Dosing of Ceftriaxone and Metronidazole for Children With Severe Acute Malnutrition

Joseph F Standing, Martin O Ongas, Caroline Ogwang, Nancy Kagwanja, Sheila Murunga, Shalton Mwaringa, Rehema Ali, Neema Mturi, Moline Timbwa, Christine Manyasi, Laura Mwalekwa, Victor L Bandika, Bernhards Ogutu, Joseph Waichungo, Karin Kipper, James A Berkley, FLACSAM-PK Study Group, Joseph F Standing, Martin O Ongas, Caroline Ogwang, Nancy Kagwanja, Sheila Murunga, Shalton Mwaringa, Rehema Ali, Neema Mturi, Moline Timbwa, Christine Manyasi, Laura Mwalekwa, Victor L Bandika, Bernhards Ogutu, Joseph Waichungo, Karin Kipper, James A Berkley, FLACSAM-PK Study Group

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.

© 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Prediction corrected visual predictive check (VPC) for total and unbound ceftriaxone (top row) showing model simulated 95% confidence intervals for the simulated 2.5th, 50th, and 97.5th percentiles.
Figure 2
Figure 2
Prediction corrected visual predictive check (VPC) for metronidazole and hydroxymetronidazole showing model simulated 95% confidence intervals for the simulated 2.5th, 50th, and 97.5th percentiles.
Figure 3
Figure 3
ft > MIC for 50, 80, and 100 mg/kg once daily. The 5th, 10th, 20th, and 50th percentiles show the cutoffs for ft > MIC for 95, 90, 80, and 50% of patients, respectively. Lines at a MIC cutoff of 2 mg/L and ft > MIC of 0.5 show the proposed MIC target.
Figure 4
Figure 4
Simulations for free metronidazole plus hydroxymetronidazole under 10, 12.5, and 15 mg/kg twice daily dosing, with hydroxymetronidazole concentrations being multiplied by 0.65 to reflect the assumed lower activity. A break‐point of 8 mg/L is highlighted. (a) Yhe ft > MIC with a value of 0.9 highlighted; whereas (b) shows the AUC:MIC ratio with a cutoff of 70 mg.h/L highlighted. A comparison of 24‐ and 48‐hour target attainment is given in the upper and lower panels, respectively.
Figure 5
Figure 5
Boxplots to illustrate simulated covariate effects on translation to ft > MIC. Probability of target attainment reported beneath each box with a target of 50% of the dosing interval with concentrations above 2 mg/L at 24 hours for free ceftriaxone, and 90% of the dosing interval with concentrations of free metronidazole and 0.65 x hydroxymetronidazole above 8 mg/L at 48 hours. (a) Effect of edema score of 1 or more on ceftriaxone target attainment. (b) Effect of edema score of 2 or more on metronidazole target attainment. (c) Effect of serum creatinine on ceftriaxone target attainment.

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