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Fluconazole Versus Itraconazole for the Prevention of Fungal Infections

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Fluconazole Versus Itraconazole for the Prevention of Fungal Infections 376 J Clin Pathol 1999;52:376–380 Fluconazole versus itraconazole for the prevention of fungal infections in haemato-oncology J Clin Pathol: first published as 10.1136/jcp.52.5.376 on 1 May 1999. Downloaded from P C Huijgens, A M Simoons-Smit, A C van Loenen, E Prooy, H van Tinteren, G J Ossenkoppele, A R JonkhoV Abstract Superficial and disseminated fungal disease Aims—To compare the eYcacy of and tol- remains a challenging problem for clinicians erance to oral fluconazole and intracona- caring for neutropenic patients with haemato- zole in preventing fungal infection in logical malignancies.1–4 It is the most important neutropenic patients with haematological cause of morbidity and mortality, and because malignancies. it is diYcult to detect, most centres give intra- Patients—213 consecutive, afebrile adult venous antifungal agents to febrile patients patients treated with or without autolo- who do not readily respond to antibacterial 5–7 gous stem cell transplantation for haema- treatment. tological malignancies. Antifungal prophylaxis is widely used. Oral amphotericin has been used in doses of around Methods—A randomised, double blind, 1 to 3 g daily. Its acceptability to patients is single centre study. Patients were ran- poor. In randomised trials, oral polyenes did domly assigned to receive fluconazole 50 not prevent haematogenous candidiasis.8–11 mg or itraconazole 100 mg, both twice Fluconazole has emerged as the most widely daily in identical capsules. An intention to used prophylactic agent in neutropenic pa- treat analysis was performed on 202 tients. The drug eVectively prevents oropha- patients, 101 in each group. ryngeal candidiasis. In doses of 400 mg daily, it Results—Microbiologically documented was shown to reduce fungal colonisation, can- systemic fungal infections occurred in didiasis, and mortality in two randomised four patients in each group. Clinical trials.12 13 The optimal dose remains to be fungal infection was thought to be present determined. In both single arm and ran- in seven recipients of fluconazole and four domised trials, doses as low as 50, 100, and 200 of itraconazole. In all 202 patients, 29 pro- mg daily were associated with a very low ceeded to intravenous amphotericin (am- incidence of superficial and systemic Department of photericin B), 16 in the fluconazole group candidiasis.14–17 A drawback of fluconazole Haematology, and 13 in the itraconazole group. Superfi- prophylaxis is its lack of activity against University Hospital cial fungal infection was seen only in three Aspergillus spp. http://jcp.bmj.com/ Vrije Universiteit, De Itraconazole, another imidazole, has in vitro Boelelaan 1117, 1081 non-compliant patients in the fluconazole HV Amsterdam, The group. All these infections were oral. No and in vivo activity against Aspergillus spp. Netherlands major diVerences were noted in the iso- An important limitation is its erratic bio- P C Huijgens lates of fungi in mouth washes and fecal availability in certain settings.18 19 Rather lim- G J Ossenkoppele samples. Overall mortality was 8.9% (18 ited data are available regarding its eYcacy in A R JonkhoV deaths; seven in the fluconazole group, 11 prevention of fungal disease in neutropenic patients. In a small double blind trial, 200 mg on October 1, 2021 by guest. Protected copyright. Department of Clinical in the itraconazole group). Mortality from Microbiology and microbiologically and clinically docu- of itraconazole twice daily had no additional Infection Control, benefit over oral amphotericin with respect to mented fungal infection was 4.5% (nine 20 University Hospital deaths; three in the fluconazole group, six preventing aspergillosis. Vrije Universiteit in the itraconazole group). Median time to We decided to compare fluconazole 100 mg A M Simoons-Smit daily with itraconazole 200 mg daily in a dou- suspected or proven fungal infection was ble blind, randomised trial in patients with Department of 16 days in both groups. None of these haematological malignancies. Pharmacy, University comparisons reached statistical signifi- Hospital Vrije cance (p < 0.05). No major clinical toxic- Universiteit Methods A C van Loenen ity was noted and compliance was Eligible patients included consecutive adults excellent. who had a haematological malignancy and Pfizer bv, Capelle a/d Conclusions—In neutropenic patients were to receive cytotoxic treatment likely to IJssel, The Netherlands treated for haematological malignancies × E Prooy induce neutropenia (neutrophil count < 0.5 with or without autologous stem cell 109/l) with a duration of at least 10 days. All Comprehensive transplantation, fluconazole and itracona- patients were treated according