Superiority of voriconazole over amphotericin B in the treatment of invasive aspergillosis after heart transplantation.

Invasive aspergillosis in immuncompromised patients occurs frequently. Surgical therapy in combination with chemotherapy with amphotericin B and itraconazole is standard therapy. We describe a heart transplant recipient with invasive Aspergillus fumigatus infection in the lung, which was treated successfully with voriconazole after systemically high-dose intravenous therapy with amphotericin B failed.     

Voriconazole Prophylaxis in Lung Transplant Recipients

Lung transplant recipients have one of the highest rates of invasive aspergillosis (IA) in solid organ transplantation. We used a single center, nonrandomized, retrospective, sequential study design to evaluate fungal infection rates in lung transplant recipients who were managed with either universal prophylaxis with voriconazole (n = 65) or targeted prophylaxis (n = 30) with itraconazole ± inhaled amphotericin in patients at high risk (pre- or posttransplant Aspergillus colonization [except Aspergillus niger ]). The rate of IA at 1 year was better in lung transplant recipients receiving voriconazole prophylaxis as compared to the cohort managed with targeted prophylaxis (1.5% vs. 23%; p = 0.001). Twenty-nine percent of cases in the targeted prophylaxis group were in patients colonized with A. niger who did not receive itraconazole. A threefold or higher increase in liver enzymes was noted in 37–60% of patients receiving voriconazole prophylaxis as compared to 15–41% of patients in the targeted prophylaxis cohort. Fourteen percent in the voriconazole group as compared to 8% in the targeted prophylaxis group had to discontinue antifungal medications due to side effects. Voriconazole prophylaxis can be used in preventing IA in lung transplant recipients. Regular monitoring of liver enzymes and serum concentrations of calcineurin inhibitors are required to avoid hepatotoxicity and nephrotoxicity.     

Voriconazole and itraconazole in lung transplant recipients receiving tacrolimus (FK 506): efficacy and drug interaction

Kramer MR, Amital A, Fuks L, Shitrit D. Voriconazole and itraconazole in lung transplant recipients receiving tacrolimus (FK 506): efficacy and drug interaction.
Clin Transplant 2011: 25: E163–E167. © 2010 John Wiley & Sons A/S. Abstract: Background: The aim of this study was to compare the extent of interaction between tacrolimus and itraconazole vs. voriconazole. Patients and methods: This retrospective study included 60 lung transplant recipients who were treated with a tacrolimus‐based regimen; 40 received prophylactic itraconazole for the first six months following lung transplantation (LTX), and 20 were treated with voriconazole. All patients had at least 12 months of follow‐up. Tacrolimus levels and dosage requirements were compared during and after azole therapy. We assessed the rejection rate, fungal infection rate, and renal function during the study period. Results: The mean tacrolimus dose during itraconazole treatment was 3.26 ± 2.1 mg/d compared with 5.74 ± 2.9 mg/d after itraconazole was stopped, p < 0.0001. Similarly, the mean tacrolimus dose during voricnoazole treatment was 1.75 ± 0.9 mg/d compared with 4.85 ± 0.38 mg/d after voriconazole was stopped (p = 0.002). Thus, the mean increase in the total daily dose of tacrolimus after itraconazole and voriconazole withdrawal was 76% and 64%, respectively. No differences in the rejection or fungal infection rates or renal toxicity were observed during the study period, although an increase in positive fungal isolates was noted during itraconazole therapy. Conclusion: The tacrolimus dose was reduced more with itraconazole than with voriconazole, without an increase in the rejection rate and with renal function preservation.     

Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study

BACKGROUND.: The efficacy of the combination of voriconazole and caspofungin when used as primary therapy for invasive aspergillosis in organ transplant recipients has not been defined. METHODS.: Transplant recipients who received voriconazole and caspofungin (n=40) as primary therapy for invasive aspergillosis (proven or probable) in a prospective multicenter study between 2003 and 2005 were compared to a control group comprising a cohort of consecutive transplant recipients between 1999 and 2002 who had received a lipid formulation of AmB as primary therapy (n=47). In vitro antifungal testing of Aspergillus isolates to combination therapy was correlated with clinical outcome. RESULTS.: Survival at 90 days was 67.5% (27/40) in the cases, and 51% (24/47) in the control group (HR 0.58, 95% CI, 0.30-1.14, P=0.117). However, in transplant recipients with renal failure (adjusted HR 0.32, 95% CI: 0.12-0.85, P=0.022), and in those with A. fumigatus infection (adjusted HR 0.37, 95% CI: 0.16-0.84, P=0.019), combination therapy was independently associated with an improved 90-day survival in multivariate analysis. No correlation was found between in vitro antifungal interactions of the Aspergillus isolates to the combination of voriconazole and caspofungin and clinical outcome. CONCLUSIONS.: Combination of voriconazole and caspofungin might be considered preferable therapy for subsets of organ transplant recipients with invasive aspergillosis, such as those with renal failure or A. fumigatus infection.     

