ITRACONAZOLE VERSUS FLUCONAZOLE IN NEUTROPENIC PATIENTS

We read with interest the paper on itraconazole versus ̄uconazole in neutropenic patients (Morgenstern et al, 1999). Morgenstern et al (1999) stated that `no direct comparisons have been published'. In fact, we published in June 1998 the ®rst report of a randomized trial comparing both drugs in neutropenic patients with haematological malignancies as an abstract of the 1998 EHA meeting (Huijgens et al, 1998). The full report was published very recently (Huijgens et al, 1999). In contrast to the Morgenstern trial, ours is a doubleblind trial in which 202 patients received either itraconazole 200 mg or ̄uconazole 100 mg daily, in capsules. We found no differences in overall mortality or motality due to suspected or proven fungal infections. In both the itraconazole and ̄uconazole group, we found four cases of Aspergillus and/or Mucor infection. The trough plasma levels of itraconazole were well within the published range and almost equal to the minimal inhibitory concentration (MIC) breakpoint for itraconazole in candidal disease. There are no published data on itraconazole plasma levels and clinical ef®cacy against Aspergillus and Mucor species. However, the levels we found were in the range of the MICs of Aspergillus strains found in two recent studies (Rath, 1998; Verweij et al, 1998). We concluded that there was little to choose between the drugs, except for the easier handling of ̄uconazole. Morgenstern et al (1999) explained their unblinded design by pointing to the need for a double-placebo technique in a blinded study. This is not a very strong reason, and an unblinded design calls for rigid de®nitions of end-points, standardized antibacterial strategies and very precise explanations for exclusions and drop-outs, especially when one or two patient outcomes may make a difference. The de®nition of suspected fungal infection is given twice, in rather different terms. Furthermore, the antibacterial regimens do not seem to be standardized and the duration of therapy before going to empirical antifungal therapy ranges between 72 and 96 h, which in an unblinded study suggests bias. Furthermore, analysing oral infections is very dif®cult as many patients harbour Candida species in their mouth during azole therapy and clinical diagnosis is therefore unreliable. The number of withdrawals was considerable. Even a single case of proven fungal infection would substantially in ̄uence statistical analysis and outcome. The question remains why an intention-to-treat analysis of data has not been performed. This would have provided more insight in the occurrence of fungal infections in the two treatment groups as a whole and would de®nitely have better re ̄ected daily clinical practice, in which therapy failure due to noncompliance or adverse events is a frequent and signi®cant problem. Since small numbers have major effects on statistical outcome, there should be a critical note on the number of deaths due to Aspergillus. Of the ®ve cases of fatal aspergillosis in the ̄uconazole group, including those observed after the of®cial study period, three occurred at one centre. As a consequence, the most important risk factor for death due to invasive aspergillosis seems to be not the use of either itraconazole or ̄uconazole but admission to that particular clinic. The authors concluded that `presumably physicians will choose between ̄uconazole and itraconazole depending on their views of the risk of aspergillus in their patient population'. This advice is rather vague, probably re ̄ecting their awareness that their trial has some important ̄aws, making clearer conclusions impossible. The jury on which type of prophylaxis against fungal disease in neutropenic patients is preferable is still out! Department of Haematology, P. C. H U I J G E N S 1 , Department of Clinical G. J. T I M M E R S 1 , Microbiology and Infection A. M. S I M O O N S -S M I T 2 , Control and A.C. VA N L O E N E N 3