Population Pharmacokinetics of Trimethoprim-Sulfamethoxazole in Infants and Children

• Published in: Antimicrobial agents and chemotherapy Vol. 62; no. 1
• Main Authors: Autmizguine, Julie, Melloni, Chiara, Hornik, Christoph P., Dallefeld, Samantha, Harper, Barrie, Yogev, Ram, Sullivan, Janice E., Atz, Andrew M., Al-Uzri, Amira, Mendley, Susan, Poindexter, Brenda, Mitchell, Jeff, Lewandowski, Andrew, Delmore, Paula, Cohen-Wolkowiez, Michael, Gonzalez, Daniel
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.01.2018
• Subjects: Adolescent; Adult; Anti-Bacterial Agents; Anti-Bacterial Agents - pharmacokinetics; Child; Child, Preschool; Clinical Therapeutics; Female; Humans; Infant; Infant, Newborn; Male; Methicillin-Resistant Staphylococcus aureus - drug effects; Prospective Studies; Staphylococcal Infections - drug therapy; Trimethoprim, Sulfamethoxazole Drug Combination; Trimethoprim, Sulfamethoxazole Drug Combination - pharmacokinetics; Young Adult; pharmacokinetics; methicillin-resistant Staphylococcus aureus; infants; children; trimethoprim; sulfamethoxazole
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/AAC.01813-17

Trimethoprim (TMP)-sulfamethoxazole (SMX) is used to treat various types of infections, including community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) and Pneumocystis jirovecii infections in children. Pharmacokinetic (PK) data for infants and children are limited, and the optimal dosing is not known. We performed a multicenter, prospective PK study of TMP-SMX in infants and children. Separate population PK models were developed for TMP and SMX administered by the enteral route using nonlinear mixed-effects modeling. Optimal dosing was determined on the basis of the matching adult TMP exposure and attainment of the surrogate pharmacodynamic (PD) target for efficacy, a free TMP concentration above the MIC over 50% of the dosing interval. Data for a total of 153 subjects (240 samples for PK analysis) with a median postnatal age of 8 years (range, 0.1 to 20 years) contributed to the analysis for both drugs. A one-compartment model with first-order absorption and elimination characterized the TMP and SMX PK data well. Weight was included in the base model for clearance (CL/ F ) and volume of distribution ( V / F ). Both TMP and SMX CL/ F increased with age. In addition, TMP and SMX CL/ F were inversely related to the serum creatinine and albumin concentrations, respectively. The exposure achieved in children after oral administration of TMP-SMX at 8/40 mg/kg of body weight/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 320/1,600 mg/day divided into administration every 12 h and achieved the PD target for bacteria with an MIC of 0.5 mg/liter in >90% of infants and children. The exposure achieved in children after oral administration of TMP-SMX at 12/60 and 15/75 mg/kg/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 640/3,200 mg/day divided into administration every 12 h in subjects 6 to <21 years and 0 to <6 years of age, respectively, and was optimal for bacteria with an MIC of up to 1 mg/liter.