伏立康唑在造血干细胞移植所致真菌感染二级预防中的应用

目的探讨伏立康唑对造血干细胞移植所致真菌感染二级预防的作用。方法收集北京军区总医院血液科2007年1月以来收治的造血干细胞移植患者160例,分为伏立康唑注射液组（治疗组）和氟康唑口服组（对照组）,每组各80例,观察两组患者造血干细胞移植后发生真菌感染的情况。结果治疗组经过伏立康唑注射液二级预防,移植后3个月内共发生真菌感染者6例,发生率为7.5%（6/80）;对照组80例中发生真菌感染者16例,发生率为20%（16/80）,治疗组移植后真菌感染发生率显著低于对照组,差异具有统计学意义（P〈0.05）。结论伏立康唑的二级预防能显著降低移植后真菌感染的发生率,疗效确切、应用安全。     

Salvage therapy with voriconazole for invasive fungal infections in patients failing or intolerant to standard antifungal therapy

BACKGROUND: Invasive fungal infections (IFI), particularly those caused by Aspergillus and other angioinvasive molds, are associated with an excessive mortality despite therapy. METHODS: Voriconazole was prescribed on a compassionate basis to patients with IFI who were intolerant to or who had progressed despite standard therapy. Outcome was determined by protocol-based criteria as established by the consensus definitions (complete response [CR], partial response [PR], stable disease, failure, and intolerance). RESULTS: Forty-five patients were enrolled in a compassionate release program (29 [64%] because of failure of response to standard therapy), between 1998 and 2002. Of the 45 patients enrolled, 35 (78%) had invasive Aspergillus, 3 (7%) had Fusarium, and 2 (4%) had Scedosporium infections. Underlying illnesses were as follows: 13 (29%) solid-organ transplant (SOT), 11 (24%) BMT, and 7 (13%) hematologic malignancy. Site of infection was as follows: 26 (58%) pulmonary, 9 (20%) disseminated, 5 (11%) central nervous system (CNS), and 3 (7%) sinus. Overall response rates were as follows: 9 (20%) CR, 17 (38%) PR, 15 (33%) failure, and 4 (9%) intolerant. Seven of the eight (88%) patients with sinus or CNS disease demonstrated stabilization of the IFI. The median duration of voriconazole therapy was 79 days with 9 (20%) patients receiving over 1 year of therapy. Nine thousand one hundred twenty-eight days of therapy were given with only four serious adverse events in two cases considered possibly or probably drug related. CONCLUSIONS: In this population of severely immunocompromised patients with life-threatening IFI who have failed or were intolerant to standard antifungal therapy, voriconazole demonstrated substantial efficacy and an acceptable level of toxicity.     

Fungal infections in transplant recipients receiving alemtuzumab

Recently, we have used an anti-T-cell agent, alemtuzumab, as induction or conversion therapy to achieve a calcineurin (CNI) and steroid-free immunosuppressive regimen. We identified recipients who developed systemic fungal infections after the initiation of alemtuzumab and looked at their outcomes. The study population consisted of all pancreas transplant recipients who received alemtuzumab. Only invasive fungal infections were included in the analysis (eg, fungemia, meningitis, or pneumonia; fungal urinary tract infections were excluded). The organism was confirmed by culture, histopathology, or latex antigen test. Between February 2003 and February 2004, a total of 121 pancreas transplant recipients received alemtuzumab-56 as part of induction, and 65 as part of conversion. Of these, 8 (6.6%) developed an invasive fungal infection; 2 (3.6%) recipients as part of induction therapy and 6 (9.2%) as part of conversion therapy. Mean recipient age was 42.1 years. The mean length of time from alemtuzumab administration (first dose) to the diagnosis of the fungal infection was 115.9 days (range 5 to 318). The organisms identified initially were: Cryptococcus, Histoplasma, Aspergillus, and Candida. Overall, 3 (38%) of the eight patients died during ongoing treatment of their fungal infection: two from sepsis, one due to myocardial infarction. The other five recipients were treated successfully and have functioning grafts. The initial therapeutic agents used included: amphotericin B/liposomal AMB (n = 6), voriconazole (n = 3), capsofungin (n = 2), and fluconazole (n = 1). The use of alemtuzumab as induction or conversion therapy in pancreas transplant recipients may predispose patients to the development of systemic fungal infections. It would be important to determine what the most appropriate prophylaxis regimen would be for these patients.     

