Ashley Ross

Population Pharmacokinetics of Metronidazole Evaluated Using Scavenged Samples from Preterm Infants

ABSTRACT Pharmacokinetic (PK) studies in preterm infants are rarely conducted due to the research challenges posed by this population. To overcome these challenges, minimal-risk methods such as scavenged sampling can be used to evaluate the PK of commonly used drugs in this population. We evaluated the population PK of metronidazole using targeted sparse sampling and scavenged samples from infants that were ≤32 weeks of gestational age at birth and <120 postnatal days. A 5-center study was performed. A population PK model using nonlinear mixed-effect modeling (NONMEM) was developed. Covariate effects were evaluated based on estimated precision and clinical significance. Using the individual Bayesian PK estimates from the final population PK model and the dosing regimen used for each subject, the proportion of subjects achieving the therapeutic target of trough concentrations >8 mg/liter was calculated. Monte Carlo simulations were performed to evaluate the adequacy of different dosing recommendations per gestational age group. Thirty-two preterm infants were enrolled: the median (range) gestational age at birth was 27 (22 to 32) weeks, postnatal age was 41 (0 to 97) days, postmenstrual age (PMA) was 32 (24 to 43) weeks, and weight was 1,495 (678 to 3,850) g. The final PK data set contained 116 samples; 104/116 (90%) were scavenged from discarded clinical specimens. Metronidazole population PK was best described by a 1-compartment model. The population mean clearance (CL; liter/h) was determined as 0.0397 × (weight/1.5) × (PMA/32)2.49 using a volume of distribution (V) (liter) of 1.07 × (weight/1.5). The relative standard errors around parameter estimates ranged between 11% and 30%. On average, metronidazole concentrations in scavenged samples were 30% lower than those measured in scheduled blood draws. The majority of infants (>70%) met predefined pharmacodynamic efficacy targets. A new, simplified, postmenstrual-age-based dosing regimen is recommended for this population. Minimal-risk methods such as scavenged PK sampling provided meaningful information related to development of metronidazole PK models and dosing recommendations.

Population Pharmacokinetics of Piperacillin Using Scavenged Samples from Preterm Infants

Objectives: Piperacillin is often used in preterm infants for intra-abdominal infections; however, dosing has been derived from small single-center studies excluding extremely preterm infants at a highest risk for these infections. We evaluated the population pharmacokinetics (PK) of piperacillin using targeted sparse sampling and scavenged samples obtained from preterm infants ⩽32 weeks of gestational age at birth and <120 postnatal days. Materials and Methods: A 5-center study was performed. A population PK model using nonlinear mixed effect modeling was developed. Covariate effects were evaluated based on the estimated precision and clinical significance. Results: Fifty-six preterm infants were evaluated and had a median (range) gestational age at birth of 25 (22–32) weeks, a postnatal age of 17 (1–77) days, a postmenstrual age of 29 (23–40) weeks, and a weight of 867 (400–2580) g. The final PK data set contained 211 samples; 202/211 (96%) were scavenged from the discarded clinical specimens. Piperacillin population PK was best described by a 1-compartment model. The population mean clearance (CL) was derived by the equation CL (L/h) = 0.479 × (weight)0.75 × 0.5/serum creatinine and using a volume of distribution (V) (L) of 2.91 × (weight). The relative standard errors around parameter estimates ranged from 13.7% to 32.2%. A trend toward increased CL was observed with increasing gestational age at birth; infants with serum creatinine ≥1.2 mg/dL had a 60% reduction in piperacillin CL. The majority (>70%) of infants did not meet predefined pharmacodynamic efficacy targets. Conclusions: Scavenged PK sampling is a minimal-risk approach that can provide meaningful information related to the development of PK models but not dosing recommendations for piperacillin. The utility of scavenged sampling in providing definitive dosing recommendations may be drug dependent and needs to be further explored.

Neonatal herpes virus infection and extracorporeal life support.

Objectives: To investigate outcomes among neonates with herpes virus infection reported to the Extracorporeal Life Support Organization (ELSO) Registry and analyze factors associated with death before hospital discharge with this virus. Currently, scant data exist regarding extracorporeal membrane oxygenation support in neonates with herpes virus infection. Design: Retrospective analysis of ELSO Registry data set from 1985 to 2005. Setting: A total of 114 extracorporeal membrane oxygenation centers contributing data to the ELSO Registry. Patients: Patients, 0 to 31 days of age, with herpes simplex virus infection supported with extracorporeal membrane oxygenation and reported to the ELSO Registry. Interventions: None. Measurements and Main Results: Clinical characteristics, outcomes, and factors associated with death before hospital discharge were investigated for patients in the virus group. Kaplan-Meier estimates of survival to hospital discharge according to virus type were investigated. Newborns with herpes simplex virus infection requiring extracorporeal membrane oxygenation support demonstrated much lower hospital survival rates (25%). Clinical presentation with septicemia/shock was significantly associated with mortality for the herpes simplex virus group on multivariate analysis. There was no difference in herpes simplex virus mortality when comparing two eras (≥2000 vs. <2000). Conclusions: In this cohort of neonatal patients with overwhelming infections due to herpes simplex virus who were supported with extracorporeal membrane oxygenation, survival was dismal. Patients with disseminated herpes simplex virus infection presenting with septicemia/shock are unlikely to survive, even with aggressive extracorporeal support.

