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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 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 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 fungal infections were seen in patients on voriconazole infections.3 (18% actuarial probability at 1 year): However, fluconazole has no activity against Aspergillus (n ¼ 5), (n ¼ 1), (n ¼ 1), or the more recently recognized emerging non-Aspergillus (n ¼ 2) and (n ¼ 1). Two of the four 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 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 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 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 71 42 mg/ml (P ¼ 0.061; Fisher’s exact test). Including the Male 40 (56%) four zygomycosis cases, the six candidiasis cases were seen Acute myeloid leukemia 30 (42%) Non-Hodgkin’s lymphoma 8 (25%) among the 44 patients with voriconazole levels of p2 mg/ml Acute lymphoblastic leukemia 6 (8%) and none among the 27 with levels of 42 mg/ml (P ¼ 0.049; Chronic lymphocytic leukemia 5 (7%) Fisher’s exact test). Multiple myeloma 5 (7%) Other MDS 7 (10%) Matched sibling donor, myeloablative 35 (49%) Matched unrelated donor, submyeloablative 27 (38%) Discussion Matched unrelated donor, myeloablative 7 (10%) Matched sibling donor, submyeloablative 2 (3%) Our data show that voriconazole is effective in preventing Graft-versus-host disease 61 (86%) Aspergillus infections in immunocompromised allogeneic Corticosteroid therapy 62 (87%) Duration of voriconazole therapy 12–956 days (median 117) HSCT recipients. While there is some breakthrough zygomycosis, the incidence appears to be low. The study Abbreviation: MDS ¼ myelodysplastic syndrome. also suggests that there may be a link between low plasma

Bone Marrow Transplantation Voriconazole after allogeneic HSCT S Trifilio et al 453 1.0 to death of fungus

Contribution 0.8 matched sibling ¼ 0.6 isolation Outcome at 2 months after fungus

0.4 mg/kg total and dose in mg; Voriconazole 0.2 Probability of invasive fungal infection before

infection) 0.0 level (weeks Voriconazole 0 200 400 600 800 1000 myelodyspastic syndrome; MSD

¼ Days on voriconazole Figure 1 Probability of development of invasive fungal infection after

(days) starting voriconazole. exposure Voriconazole /l) 9 10

 1.00 0.5 Neutropenia o ( Hodgkin’s disease; MDS

¼ 0.80

methyl 0.60 2 weeks (mg) prednisolone or prednisone dose in the preceding

0.40 GVHD Cumulative Probability of zygomycosis 80 Yes 400 Yes 17 1.1 (2) 800; 7.3 Dead Yes

broncho-alveolar lavage; HD 0.20 ¼ transplant Days post-

0.00 0 200 400 600 800 1000 Days on voriconazole Figure 2 Probability of development of zygomycosis after starting BAL, blood 179 Yestube aspirate 600 Yes 159 1.78 (5) 400; 4.4 Dead Yes material voriconazole. blood acute myeloid leukemia; BAL /l.

9 Table 3 Voriconazole levels ¼ 10

 Range (mg/ml) o0.2 to 6.97 Median (mg/ml) 1.04 0.5 non-Hodgkin’s lymphoma. o Level range (mg/ml) n (%)

¼ o0.2 2 (17%) 0.2–0.5 10 (14%) 40.5 up to 1.0 11 (15%) 41.0 up to 2.0 11 (15%) 42.0 up to 5.0 20 (28%) 45.0 7 (10%) Transplant Fungus Site Diagnostic acute lymphoblastic leukemia; AML

¼ voriconazole levels and breakthrough infections with fungi that are otherwise susceptible to the drug, a relationship matched unrelated donor; NHL ¼