Pulmonary Aspergillosis in Solid Organ Transplant Patients: A Report From Iran

Background

Aspergillosis is one of the most important opportunistic infections after organ transplantation. Early diagnosis and initiation of appropriate antifungal therapy are key factors for better prognosis.

Methods

We reviewed the medical records of patients with solid organ transplantation with evidence of Aspergillus infections from December 2001 to January 2008, evaluating patient demographics, time of onset after transplantation, risk factors, radiologic appearance, diagnostic criteria, antifungal therapy, and outcome.

Results

We observed aspergillosis in 8 lung, 3 kidney, and 1 heart recipient, with overall mean age of 40.6 years. Seven cases of Aspergillus tracheobronchitis were diagnosed in lung transplant recipients, all of them in the first 6 months after transplantation. All patients responded to antifungal therapy and bronchoscopic debridement. We observed 5 cases of invasive pulmonary aspergillosis. Three patients survived in response to antifungal treatment. The two patients who died were treated with a combination of itraconazole and amphotericin B, whereas all cured patients had been treated with voriconazole alone or in combination with caspofungin.

Conclusion

It seems that the prognosis of aspergillosis in solid organ recipients is improving with new treatment regimens, particularly if they are used in early stages of infection.     

Failure of voriconazole therapy due to acquired azole resistance in Aspergillus fumigatus in a kidney transplant recipient with chronic necrotizing aspergillosis

Invasive aspergillosis (IA) affects the lungs and disseminates mostly in patients with neutropenia and/or patients who are receiving immunosuppressive and steroid therapies. Despite progress in the diagnosis of and therapy for IA, it is still characterized by a high mortality rate. Currently, voriconazole is considered as the standard therapy for IA. Over recent years, triazole‐resistant Aspergillus fumigatus isolates have emerged in the environment due to the use of fungicidal agricultural products, with the risk of developing IA related to a resistant isolate. However, resistance may also develop in patients who are undergoing long‐term triazole therapy, particularly in the setting of chronic forms of pulmonary aspergillosis. Herein we describe a kidney transplant recipient who failed to respond to voriconazole therapy due to acquired resistance secondary to the appearance of a de novo mutation (Y121F) in the cyp51A gene during chronic necrotizing pulmonary aspergillosis. The infecting isolate acquired voriconazole resistance in 8 months despite plasma concentrations within the recommended range of the drug, necessitating lobectomy in association with a new antifungal strategy consisting of liposomal amphotericin and caspofungin with a good outcome over 36 months.     

Invasive aspergillosis in the recipients of liver retransplantation.

Retransplantation is a major risk factor for invasive aspergillosis in liver transplant recipients. However, the risk for invasive aspergillosis with time elapsed since retransplantation, clinical characteristics, and outcome of patients who develop this infection after retransplantation of the liver has not been defined. Patients comprised 17 liver retransplant recipients with invasive aspergillosis between 1990 and 2004. Retransplantation was considered early if it was performed within 30 days and late if performed after 30 days of the first or primary transplant. Retransplant recipients comprised 25% of all cases of invasive aspergillosis after liver transplantation. Fifty-three percent of the Aspergillus infections occurred within 30 days, and 76% within 90 days of retransplantation. In all, 53% (9/17) of the patients were late retransplant recipients. Late compared to early retransplant recipients with invasive aspergillosis were more likely to have central nervous system involvement with invasive aspergillosis (56% vs. 0%, P = 0.03). Mortality rate was 100% for late and 63% for early retransplant recipients with Aspergillus infections. In conclusion, time-varying risk for invasive aspergillosis after retransplantation has implications relevant for guiding antifungal prophylaxis. Given a greater risk for disseminated infection and poor outcome in late retransplant recipients with aspergillosis, potent and aggressive antifungal therapy should be considered upfront in these patients.     

