CLINICAL RESEARCH. Drew J. Winston, Kathy Bartoni, Mary C. Territo, Gary J. Schiller

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1 CLINICAL RESEARCH Efficacy, Safety, and Breakthrough Infections Associated with Standard Long-Term Posaconazole Antifungal Prophylaxis in Allogeneic Stem Cell Transplantation Recipients Drew J. Winston, Kathy Bartoni, Mary C. Territo, Gary J. Schiller Based on favorable results from randomized clinical trials, oral posaconazole has been approved for prophylaxis in neutropenic patients and stem cell transplantation (SCT) recipients. However, routine use of a prophylactic drug may yield different results than those from clinical trials. We collected data on the efficacy, safety, breakthrough infections, and antimicrobial resistance associated with standard long-term posaconazole prophylaxis in adult allogeneic SCTrecipients at the UCLA Medical Center. Oral posaconazole (200 mg 3 times daily) was started on day 1 after SCT and continued until day 100. After day 100, posaconazole was continued in patients who still required corticosteroids for prevention or treatment of graft-versus-host disease. From January 2007 through December 2008, 106 consecutive patients received prophylactic posaconazole. Breakthrough invasive fungal infections on posaconazole occurred in 8 patients (7.5%) within 6 months after SCT; 3 additional patients developed invasive fungal infection after discontinuation of prophylactic posaconazole. The infective organisms were Candida (8 cases), Aspergillus (2 cases), and Aspergillus plus Coccidioides immitis (1 case). There were no Zygomycetes infections. Only 2 (both Candida glabrata) of 9 infecting isolates tested were resistant to posaconazole (minimal inhibitory concentration.1 mg/ml). Mortality from invasive fungal infection occurred in 4 patients (3.7%). Except for nausea in 9 patients, no clinical adverse event or laboratory abnormality could be attributed to posaconazole. Mean peak and trough plasma posaconazole concentrations were relatively low (\400 ng/ml) in neutropenic patients with oral mucositis and other factors possibly affecting optimal absorption of posaconazole. These results demonstrate that standard long-term oral posaconazole prophylaxis after allogeneic SCT is safe and associated with few invasive mold infections. However, breakthrough infections caused by posaconazole-susceptible organisms (frequently Candida) may occur at currently recommended prophylactic doses. Thus, strategies to improve posaconazole exposure, including the use of higher doses, administration with an acidic beverage, and restriction of proton pump inhibitors, need to be considered when using prophylactic posaconazole. Biol Blood Marrow Transplant 17: (2011) Ó 2011 American Society for Blood and Marrow Transplantation KEY WORDS: Fungal infection, posaconazole prophylaxis, stem cell transplantation INTRODUCTION Invasive fungal infections can be a common cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (SCT). During the past decade, significant changes in both the epidemiology and risk factors for these infections have occurred. From the Division of Hematology-Oncology, Department of Medicine, UCLA Medical Center, Los Angeles, California. Financial disclosure: See Acknowledgments on page 513. Correspondence and reprint requests: Drew J. Winston, MD, Room CHS, Department of Medicine, UCLA Medical Center, Los Angeles, CA ( dwinston@mednet.ucla.edu). Received March 2, 2010; accepted April 30, 2010 Ó 2011 American Society for Blood and Marrow Transplantation /$36.00 doi: /j.bbmt Aspergillus, Zygomycetes, and other molds have now surpassed Candida organisms as the predominant cause of invasive fungal infections in allogeneic SCT recipients [1-3]. The majority of cases of invasive candidiasis are now caused by non-albicans species of Candida. Recent changes in transplantation practices also have greatly increased the number of transplant recipients at high risk for invasive fungal infections. The older age of many current transplant recipients, increased use of unrelated donors and cord blood (CB) as a source of stem cells, and more intense immunosuppression with high-dose corticosteroids and antithymocyte globulin to prevent or treat severe graft-versus-host disease (GVHD) have all contributed to an increased risk for invasive fungal infections [4]. At many transplant centers, invasive fungal infection is the leading cause of death from infection [5]. 507

