Plasma and CSF pharmacokinetics of meropenem in neonates and young infants: results from the NeoMero studies

• Published in: Journal of antimicrobial chemotherapy Vol. 73; no. 7; pp. 1908 - 1916
• Main Authors: Germovsek, Eva, Lutsar, Irja, Kipper, Karin, Karlsson, Mats O, Planche, Tim, Chazallon, Corine, Meyer, Laurence, Trafojer, Ursula M T, Metsvaht, Tuuli, Fournier, Isabelle, Sharland, Mike, Heath, Paul, Standing, Joseph F
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-07-2018
• Subjects: Original Research
• ISSN: 0305-7453; 1460-2091; 1460-2091
• DOI: 10.1093/jac/dky128

Abstract
Background
Sepsis and bacterial meningitis are major causes of mortality and morbidity in neonates and infants. Meropenem, a broad-spectrum antibiotic, is not licensed for use in neonates and infants below 3 months of age and sufficient information on its plasma and CSF disposition and dosing in neonates and infants is lacking.
Objectives
To determine plasma and CSF pharmacokinetics of meropenem in neonates and young infants and the link between pharmacokinetics and clinical outcomes in babies with late-onset sepsis (LOS).
Methods
Data were collected in two recently conducted studies, i.e. NeoMero-1 (neonatal LOS) and NeoMero-2 (neonatal meningitis). Optimally timed plasma samples (n = 401) from 167 patients and opportunistic CSF samples (n = 78) from 56 patients were analysed.
Results
A one-compartment model with allometric scaling and fixed maturation gave adequate fit to both plasma and CSF data; the CL and volume (standardized to 70 kg) were 16.7 (95% CI 14.7, 18.9) L/h and 38.6 (95% CI 34.9, 43.4) L, respectively. CSF penetration was low (8%), but rose with increasing CSF protein, with 40% penetration predicted at a protein concentration of 6 g/L. Increased infusion time improved plasma target attainment, but lowered CSF concentrations. For 24 patients with culture-proven Gram-negative LOS, pharmacodynamic target attainment was similar regardless of the test-of-cure visit outcome.
Conclusions
Simulations showed that longer infusions increase plasma PTA but decrease CSF PTA. CSF penetration is worsened with long infusions so increasing dose frequency to achieve therapeutic targets should be considered.