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Breakthrough Fungal Infections After Allogeneic Hematopoietic Stem Cell Transplantation in Patients on Prophylactic Voriconazole

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Breakthrough Fungal Infections After Allogeneic Hematopoietic Stem Cell Transplantation in Patients on Prophylactic Voriconazole Bone Marrow Transplantation (2007) 40, 451–456 & 2007 Nature Publishing Group All rights reserved 0268-3369/07 $30.00 www.nature.com/bmt ORIGINAL ARTICLE Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole S Trifilio1, S Singhal2, S Williams2, O Frankfurt2, L Gordon2, A Evens2, J Winter2, MTallman 2, JPi1 and J Mehta2 1Northwestern Memorial Hospital, Chicago, IL, USA and 2The Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Seventy-one allograft recipients receiving voriconazole, stem cell transplantation (HSCT). The majority of in whom complete clinical, microbiologic and pharmaco- infections are caused by Candida and Aspergillus species, kinetic data were available, were studied to determine the usually several weeks to months post-transplant.1 The efficacy of voriconazole in preventing fungal infections. incidence of aspergillosis in transplant patients has been The length of voriconazole therapy was 6–956 days increasing, and mortality rates remain high.2 Current (median 133). The total number of patient-days on evidence-based guidelines recommend 400 mg fluconazole voriconazole was 13 805 (B38 years). A total of 10 daily after HSCT for the prevention of invasive yeast fungal infections were seen in patients on voriconazole infections.3 (18% actuarial probability at 1 year): Candida glabrata However, fluconazole has no activity against Aspergillus (n ¼ 5), Candida krusei (n ¼ 1), Cunninghamella (n ¼ 1), or the more recently recognized emerging non-Aspergillus Rhizopus (n ¼ 2) and Mucor (n ¼ 1). Two of the four mold infections. As a result, while many centers continue zygomycosis cases were preceded by short durations of using fluconazole, a number of centers have broadened voriconazole therapy, but prolonged itraconazole prophy- coverage with more potent antifungal drugs to prevent laxis. The plasma steady-state trough voriconazole levels mold infections.4 Emergence of resistant Candida infections around the time the infection occurred were o0.2, o0.2, has been reported with prolonged exposure to azole drugs, 0.33, 0.55, 0.63 and 1.78 lg/ml in the six candidiasis especially at non-lethal concentrations.5 cases. Excluding the four zygomycosis cases, all the six Voriconazole, an extended spectrum triazole agent, has candidiasis cases were seen among the 43 patients with excellent clinical activity in aspergillosis and has been voriconazole levels of p2 lg/ml and none among the 24 shown to be particularly effective in the prevention of with levels of 42 lg/ml (P ¼ 0.061). We conclude that breakthrough fungal infections, especially in patients at voriconazole is effective at preventing aspergillosis. high risk for aspergillosis.6 It also has excellent in vitro However, breakthrough zygomycosis is seen in a small activity against many Candida species, although the in vitro proportion of patients. The role of therapeutic voricona- MIC90 (Minimum Inhibitory Concentration required to zole monitoring with dose adjustment to avoid break- inhibit the growth of 90% of organisms) for Candida through infections with fungi that are otherwise glabrata are higher than for other fluconazole-sensitive susceptible to the drug needs to be explored prospectively. Candida species (0.5–1 versus 2).7 Voriconazole has no Bone Marrow Transplantation (2007) 40, 451–456; activity against zygomycetes. Although voriconazole is not doi:10.1038/sj.bmt.1705754; published online 25 June 2007 approved for empiric use in neutropenic fever, the Keywords: voriconazole; Mucor; Candida; HSCT reduction in breakthrough fungal infections seen in patients receiving the drug8 makes it an attractive candidate for prevention of aspergillosis. A recent study has reported an association between successful therapeutic outcome in Aspergillus infections and sustaining voriconazole concen- Introduction trations above the MIC;9 suggesting the possible need for therapeutic drug monitoring. Invasive fungal infections are a significant cause of While our standard antifungal prophylaxis for allograft morbidity and mortality in recipients of hematopoietic recipients is itraconazole,10 we switch to voriconazole when patients receive corticosteroids or have had a mold infection in the past. We have also implemented voricona- Correspondence: Dr J Mehta, Department of Hematology/Oncology, zole therapeutic drug monitoring.11 The purpose of this Northwestern University Medical School, 676 N St Clair Street, Suite retrospective review was to determine the efficacy of 850, Chicago, IL 60611-2927, USA. E-mail: [email protected] voriconazole in preventing invasive fungal