Opportunistic dried blood spot sampling validates and optimizes a pediatric population pharmacokinetic model of metronidazole.

Pharmacokinetic models rarely undergo external validation in vulnerable populations such as critically ill infants, thereby limiting the accuracy, efficacy, and safety of model-informed dosing in real-world settings. Here, we describe an opportunistic approach using dried blood spots (DBS) to evaluate a population pharmacokinetic model of metronidazole in critically ill preterm infants of gestational age (GA) ≤31 weeks from the Metronidazole Pharmacokinetics in Premature Infants (PTN_METRO, NCT01222585) study. First, we used linear correlation to compare 42 paired DBS and plasma metronidazole concentrations from 21 preterm infants [mean (SD): post natal age 28.0 (21.7) days, GA 26.3 (2.4) weeks]. Using the resulting predictive equation, we estimated plasma metronidazole concentrations (ePlasma) from 399 DBS collected from 122 preterm and term infants [mean (SD): post natal age 16.7 (15.8) days, GA 31.4 (5.1) weeks] from the Antibiotic Safety in Infants with Complicated Intra-Abdominal Infections (SCAMP, NCT01994993) trial. When evaluating the PTN_METRO model using ePlasma from the SCAMP trial, we found that the model generally predicted ePlasma well in preterm infants with GA ≤31 weeks. When including ePlasma from term and preterm infants with GA >31 weeks, the model was optimized using a sigmoidal Emax maturation function of postmenstrual age on clearance and estimated the exponent of weight on volume of distribution. The optimized model supports existing dosing guidelines and adds new data to support a 6-hour dosing interval for infants with postmenstrual age >40 weeks. Using an opportunistic DBS to externally validate and optimize a metronidazole population pharmacokinetic model was feasible and useful in this vulnerable population.

Dosing and Safety of Off-label Use of Caffeine Citrate in Premature Infants.

OBJECTIVE: To characterize the dosing and safety of off-label caffeine citrate in a contemporary cohort of extremely premature infants. STUDY DESIGN: We used electronic health records (2010-2013) from 4 neonatal intensive care units to identify infants of ≤28 weeks of gestational age exposed to caffeine citrate. Safety outcomes included death, bronchopulmonary dysplasia, necrotizing enterocolitis, spontaneous intestinal perforation, intraventricular hemorrhage, patent ductus arteriosus ligation, seizures, and arrhythmias. We used multivariable logistic regression to evaluate the association of caffeine citrate exposure with clinical events. RESULTS: Of 410 infants with a median (IQR) gestational age of 26 (24-27) weeks, 95% received caffeine citrate for >0 days. Infants received a median (IQR) daily dose of 8 (5-10) mg/kg/day. Incidences of clinical events on day of caffeine citrate exposure were death 2%, patent ductus arteriosus ligation 12%, and medical and surgical necrotizing enterocolitis 5% and 4%, respectively. Bronchopulmonary dysplasia occurred in 37% of infants and was not associated with caffeine dose. Increased caffeine citrate dose was associated with lower odds of patent ductus arteriosus ligation and necrotizing enterocolitis. CONCLUSIONS: Caffeine citrate was used in extremely premature infants at younger gestation, at higher doses, and for longer durations than recommended on the drug label. Increased caffeine citrate exposure, dose, or therapy duration was not associated with increased risk of necrotizing enterocolitis.

Minilaparotomy radical cystoprostatectomy (Minilap RCP) in the surgical management of urinary bladder carcinoma: early experience.

OBJECTIVE: To assess the feasibility of minilaparotomy for radical cystoprostatectomy (RCP) and urinary diversion in the management of urinary bladder carcinoma. METHODS: A total of 45 consecutive patients with muscle invasive urinary bladder cancer underwent RCP and urinary diversion [32, 12 and 1 patients with pitchers pot orthotopic neobladder (NB), ileal conduit (IC) and sigma rectal pouch respectively], between May 2006 and June 2007, using 8-12 cm infraumbilical midline vertical incision from pubic symphysis, were prospectively analyzed for technical feasibility, operative time, blood loss, intraoperative and postoperative complications and return of bowel function. RESULTS: All the patients were males with average age of 59.65 years (44-79 years) and average body mass index of 23.97(17.7-29.5). The length of the incision was 8, 10 and 12 cm in 4, 39 and 2 patients, respectively. The average number of lymph nodes removed on the right and left side was 14 and 16, respectively. The average blood loss was 1046 ml (595-2100 ml). Return of bowel sounds was observed on an average by second postoperative day (1-5 days). Average postoperative stay was 14 days (range 10-24 days) for NB and 7 days (6-8 days) for IC patients. One (2.22%) patient died on the 18th postoperative day due to septicemia and acute renal failure. CONCLUSION: Minilaparotomy RCP is technically feasible without compromising the oncological principles. Complete removal of urachus and adequate clearance of pelvic lymph nodes is not difficult with the small incision. Early restoration of bowel function, early postoperative recovery and good cosmesis seem to be the main advantages.