Dosage Regimens for Meropenem in Children with Pseudomonas Infections Do Not Meet Serum Concentration Targets

Abstract

There have been literature reports that some recommended meropenem dosage regimens may fail to meet therapeutic targets in some high‐risk children and adults. We evaluated this observation in children using literature studies conducted in infants and children. Observed and, as necessary, simulated data from the literature were combined, yielding a data set of 288 subjects (1 day to ~ 17 years). A population pharmacokinetic model was fit to the data and then used to simulate the recommended dosing regimens and estimate the proportion of subjects achieving recommended target exposures. A two‐compartment model best fit the data with weight, postnatal age, gestational age, and serum creatinine as covariates. The US Food and Drug Administration (FDA)‐approved dosing regimens achieved targets in ~ 90% or more of subjects less than 3 months of age for organisms with minimum inhibitory concentration (MIC)'s of 2 and 4 mg/L; however, only 68.4% and 41.7% of subjects older than 3 months and weighing < 50 kg achieved target exposures for organisms with MIC's of 2 and 4 mg/L, respectively [Correction added on January 23, 2020, after first online publication: "> 3 months" corrected to "less than 3 months".]. Moreover, for subjects weighing more than 50 kg, only 41.3% and 17% achieved these respective targets. Simulation studies were used to explore the impact of changing dose, dosing interval, and infusion duration on the likelihood of achieving therapeutic targets in these groups. Our findings illustrate that current dosing recommendations for children over 3 months of age fail to meet therapeutic targets in an unacceptable fraction of patients. Further investigation is needed to develop new dosing strategies in these patients.

Reappraisal of the Optimal Dose of Meropenem in Critically Ill Infants and Children: a Developmental Pharmacokinetic-Pharmacodynamic Analysis

“…Then, we simulated the general optimal regimen and demonstrated that prolonging infusion to 4 h and 24 h with a lower dose (110 mg/kg/day) than those used previously by Cies et al (120 and 160 mg/kg/day as a continuous infusion against all susceptible Gramnegative bacteria [7]) would be efficacious and would reduce the overuse of meropenem. Hassan et al (15) illustrated that a 40 mg/kg/dose (q8h), 20 mg/kg/dose (q6h), or 20 mg/kg/dose (q8h) administered as a 3-h infusion should be efficacious. However, they did not enroll children with abnormal renal function or target critically ill children only.…”

“…The standard dosing regimen for meropenem administered as 10 to 40 mg/kg of body weight/dose every 8 h (q8h) infused for 0.5 h has been shown to achieve the pharmacodynamic (PD) target of 40% fT ϾMIC in clinically stable children (13). However, it does not meet an appropriate PD target in critically ill children and should be optimized (7,14,15). Two studies have assessed the PK to explore the appropriate dose in critically ill children (7,14), but no covariates were identified due to the small number of children enrolled.…”

Extended or Continuous Infusion of Carbapenems in Children with Severe Infections: A Systematic Review and Narrative Synthesis

“…At MICs of 2 and 4 mg/L, the PTAs were below 80%, the 3 h infusions increased PTAs to more than 99% at these MICs, and the PTAs could still reach 82.8% at 8 mg/L with good tolerability. In addition, Hassan et al [ 19 ] built PPK models using data pooled from published studies. The researchers also found that MICs of 2 and 4 mg/L and an EI time of 3 h yielded higher PTAs than conventional 0.5 h infusions did.…”

“…The Grading of Recommendations Assessment, Development and Evaluation approach (GRADE) was not performed, owing to the insufficient data. [19] PPK modeling and simulation children with infections 288/NA MER 10-40 mg/kg/dose q8 h-q12 h 1000 MER < 50 kg: 20 mg/kg/dose q8 h 0.5 h; 40 mg/kg/dose q8 h 0.5 h; 20 mg/kg/dose q6 h 0.5 h; 20 mg/kg/dose q8 h 3 h EI > 50 kg: 1 g/dose q8 h 0.5 h; 2 g/dose q8 h 0.5 h; 1 g/dose q6 h 0.5 h; 1 g/dose q8 h 3 h EI…”

Improving the efficacy for meropenem therapy requires a high probability of target attainment in critically ill infants and children

“…Meropenem shows time-dependent antibacterial activity related to the time that the plasma free concentration of meropenem exceeds the minimum inhibitory concentration (MIC) of the pathogen ( fT >MIC ) ( Mathew et al, 2016 ). Despite its wide use, the standard dosing regimen, administered as 10–40 mg/kg/dose (q8h) infused for 0.5 h, for critically ill infants, children ( Kongthavonsakul et al, 2016 ; Cies et al, 2017 ; Hassan et al, 2019 ; Wang et al, 2020 ) and adults( Alsultan et al, 2021 ) may fail to meet pharmacodynamic (PD) targets.…”