Early Bayesian Dose Adjustment of Vancomycin Continuous Infusion in Children: a Randomized Controlled Trial

Romain Berthaud; Sihem Benaboud; Déborah Hirt; Mathieu Genuini; Mehdi Oualha; Martin Castelle; Coralie Briand; Solène Artru; Lorenzo Norsa; Olivia Boyer; Frantz Foissac; Naïm Bouazza; Jean-Marc Tréluyer

doi:10.1128/AAC.01102-19

Early Bayesian Dose Adjustment of Vancomycin Continuous Infusion in Children: a Randomized Controlled Trial

Antimicrob Agents Chemother. 2019 Sep 9;63(12):e01102-19. doi: 10.1128/AAC.01102-19. Epub 2019 Oct 7.

Authors

Romain Berthaud^{1

2

3}, Sihem Benaboud^{4

2}, Déborah Hirt^{4

2}, Mathieu Genuini⁵, Mehdi Oualha^{4

2

5}, Martin Castelle⁶, Coralie Briand⁶, Solène Artru⁷, Lorenzo Norsa⁷, Olivia Boyer³, Frantz Foissac^{4

2}, Naïm Bouazza^{4

2}, Jean-Marc Tréluyer^{4

2

5}

Affiliations

¹ EA 7323 - Pharmacology and Therapeutic Evaluation in children and pregnant women, Paris Descartes University, Sorbonne Paris Cité University, Paris, France. romain.berthaud@aphp.fr.
² Clinical Research Department Paris Descartes Necker Cochin, Paris, France.
³ Department of Pediatric Nephrology, Necker-Enfants Malades hospital, Assistance Publique-Hoôpitaux de Paris, Paris, France.
⁴ EA 7323 - Pharmacology and Therapeutic Evaluation in children and pregnant women, Paris Descartes University, Sorbonne Paris Cité University, Paris, France.
⁵ Pediatric Intensive Care Unit, Necker-Enfants Malades hospital, Assistance Publique-Hoôpitaux de Paris, Paris, France.
⁶ Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades hospital, Assistance Publique-Hoôpitaux de Paris, Paris, France.
⁷ Department of Pediatric Gastroenterology, Hepatology and Nutrition, Necker-Enfants Malades hospital, Assistance Publique-Hoôpitaux de Paris, Paris, France.

Abstract

Methicillin-resistant staphylococcal infections are a global burden. Area under the serum concentration-time curve to minimum inhibitory concentration (AUC/MIC) ratio is the pharmacokinetic (PK) parameter that best predicts vancomycin efficacy. Its therapeutic range is narrow, difficult to achieve because of a wide intersubject variability, especially in children, and is not routinely targeted since the AUC is rarely available. We investigated if an early Bayesian dose adjustment would increase the rate of vancomycin target attainment, in the first 24 hours of treatment (H24), in children.We conducted a single-centre randomized controlled trial in 4 pediatric departments of Necker-Enfants Malades hospital (Paris, France). Patients aged 3 months to 17 years for whom intravenous vancomycin was started were eligible and randomized in a 1:1 ratio: routine care were compared with an early vancomycin therapeutic drug monitoring (3h after treatment initiation) followed by an early Bayesian dose adjustment using a previously published population-based PK model that included age, bodyweight and serum creatinine as covariates. The primary outcome was the proportion of patients of each group achieving vancomycin therapeutic range at H24, defined by AUC_0-24/MIC≥400 and AUC_0-24 ≤800mg-h/L.Ninety-nine patients were enrolled: 49 were randomized to the Bayesian group and 50 to the control group. Modified intention-to-treat analysis included 82 patients: 85% of Bayesian group patients achieved H24 vancomycin target versus 57% of control group patients (p=0.007) with no difference regarding iatrogenic events. Early Bayesian dose adjustment increased the proportion of children achieving vancomycin target at H24, which may improve clinical outcomes of methicillin-resistant staphylococcal infections.