Breakthrough fungal infections that requires exploration in a prospective study. The limitations of the data are their retrospective nature, a status relatively small number of patients, and the lack of availability of MICs in the specific fungi isolated in All patients had an absolute lymphocyte count of 123 ALL,4 CR NHL, active HD, CR MSD, MSD, MDS, myeloablative submyeloablative active MUD, C. submyeloablative glabrata MUD, submyeloablative C. Krusei C. glabrata C. glabrata Lungs BAL Lungs, Lungs Lungs BAL BAL 145 183 837 Yes Yes Yes 160 280 40 Yes No No 136 832 157 0.63 (2) 0.53 (12) 0.2 (1) 400; 8 400; 5.3 500; 6.2 Alive Dead Dead No Yes No donor; MUD 567 AML,8 active MDS,9 active MSD, submyeloablative ALL,10 active MSD, ALL, myeloablative active C. MUD, NHL, glabrata submyeloablative CR AML, active MUD, submyeloablative Rhizopus C. MSD, glabrata myeloablative MUD, Lungs Rhizopus myeloablative BAL Lungs Lungs Cunnninghamella Mucor Lungs Sinuses BAL Tissue Tissue Endotracheal Lungs 178 Tissue 135 135 Yes 9 Yes No Yes 360 78 330 Yes 0 0 Yes No 0 Yes Yes 56 128 0.33 No (1) 7 7 4.1 (12) 600; 4.6 5.9 0.33 (1) (4) 400; 78 5.1 Dead 400; 7.4 400; Dead 4 3.5 (1) No Alive Yes Alive 400; 5 No No Alive No Table 2 Patient Disease and Abbreviations: ALL patients.

Bone Marrow Transplantation Voriconazole after allogeneic HSCT S Trifilio et al 454 The observed efficacy of voriconazole in preventing geneic HSCT recipients by eliminating itraconazole entirely Aspergillus infections confirms the results reported by and administering voriconazole from the beginning in all Siwek et al.13 who found no cases of aspergillosis among patients. The recent approval of posaconazole raises 92 allogeneic HSCT recipients. Prophylactic fluconazole the intriguing possibility of alternating prophylaxis between improves survival of HSCT recipients.14 Since fluconazole voriconazole and posaconazole every 1–2 months in has no activity against Aspergillus species, it is not patients who require prolonged broad-spectrum antifungal unreasonable to expect that voriconazole would have prophylaxis. The experience with itraconazole and vorico- similar benefit on survival because of its broader spectrum nazole suggests that switching to posaconazole exclusively of activity. However, there are no randomized data to for prophylaxis may not be an optimum solution as support or refute this hypothesis. other serious mycoses may emerge – and such an The overall incidence of zygomycosis in cancer patients approach should ideally be undertaken only in the setting appears to be increasing.15,16 However, there is a concern of a clinical trial. that prior voriconazole use predisposes to zygomyco- The rate of breakthrough Candida infections in this study sis.13,17,18 Our data appear to support the suggestion of appears similar to that reported with fluconazole20 with a breakthrough zygomycosis. However, we do not believe shift towards more resistant species. It is interesting that that it is a problem unique to voriconazole or one that plasma steady-state trough voriconazole levels around the is solely attributable to it. Two patients in this study time the infection occurred were o0.2, o0.2, 0.33, 0.55, (Patients 8 and 10; Table 2) had received prophylactic 0.63 and 1.78 