Seventy-one allograft recipients receiving voriconazole, in whom complete clinical, microbiologic and pharmacokinetic data were available, were studied to determine the efficacy of voriconazole in preventing fungal infections. The length of voriconazole therapy was 6-956 days (median 133). The total number of patient-days on voriconazole was 13 805 (B38 years). A total of 10 fungal infections were seen in patients on voriconazole (18% actuarial probability at 1 year): Candida glabrataand Mucor (n ¼ 1). Two of the four zygomycosis cases were preceded by short durations of voriconazole therapy, but prolonged itraconazole prophylaxis. The plasma steady-state trough voriconazole levels around the time the infection occurred were o0.2, o0.2, 0.33, 0.55, 0.63 and 1.78 lg/ml in the six candidiasis cases. Excluding the four zygomycosis cases, all the six candidiasis cases were seen among the 43 patients with voriconazole levels of p2 lg/ml and none among the 24 with levels of 42 lg/ml (P ¼ 0.061). We conclude that voriconazole is effective at preventing aspergillosis. However, breakthrough zygomycosis is seen in a small proportion of patients. The role of therapeutic voriconazole monitoring with dose adjustment to avoid breakthrough infections with fungi that are otherwise susceptible to the drug needs to be explored prospectively.

Summary:Voriconazole, a new antifungal agent, is increasingly being used after HSCT. The hepatic cytochrome P450 isoenzyme 2C19 plays a significant role in voriconazole metabolism. As CYP2C19 exhibits significant genetic polymorphism, some patients metabolize voriconazole poorly resulting in increased plasma drug levels. The clinical significance of this is unknown, and the utility of monitoring voriconazole levels is unclear. Steady-state trough plasma voriconazole levels were obtained in 25 allogeneic HSCT recipients using an HPLC assay. Patients had drug levels checked once (n ¼ 13), twice (n ¼ 10), or X3 times (n ¼ 2) 5-18 days (median 10) after starting voriconazole or dose modification. The 41 voriconazole levels were 0.2-6.8 lg/ml (median 1.6); 6 (15%) were o0.5 (possibly below the in vitro MIC 90 for Aspergillus spp.). Voriconazole concentrations correlated with aspartate aminotranferase (AST) (r ¼ 0.5; P ¼ 0.0009) and alkaline phosphatase (r ¼ 0.34; P ¼ 0.03), but not with creatinine, bilirubin and alanine aminotransferase (ALT). Since liver dysfunction is common after HSCT, it was not possible to determine if elevated AST and alkaline phosphatase levels were the cause or the consequence of higher voriconazole levels. We conclude that trough voriconazole levels vary considerably between patients, and suggest monitoring levels in patients receiving voriconazole for confirmed fungal infections, and in those with elevated AST or alkaline phosphatase levels. Bone Marrow Transplantation (2005) 35, 509-513.

BACKGROUND. Low voriconazole levels have been associated with a higher failure rate in patients with confirmed fungal infections. METHODS. Steady‐state plasma trough voriconazole levels were measured after at least 5 days of therapy in 87 patients with hematologic malignancies on 201 separate occasions (1–5 levels per patient; median, 2). Most patients (90%) had undergone allogeneic hematopoietic stem cell transplantation. The daily voriconazole dose, administered in 2 divided doses, was 200 mg (n = 4), 400 mg (n = 151), 500 mg (n = 20), 600 mg (n = 18), and 800 mg (n = 8); corresponding to 2.0–16.3 (median, 5.4) mg/kg. Plasma voriconazole levels were 0–12.5 μg/mL (median, 1.2). Voriconazole was undetectable (<0.2 μg/mL) in 15%. RESULTS. The correlation between dose and levels was weak (r = 0.14; P = .045). The median absolute daily drug dose (400 mg) was identical in groups of patients with levels of 0, 0.2 to 0.5, >0.5 to 2.0, >2.0 to 5.0, and >5.0. Whereas the daily drug dose in mg/kg was significantly higher when the levels were >5.0 μg/mL, there was no consistent relation between dose and level below that threshold. In adult patients getting standard doses of voriconazole orally, the drug levels are highly variable. Based on limited available data, between a quarter and two‐thirds of these levels could potentially be associated with a lower likelihood of response or a higher likelihood of failure. CONCLUSIONS. Future voriconazole studies should incorporate prospective therapeutic drug monitoring and consideration should be given to checking levels in patients receiving the drug for confirmed, life‐threatening fungal infections. Cancer 2007. © 2007 American Cancer Society.

The incidence and severity of Clostridium difficile-associated disease (CDAD) within the general population has risen dramatically over the past decade, yet little data are available from hematopoietic stem cell transplantation (HSCT) centers. In the present study, we performed a chart review of 822 consecutive autologous and allogeneic HCST recipients treated at Northwestern Memorial Hospital between 2004 and 2008 to determine the incidence of CDAD at our institution. Variables including age, sex, diagnosis, chemotherapy regimen, transplantation type, microbial colonization, coinfections, diet, antibiotic use, neutropenic fever, comorbid conditions, time to engraftment, growth factor administration, and occurrence of graft-versus-host disease were assessed as potential risk factors for the development of CDAD. Eighty-five CDAD cases (10.3%) were identified. Bivariate analysis revealed a significant association between CDAD and neutropenic fever, administration of a neutropenic diet, ciprofloxacin and aztreonam use and duration of therapy, vancomycin and aztreonam use and duration of therapy, receipt of an allogeneic transplantation, bacterial coinfection, and vancomycin-resistant Entereococcus faecium (VRE) colonization. Cox regression analysis identified the following as factors associated with the development of CDAD: age >60 years, allogeneic transplantation, and prior VRE colonization. Allogeneic recipients with CDAD experienced increased higher rates of grades II to IV gastrointestinal graft-versus-host disease and nonrelapse mortality. A risk stratification model was developed to identify HSCT recipients at different levels of risk. With an incidence >10%, CDAD is a significant infectious complication of stem cell transplantation.

The use of a neutropenic diet (ND) after hematopoietic stem cell transplantation (HSCT) was instituted more than 30 years ago as a means of preventing infection from organisms colonizing the gastrointestinal tract. Evidence supporting this practice is lacking, however, and the actual efficacy of the ND remains unknown. Institutional policy at Northwestern Memorial Hospital discontinued the use of ND in 2006. We conducted a retrospective study of 726 consecutive HSCT recipients, 363 who received an ND and 363 who received a general hospital diet, to determine the incidence of microbiologically confirmed infections during and after transplantation. Our findings indicate a higher rate of infections in the HSCT recipients who received an ND.