2 508 D. J. Winston et al. Biol Blood Marrow Transplant 17: , 2011 Based on the results of randomized studies performed in the 1990s and several published guidelines, fluconazole is commonly used for antifungal prophylaxis in allogeneic SCT recipients [6-8]. However, a major limitation of fluconazole prophylaxis is the lack of activity against Aspergillus and other molds. Indeed, in several recent randomized clinical trials, azole agents active against molds (eg, itraconazole, voriconazole) were shown to be more effective than fluconazole for preventing aspergillosis in allogeneic SCT recipients [9-11]. Consequently, at the UCLA Medical Center, we have routinely used a mold-active azole for antifungal prophylaxis in all adult allogeneic SCT recipients since 2002 [12,13]. Both itraconazole and voriconazole have been effective in preventing Aspergillus infections as well as Candida infections. However, the effectiveness of oral itraconazole solution has been limited by gastrointestinal intolerance [9,10], whereas breakthrough Zygomycetes infections have been problematic in patients on long-term voriconazole prophylaxis at both the UCLA Medical Center and other transplant centers [14-16]. Posaconazole is a relatively new oral triazole agent with an enhanced spectrum of in vitro activity against a wide range of medically important fungi, including Candida, Aspergillus, the emerging Zygomycetes, and other filamentous fungi [17]. In 2 multicenter, double-blinded trials involving either allogeneic SCT patients with GVHD or nontransplantation patients with a hematologic malignancy and prolonged neutropenia, posaconazole was superior to fluconazole in preventing invasive aspergillosis and death from invasive fungal infection [18,19]. In addition, a study of the pharmacokinetics and safety of oral posaconazole in neutropenic SCT recipients showed that posaconazole is systemically available, safe, and well tolerated immediately after transplantation [20]. In view of these results and our experience with the limitations of oral itraconazole solution and voriconazole for prophylaxis, we introduced in 2007 long-term oral posaconazole as standard antifungal prophylaxis in all adult allogeneic SCT recipients at UCLA Medical Center. Prophylactic posaconazole is used both during the neutropenic period immediately after transplantation and for several months after engraftment. We report the efficacy, safety, breakthrough infections, and antimicrobial resistance associated with this routine prophylaxis with posaconazole. METHODS We collected data from 106 consecutive adult patients who received prophylactic oral posaconazole after undergoing allogeneic SCT at the UCLA Medical Center between January 1, 2007, and December 31, Data were collected for up to 6 months after transplantation. The data collection was approved by UCLA s Human Subject Protection Committee. All patients were given high-dose chemotherapy alone or with radiation therapy, followed by i.v. infusion of stem cells from a related donor or an unrelated donor. Cyclosporine alone or in combination with corticosteroids, methotrexate, or mycophenolate was used to prevent GVHD. Patients who developed GVHD were evaluated using standard criteria and treated with either corticosteroids or increased doses of their maintenance immunosuppressive drugs. After engraftment, trimethoprim-sulfamethoxazole, or atovaquone in patients intolerant of trimethoprimsulfamethoxazole, was given to prevent Pneumocystis pneumonia. Similarly, except for 34 patients participating in a study of prophylactic maribavir [21], i.v. ganciclovir (cytomegalovirus [CMV]-seropositive patient or donor) or CMV-seronegative blood products (CMVseronegative patient with a CMV-seronegative donor) was used to prevent CMV disease. Intravenous immunoglobulin was administered to patients with an unrelated or mismatched donor and to any patient aged.40 years for modification of GVHD. Patients receiving corticosteroid therapy for the prevention or treatment of GVHD and patients with severe epigastric symptoms received the proton pump inhibitor pantoprazole. Oral