J. Pi

Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole

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 (∼38 years). A total of 10 fungal infections were seen in patients on voriconazole (18% actuarial probability at 1 year): Candida glabrata (n=5), Candida krusei (n=1), Cunninghamella (n=1), Rhizopus (n=2) and Mucor (n=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 <0.2, <0.2, 0.33, 0.55, 0.63 and 1.78 μg/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 ⩽2 μg/ml and none among the 24 with levels of >2 μg/ml (P=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.

Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients

Low voriconazole levels have been associated with a higher failure rate in patients with confirmed fungal infections.

Reduced-dose rasburicase (recombinant xanthine oxidase) in adult cancer patients with hyperuricemia

Recombinant urate oxidase (rasburicase) lowers uric acid levels rapidly to very low levels at the labeled dose of 0.15–0.2 mg/kg daily for 5 days. Our past experience showed that a lower dose (3 mg) lowered uric acid levels sufficiently in most patients. A retrospective review was conducted to determine the effect of a fixed 3 mg dose of rasburicase in 43 adult patients with cancer undergoing hematopoietic stem cell transplantation or receiving chemotherapy who had elevated or rising uric acid levels (6.4–16.8 mg/dl; median 9.6). Six patients received a second dose of rasburicase (3 mg in four patients and 1.5 mg in two patients) 24 h later. Patients received allopurinol, adequate hydration, as well as other supportive therapy as required. Uric acid levels declined by 6–95% (median 43%) within the first 24 h after rasburicase administration, and levels at 48 h were 9–91% (median 65%) lower than the baseline levels. Serum creatinine changed by ⩽10% in 21 patients, increased by >10% in four patients and decreased by >10% in 18 patients. No significant renal dysfunction developed in any of the patients. We conclude that rasburicase is effective in lowering uric acid levels at a fixed dose of 3 mg, which is much lower than the recommended dose.

Serial Plasma Voriconazole Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation

ABSTRACT Plasma voriconazole concentrations vary considerably between patients receiving standard dosing, and trough voriconazole concentrations are known to affect efficacy and toxicity. Temporal variations in serial plasma voriconazole concentrations through the course of therapy in hematopoietic stem cell transplantation patients has not been carefully described. Paired voriconazole concentrations in 64 patients were studied to determine the predictability of the second concentration based on the first. The difference between the two values was ≤5% in six patients. In 25 patients, the second concentration was higher by a median of 40%. In 33 patients, the subsequent concentration was lower by a median of 59%. For patients with an initial concentration of <2 μg/ml, the correlation between the two values was poor (r = 0.24; P < 0.17). For those with an initial concentration of ≥2 μg/ml, the correlation was good (r = 0.72; P < 0.0001). There was no relationship between the magnitude of the change and the time elapsing between the two measurements. Among the 43 patients who had an initial concentration of ≥1 μg/ml, the two voriconazole measurements were strongly correlated (r = 0.66, P < 0.0001), but only 67% had a voriconazole serum concentration of ≥1 μg/ml on the second measurement. No studied variables were reliable predictors in identifying concentrations above or below 1 or 2 μg/ml. Our data suggest that variations in voriconazole concentrations are unpredictable despite standard dosing, and the acceptability of a concentration on one occasion cannot be extrapolated to future concentrations in the same patient. This suggests that ongoing therapeutic drug monitoring and dose adjustment may be beneficial in patients requiring prolonged voriconazole therapy.

Changing Epidemiology of Clostridium difficile–Associated Disease during Stem Cell Transplantation

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.

Effectiveness of a single 3-mg rasburicase dose for the management of hyperuricemia in patients with hematological malignancies

Rasburicase was administered at a fixed dose of 3 mg to treat 287 episodes of elevated serum uric acid levels (>7 mg/dL) in 247 adult patients with hematological malignancies. The median total dose of 36 μg/kg (range: 18–65) was a fraction of the recommended total pediatric dose of 0.75–1.0 mg/kg. The median change in uric acid levels at 24 h was −4.1 mg/dL (range: −12 to +1) and −45% (range: −95 to +9). Uric acid levels normalized at 24 h in 72% of patients. There was no relationship between the weight-based dose and uric acid decline. The only predictor of success was the baseline uric acid; the failure rate was 84% with baseline level >12 mg/dL and 18% if it was ⩽12. Uric acid levels continued to decline beyond 24 h in most patients without additional treatment. Serum creatinine remained stable over 24 h, and declined over 48 h and 7 days. There was no relationship between the extent of reduction in uric acid levels and serum creatinine. We conclude that a single 3-mg dose of rasburicase, used with close monitoring, is sufficient to treat most adults with uric acid levels up to 12 mg/dL.

Questioning the Role of a Neutropenic Diet following Hematopoetic 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.

Tacrolimus use in adult allogeneic stem cell transplant recipients receiving voriconazole: preemptive dose modification and therapeutic drug monitoring

Concomitant use of tacrolimus and voriconazole, both competitive inhibitors of the CYP450 3A4 isoenzyme, requires tacrolimus dose reduction. On the basis of clinical observations, we developed a preemptive dose-reduction strategy in allograft recipients who received voriconazole to maintain tacrolimus concentrations within a target range. A total of 27 patients started i.v. tacrolimus at an average daily dose of 0.022 mg/kg on day −1 (30% lesser than the usual starting dose). The dose was reduced by 30–40% if the 48-h steady-state concentration was 7–10 ng/ml, and by 40–50% if it was 10–15 ng/ml. No change was made if the concentration was <7 ng/ml. Subsequently, concentrations were generally monitored 2–3 times a week with dose adjustments as necessary. None of the 170 levels (3–12 per patient; median 5) obtained between days +1 and +16 were subtherapeutic (<5 ng/ml) and only 34 levels (20%) were >15 ng/ml. Each patient required dose reduction at least twice. The dose had to be increased in only two patients after the initial dose reduction. The median tacrolimus doses in mg/kg declined with time; being 0.022, 0.008 and 0.006 on days 0, 7 and 14, respectively. We conclude that a preemptive dose-reduction strategy is effective in maintaining tacrolimus concentrations within the desired therapeutic range, although serial monitoring remains prudent.

Idarubicin appears equivalent to dose-intense daunorubicin for remission induction in patients with acute myeloid leukemia

Daunorubicin has historically been considered the anthracycline of choice at many cancer centers for the treatment of acute myeloid leukemia (AML). Drug shortages have required the substitution of daunorubicin with idarubicin. Randomized studies have shown idarubicin (10-12mg/m(2)) to be comparable or superior to standard dose daunorubicin (45-60mg/m(2)) for achieving complete remission (CR). Whether these results can be extrapolated to dose-intense daunorubicin (90mg/m(2)), recently shown to improve CR rates when compared to standard daunorubicin doses remains uncertain. This observational study was conducted at Northwestern Memorial Hospital (NMH) to compare CR rates. The results suggest idarubicin is equivalent to daunorubicin, and for some subsets of patients, idarubicin may have superior CR rates.