Variation in Target Attainment of Beta-Lactam Antibiotic Dosing Between International Pediatric Formularies

Abstract

As antimicrobial susceptibility of common bacterial pathogens decreases, ensuring optimal dosing may preserve the use of older antibiotics in order to limit the spread of resistance to newer agents. Beta-lactams represent the most widely prescribed antibiotic class, yet most were licensed prior to legislation changes mandating their study in children. As a result, significant heterogeneity persists in the pediatric doses used globally, along with quality of evidence used to inform dosing. This review summarizes dosing recommendations from the major pediatric reference sources and tries to answer the questions: Does beta-lactam dose heterogeneity matter? Does it impact pharmacodynamic target attainment? For three important severe clinical infections-pneumonia, sepsis, and meningitis-pharmacokinetic models were identified for common for beta-lactam antibiotics. Real-world demographics were derived from three multicenter point prevalence surveys. Simulation results were compared with minimum inhibitory concentration distributions to inform appropriateness of recommended doses in targeted and empiric treatment. While cephalosporin dosing regimens are largely adequate for target attainment, they also pose the most risk of neurotoxicity. Our review highlights aminopenicillin, piperacillin, and meropenem doses as potentially requiring review/optimization in order to preserve the use of these agents in future.

Figure 1

Weight compared with age for the three simulated subpopulations: pneumonia, sepsis, and meningitis. Black dots are single subjects filtered from GARPEC / ARPEC / Global PPS. Gray lines represent the median, 3rd, and 97th percentiles from demographic surveys by Fenton et al., CDC (Centers for Disease Control and Prevention), and WHO (World Health Organization).

Figure 2

Probability of target attainment (100%fT > MIC) for simulated dosing regimen in the pneumonia subpopulation. Solid line, median for common regimen; dark gray area, 90% prediction interval for common regimen; light gray area, 5th percentile of minimal regimen to 95th percentile of maximal regimen. Colored histograms refer to the MIC distribution for common pathogens Haemophilus influenzae (red), Streptococcus Pneumoniae (blue) and Staphylococcus aureus (green) according to EUCAST (European Committee on Antimicrobial Susceptibility Testing). The gray solid vertical line represents the nonspecies‐specific breakpoint values for each drug to guide empiric treatment. fT > MIC, fraction of time of the free drug concentration being above the MIC; IV, intravenous; MIC, minimum inhibitory concentration; R, resistant breakpoint; S, sensitive breakpoint.

Figure 3

Probability of target attainment (100%fT > MIC) for simulated dosing regimen in the sepsis subpopulation. Solid line, median for common regimen; dark gray area, 90% prediction interval for common regimen; light gray area, 5th percentile of minimal regimen to 95th percentile of maximal regimen. Colored histograms refer to the MIC distribution for common pathogens Escherichia coli (red), Klebsiella pneumoniae (green), and Pseudomonas aeruginosa (blue) according to EUCAST (European Committee on Antimicrobial Susceptibility Testing). The gray solid vertical line represents Enterobacterales breakpoints for each drug to guide empiric treatment. fT > MIC, fraction of time of the free drug concentration being above the MIC; MIC, minimum inhibitory concentration; R, resistant breakpoint; S, sensitive breakpoint.

Figure 4

Probability of target attainment (100%fT > MIC) for simulated dosing regimen in the meningitis subpopulation. Solid line, median for common regimen; dark gray area, 90% confidence interval for common regimen; light gray area, 5th percentile of minimal regimen to 95th percentile of maximal regimen. Colored histograms refer to the MIC distribution for common pathogens Neisseria meningitidis (green), Streptococcus pneumoniae (blue) and Escherichia coli (red) according to EUCAST (European Committee on Antimicrobial Susceptibility Testing). The dark gray solid vertical line represents Enterobacterales breakpoints for each drug to guide empiric treatment. fT > MIC, fraction of time of the free drug concentration being above the MIC; MIC, minimum inhibitory concentration; R, resistant breakpoint; S, sensitive breakpoint.

Figure 5

Coverage calculated as percentage of individuals above the PKPD target of 100%fT > MIC for each simulated drug for the three different syndromes. Each bar represents the coverage of the common regimen, with the error bar showing results of the minimal to maximal simulated regimen. Bars are split up by sensitive and resistant MIC breakpoints for Enterobacteraes (sepsis and meningitis) or nonspecific (pneumonia). fT > MIC, fraction of time of the free drug concentration being above the MIC; IV, intravenous; MIC, minimum inhibitory concentration; PKPD, pharmacokinetic‐pharmacodynamic.

Figure 6

Percentage of subjects above toxicity threshold (>35 mg/L) for cephalosporins and the respective syndrome. Plots are grouped by age. Each bar represents the fraction of simulated individual with a trough concentration at steady state above the toxicity threshold. min, minimal; max, maximal.