posaconazole suspension (200 mg 3 times daily) was administered with meals whenever possible, beginning on day 1 after SCT and continuing until day 100. After day 100, posaconazole was continued in those patients who still required corticosteroids for prevention or treatment of GVHD. If a patient could not take the oral drug, i.v. itraconazole (200 mg i.v. every 12 hours for 2 days, followed by 200 mg i.v. every 24 hours) was temporarily substituted for oral posaconazole. When i.v. itraconazole became unavailable in the United States, i.v. voriconazole (6 mg/kg i.v. every 12 hours for 1 day, followed by 4 mg/kg i.v. every 12 hours) was used as a temporary replacement for posaconazole. All patients were followed closely for the development of fungal infections. Cultures of blood and other suspected sites of fungal infection, computed tomography scans of the chest and abdomen, and blood specimens for the Aspergillus galactomannan assay (Platelia; Bio-Rad Laboratories, Redmond, WA) were obtained to evaluate patients whose clinical condition suggested the possibility of fungal infection. Based on the results of these diagnostic studies, other systemic antifungal agents were started for treatment of invasive fungal infection. Invasive fungal infections were diagnosed using the consensus criteria established by the European Organization for Research and Treatment of Cancer and the Mycoses Study Group [22]. Fungal isolates causing invasive fungal infection were tested for susceptibility to posaconazole and other

3 Biol Blood Marrow Transplant 17: , 2011 Standard Posaconazole Prophylaxis in Stem Cell Transplantation 509 antifungal agents by a microbroth dilution assay, in accordance with Clinical Laboratory Standards Institute standards [23,24]. Plasma concentrations of posaconazole were determined using a validated highperformance liquid chromatography method [25]. RESULTS Table 1 summarizes the characteristics of the 106 patients who received standard antifungal prophylaxis with posaconazole. These patients had many of the characteristics associated with high risk for invasive fugal infection after allogeneic SCT, including older age (median age, 46 years), advanced hematologic disease (56%), unrelated donor (42%), mismatched donor (20%), use of CB as the stem cell source (26%), myeloablative conditioning regimen (89%), treatment with high-dose corticosteroids (76%), and acute GVHD (agvhd; 60%). The mean duration of neutropenia was 19.6 days. 85% of the patients had oral mucositis during the period of neutropenia immediately after transplantation and before engraftment. The proton pump inhibitor pantoprazole was used in.90% of the patients. The mean duration of prophylaxis with posaconazole was 113 days (range, days). Because of severe oral mucositis or inability to take oral medication, 34 patients (32%) were temporarily changed to either i.v. itraconazole or i.v. voriconazole (mean duration, 9.6 days; range, 3-24 days). Within 6 months after transplantation, 8 of the 106 patients (7.5%) developed a breakthrough invasive fungal infection while on prophylactic posaconazole (Table 2). Three other patients had an invasive fungal infection between 53 and 66 days after completion of posaconazole prophylaxis (Table 3). These 3 patients developed infections while receiving another systemic antifungal agent. Two of these patients were restarted on antifungal prophylaxis with oral voriconazole or fluconazole by their primary physician at 2 months after discontinuation of posaconazole. Another patient with agvhd and severe renal failure was changed to prophylaxis with i.v. caspofungin when he could no longer take oral posaconazole or an i.v. azole drug. The median time of onset of the 11 invasive fungal infections was day 65 after transplantation (range, days after transplantation). Three infections occurred within 2 weeks after transplantation, before engraftment. Factors associated with breakthrough infections included neutropenia (4 cases), infected central i.v. line (3 cases), poor compliance with oral medications (2 cases), administration of posaconazole through a gastric tube (1 case), and engraftment failure (1 case). GVHD was associated with 2 of the 3 infections that occurred after discontinuation of posaconazole prophylaxis. All 