Schering-Plough.
References
1. Glasmacher A, Prentice AG. Evidence-based review of antifungal prophylaxis in neutropenic patients with haematological malignancies. J Antimicrob Chemother 2005; 56 Suppl S1: i23–32.[Abstract]
2. Kish MA. Guide to development of practice guidelines. Clin Infect Dis 2001; 32: 851–4.[CrossRef][Web of Science][Medline]
3.
Cornely OA, Ullmann AJ, Karthaus M. Evidence-based assessment of primary antifungal prophylaxis in patients with hematologic malignancies. Blood 2003; 101: 3365–72.
4. Slavin MA, Osborne B, Adams R et al. Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation—a prospective, randomized, double-blind study. J Infect Dis 1995; 171: 1545–52.[Web of Science][Medline]
5. van Burik JA, Ratanatharathorn V, Stepan DE et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis 2004; 39: 1407–16.[CrossRef][Web of Science][Medline]
6.
Petticrew M. Systematic reviews from astronomy to zoology: myths and misconceptions. Br Med J 2001; 322: 98–101.
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  A. Glasmacher and A. Prentice The role of meta-analysis in the evaluation of antifungal prophylaxis: authors' response J. Antimicrob. Chemother., January 1, 2006; 57(1): 152 - 154. [Full Text] [PDF]
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