Clinical utiliy of a model‐based piperacillin dose in neonates with early‐onset sepsis

Abstract

AimsEarly‐onset sepsis (EOS) is a common disease in neonates with a high morbidity and mortality rate. Piperacillin/tazobactam has been used extensively and empirically for EOS treatment without clinically validated dosing regimens, although the population pharmacokinetics (PPK) of piperacillin in neonates has been reported. Therefore, we wanted to study the effectiveness and tolerance of a PPK model‐based dosing regimen of piperacillin/tazobactam in EOS patients.MethodsA prospective, single‐centre, phase II clinical study of piperacillin/tazobactam in neonates with EOS was conducted. The dosing regimen (90 mg·kg−1, q8h) was determined based on a previous piperacillin PPK model in young infants using NONMEM v7.4. The pharmacodynamics (PD) target (70%fT > MIC, free drug concentration above MIC during 70% of the dosing interval) attainment was calculated using NONMEM combined with an opportunistic sampling design. The clinical treatment data were collected.ResultsA total of 52 neonates were screened and 49 neonates completed their piperacillin/tazobactam treatment course and were included in this analysis. The median (range) values of postmenstrual age were 33.57 (range 26.14–41.29) weeks. Forty‐seven (96%) neonates reached their PD target. Eight (16%) neonates experienced treatment failure clinically. The mean (SD, range) duration of treatment and length of hospitalization were 100.1 (62.2, 36.2–305.8) hours and 31 (30, 5–123) days. There were no obvious adverse events and no infection‐related deaths occurred in the first month of life.ConclusionsA model‐based dosing regimen of piperacillin/tazobactam was evaluated clinically, was tolerated well and was determined to be effective for EOS treatment.

Clinical utility of a model‐based amoxicillin dosage regimen in neonates with early‐onset sepsis

“…This may be due to the fact that the other 2 studies discontinued treatment timely based on the discontinuation assessment in the NICE guideline, which had the potential to shorten the course of treatment. Treatment failure rate was somewhat different from the previous study for neonates EOS treatment, it may be due to the variation of centre and population 15,17 …”

“…, 43 in which the median antibiotic treatment period using the standard empirical treatment in term neonates was 6 days for EOS. However, it was longer than the study of azlocillin and piperacillin, 15,17 in which the mean duration of antibiotic administration was 4.1 and 4.2 days for the treatment of EOS in neonates, respectively. This may be due to the fact that the other 2 studies discontinued treatment timely based on the discontinuation assessment in the NICE guideline, which had the potential to shorten the course of treatment.…”

“…Treatment failure rate was somewhat different from the previous study for neonates EOS treatment, it may be due to the variation of centre and population. 15,17 We realize that our study also has some limitations. Firstly, our data did not include extreme preterm neonates.…”

“…15 Presently, many broadspectrum antibiotics, such as piperacillin-tazobactam and amoxicillin, are increasingly being used in the management of EOS. [14][15][16][17] Amoxicillin, a semi-synthetic antibiotic belonging to the subclass of aminopenicillins, is active against both Gram-positive and Gram-negative pathogens such as E. coli and S. agalactiae, [18][19][20][21] and generally considered safe. However, excessive accumulation of amoxicillin may lead to seizures.…”

“…In China, however, the use of aminoglycosides in neonates is forbidden by law 15 . Presently, many broad‐spectrum antibiotics, such as piperacillin–tazobactam and amoxicillin, are increasingly being used in the management of EOS 14–17 …”