11 patients with an invasive fungal Table 1. Patient Characteristics Number of patients 106 Median age, years (range) 46 (18-64) Sex, male/female, n 56/50 Underlying disease Acute leukemia 60 (57) Lymphoma 16 (15) Myelodysplastic syndrome 13 (12) Chronic myelogenous leukemia 8 (7) Aplastic anemia 6 (6) Other* 3 (3) Advanced hematologic disease 59 (56) Donor type Related 61 (58) Unrelated 45 (42) HLA matching Matched 78 (74) Mismatched 28 (26) Stem cell source Peripheral blood 60 (57) Cord blood 28 (26) Bone marrow 18 (17) Transplant type Myeloablative 93 (89) Nonmyeloablative 13 (11) Conditioning regimen Chemotherapy alone 57 (54) Radiation and chemotherapy 49 (46) GVHD prophylaxis Cyclosporine, corticosteroids, methotrexate 51 (48) Cyclosporine, mycophenolate 27 (25) Cyclosporine, methotrexate 11 (10) Cyclosporine alone 13 (12) Cyclosporine, corticosteroids, mycophenolate 2 (2) Tacrolimus, methotrexate, or mycophenolate 2 (2) Mean duration of neutropenia (neutrophil count 19.6 (2-117) <500 cells/mm 3 ), days (range) Oral mucositis during neutropenia 90 (85) Acute GVHD None (grade 0-I) 42 (40) Yes (grade II-IV) 64 (60) Chronic GVHD None 82 (77) Yes 24 (23) Corticosteroids for prevention or treatment of GVHD 81 (76) CMV disease 1 (0.9) GVHD indicates graft-versus-host disease. Data are n (%) of patients unless specified otherwise. *Plasma cell leukemia, chronic lymphocytic leukemia, and histiocytic sarcoma. infection were receiving the proton pump inhibitor pantoprazole at the time of the infection, and 8 of these 11 patients had concurrent oral mucositis or diarrhea. Candida species were the most common organisms causing invasive fungal infection (8 cases), followed by Aspergillus species alone (2 cases) and Aspergillus species plus Coccidioides immitis (1 case) (Table 3). There were no cases of zygomycosis. Of note, only 2 of the 9 infecting isolates tested for susceptibility were resistant to posaconazole (minimum inhibitory concentration [MIC].1.0 mg/ml). Both of these resistant isolates were Candida glabrata. Caspofungin alone was used to treat the Candida infections, whereas either caspofungin plus voriconazole or amphotericin B lipid complex alone was used to treat the Aspergillus infections. Four of the 11 infections were classified as fatal. Two patients with candidemia complicating severe

4 510 D. J. Winston et al. Biol Blood Marrow Transplant 17: , 2011 Table 2. Clinical Characteristics of SCT Patients with Breakthrough Invasive Fungal Infection While Receiving Prophylactic Posaconazole MIC (mg/ml) of Conditions at Time of Infection Proton Pump Inhibitor Other Oral Mucositis Diarrhea Outcome from Fungal Infection Day of Infection* POS FLU ITRA VOR CASPO AMPHO Therapy Site of Infection Patient Organism 1 Candida glabrata Blood CASPO Survived Yes Yes POS given through gastric tube Fatal Yes Yes Neutropenia CASPO, VOR, ABLC >64 Lung Aspergillus niger, Coccidioides immitis 3 Aspergillus spp Lung 7 ABLC Survived Yes Neutropenia 4 Candida albicans Blood 37 #0.015 #0.12 # CASPO Survived Yes Yes Yes Poor compliance with all medications 5 Candida glabrata Blood 69 4 > CASPO Survived Yes Yes Line-related infection 6 Candida albicans Blood 2 # # CASPO Survived Yes Yes Neutropenia; line-related infection 7 Candida glabrata Blood 45 2 > CASPO Survived Yes Yes Poor compliance with all medications; line-related infection. 8 Aspergillus spp Lung 117 CASPO, VOR Fatal Yes Prolonged neutropenia due to engraftment failure POS indicates posaconazole; FLU, fluconazole; ITRA, itraconazole; VOR, voriconazole; CASPO, caspofungin; AMPHO, amphotericin;, not available; ABLC, amphotericin B lipid complex. *Day post-sct on which infection was diagnosed. GVHD were not treated for their fungal infection, as medical care was withdrawn because of the poor prognosis of their GVHD. Because previous studies of prophylactic oral posaconazole in patients with neutropenia and patients with GVHD demonstrated efficacy at a dose of 200 mg 3 times daily, and a plasma concentration target for prophylactic efficacy had not yet been established [18,19], we initially did not monitor plasma posaconazole levels in our patients. However, after several patients developed breakthrough infections caused by posaconazole-susceptible organisms, we measured both