Achieving therapeutic antibiotic levels during intermittent dosing of meropenem and piperacillin-tazobactam in critically ill children: the ATACC study

ABSTRACT Achieving antibiotic pharmacodynamic targets is critical to surviving sepsis. The purpose of this study was to determine the achievement of pharmacodynamic target—free minimum plasma concentration (fCmin)—during the first 2 days of high-dose 6-h intravenous meropenem or piperacillin-tazobactam in critically ill children, and to identify its predictors. This was a prospective observational study conducted in two pediatric intensive care units of children admitted between 2022 and 2023 who were prescribed meropenem or piperacillin-tazobactam. Primary outcomes were achievement of pharmacodynamic target fCmin (defined as fCmin>MIC or fCmin>4×MIC). Secondary outcomes included predictors of target concentrations and time to resolution of signs of severe infection using univariate and multivariable regressions. Of 49 patients, 47 had an antibiotic concentration measured at 24 h, and 38 at 48 h. At 24 h, 48 h, or either time point, augmented renal clearance (ARC) occurred in 13/30 (43%), 14/22 (64%), and 17/30 (57%), respectively. For epidemiologic cutoff values, fCmin>MIC occurred in 17/47 (36%) and 13/38 (34%) at 24 and 48 h, and fCmin>4×MIC occurred in 3/47 (6%) and 4/38 (11%). Target tazobactam concentrations (fCmin>0.5 or >2mg/L) occurred in 48% or 64% of the patients and 28% or 39% of the patients at 24 and 48 h. Potentially neurotoxic concentrations occurred in 1/9 (11%) patients on meropenem at 48 h, and in none receiving piperacillin-tazobactam. Only ARC independently predicted not achieving fCmin>MIC at 48 h (odds ratio 0.04 [95% CI 0.00, 0.69] P = 0.026). Therapeutic antibiotic concentration did not predict the time to resolution of severe symptoms and signs of sepsis (n = 32). In this cohort of critically ill children, high doses of piperacillin-tazobactam or meropenem did not often achieve pharmacodynamic targets and were rarely toxic.