Isolated Acute Appendicitis Caused by Aspergillus in a Patient Who Underwent Lung Transplantation: A Case Report

Invasive aspergillosis is an important cause of morbidity and mortality in patients who have undergone lung transplantation. Aspergillus infections usually involve the respiratory tract, with vascular invasion and subsequent dissemination. However, acute appendicitis associated with localized aspergillosis is rare, especially among patients who have undergone prophylaxis with voriconazole. We present a case of primary Aspergillus appendicitis diagnosed by histologic examination in a patient who underwent lung transplantation. A 51-year-old woman with dermatomyositis underwent lung transplantation for acute interstitial pneumonitis. According to our institution's protocol, the patient was treated with immunosuppressive therapy and prophylaxis with voriconazole, ganciclovir, and trimethoprim sulfamethoxazole during the post-transplantation period. Twenty-eight days after transplantation, the patient developed mild abdominal pain and paralytic ileus. There was no apparent infection sign. Abdominal computerized tomography indicated a wall defect of the appendix with multifocal fluid collection, mesenteric leave thickening, and pneumoperitoneum. These findings were consistent with perforated appendicitis, and the patient underwent an appendectomy. The histopathology examination of the resected appendix showed inflammation and abscess. Periodic acid–Schiff–positive and Grocott-Gomori methenamine silver–positive fungal hyphae with acute-angle branching were observed, demonstrating muscular invasion. A galactomannan antigen test obtained on the same day had negative results. The trough level of voriconazole was well maintained and was subsequently adjusted through monitoring of circulating drug concentration. Simultaneously, other potential sites of disseminated Aspergillus were considered and examined, but no other site of systemic Aspergillus infection was detected. Voriconazole treatment was maintained for 3 months, and no aspergillosis relapse or other invasive fungal infections were observed.     

Control of early Aspergillus mortality after lung transplantation: outcome and risk factors

Historic treatment strategies in our institute had resulted in 10% Aspergillus mortality within the first posttransplant year. Despite nebulized amphotericin B (nAmB) prophylaxis, a significant incidence of Aspergillus infection, usually with poor outcome, is still reported. The aim of this single-center retrospective study was to evaluate the outcomes of patients receiving either standard nAmB or additional systemic caspofungin prophylaxis for selected high-risk patients. We also tried to define independent risk factors for either fungal infection or death. We followed 76 consecutive lung transplant patients performed at our center between 2002 and 2010 from the day of transplantation. The median follow-up duration was 953 days (2.6 years; range, 16-2,751 days). The endpoints were postoperative Aspergillus colonization or disease or death due to any cause. All patients received either nAmB deoxycholate (nAmBd, 15 patients) or nAmB lipid complex (nAmBLC, 61 patients). In addition, 33 patients also received short-term caspofungin prophylaxis. The overall cumulative mortality during the entire follow up was 14.5%. No clinically confirmed invasive Aspergillus infections (IPA) occurred during the first 2 postoperative years; however, there was 1 possible and 1 probable IPA. One patient died of bronchiolitis obliterans and IPA at 2 years 3 months. Twelve patients showed transient Aspergillus colonization. The antifungal prophylactic regimens were well tolerated. The risk factors for death were age >55 years and postoperative Aspergillus detection (P = .011 and P = .015, respectively). Preoperative Aspergillus colonization/disease was not a risk factor for death (P = 1.000). The strongest predictor of death was age >55 years, due to the elder probably being more susceptible to the adverse effects of immunosuppressants. Postoperative detection of Aspergillus still seems to be an indicator of a poorer outcome. Preoperative Aspergillus colonization is not necessarily a threat with prompt institution of antifungal prophylaxis.     

Lung nodular lesions in heart transplant recipients.