peak and trough plasma posaconazole concentrations on days 2, 8, and 15 after transplantation in 15, 14, and 10 neutropenic patients, respectively. The clinical characteristics of the 19 patients with plasma posaconazole levels included underlying diseases of acute leukemia (9 patients), myelodysplastic syndrome (5 patients), chronic myelogenous leukemia (3 patients), and lymphoma (2 patients); advanced hematologic disease (10 patients); a conditioning regimen of chemotherapy alone (14 patients) or radiation plus chemotherapy (5 patients); oral mucositis (15 patients); diarrhea (9 patients); and use of pantoprazole (16 patients). The respective mean peak and trough plasma posaconazole levels were 168 ng/ml and 121 ng/ml on day 2 posttransplantation, 306 ng/ml and 276 ng/ml on day 8, and 257 ng/ml and 211 ng/ ml on day 15. Three of the 19 patients in whom plasma posaconazole levels were measured developed an invasive fungal infection. One of these fungal infections (Aspergillus pneumonia) occurred during posaconazole therapy, whereas the other 2 infections (candidemia) occurred after discontinuation of posaconazole. Plasma posaconazole levels in the patients who subsequently developed invasive fungal infections were similar to those levels in patients who did not develop an invasive fungal infection. Generally, oral posaconazole was well tolerated. Except for nausea in 9 patients, we were unable to attribute any adverse clinical event or laboratory abnormality to posaconazole. Two of the 9 patients with nausea temporarily stopped taking posaconazole, but later resumed their antifungal prophylaxis with no further drug-related adverse events. Similarly, posaconazole was temporarily discontinued in 4 patients who developed abnormally elevated serum bilirubin or hepatic enzyme levels. However, in each of these cases, the elevated level could be attributed to other causes (ie, veno-occlusive disease or GVHD), and prophylactic posaconazole was resumed with no further deterioration of hepatic function. At 6 months posttransplantation, overall patient survival was 65%, and fungal-free survival (ie, freedom from invasive fungal infection or death) was 62%. Causes of death are summarized in Table 4. Relapse of malignancy, GVHD, and infection were the most

5 Biol Blood Marrow Transplant 17: , 2011 Standard Posaconazole Prophylaxis in Stem Cell Transplantation 511 Table 3. Clinical Characteristics of SCT Patients with Invasive Fungal Infection after Discontinuation of Prophylactic Posaconazole MIC (mg/ml) of Conditions at Time of Infection Proton Pump Inhibitor Other Oral Mucositis Diarrhea Outcome from Fungal Infection Antifungal on Which Infection Occurred POS FLU ITRA VOR CASPO AMPHO Therapy Days after POS Stopped Day of Infection* Site of Infection Patient Organism 1 Candida tropicalis Blood Oral VOR < # CASPO Survived Yes Yes Line-related infection 2 Candida parapsilosis Blood CASPO < #0.03 # None Fatal Yes Yes Severe acute GVHD; care withdrawn 3 Candida lusitaniae Blood Oral FLU < #0.03 # None Fatal Yes Chronic GVHD; care withdrawn POS indicates posaconazole; FLU, fluconazole; ITRA, itraconazole; VOR, voriconazole; CASPO, caspofungin; AMPHO, amphotericin. *Day post-sct on which infection was diagnosed. Table 4. Causes of Death Number of patients 106 Number of deaths, n (%) 37 (35) Relapse of malignancy, n 12 Toxicity of chemotherapy, n 5 GVHD, n 4 Infection, n 8 Bacterial sepsis 4 Invasive fungal infection 2 Invasive fungal infection, bacterial sepsis, GVHD 1 Invasive fungal infection, viral pneumonia, GVHD 1 Idiopathic interstitial pneumonia 3 Other* 5 *Thrombotic thrombocytopenia purpura, n 5 2; hemorrhage, n 5 1; transfusion reaction, n 5 1; myocardial infarction, n 5 1. common causes of death. Four deaths were associated with invasive fungal infection (Aspergillus pneumonia, Aspergillus plus Coccidioides pneumonia, and 2 cases of candidemia) among the 106 patients (3.7%). However, the 2 patients with candidemia were not treated for their infection, as medical care was withdrawn because of the poor prognosis of their GVHD plus other infectious complications. DISCUSSION Although debate is ongoing regarding the optimal approach to the prevention of invasive fungal infections in allogeneic SCT recipients [26,27], recent guidelines