Anand Kantak

Population pharmacokinetics of meropenem in plasma and cerebrospinal fluid of infants with suspected or complicated intra-abdominal infections

Background: Suspected or complicated intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial agent with excellent activity against pathogens associated with intra-abdominal infections in this population. The purpose of this study was to determine the pharmacokinetics (PK) of meropenem in young infants as a basis for optimizing dosing and minimizing adverse events. Methods: Premature and term infants <91 days old hospitalized in 24 neonatal intensive care units were studied. Limited PK sampling was performed following single and multiple doses of meropenem 20 to 30 mg/kg of body weight every 8 to 12 hours based on postnatal and gestational age at birth. Population and individual patient (Bayesian) PK parameters were estimated using NONMEM. Results: In this study, 200 infants were enrolled and received the study drug. Of them, 188 infants with 780 plasma meropenem concentrations were analyzed. Their median (range) gestational age at birth and postnatal age at PK evaluation were 28 (23–40) weeks and 21 (1–92) days, respectively. In the final PK model, meropenem clearance was strongly associated with serum creatinine and postmenstrual age (clearance [L/h/kg] = 0.12*[(0.5/serum creatinine)**0.27]*[(postmenstrual age/32.7)**1.46]). Meropenem concentrations remained >4 &mgr;g/mL for 50% of the dose interval and >2 &mgr;g/mL for 75% of the dose interval in 96% and 92% of patients, respectively. The estimated penetration of meropenem into the cerebrospinal fluid was 70% (5–148). Conclusions: Meropenem dosing strategies based on postnatal and gestational age achieved therapeutic drug exposure in almost all infants.

Safety and effectiveness of meropenem in infants with suspected or complicated intra-abdominal infections.

BACKGROUND Intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial with excellent activity against pathogens associated with intra-abdominal infections. The purpose of this study was to determine the safety and effectiveness of meropenem in young infants with suspected or complicated intra-abdominal infections. METHODS Preterm and term infants <91 days of age with suspected or confirmed intra-abdominal infections hospitalized in 24 neonatal intensive care units were studied in an open-label, multiple-dose study. Adverse events and serious adverse events were collected through 3 and 30 days following the last meropenem dose, respectively. Effectiveness was assessed by 3 criteria: death, bacterial cultures, and presumptive clinical cure score. RESULTS Of 200 subjects enrolled in the study, 99 (50%) experienced an adverse event, and 34 (17%) had serious adverse events; no adverse events were probably or definitely related to meropenem. The most commonly reported adverse events were sepsis (6%), seizures (5%), elevated conjugated bilirubin (5%), and hypokalemia (5%). Only 2 of the serious adverse events were determined to be possibly related to meropenem (isolated ileal perforation and an episode of fungal sepsis). Effectiveness was evaluable in 192 (96%) subjects, and overall treatment success was 84%. CONCLUSIONS Meropenem was well tolerated in this cohort of critically ill infants, and the majority of infants treated with meropenem met the definition of therapeutic success. CLINICAL TRIALS REGISTRATION NCT00621192.

Evaluation and Development of Potentially Better Practices for Perinatal and Neonatal Communication and Collaboration

Objective. The obstetric and neonatal exploratory focus group of the Vermont Oxford Network Neonatal Intensive Care Quality Improvement Collaborative 2002 set out to improve collaboration, communication, and coordination between maternal and neonatal caregivers in 3 areas: the pregnancy at 22 to 26 weeks, measurement of maternal outcomes that are linked with neonatal outcomes, and team performance during high-risk delivery. Antepartum and intrapartum maternal attributes and interventions also were considered important measurements to identify practice variations and their relationship to neonatal outcomes for ongoing obstetric and neonatal collaboration. Methods. Potentially better practices were developed on the basis of evidence in the literature, expert opinion, and internal analysis at the participating perinatal centers. The potentially better practices include development of local guidelines at each center for the care and counseling of pregnant women who are at risk for delivering at the margin of viability; communication strategies for obstetric and neonatology providers relating to high-risk pregnancy treatment plans; team communication and performance at high-risk deliveries; design of organizational structures and processes that facilitate obstetric and neonatal collaboration; and development of perinatal data to evaluate effects of perinatal practices on maternal, fetal, and neonatal outcomes. Results. As a result of the project, participating centers developed local guidelines for pregnancies between 22 and 26 weeks, created a cross-center maternal database that currently is being linked to neonatal outcomes, and completed a pilot study on video simulation of neonatal–perinatal team communication. Conclusions. Increased understanding of practice variation in the management of care for infants who are at the margins of viability, locally developed guidelines, and a focus on improved team communication during delivery can be accomplished with a multicenter collaborative approach.

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.

Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams

ABSTRACT Fluconazole is an effective agent for prophylaxis of invasive candidiasis in premature infants. The objective of this study was to characterize the population pharmacokinetics (PK) and dosing requirements of fluconazole in infants with birth weights of <750 g. As part of a randomized clinical trial, infants born at <750 g birth weight received intravenous (i.v.) or oral fluconazole at 6 mg/kg of body weight twice weekly. Fluconazole plasma concentrations from samples obtained by either scheduled or scavenged sampling were measured using a liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using NONMEM 7.2. Population PK parameters were allometrically scaled by body weight. Covariates were evaluated by univariable screening followed by multivariable assessment. Fluconazole exposures were simulated in premature infants using the final PK model. A population PK model was developed from 141 infants using 604 plasma samples. Plasma fluconazole PK were best described by a one-compartment model with first-order elimination. Only serum creatinine was an independent predictor for clearance in the final model. The typical population parameter estimate for oral bioavailability in the final model was 99.5%. Scavenged samples did not bias the parameter estimates and were as informative as scheduled samples. Simulations indicated that the study dose maintained fluconazole troughs of >2,000 ng/ml in 80% of simulated infants at week 1 and 59% at week 4 of treatment. Developmental changes in fluconazole clearance are best predicted by serum creatinine in this population. A twice-weekly dose of 6 mg/kg achieves appropriate levels for prevention of invasive candidiasis in extremely premature infants.

Management of High-Order Multiple Births: Application of Lessons Learned Because of Participation in Vermont Oxford Network Collaboratives

OBJECTIVES. The delivery and care of sextuplets is complex. Potentially better practices that were developed as part of the Vermont Oxford Network improvement collaboratives were used to prepare for a sextuplet delivery at Akron Childrens Hospital. METHODS. The team used potentially better practices that were learned from the Neonatal Intensive Care Quality Improvement Collaborative 2002 using multidisciplinary teams. There was extensive media coverage of the delivery. RESULTS. The goal was to use nearly all potentially better practices that focused on the goals of reducing nosocomial infection, reducing chronic lung disease, reducing radiograph use, reducing length of stay, reducing blood gas use, promoting nutrition, reducing intraventricular hemorrhage, and enriching family-centered care. The center aimed to use these 97 potentially better practices. Of the 97 possible potential better practices as set by the Neonatal Intensive Care Quality Improvement Collaborative 2002, 96 (99%) were used. CONCLUSIONS. This is a blueprint that any center that is faced with high-order multiple births could use as a reference point to begin planning. The team created a benchmark to achieve in every birth of very low birth weight infants and not just a special situation of high-order multiple births.

Assessment of adherence to guidelines for using progesterone to prevent recurrent preterm birth

Abstract Objective: To assess if women with recurrent preterm birth had been offered, received, and adhered to progesterone supplementation guidelines and to ascertain reasons for failure to follow guidelines. Methods: Charts of infants who were products of recurrent spontaneous preterm birth were reviewed at four neonatal intensive care units of Akron Children’s Hospital. Mothers of identified infants were interviewed and charts abstracted to determine: if progesterone was offered; acceptance of progesterone; compliance with progesterone; and reasons why progesterone was declined. Results: One hundred twenty-eight mothers with a recurrent spontaneous preterm birth were identified and 98 consented to participate. 62.2% (61/98) of the interviewed mothers reported that they were offered progesterone. Of the women offered progesterone, 82% (50/61) accepted treatment and 18.0% (11/61) declined. One woman who accepted progesterone did not receive it. Of the women who received progesterone, 18.4% (9/49) reported compliance failure. Of the women who did not receive progesterone, 75.5% (37/49) reported that they were not offered progesterone and 89.2% (33/37) of the women not offered progesterone reported that their care providers were aware of their prior preterm delivery. Conclusions: Only 50% (49/98) of women who were candidates for progesterone received treatment. The main reason for women not receiving treatment was not being offered progesterone by their caregiver.

Collaborative Quality Improvement for Neonatal Intensive Care. |[dagger]| 1026

We evaluated the effects of collaborative quality improvement and benchmarking on two specific neonatal outcomes in a study of 10 neonatal intensive care units (NICUs) in the Vermont Oxford Network. Multidisciplinary teams of neonatologists, nurses, quality coaches and administrators from the 10 NICUs worked closely together in facilitated large group meetings and conference calls beginning in January 1995. They chose specific clinical improvement goals, performed analyses of their care processes, evaluated the published evidence and performed site visits to project NICUs and others in the Network with superior performance. Reducing nosocomial infection for infants 501 to 1500 grams was the goal chosen by 6 NICUs; reducing chronic lung disease or death for infants 501 to 1000 grams was chosen by the other group of 4 NICUs. The groups developed lists of “potentially better practices” and each NICU implemented selected practices by the beginning of 1996. Outcomes were monitored with the Network Database. The project was evaluated by comparing outcomes in 1994 (pre-intervention) to those in 1996(post-intervention) and by comparing changes in outcomes at the project NICUs with those at the other 66 North American NICUs participating in the Vermont Oxford Network from 1994 to 1996. The rate of infection with coagulase negative Staphylococcus (cnS) decreased at the 6 infection group NICUs from 22.0% to 16.6% (p=0.007); infections with other pathogens did not change significantly. The 5.4% decline in cnS at the 6 NICUs was greater than the 0.8% decline seen at the 66 comparison NICUs (p=0.026). At the 4 NICUs in the chronic lung disease group, the percentage of infants receiving supplemental oxygen at 36 weeks post-conceptional age decreased from 43.5% to 31.5%(p=0.03); mortality did not change significantly. The 12% decline in oxygen at 36 weeks at the 4 NICUs was greater than the 0.1% decline seen at the 66 comparison NICUs (p=0.045). The magnitude of improvement in both cnS infection and oxygen at 36 weeks varied significantly among the NICUs. We conclude that collaborative quality improvement has the potential to improve the outcomes of neonatal intensive care.