Dosing of Ceftriaxone and Metronidazole for Children With Severe Acute Malnutrition

Abstract

Infants and young children with severe acute malnutrition (SAM) are treated with empiric broad‐spectrum antimicrobials. Parenteral ceftriaxone is currently a second‐line agent for invasive infection. Oral metronidazole principally targets small intestinal bacterial overgrowth. Children with SAM may have altered drug absorption, distribution, metabolism, and elimination. Population pharmacokinetics of ceftriaxone and metronidazole were studied, with the aim of recommending optimal dosing. Eighty‐one patients with SAM (aged 2–45 months) provided 234 postdose pharmacokinetic samples for total ceftriaxone, metronidazole, and hydroxymetronidazole. Ceftriaxone protein binding was also measured in 190 of these samples. A three‐compartment model adequately described free ceftriaxone, with a Michaelis–Menten model for concentration and albumin‐dependent protein binding. A one‐compartment model was used for both metronidazole and hydroxymetronidazole, with only 1% of hydroxymetronidazole predicted to be formed during first‐pass. Simulations showed 80 mg/kg once daily of ceftriaxone and 12.5 mg/kg twice daily of metronidazole were sufficient to reach therapeutic targets.

The effect of acute malnutrition on enteric pathogens, moderate-to-severe diarrhoea, and associated mortality in the Global Enteric Multicenter Study cohort: a post-hoc analysis

“…A recent study in Mozambique 22 noted dysentery to have an inverse association with death, and suggested that this could be linked to the treatment of dysentery with antibiotics. Antibiotic effectiveness among malnourished children might be decreased by delayed presentation to hospital, increased prevalence of antibiotic-resistant organisms, 23 or an altered pharmacokinetic profile, 24 which could explain the stronger association between dysentery and death in this group. Additionally, children with acute malnutrition are thought to be particularly vulnerable to dehydration, fluid overload, and electrolyte imbalances.…”

Pediatric Drug–Drug Interaction Studies: Barriers and Opportunities

“…Quantitative approaches, such as population PK (PopPK) and PBPK modeling and simulation, can be used to evaluate pediatric DDIs during drug development. PopPK modeling combined with sparse sampling is widely used to characterize drug disposition in neonates and children . Implementing allometric scaling for size in addition to a sigmoidal function accounting for organ maturation may be able to distinguish age and size effects on clearance from other patient‐specific factors, including DDIs .…”

“…PopPK modeling combined with sparse sampling is widely used to characterize drug disposition in neonates and children. 7 Implementing allometric scaling for size in addition to a sigmoidal function accounting for organ maturation may be able to distinguish age and size effects on clearance from other patientspecific factors, including DDIs. 8 If a concomitant drug is identified as a significant predictor of variability in a PK parameter, simulations can be performed to optimize dosing for children receiving the drug combination.…”

Population pharmacokinetic models of first choice beta-lactam antibiotics for severe infections treatment: What antibiotic regimen to prescribe in children?

“…Other covariates such as comedications with vasopressor drugs or gentamicin, and pathology with severity score or edema are used in some specific studies (20,24,31,49).…”