and consensus statements support the use of prophylactic antifungal agents in these patients [4,28,29]. In addition, the unique experiences of each local transplant center must be considered when designing effective strategies for reducing morbidity and mortality from invasive fungal infections. For many years, antifungal prophylaxis with fluconazole was the standard at most transplant centers [6-8]. However, with the emergence of Aspergillus and other molds as the most common causes of invasive fungal infections after allogeneic SCT, and with increasing number of high-risk patients undergoing transplantation, fluconazole is now being replaced with a mold-active agent for prophylaxis at many transplant centers [4,26,28]. At the UCLA Medical Center, in both randomized controlled trials and in routine clinical practice, we have found that prophylaxis with a mold-active azole is more effective than fluconazole for preventing invasive fungal infections after allogeneic SCT [9,12,13]. Before the use of a mold-active azole became routine practice, the incidence of invasive aspergillosis in allogeneic SCT patients at UCLA was approximately 15%; this dropped to \5% after the introduction of mold-active prophylactic agents [12,13]. Because so many of the allogeneic SCT recipients at UCLA either receive high doses of corticosteroids early after transplantation for prevention of GVHD or receive an unrelated umbilical CB transplant with delayed

6 512 D. J. Winston et al. Biol Blood Marrow Transplant 17: , 2011 engraftment, we start mold-active azole prophylaxis on day 1 after transplantation and continue prophylaxis until day 100. After day 100, patients are maintained on a mold-active azole if they are still receiving corticosteroids for prevention or treatment of GVHD. A similar strategy is followed by other transplant centers [4,10,30]. Itraconazole, administered either i.v. or as an oral solution, was initially used successfully at UCLA to prevent aspergillosis and other invasive fungal infections [12,13]. However, because of gastrointestinal intolerance of the oral itraconazole solution and the subsequent nonavailability of i.v. itraconazole in the United States, oral and i.v. voriconazole briefly replaced itraconazole for prophylaxis in many of our allogeneic SCT patients. Unfortunately, similar to the experience at other oncology centers [14-16], we observed for the first time at UCLA the emergence of Zygomycetes infections in patients who had been on long-term voriconazole. For reasons of cost and lack of an oral formulation, we have not used an echinocandin for antifungal prophylaxis [31]. We began using prophylactic posaconazole in all of our allogeneic SCT patients in 2007, after posaconazole had been shown to be more effective than fluconazole in preventing invasive fungal infections in randomized controlled trials and had been approved for antifungal prophylaxis in both neutropenic patients and SCT patients [18,19]. As we report here, the incidence of breakthrough invasive fungal infections within the first 6 months after transplantation in allogeneic SCT patients on standard prophylactic posaconazole at UCLA was 7.5%. This incidence is somewhat higher than the 2%-5.3% incidences of invasive fungal infections reported in previous randomized clinical trials of prophylactic posaconazole [18,19], but is comparable to those reported in trials of prophylactic itraconazole (7%-9%) and prophylactic voriconazole (6.6%) after allogeneic SCT [9-11]. The higher incidence of invasive fungal infections in our UCLA patients on standard long-term prophylactic posaconazole might be explained by the longer follow-up of our patients, as well as by patient selection factors in the clinical trials that were not applicable to our routine use of posaconazole in all patients. Similar patient selection factors, as well as differences in the types of patients undergoing transplantation, also might explain the higher 6-month mortality rate in our patients (35%) compared with the rates reported in clinical trials of prophylactic posaconazole (25%) and prophylactic voriconizole (20%) after allogeneic SCT [11,18]. A well-controlled randomized trial comparing posaconazole with voriconazole for antifungal prophylaxis might be useful to address the relative