meropenem and Enterocolitis--Necrotizing

Prolonged infusion of meropenem has been suggested in studies with population pharmacokinetic modeling but has not been tested in neonates. We compared the steady-state pharmacokinetics (PK) of meropenem given as a short (30-min) or prolonged (4-h) infusion to very-low-birth-weight (gestational age, <32 weeks; birth weight, <1,200 g) neonates to define the appropriate dosing regimen for a phase 3 efficacy study. Short (n = 9) or prolonged (n = 10) infusions of meropenem were given at a dose of 20 mg/kg every 12 h. Immediately before and 0.5, 1.5, 4, 8, and 12 h after the 4th to 7th doses of meropenem, blood samples were collected. Meropenem concentrations were measured by ultrahigh-performance liquid chromatography. PK analysis was performed with WinNonlin software, and modeling was performed with NONMEM software. A short infusion resulted in a higher mean drug concentration in serum (C(max)) than a prolonged infusion (89 versus 54 mg/liter). In all but two patients in the prolonged-infusion group, the free serum drug concentration was above the MIC (2 mg/liter) 100% of the time. Meropenem clearance (CL) was not influenced by postnatal or postmenstrual age. In population PK analysis, a one-compartment model provided the best fit and the steady-state distribution volume (V(ss)) was scaled with body weight and CL with a published renal maturation function. The covariates serum creatinine and postnatal and gestational ages did not improve the model fit. The final parameter estimates were a V(ss) of 0.301 liter/kg and a CL of 0.061 liter/h/kg. Meropenem infusions of 30 min are acceptable as they balance a reasonably high C(max) with convenience of dosing. In very-low-birth-weight neonates, no dosing adjustment is needed over the first month of life.

Topics: Anti-Bacterial Agents; Chromatography, High Pressure Liquid; Creatinine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Dosage Calculations; Enterocolitis, Necrotizing; Female; Gram-Negative Bacteria; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Infusions, Intravenous; Male; Meropenem; Models, Statistical; Pneumonia; Sepsis; Software; Thienamycins

Previous studies have identified numerous risk factors associated with necrotizing enterocolitis (NEC) in very low birth weight (VLBW; birth weight less than 1500 g) infants. One of the potential pathophysiological contributors could be antibiotic therapy. Our aim was to explore the association between antibiotic exposure and NEC in VLBW infants. We designed a retrospective 1:2 case-control cohort study in a level III neonatal intensive care unit. Our study group composed of VLBW infants born between January 2012 and December 2014 with a diagnosis of NEC stage IIA or greater (Bell's modified criteria). Our intent was to match every case in the study group to two controls. Our primary outcome was an association between antibiotic exposure and NEC. Twenty-two cases of NEC were matched to 32 controls. The infants who developed NEC were exposed to a statistically significantly more frequent number of antibiotic courses and to more days on any antibiotic prior to the development of NEC. There were significant differences between cases and controls with respect to the duration of exposure to gentamicin and meropenem specifically.Conclusion: The data from our study demonstrate that prolonged exposure to antibiotic therapy is associated with an increased risk of NEC among VLBW infants. Furthermore, gentamicin and meropenem, but not other antibiotics, had a significant association with the incidence of NEC. What is known: • Early antibiotic exposure is a risk factor for the development of necrotising enterocolitis (NEC) in very low birth weight infants • Prolonged initial empirical antibiotic course for ≥ 5 days, despite sterile blood culture, is associated with an increased risk of developing NEC What is new: • The cumulative total number of days of antibiotic exposure is associated with an increased risk of developing NEC • Gentamicin and meropenem, but not other antibiotics, had a significant association with the incidence of NEC in our study.

Topics: Anti-Bacterial Agents; Case-Control Studies; Enterocolitis, Necrotizing; Female; Gentamicins; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Intensive Care Units, Neonatal; Meropenem; Retrospective Studies; Risk Factors