Simultaneous pharmacokinetic/pharmacodynamic (PKPD) assessment of ampicillin and gentamicin in the treatment of neonatal sepsis

Abstract

Objectives: This study aimed to simultaneously investigate the pharmacokinetics of ampicillin and gentamicin, currently the WHO standard of care for treating neonatal sepsis.

Methods: Pharmacokinetic data were collected in 59 neonates receiving ampicillin and gentamicin for suspected or proven sepsis in the NeoFosfo trial (NCT03453177). A panel of 23 clinical Escherichia coli isolates from neonates with sepsis, resistant to either ampicillin, gentamicin or both, were tested for susceptibility using chequerboards. Pharmacokinetic/pharmacodynamic (PKPD) modelling and simulations were used to compare single-agent (EUCAST MIC) and combination (chequerboard MIC) target attainment with standard dosing regimens.

Results: A model was established that simultaneously estimated parameters of a one-compartment ampicillin model and a two-compartment gentamicin model. A common clearance for both drugs was used (6.89 L/h/70 kg) relating to glomerular filtration (CLGFR), with an additional clearance term added for ampicillin (5.3 L/h/70 kg). Covariate modelling included a priori allometric weight and post-menstrual age scaling of clearance. Further covariate relationships on renal clearance were postnatal age and serum creatinine.Simulation-based PKPD assessments suggest good Gram-positive (MIC ≤ 0.25 mg/L) cover. However, less than one-quarter of neonates were predicted to receive efficacious coverage against Enterobacterales (MIC ≤ 2 mg/L). The benefit of the ampicillin/gentamicin combination was limited, with only 2/23 E. coli clinical strains showing FIC index < 0.5 (synergy) and most in the range 0.5-1 (suggesting additivity). Simulations showed that feasible dosing strategies would be insufficient to cover resistant strains.

Conclusions: PKPD simulations showed ampicillin and gentamicin combination therapy was insufficient to cover Enterobacterales, suggesting the need for alternative empirical treatment options for neonatal sepsis.

Figure 1.

Observed plasma concentration versus time since last dose for ampicillin (left) and gentamicin (middle). Each line represents a single patient’s profile. Correlation of observed ampicillin and gentamicin concentrations is shown on the right.

Figure 2.

VPC for joint ampicillin and gentamicin model. Black dots, observed values; solid line, median; dashed lines, 5th and 95th percentiles for the observed values; grey areas, 95% prediction interval of respective median and percentiles.

Figure 3.

Target attainment as %fT_>MIC against MICs for simulated ampicillin regimen. Solid line, population median; grey area, 90% prediction interval; dashed lines, EUCAST breakpoints for Enterobacterales and CoNS.

Figure 4.

Target attainment as C_max/MIC ratio against MICs for simulated gentamicin regimen. Solid line, population median; grey area, 90% prediction interval; dashed line, EUCAST breakpoint for Enterobacterales.

Figure 5.

Resistance testing, FICI results and PTA for coverage of MICs for neonatal clinical specimens with the respective combination treatment. Light grey bars, gentamicin; dark grey bars, ampicillin.