Fluconazole Prophylaxis for the Prevention of Candidiasis in Premature Infants: A Meta-analysis Using Patient-level Data

BACKGROUND Invasive candidiasis (IC) is an important cause of sepsis in premature infants and is associated with a high risk of death and neurodevelopmental impairment. Prevention of IC has become a major focus in very low birth weight infants, with fluconazole increasingly used as prophylaxis. METHODS We identified all randomized, placebo-controlled trials evaluating fluconazole prophylaxis in premature infants conducted in the United States. We obtained patient-level data from the study investigators and performed an aggregated analysis. The occurrence of each endpoint in infants who received prophylaxis with fluconazole vs placebo was compared. Endpoints evaluated were IC or death, IC, death, Candida colonization, and fluconazole resistance among tested isolates. Safety endpoints evaluated included clinical and laboratory parameters. RESULTS Fluconazole prophylaxis reduced the odds of IC or death, IC, and Candida colonization during the drug exposure period compared with infants given placebo: odds ratios of 0.48 (95% confidence interval [CI], .30-.78), 0.20 (95% CI, .08-.51), and 0.28 (95% CI, .18-.41), respectively. The incidence of clinical and laboratory adverse events was similar for infants who received fluconazole compared with placebo. There was no statistically significant difference in the proportion of tested isolates that were resistant to fluconazole between the fluconazole and placebo groups. CONCLUSIONS Fluconazole prophylaxis is effective and safe in reducing IC and Candida colonization in premature infants, and has no impact on resistance.

Smooth Implementation of Critical Congenital Heart Defect Screening in a Newborn Nursery

In January of 2012, University of Arkansas for Medical Sciences began implementation of a critical congenital heart disease screening program to identify newborns with structural heart defects. The screening used motion tolerant pulse oximeters in direct sequence to measure the oxygen levels in the right hand and either foot of eligible newborns. Exclusion criteria included echocardiogram prior to discharge, age greater than 7 days with continuous neonatal intensive care unit monitoring, or death or transfer prior to discharge. Of the 1905 infants screened, 3 infants failed screening. Two of the infants had atrial septal defects, and 1 had a patent foramen ovale, which was considered a false positive. After planning and education, the implementation of critical congenital heart disease pulse oximetry screening was successful. With only 1 false positive in our high-risk population, this should encourage other institutions to begin screening eligible infants.

Retinitis following varicella in a vaccinated child with acute lymphoblastic leukemia.

Serious ocular disease following varicella (chickenpox) is rare in children. In addition, retinitis in children with hematologic malignancies may present a difficult diagnostic challenge because infectious retinitis may mimic leukemic involvement of the eye. We report a 7‐year‐old patient with T‐cell acute lymphoblastic leukemia in remission who presented with visual complaints 2 weeks after developing chickenpox. Ophthalmologic evaluation revealed acute retinitis in the right eye. Prolonged therapy with acyclovir resulted in near complete recovery. Early diagnosis of VZV retinopathy and aggressive antiviral treatment is critical to prevent acute and long‐term ocular sequelae.

A Multistep Synthesis of 4-Nitro-1-ethynylbenzene Involving Palladium Catalysis, Conformational Analysis, Acetal Hydrolysis, and Oxidative Decarbonylation

Palladium-catalyzed reactions, particularly carbon-carbon bond formations, are rapidly becoming a mainstay of organic synthesis in industrial and academic laboratories. Although these important procedures are covered in advanced organic chemistry texts, they have rarely permeated into introductory organic texts or laboratory manuals. One of the more useful processes involves the coupling of a terminal alkyne to an aromatic bromide or iodide. We describe a convenient coupling procedure for the preparation of the tetrahydropyranyl ether of a propargyl alcohol derivative. This product can be easily hydrolyzed to the propargyl alcohol, then oxidatively decarbonylated to produce 4-nitro-1-ethynylbenzene. Several important topics may be illustrated and discussed in conjunction with the multistep microscale reaction series which has been developed. These include the following: palladium-catalyzed carbon-carbon bond formation, conformational analysis by NMR spectroscopy and molecular modeling, hydrolysis of an ac...