To describe the characteristics and etiology of lung nodules after heart transplantation (HT).During a 6-year period 147 patients received HT and 130 survived more than 1 week. Nodular lesions were demonstrated after HT in 13 patients (10%).Median age was 53 years, and all patients were male. Nodules were detected 23 to 158 days after HT (median, 66 days). An etiologic diagnosis was made in all but 1 case: Aspergillus (5), Nocardia-Rhodococcus (4), and cytomegalovirus (CMV) (3). Previous severe infection was present in 50% of the patients and rejection in 33% (75% with nocardiosis). Initially all patients with Nocardia but only 1 patient with aspergillosis were asymptomatic. The most common symptoms were fever (67%) and cough (50%). Central nervous system (CNS) involvement appeared in only one Aspergillus-infected patient. An average of 1.8 diagnostic procedures per patient were performed. Median time to establish a diagnosis was 8 days (0 to 24). Median hospital stay was 36 days and reached 60 in patients with Aspergillus. No patient died, although aspergillosis, which must be suspected in the presence of dyspnea, pleuritic pain, and CNS symptoms, caused the highest morbidity. Overall diagnostic yield was 60% for transtracheal aspiration, 70% for bronchoalveolar lavage, and 75% for transthoracic aspiration.Ten percent of HT patients developed lung nodules that were mainly caused by Aspergillus, Nocardia, and CMV. The time of appearance and some clinical manifestations may suggest the etiology and may help in the empirical treatment.     

构巢曲霉致肺曲霉病患者二例临床特征和病原学分析

目的探讨构巢曲霉致肺曲霉病的临床及病原学特点。 方法收集首都医科大学宣武医院2017年1月2例住院慢性阻塞性肺疾病患者的病例信息,分析患者的临床资料和实验室对病原菌的分离鉴定并复习相关文献。 结果两例患者均有慢性阻塞性肺部疾病史及多种基础疾病,临床表现为发热、咳嗽、喘息等,胸部影像学显示肺部斑片状高密度影;实验室检测G试验和GM试验均为阳性;痰液直接涂片镜检可见隔菌丝,分支45°角,分离菌经质谱和测序分析确定为构巢曲霉。临床根据病原学结果改用伏立康唑治疗后患者症状及体征好转出院。 结论构巢曲霉致肺曲霉病相对少见,病原学诊断对临床早期有效治疗肺曲霉病很重要。     

Induction immunosuppression for lung transplantation with OKT3

BACKGROUND: The use of OKT3, an anti-CD3 monoclonal antibody, for immunosuppressive therapy for lung transplantation has been restricted because of concerns regarding infectious risk and cardiopulmonary instability after its administration. METHODS: Fifty-two patients received OKT3 (5 mg/d intravenously for 10 days) for induction of immunosuppressive therapy, along with azathioprine (1.5 mg x kg(-1) x d(-1) intravenously) and enteral cyclosporine (12 mg x kg(-1) x d(-1)). Maintenance steroid therapy was begun on postoperative day 8. Prophylactic antifungal therapy (fluconazole or amphotericin B) and ganciclovir was used in all patients. Serial transbronchial biopsy and measurements of pulmonary function were used to assess patients for evidence of infection or rejection. Cytomegalovirus infection was diagnosed by biopsy or the presence of cytomegalovirus antigenemia. RESULTS: The 30-day mortality rate was 4%; the in-hospital mortality rate was 8%. Acute graft failure was seen in 6 patients. The median length of intubation was 5 days, and the median hospital stay was 30 days. Systemic and pulmonary artery systolic pressures, cardiac index, and ratio of arterial partial oxygen pressure to fraction of inspired oxygen showed no significant alteration after OKT3 dosage. Gram-negative pulmonary infections were identified in 12 patients. Aspergillus infection was seen in 7 patients. Cytomegalovirus infection in 8 patients responded to ganciclovir and did not affect mortality. Respiratory syncytial viral infection was seen in 7 patients. Acute rejection was never seen during OKT3 administration. No episodes of acute rejection were identified in 14 patients at any time postoperatively. In the remainder, episodes of acute rejection responded to steroid or antithymocyte globulin therapy. At a median length of follow-up of 31 months, freedom from obliterative bronchiolitis was 69%+/-9% at 36 months. The overall survival rate was 88%+/-5% at 12 months, 82%+/-6% at 24 months, and 74%+/-7% at 36 months after transplantation. CONCLUSIONS: OKT3 is a safe and effective agent for induction immunosuppressive therapy in lung transplant recipients that limits the incidence of acute rejection and may decrease the incidence of obliterative bronchiolitis.     

