Clindamycin Pharmacokinetics and Safety in Preterm and Term Infants

Abstract

Clindamycin may be active against methicillin-resistant Staphylococcus aureus, a common pathogen causing sepsis in infants, but optimal dosing in this population is unknown. We performed a multicenter, prospective pharmacokinetic (PK) and safety study of clindamycin in infants. We analyzed the data using a population PK analysis approach and included samples from two additional pediatric trials. Intravenous data were collected from 62 infants (135 plasma PK samples) with postnatal ages of <121 days (median [range] gestational age of 28 weeks [23 to 42] and postnatal age of 17 days [1 to 115]). In addition to body weight, postmenstrual age (PMA) and plasma protein concentrations (albumin and alpha-1 acid glycoprotein) were found to be significantly associated with clearance and volume of distribution, respectively. Clearance reached 50% of the adult value at PMA of 39.5 weeks. Simulated PMA-based intravenous dosing regimens administered every 8 h (≤32 weeks PMA, 5 mg/kg; 32 to 40 weeks PMA, 7 mg/kg; >40 to 60 weeks PMA, 9 mg/kg) resulted in an unbound, steady-state concentration at half the dosing interval greater than a MIC for S. aureus of 0.12 μg/ml in >90% of infants. There were no adverse events related to clindamycin use. (This study has been registered at ClinicalTrials.gov under registration no. NCT01728363.).

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Figures

FIG 1

(A) Alpha-1 acid glycoprotein versus volume of distribution (V); (B) postmenstrual age versus V. The black line and shaded area denote the loess curve and an associated 95% confidence region.

FIG 2

Simulated steady-state area under the total clindamycin concentration versus time curve from 0 to 8 h (AUCss,0–8) after intravenous dosing to achieve exposure comparable to observed adult values after 600 mg intravenously every 8 h (mean [standard deviation], 31.8 μg · h/ml [6.7]) (19). (A and B) AUCss,0–8 versus postmenstrual age and total body weight after age-based dosing: ≤32 weeks' postmenstrual age, 5 mg/kg every 8 h; >32 to 40 weeks' postmenstrual age, 7 mg/kg every 8 h; and >40 to 60 weeks' postmenstrual age, 9 mg/kg every 8 h. (C and D) AUCss,0–8 versus postnatal age and total body weight after 12 mg/kg every 8 h for infants > 5 months to 1 year of age. The shaded regions denote the 90% (95th and 5th percentiles), 80% (90th and 10th percentiles), and 50% (75th and 25th percentiles) prediction intervals from lightest to darkest color intensity, respectively. The dashed black lines denote the 95th, 75th, 25th, and 5th percentiles, respectively. The solid black line is the median.