infections in Received 16 November 2006; revised 27 March 2007; accepted 2 May our patient population and to find out if there was any 2007; published online 25 June 2007 correlation between drug levels and efficacy. Voriconazole after allogeneic HSCT S Trifilio et al 452 Patients and methods patients (81%) receiving intravenous methylprednisolone. The maximum daily dose of corticosteroids was X2 mg/kg Seventy-one adult allogeneic HSCT recipients with hema- (median maximum daily dose 500 mg). tologic malignancies who received voriconazole post- Ten microbiologically confirmed fungal infections were transplant for at least 7 days, and in whom complete seen, six Candida and four Zygomycetes. Not a single case clinical, microbiological and pharmacokinetic data were of aspergillosis was seen. Patients in whom the fungus was available were studied. Fifty-four patients switched from seen on bronchoalveolar lavage or endotracheal tube itraconazole to voriconazole after starting corticosteroid aspirate had lung infiltrates compromising pulmonary therapy for acute or chronic graft-versus-host disease status, and no other known cause for the pulmonary (GVHD). These patients had started itraconazole on the infiltrates (compatible with possible to probable infection day of stem cell infusion. The remaining 17 patients by the European Organization for Research and Treatment received voriconazole from the day of stem cell infusion of Cancer criteria). Table 2 provides detailed information because of a prior history of suspected or confirmed on the 10 cases. Concomitant bacteremia was seen in all six aspergillosis. patients with candidiasis and in two of the patients with Voriconazole was usually administered at the dose of zygomycosis. 200 mg twice daily orally, and was continued until a month All the patients with candidiasis received caspofungin. beyond discontinuation of all immunosuppression or The two candidiasis cases (Patients 1 and 4) in which the development of a fungal infection requiring change in fungal infection was felt to have contributed died of therapy. Steady-state trough blood levels of voriconazole polymicrobial sepsis. Clearance of Candida was demon- were drawn before the morning dose and measured at least strated on repeat bronchoscopy in three patients (Patients 5 days after the drug was initiated and measured as 2, 3 and 6). As most patients had concomitant infections, previously described.11,12 Although the period following attributable mortality could not be definitely established. stem cell transplantation includes the administration of Patients in whom death was felt to be at least partly due to many drugs metabolized by the cytochrome P450 system, the fungal infection were those in whom pulmonary there were no drugs given concomitantly that were known infiltrates did not resolve (and indeed progressed), and in to change voriconazole disposition. whom there was no other predominant cause of death. Patients underwent radiologic studies as clinically Among the zygomycosis cases, patients 7 and 9 were indicated. Sequential galactomannan testing was not treated with posaconazole, patient 8 received amphotericin performed. Patients were treated between January 2003 B lipid complex, and patient 10 received liposomal and May 2006. The retrospective review was approved by ampotericin B. Patient 8 had received prophylactic Northwestern University’s institutional review board as itraconazole for over 4 months before a change was made part of a project evaluating outcome of allogeneic HSCT. to voriconazole prophylaxis when signs and symptoms of sinusitis developed. Zygomycosis involving the sinuses was confirmed 7 days later. It is unlikely that voriconazole Results contributed to the development of zygomycosis in this case. Similarly, patient 10 had received itraconazole for almost Table 1 shows patient characteristics. The duration of prior 2.5 months before a change was made to voriconazole. itraconazole therapy in the 54 patients who switched from Zygomycosis was diagnosed less than 3 weeks later, itraconazole to voriconazole was 1–161 days (median 14). suggesting that the contribution of voriconazole therapy The total duration of exposure to voriconazole was 13 805 to zygomycosis in this case is debatable. Figures 1 and 2 patient-days (B38 years). show the actuarial probability of invasive fungal infections Most patients received corticosteroids at some point in (18% at 1 year) and zygomycosis (7% at 1 year), time while on voriconazole. The dose of steroids varied respectively, from the initiation of voriconazole therapy. according to severity of GVHD, with the majority of Table 3 shows plasma voriconazole trough levels. Excluding the four zygomycosis cases, all six candidiasis Table 1 Patient characteristics cases were seen among the 43 patients with voriconazole levels of p2 mg/ml and none among the 24 with levels of N
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