efficacy of these two agents, especially in preventing breakthrough infections by Zygomycetes. We did not find any cases of zygomycosis in this retrospective study of UCLA patients on prophylactic posaconazole, but the incidence of zygomycosis may vary among transplant centers. Furthermore, despite posaconazole s superior in vitro activity for Zygomycetes species compared with other azole antifungal agents, 2 cases of beakthrough zygomycosis have been reported recently in allogeneic SCT recipients receiving prophylactic posaconazole [32,33]. Candida species were the most common organisms causing breakthrough infections in our patients both during and after discontinuation of posaconazole prophylaxis (Tables 2 and 3). In contrast, only 3 of our 106 patients (2.8%) developed invasive aspergillosis, and none had Zygomycetes infection. Only 2 of the 9 organisms causing infection and tested for susceptibility were found to be resistant to posaconazole (MIC.1.0 mg/ ml). Both resistant isolates were Candida glabrata organisms. In the 2 previous clinical trials of prophylactic posaconazole, Candida glabrata was also the colonizing species that most frequently exhibited decreased susceptibility to posaconazole and caused breakthrough infection [34]. Generally, there was concordance in these 2 trials between the colonizing Candida species in the gastrointestinal tract and the species causing invasive infection, suggesting that the route of infection was translocation of Candida species across gastrointestinal mucosal surfaces damaged by cytotoxic chemotherapy or GVHD. Similarly, although 4 of the 8 cases of candidemia in our study were clearly related to a central i.v. catheter infected with the same Candida species as the blood isolate (Tables 2 and 3), the other 4 cases of candidemia were associated with oral mucositis, diarrhea, and/or GVHD and thus were likely related to the transit of colonizing organisms across damaged mucosal surfaces. The occurrence of breakthrough invasive fungal infections caused by organisms still susceptible to posaconazole in several of our patients suggests that these patients may have had an inadequate plasma posaconazole concentration for effective prophylaxis. When we started using standard prophylactic posaconazole in 2007, pharmacokinetic analyses in the patients participating in the trials of prophylactic posaconazole during neutropenia and after SCT suggested no need for adjustment of posaconazole dosage based on variables that could affect absorption [35,36]. Furthermore, a plasma posaconazole concentration for prophylactic efficacy had not yet been established, although a study of posaconazole salvage therapy for invasive aspergillosis had suggested a relationship between posaconazole concentration and response rate [37]. Consequently, we initially did not perform therapeutic drug monitoring. More recent pharmacokinetic studies in both healthy volunteers and patients have suggested that poor nutritional status, higher gastric ph, increased gastrointestinal motility, oral mucositis, and the use of

7 Biol Blood Marrow Transplant 17: , 2011 Standard Posaconazole Prophylaxis in Stem Cell Transplantation 513 proton pump inhibitors may adversely affect the absorption of posaconazole [30,38,39]. Many of these factors were operative in our UCLA patients receiving standard long-term prophylactic posaconazole (Tables 2 and 3) and could have contributed to relatively lower plasma levels of posaconazole and subsequent breakthrough infections. Of note, one of our patients (patient 1; Table 2) developed breakthrough candidemia while receiving posaconazole administered through a gastric tube. Lower plasma posaconazole concentrations have been reported in healthy volunteers receiving posaconazole via a nasogastric tube [40]. The development of several breakthrough invasive fungal infections by posaconazole-susceptible organisms eventually prompted us to measure plasma posaconazole concentrations. Because of financial issues related to the cost of frequent plasma posaconazole measurements, we confined our therapeutic drug monitoring to the neutropenic period immediately after transplantation. Neutropenic allogeneic SCT recipients experience many adverse events that could potentially affect the absorption of