Safety, Tolerability, and Population Pharmacokinetics of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients.

Isavuconazole, administered as the water-soluble prodrug isavuconazonium sulfate, is a new triazole agent used to treat invasive fungal infections. This phase 1 study evaluated the pharmacokinetics (PK), safety, and tolerability of isavuconazole in 46 immunocompromised pediatric patients, stratified by age (1 to <6 [intravenous (i.v.) only], 6 to <12, and 12 to <18 years), receiving 10 mg/kg body weight (maximum, 372 mg) isavuconazonium sulfate either i.v. or orally. A population PK model using weight-based allometric scaling was constructed with the pediatric i.v. and oral data plus i.v. data from a phase 1 study in adults. The best model was a 3-compartment model with combined zero-order and first-order input, with linear elimination. Stepwise covariate modeling was performed in Perl-speaks-NONMEM version 4.7.0. None of the covariates examined, including age, sex, race, and body mass index, were statistically significant for any of the PK parameters. The area under the concentration-time curve at steady state (AUCSS) was predicted for pediatric patients using 1,000 Monte Carlo simulations per age cohort for each administration route. The probability of target attainment (AUCSS range, 60 to 233 µg · h/ml) was estimated; this target range was derived from plasma drug exposures in adults receiving the recommended clinical dose. Predicted plasma drug exposures were within the target range for >80% and >76% of simulated pediatric patients following i.v. or oral administration, respectively. Intravenous and oral administration of isavuconazonium sulfate at the studied dosage of 10 mg/kg was well tolerated and resulted in exposure in pediatric patients similar to that in adults. (This study has been registered at ClinicalTrials.gov under identifier NCT03241550).

Complications of Cryptosporidium infection after pediatric liver transplantation: Diarrhea, rejection, and biliary disease.

BACKGROUND: Cryptosporidium enteritis can be devastating in the immunocompromised host. In pediatric liver transplant recipients, infection may be complicated by prolonged carriage of the parasite, rejection, and biliary tree damage and fibrosis. Herein, we report on six patients and their long-term outcomes following cryptosporidiosis. METHODS: We reviewed all cases of cryptosporidiosis in a pediatric liver transplant population over a 17-year period at a single center. Six patients with infection were identified, and their outcomes were analyzed. RESULTS: Infection was associated with significant diarrhea and dehydration in all cases, and led to hospitalization in one-half of patients. Four of the six patients developed biopsy-proven rejection following infection, with three of those patients developing rejection that was recalcitrant to intravenous steroid treatment. Additionally, three patients developed biliary tree abnormalities with similarity to sclerosing cholangitis. In one patient, those biliary changes led to repeated need for biliary drain placement and advancing fibrotic liver allograft changes. CONCLUSIONS: Cryptosporidiosis in pediatric liver transplant recipients may lead to significant complications, including recalcitrant episodes of rejection and detrimental biliary tree changes. We advocate for increased awareness of this cause of diarrheal disease and the allograft injuries that may accompany infection.

Tunneled hemodialysis catheter care practices and blood stream infection rate in children: results from the SCOPE collaborative.

OBJECTIVE: The Standardizing Care to Improve Outcomes in Pediatric End Stage Renal Disease (SCOPE) collaborative seeks to reduce hemodialysis (HD) catheter-associated blood stream infections (CA-BSI) by increasing implementation of standardized HD catheter care bundles. We report HD catheter care practices and HD CA-BSI rates from SCOPE. METHODS: Catheter care practices and infection events were collected prospectively during the study period, from collaborative implementation in June 2013 through May 2017. For comparative purposes, historical data, including patient demographics and HD CA-BSI events, were collected from the 12 months prior to implementation. Catheter care bundle compliance in 5 care bundle categories was monitored across the post-implementation reporting period at each center via monthly care observation forms. CA-BSI rates were calculated monthly, and reported as number of infections per 100 patient months. Changes in CA-BSI rates were assessed using generalized linear mixed model (GLMM) techniques. RESULTS: Three hundred twenty-five patients with tunneled HD catheters [median (IQR) age 12 years (6, 16), M 53%, F 47%] at 15 centers were included. A total of 3996 catheter care observations over 4170 patient months were submitted with a median (IQR) 5 (2, 14) observations per patient. Overall bundle compliance was high at 87.6%, with a significant and progressive increase (p < 0.001) in compliance for 4/5 bundle categories over the 48-month study period. The adjusted CA-BSI rate significantly decreased over time from 3.3/100 patient months prior to implementation of the care bundles to 0.8/100 patient months 48 months after care bundle implementation (p < 0.001). CONCLUSIONS: Using quality improvement methodology, SCOPE has demonstrated a significant increase in compliance with a majority of HD catheter care practices and a significant reduction in the rate of CA-BSI among children maintained on HD.