mg/ml in the six candidiasis cases (Table 2). itraconazole for 122 and 63 days, respectively, before The lack of occurrence of breakthrough candidiasis in switching to voriconazole on account of GVHD requiring patients with drug levels of 42 mg/ml appears to be corticosteroids, and had been on voriconazole for only statistically significant. Of course, it should be noted that 7 and 17 days, respectively, before zygomycosis was the interval between obtaining drug level and diagnosis of a diagnosed. Patient 8 had symptoms of sinusitis for a fungal infection exceeded 4 weeks in two Candida cases few days before the diagnosis being made, and patient 10 and one mucor case. Likewise, as the diagnosis of had pulmonary infiltrates for approximately a week Candida infection was determined from broncho-alveolar before the diagnosis was made. This suggests that prior lavage in 5/6 patients, the possibility of colonization or itraconazole therapy may have been responsible for contamination cannot be ruled out. This is not unexpected the development of zygomycosis in two of the four considering the retrospective nature of the study. patients. We have reported another case of breakthrough Analysis of data for 249 patients from six phase III zygomycosis and aspergillosis on itraconazole prophylaxis.19 clinical trials of voriconazole has demonstrated a significant Indeed, as Figure 3 (measured from the time of starting correlation between drug levels and end-of-treatment out- itraconazole in those who started it before switching to come assessment.21 Using MIC data for voriconazole in voriconazole, or from the time of starting voriconazole in over 8000 clinical isolates, the Antifungal Susceptibility those who did not receive itraconazole) shows, over 2.5 Subcommittee of the Clinical and Laboratory Standards months of combined itraconazole/voriconazole therapy Institute has now proposed interpretive breakpoints for have elapsed before the first episode of zygomycosis occurs. voriconazole and Candida species.22 These are as follows: This suggests that therapy/prophylaxis effective against o1 mg/ml susceptible, 2 mg/ml susceptible dose dependent, aspergillosis may need to continue for several weeks before and 44 mg/ml resistant. Although the majority of C breakthrough zygomycosis becomes a risk. glabrata isolates were susceptible to voriconazole, among After seeing the results of this analysis, we have the fluconazole-resistant isolates, 44% were susceptible to streamlined our antifungal prophylaxis practice in allo- voriconazole in a dose-dependent manner (MIC 2 mg/ml). Such organisms would require higher plasma concentra- tions to eradicate infection. 1.00 Previously published data suggest that drug levels can affect outcome of antifungal therapy in clinical practice. 0.80 The maximum amount of information is available for itraconazole showing that blood levels of itraconazole exceeding a threshold are needed to reduce the risk of 0.60 Aspergillus infections.23–25 Data on file at the United States Food and Drug Administration show that success rate in patients with fungal 0.40 infections, whose mean voriconazole plasma levels were o0.5 g/ml, was 46% compared to 56% with mean plasma levels 40.5 g/ml.21 A recent study9 reported a significant