to protocols of Cancer Centre zole in low doses result in a similar low the Dutch Cooperative Haematooncological Amsterdam, The frequency of fungal disease. Fluconazole Study Group (HOVON) or received high dose Netherlands may be the preferable drug because of the chemotherapy with autologous stem cell res- H van Tinteren smaller number of capsules and lack of cue, or both. Correspondence to: need for timing relative to meals. Patients were excluded if they were younger Dr Huijgens. (J Clin Pathol 1999;52:376–380) than 18 years, if they were known to have email: [email protected] hypersensitivity to triazoles, if they were treated Accepted for publication Keywords: fungal infection; haematological with antifungal agents in the previous 14 days, 13 January 1999 malignancy; imidazoles or if there was overt infection. Fluconazole v itraconazole in haemato-oncology 377 STUDY PROTOCOL DEFINITION OF INFECTION After informed consent was obtained accord- Microbiologically documented infection was ing to the protocol of the ethics committee of defined as infection established by one positive J Clin Pathol: first published as 10.1136/jcp.52.5.376 on 1 May 1999. Downloaded from our institution, patients were randomised to culture of sputum, bronchiolar alveolar lavage, receive 50 mg of fluconazole or 100 mg of itra- tissue biopsy, or blood. For coagulase negative conazole twice daily. Study drugs were given in staphylococci or candida septicaemia to be identical capsules, in a double blind fashion, diagnosed, two separate positive blood cultures directly after a meal. All patients received were required. ciprofloxacin 500 mg twice daily and roxitro- Clinically documented infection was defined mycine 150 mg twice daily, both orally. Nasal whenever typical signs of infection were found on physical examination, rays, or other imag- amphotericin was also given, 2 mg three times x ing tests without positive cultures. Those were daily into both nostrils. All these four prophy- judged to be bacterial when they responded to lactic drugs were given from the day of start of intravenous antibiotic treatment and to be fun- chemotherapy until the neutrophil count was gal when they persisted during antibiotic treat- × 9 above 0.5 10 /l. A single lumen subclavian ment and required empirical amphotericin intravenous catheter was inserted, and the treatment. FUO was defined as every febrile dressing was renewed daily. Antiviral treatment episode without microbiologically or clinically with acyclovir, leucocyte-poor erythrocyte con- documented infection, whether the episode led centrates, and platelets was given as clinically to amphotericin treatment or not. indicated. Granulocyte transfusions were not used. COMPLIANCE Granulocyte colony stimulating factor (G- Compliance was monitored by the attending CSF) was given according to protocols. Pa- nurses. It was deemed good if a patient missed tients were nursed in conventional single or fewer than 20% of the total number of doses double rooms, and patients receiving autolo- and poor if the patient missed more. gous stem cell transplantation after busulphan- cyclophosphamide conditioning (for acute leu- SIDE EFFECTS kaemia and multiple myeloma) were treated in Side eVects were monitored clinically on the down flow isolation rooms. daily rounds by asking about nausea and vom- All patients were examined daily for clinical iting related to the administration of the study signs of infection. When the axillary tempera- drug, and by looking for rashes. Serum electro- ture increased to more than 38.5°C or other lyte analyses and tests for liver and renal func- signs of infection appeared, samples for micro- tion were done three times weekly. biological cultures, including at least two sepa- Oral mouth washes were cultured twice rate blood specimens, were obtained, one of weekly for bacterial and fungal species. Faecal which was withdrawn through the intravenous samples were cultured once weekly. catheter. Treatment with imipenem-cilastatin http://jcp.bmj.com/ 500 mg four times daily intravenously was STATISTICAL ANALYSIS started. If fever persisted, vancomycin 1 g twice Results in all patients were analysed according daily intravenously was added after 72 hours. to the intention to treat principle. Categorical Empirical treatment with amphotericin, 0.7 data were analysed by Fisher’s exact test, and the Wilcoxon rank sum test was used for mg/kg, was added to the imipenem-cilastatin continuous data. The diVerence between the plus vancomycin combination if fever persisted two groups for the time to suspected fungal for another 72 hours. Vancomycin with or infection—defined as the time between starting on October 1, 2021 by guest. Protected copyright. without amphotericin was given earlier if the study drug and the development of fever cultures so dictated. requiring amphotericin treatment—was ana- At the beginning
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