Antifungal Prophylaxis and Treatment Among Lung Transplant Recipients in Early Postoperative Stage: A Single-Center Study

BackgroundLung transplantation remains the only feasible option for certain patients with end-stage lung disease. Lifelong immunosuppression increases the risk of infection, including fungal infections. The aim of this study was to assess the effect of antifungal prophylaxis and treatment among lung transplant recipients in the early postoperative stage.MethodsThis retrospective analysis included 127 patients who underwent lung transplantation between 2014 and 2021 in the lung transplant ward, 65.35% of whom were males. The most common indication for lung transplantation was cystic fibrosis (n = 59; 46.46%). All of the patients were receiving inhaled amphotericin B. Within this group there were patients who also were treated with intravenous caspofungin, intravenous/oral voriconazole, or both.ResultsThe difference in the efficacy against Candida spp. between caspofungin and voriconazole in the early post-transplant period was not statistically significant (χ₂ = 0.5, P = .477). Moreover, the difference in the efficacy against Candida spp. between itraconazole and voriconazole during the first post-transplant year was not statistically significant (χ₂ = 0.46, P = .496).ConclusionCaspofungin and voriconazole are proper and relatively efficient antifungal prophylaxis and treatment options after lung transplantation. There was no significant difference between voriconazole and caspofungin as antifungal agents used in the early post-transplant stage. There was no significant difference between voriconazole and itraconazole as antifungal agents used during the first post-transplant year. Further research on this issue is required.     

Aspergillus fumigatus-related spondylodiscitis in a heart transplant patient successfully treated with voriconazole

Organ transplant patients, such as heart transplant (HT) recipients, are prone to infections, among which are yeast infections. Of these, aspergillosis is usually associated with pneumopathy or facial sinusitis, and Aspergillus fumigatus is rarely responsible for osteomyelitis or spondylodiscitis. Herein we have reported a case of an 18-year-old male HT patient presenting with subacute lumbar spondylodiscitis at 6 months posttransplantation and 3 months after antirejection therapy with antithymocyte globulins. A percutaneous needle biopsy of the intervertebral disc yielded Aspergillus fumigatus. The patient had no evidence of lung aspergillosis, but did have maxillary sinusitis. He was successfully treated with voriconazole.     

Treatment of prosthetic valve endocarditis--analysis of eleven cases

A retrospective examination was made of eleven patients that developed prosthetic valve endocarditis (PVE) during the period from January 1960 to December 1987. Infection occurred in one patient within 60 days after surgery and in 10 thereafter. Causative organism was found in 6 patients. As organism, Staphylococcus species were noted in 4 patients and Peptstreptococcus was noted in one patient and Aspergyllus was noted in one patient. Three of eleven patients received medical treatment only and the other 8 patients were received surgical treatment. Mortality rate was 67% in medical group and 29% in surgical group. Two patients with medical treatment died of cerebral infarction about 40 days after the onset of PVE. In surgical group one patient died of uncontrollable Aspergillus infection and the other one died of dyspnea. No survivors who was treated surgically have developed reinfection or relapse of infection but four of them developed perivalvular leakage and needed reoperation. Absolute removal and closure of the valve ring abscess and reconstruction of defect should be considered for those needed surgical treatment to prevent reinfection and relapse developing.     

Aspergillus infection after total knee arthroplasty

The literature includes little information about the treatment protocol for Aspergillus infection after total knee arthroplasty. In this article, we describe the case of a nonimmunocompromised patient who lacked predisposing risk factors and who initially presented with aseptic loosening of a total knee prosthesis that postoperatively had grown Aspergillus niger. Intraoperative culture and frozen-section results for the pseudocapsule were negative. Two days postoperatively, culture results showed heavy growth of A niger. The patient was treated with a 6-week course of amphotericin B followed by oral antifungal therapy. She was doing well and had no symptoms 12 months after surgery.     

Candida glabrata fungemia in transplant patients receiving voriconazole after fluconazole

The clinical impact of voriconazole resistance in Candida glabrata is not well described. Five hematopoietic stem cell transplant recipients that developed breakthrough Candida glabrata bloodstream infections while receiving voriconazole are described and the clinical management and susceptibility profiles of their isolates are reported. All patients were markedly immunosuppressed, and in all cases, voriconazole use was preceded by prolonged fluconazole exposure (median 60 days); median voriconazole exposure prior to candidemia was 48 days. Isolates from 4 patients were shown to be resistant to fluconazole and itraconazole when tested in vitro; these same isolates had MICs to voriconazole and posaconazole > or = 2 microg/ml. Clinical failure to voriconazole may result from deficits in host defense, retained infected foci, and adaptation of the organism to environmental pressures, the specific sequence and mechanisms of which warrant further study. Clinicians must maintain a high index of suspicion for these infections in highly susceptible hosts despite voriconazole therapy, particularly when voriconazole use is preceded by prolonged fluconazole exposure.