Probability of zygomycosis 0.20 association between higher plasma voriconazole levels and therapeutic success in patients with documented Aspergillus 0.00 infection. Favorable responses were observed in 10 of 10 0 200 400 600 800 1000 patients with drug concentrations 42.05 mg/ml and in 10 of Days on itraconazole/voriconazole 18 patients with concentrations o2.05 mg/ml (P ¼ 0.014). Figure 3 Probability of development of zygomycosis from the day of While our observation does seem to be compelling in stem cell infusion (that is after starting itraconazole or voriconazole). combination with the above data, the lack of aspergillosis

Bone Marrow Transplantation Voriconazole after allogeneic HSCT S Trifilio et al 455 in patients with low voriconazole levels in this series would 8 Walsh TJ, Pappas P, Winston DJ, Lazarus HM, Petersen F, seem to weaken the case for a relationship between drug Raffalli J et al. Voriconazole compared with liposomal levels and outcome. One possible explanation is that the for empirical antifungal therapy in patients incidence of aspergillosis in our patient population is not with neutropenia and persistent fever. N Engl J Med 2002; 346: high enough to have this modest-sized series show a 225–234. difference in outcome between patients with low and 9 Smith J, Safdar N, Knasinski V, Simmons W, Bhavnani SM, Ambrose PG et al. Voriconazole therapeutic drug monitoring. optimum drug levels. Antimicrob Agents Chemother 2006; 50: 1570–1572. This study, our previous observations of large inter- 10 Marr KA, Crippa F, Leisenring W, Hoyle M, Boeckh M, 11 patient variability in plasma voriconazole levels, and Balajee SA et al. Itraconazole versus fluconazole for preven- other data9 are insufficient to recommend starting routine tion of fungal infections in patients receiving allogeneic stem therapeutic drug monitoring in all patients on voriconazole. cell transplants. Blood 2004; 103: 1527–1533. However, we feel that future prospective clinical trials of 11 Trifilio S, Ortiz R, Pennick G, Verma A, Pi J, Stosor V et al. voriconazole should incorporate therapeutic drug monitor- Voriconazole therapeutic drug monitoring in allogeneic ing. Consideration should be given to checking drug levels hematopoietic stem cell transplant recipients. Bone Marrow in patients who are being treated with the drug for Transplant 2005; 35: 509–513. confirmed aspergillosis, and in those who develop break- 12 Pennick GJ, Clark M, Sutton DA, Rinaldi MG. Development and validation of a high-performance liquid chromatography through infections with Candida or Aspergillus species while assay for voriconazole. Antimicrob Agents Chemother 2003; 47: on the drug. 2348–2350. We conclude that voriconazole is effective at preventing 13 Siwek GT, Pfaller MA, Polgreen PM, Cobb S, Hoth P, aspergillosis. Breakthrough zygomycosis is a potential Magalheas-Silverman M et al. Incidence of invasive aspergil- problem in a small number of patients treated with losis among allogeneic hematopoietic stem cell transplant voriconazole (or itraconazole followed by voriconazole) patients receiving voriconazole prophylaxis. Diagn Microbiol for a prolonged period of time. Breakthrough infections Infect Dis 2006; 55: 209–212. with organisms susceptible to voriconazole in a dose- 14 Marr KA, Seidel K, Slavin MA, Bowden RA, Schoch HG, dependent manner may occur in patients with low trough Flowers ME et al. Prolonged fluconazole prophylaxis is levels suggesting that the role of therapeutic drug monitor- associated with persistent protection against candidiasis- related death in allogeneic marrow transplant recipients: ing needs to be explored prospectively. long-term follow-up of a randomized, placebo-controlled trial. Blood 2000; 96: 2055–2061. 15 Roden MM, Zaoutis TE, Buchanan WL, Knudsen TA, Acknowledgements Sarkisova TA, Schaufele RL et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis 2005; 41: 634–653. No financial support was received for this work. 16 Kontoyiannis DP, Lewis RE. Invasive zygomycosis: update on pathogenesis, clinical manifestations, and management. Infect Dis Clin North Am 2006; 20: 581–607. References 17 Marty FM, Cosimi LA, Baden LR. Breakthrough zygomycosis after voriconazole treatment in recipients of 1 Nucci M, Marr KA. Emerging fungal infections. Clin Infect hematopoietic stem-cell transplants. N Engl J Med 2004; 350: Dis 2005; 41: 521–526. 950–952. 2 Singh N, Paterson DL. Aspergillus Infections in transplant 18 Kontoyiannis DP, Lionakis MS, Lewis RE, Chamilos G, patients. Clin Microbiol Rev 2005; 18: 44–69. Healy M, Perego C et al. Zygomycosis in a tertiary-care cancer 3 Sullivan KM, Dykewicz CA, Longworth DL, Boeckh M, center in the era of Aspergillus-active antifungal therapy: a Baden LR, Rubin RH et al. Preventing opportunistic case–control observational study of 27 recent cases. J Infect infections after hematopoietic stem cell transplantation: The Dis 2005; 191: 1350–1360. Centers for Disease Control, Infectious Disease Society of 19 Verma A, Williams S, Trifilio S, Zembower T, Mehta J. America, and American Society for Blood and Marrow Successful treatment of concomitant pulmonary zygomycosis Transplantation Practice Guidelines and beyond. Hematology and aspergillosis with a combination of amphotericin B lipid (Am Soc Hematol Educ Program) 2001, 392–421. complex, caspofungin, and voriconazole in a patient on 4 Trifilio SM, Verma A, Mehta J. Antimicrobial prophylaxis in immunosuppression for chronic graft-versus-host disease. hematopoietic stem cell transplant recipients: heterogeneity of Bone Marrow Transplant 2004; 33: 1065–1066. current clinical practice. Bone Marrow Transplant 2004; 33: 20 Marr KA, Seidel K, White TC, Bowden RA. Candidemia in 735–739. allogeneic blood and marrow transplant recipients: evolution 5 Andes D, Forrest A, Lepak A, Nett J, Marchillo K, Lincoln L. of risk factors after the adoption of prophylactic fluconazole. 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