Population Pharmacokinetics of Trimethoprim-Sulfamethoxazole in Infants and Children

Abstract

Trimethoprim (TMP)-sulfamethoxazole (SMX) is used to treat various types of infections, including community-acquired methicillin-resistant (CA-MRSA) and 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/) and volume of distribution (/). Both TMP and SMX CL/ increased with age. In addition, TMP and SMX CL/ 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.

Oral Fluoroquinolone or Trimethoprim-Sulfamethoxazole vs ß-Lactams as Step-Down Therapy for Enterobacteriaceae Bacteremia: Systematic Review and Meta-analysis

“…Unlike with FQs and ß-lactams, there are insufficient data to determine the optimal PD parameter for efficacy of TMP-SMX, as data are conflicting on whether it exhibits time- or concentration-dependent killing [24, 25]. Autmizguine et al utilized free TMP concentrations above the MIC for >50% of the dosing interval (fT > MIC > 50%) as a surrogate PD target for TMP efficacy; simulations of oral TMP-SMX 12/60 mg/kg/d in those aged 6–21 years showed similar exposures to those in adults dosed at 320/1600 mg (double strength) orally every 12 hours, and achieving >90% PD target attainment against bacteria with an MIC of 1 mcg/mL.…”

Acute and long-term effects of antibiotics commonly used in laboratory animal medicine on the fecal microbiota

“…However, orally administered TMS is absorbed in the upper GI tract, distributes to tissues, and is largely eliminated through renal excretion in the urine [29,30]. The fraction that is not eliminated in urine is metabolized in the liver to inactive compounds [31]. This may explain, at least partially, the relative sparing of the gut microbiota in mice receiving oral TMS.…”

Antimicrobianos en neonatología. Parte I: Recomendaciones de dosificaciones basadas, en la más reciente evidencia en recién nacidos Comité Consultivo de Infecciones Neonatales, Sociedad Chilena de Infectología

“…Antimicrobianos Documento estafilocócicas y se utiliza en el tratamiento de pacientes ambulatorios con infecciones de piel y tejidos blandos causados por S. aureus resistente a meticilina adquirido en la comunidad (SARM-AC) 61 . El clásico estudio de 1982 62 , con una cohorte de RN de término y pretérmino, mostró como resultados FC que TMT tiene un volumen de distribución mucho mayor que SMX y ambos tienen una vida media que no dependía del aclaramiento de creatinina.…”

“…Un reciente estudio sobre FC/FD en < 6 años sugiere una dosis 12 mg/kg/día del componente de TMP, fraccionado cada 12 h, siendo adecuado para la mayoría de las infecciones -a excepción de RN prematuros, en quien debe utilizarse 15 mg/kg/día del componente de TMP, fraccionado cada 12 h-para cumplir con el objetivo FD y lograr el óptimo tratamiento de P. jirovecii 61 .…”