posaconazole, yet there are limited data on plasma posaconazole concentrations in these patients. Indeed, we found mean peak and trough plasma posaconazole levels of \400 ng/ml in our patients, lower than the levels reported in the 2 previous clinical trials of prophylactic posaconazole [18,19,35,36]. Similar low plasma posaconazole levels during routine use of posaconazole at recommended doses have been noted by other investigators [41]. Consequently, in an effort to improve the prophylactic efficacy of posaconazole in our patients, we now administer prophylactic posaconazole at a higher dose (400 mg orally twice daily) in combination with an acidic beverage as well as meals [39]. Mean steady-state peak and trough plasma posaconazole concentrations at day 15 after transplantation have been higher (543 ng/ml and 410 ng/nl, respectively) in our patients receiving posaconazole according to this amended protocol. Although a higher mean plasma posaconazole level (958 ng/ml) has been reported in SCT recipients with agvhd receiving posaconazole at a dose of 200 mg 3 times a day [18,36], we continue to administer the higher dose of prophylactic posaconazole (400 mg twice daily) with an acidic beverage and meals to our patients after engraftment, to maximize posaconazole exposure. This higher dose of posaconazole has been well tolerated, but requires further evaluation in additional pharmacokinetic studies. The development of an i.v. posaconazole formulation also would likely facilitate the achievement of effective posaconazole concentrations for prophylaxis. Except for nausea in a few patients, posaconazole was well tolerated. There were no hepatotoxicity or other laboratory abnormalities that we could attribute to posaconazole. Because of a previous report describing increased toxicities associated with the administration of azole antifungal agents and certain cytotoxic chemotherapeutic agents [42], we do not administer prophylactic posaconazole during pretransplantation conditioning therapy. In summary, our experience using posaconazole for standard antifungal prophylaxis in allogeneic SCT recipients demonstrates that the drug is safe and generally well tolerated. Standard posaconazole prophylaxis at UCLA is associated with very few invasive Aspergillus infections and no apparent Zygomycetes infections. However, breakthrough fungal infections caused by posaconazole-susceptible organisms may occur when posaconazole is used at currently recommended prophylactic doses (200 mg orally 3 times daily) in patients with factors that may adversely affect absorption of the drug. Thus, strategies to improve posaconazole exposure, including the use of higher doses, administration with an acid beverage as well as a meal or nutritional supplement, and restricting the use of proton pump inhibitors, should be strongly considered. Although the relationship between therapeutic drug monitoring with prophylactic posaconazole and improved clinical outcomes requires further study, measurement of plasma posaconazole concentrations also should be considered in patients with conditions that could seriously impair effective absorption of the drug. An i.v. formulation of posaconazole is needed to overcome some of the limitations of prophylaxis with oral posaconazole. Finally, antifungal strategies using other mold-active agents as either prophylaxis or preemptive therapy based on results of serum galactomannan assays and chest computed tomography scan in high-risk patients have been used successfully in SCT patients at other institutions [11,27,31,43], and these options should be considered if the use of prophylactic posaconazole is not suitable. ACKNOWLEDGMENTS The authors thank Katherine Meneses for her assistance with data collection. Financial disclosure: Drew J. Winston has been a consultant for Schering Plough and serves on a Merck scientific advisory board. The remaining authors have no conflicts of interest. REFERENCES 1. Pagano L, Caira M, Nosari A, et al. Fungal infections in recipients of hematopoietic stem cell transplants: results of the SEIFEM B-2004 study (Sorveglianza Epidemiologica Infezioni Fungine Nelle Emopatie Maligne). Clin Infect Dis. 2007;45: Garcia-Vidal C, Upton A, Kirby KA, et al. 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