Dosing Recommendations for Ampicillin and Ceftriaxone in the Treatment of Pediatric Community-Acquired Pneumonia Using Monte Carlo- and Physiologic-Based Pharmacokinetic Simulations

Abstract

Objective: Since 2011, Ampicillin (AMP) has been recommended as the parenteral antibiotic of choice for pediatric community-acquired pneumonia (CAP), but ceftriaxone (CRO) is recommended for unvaccinated children and those with complicated CAP. Using penicillin and CRO susceptibility data for pneumococcus, we evaluated the adequacy of currently recommended doses of AMP and CRO.

Methods: With nonlinear mixed-effects modeling v7.3, Monte Carlo simulations (MCS, N = 10,000) for AMP and CRO were conducted for 6 virtual patients aged 3 months, 1, 2, 5, 10, and 15 years. PK-Sim v9.0 was used to develop physiologic-based pharmacokinetic (PBPK) models for AMP (N = 4000) and CRO (N = 3000). The probability of target attainment (PTA) was determined for both serum and lung (epithelial lining fluid [ELF]) exposure to achieve free drug concentrations above the minimum inhibitory concentration (%fT>MIC) for pneumococci at 30% to 50% of the dosing interval.

Results: We performed simulations based on susceptibility data from 21 pneumococci isolated from children with CAP and found all 21 (100%) to be susceptible to AMP and CRO using Clinical & Laboratory Standard Institute/US Food and Drug Administration breakpoints, where susceptible, intermediate, and resistant strains of Streptococcus pneumoniae were ≤1, 2, and ≥4 mg/L for CRO and ≤2, 4, and ≥8 mg/L for AMP (extrapolated from penicillin), respectively (where intermediate and resistant were considered nonsusceptible); and 18 (85.7%) were susceptible to AMP, and 19 (90.5%) to CRO using the European Committee on Antimicrobial Susceptibility Testing/European Medicines Agency breakpoints, where susceptible and nonsusceptible strains were as follows: 0.5 and 2 mg/L for CRO and 0.5 and 1 mg/L for AMP. Both the serum and ELF, antibiotic regimens achieved >99% PTA at 30% to 50% fT>MIC using MCS and PBPK.

Conclusion: In the pneumococcal conjugate era, standard doses of AMP and CRO appear to provide the appropriate serum and ELF exposure for clinical and microbiologic success for >98% of children with pediatric CAP. The required dose to achieve the desired outcomes may change if beta-lactam resistance in pneumococcus increases.

Keywords: Monte Carlo simulation; Streptococcus pneumoniae; beta-lactams; children; pharmacodynamic; physiologic-based pharmacokinetic simulation; pneumococcal vaccine.

Figure 1.

PK-Sim Models (Concentration [mcg] vs Time [h]). (a) Ampicillin. (b) Ceftriaxone.

Figure 2.

Susceptibility data for penicillin (a) and ceftriaxone (b) against S. pneumoniae respiratory isolates collected from pediatric patients from the Pre-PCV-13 Period (1993–2001) and post-PCV-13 period (2007–2018) minimum inhibitory concentration (MIC) vs percent of isolates.

Figure 3a.

(NONMEM) Probability of target attainment of beta-lactams against S. pneumoniae using Clinical & Laboratory Standard Institute (CLSI)* and European Committee on Antimicrobial Susceptibility Testing (EUCAST)† breakpoints in the serum and epithelial lining fluid (ELF).

Figure 3b.

(PK-Sim) PTA of beta-lactams against S. pneumoniae using CLSI^* and EUCAST† breakpoints in the serum and ELF.