Benzylpenicillin Serum Concentrations in Neonates With Group B Streptococci Sepsis or Meningitis

Abstract

Background: Adequate dosage recommendations are imperative for successful treatment of invasive infections. We evaluated the occurrence of sub-and supratherapeutic serum and cerebrospinal fluid (CSF) concentrations of benzylpenicillin (BPEN) in neonates treated for a severe group B streptococci (GBS) sepsis and/or meningitis as well as discrepancies in dosing recommendations provided by pediatric reference sources. Methods: Retrospective analysis of (pre)term infants treated with BPEN undergoing therapeutic drug monitoring (TDM) between May 2015 and May 2019. Outcomes included numbers of sub-and supratherapeutic concentrations, and dose adjustments, clinical evolution, and dosing recommendations from six pediatric reference sources. Results: A total of 21 TDM samples from 8 neonates were evaluated. Among serum concentrations, 9/21 (43%) were below and 8/21 (38%) above the pre-specified therapeutic target range of 10-20 mg/L. Only 1 patient had BPEN determined in CSF whose concentration was below the lower limit of quantification. TDM identified a need for dose modification in 10/21 (48%) instances. Three of eight patients exhibited complete resolution of clinical, laboratory and radiologic signs of infection. Substantial variation in dosing recommendations (50,000-400,000 IE/kg/d) was present between reference sources. Conclusions: Our data reveal that under current dosage recommendations, the predefined target serum or CSF concentrations of BPEN are not achieved in all children. In case of clinical failure, serum and/or CSF BPEN concentrations should be determined. Given the wide variation in concentrations and subsequent dose requirements, further exploration of the clinical and pharmacologic characteristics of BPEN in (pre)term neonates is essential to optimize therapeutic efficacy.

A systematic review of the effect of therapeutic drug monitoring on patient health outcomes during treatment with penicillins

“…The study characteristics of the 16 observational studies included are shown in Table S2. These studies investigated a number of different populations including: paediatric critically ill patients, 39 critically ill patients, 36,37,[40][41][42][43][44][45] critically ill patients with alternate renal functions such as receiving continuous RRT, 46 or augmented renal clearance, 47 patients treated for specific infections, 48,49 and burns patients. 38,50 The majority of studies (11/16, 69%) included non-penicillin antibiotics with analyses not separating outcomes for individual antibiotics.…”

“…Another common feature (in 9/16 studies, 56%) was the inclusion of concomitant antibiotics in the regimen, with the majority having no analysis of the impact of this on clinical outcomes. 36,39,40,42,[47][48][49]51 A key component of TDM is adjustment of doses to improve target drug level attainment and this was shown to be successful in a number of studies. [38][39][40]43,46,49 However, in others the effectiveness of dose adjustment was either not assessed 37,45,47,50 or was shown to be ineffective.…”

“…[38][39][40]43,46,49 However, in others the effectiveness of dose adjustment was either not assessed 37,45,47,50 or was shown to be ineffective. 36,41,42,44,48,51 The study carried out by Richter et al 40 (n = 484) included data from the largest number of patients and looked at the effects of TDM-guided continuous infusions of piperacillin on PK/PD outcomes and analysed mortality data in relation to piperacillin concentration as a secondary outcome. By comparing target attainment before and after antibiotic measurement and dose adjustment, the study showed that their TDM protocol was effective at significantly improving target attainment.…”

“…The effectiveness of the dosing adjustment protocol to improve target attainment was variable across the studies. Target attainment was shown to be improved, subsequent to dosing adjustments, in some studies, 33,35,[38][39][40]43,46,49 but not in others, 34,36,41,42,44,48,51 or the effectiveness of dose adjustment was not considered. 37,45,47,50 To ensure the success of a TDM intervention, dose adjustment protocols need to alter the dosing regimen sufficiently to improve target attainment.…”

Knowledge gaps in late-onset neonatal sepsis in preterm neonates: a roadmap for future research

“…124 One good example for this could be beta-lactams as recent studies have shown that in neonates with sepsis therapy failure, as little as 20% of the benzyl penicillin concentrations were within the target range. 125 MONITORING SEPSIS COURSE Assessing treatment effect LONS may compromise the cardiovascular system, leading to reduced cardiac output and/or disturbed microcirculation, but also other organ systems. Adequate biomarkers to judge effectiveness of LONS management would significantly improve clinical care; knowing you are on the right track even before the patient shows clinical recovery, potentially prevents overuse of supportive therapy and unnecessary switches to broad-spectrum antibiotics.…”