I-104 Aaqilah Fataar

Using Bayesian Modelling to Evaluate the Effect of a Neonatal Vancomycin Loading Dose on Therapeutic Target Attainment in a Low-Middle Income Country

Aaqilah Fataar (1), Veshni Pillay-Fuentes Lorente (2), Eric Decloedt (2), Andrew van Eck (1), Kessendri Reddy (3), Angela Dramowski (1), Adrie Bekker (1)

(1) Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; (2) Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; (3) Division of Medical Microbiology, Department of Pathology, Stellenbosch University and National Health Laboratory Service, Tygerberg Hospital, Cape Town, South Africa

Introduction: Vancomycin, a glycopeptide antibiotic, has served as a cornerstone in treating hospital-acquired Gram-positive infections for over five decades. Recommended for both adult and paediatric patients, the administration of loading doses aims to swiftly achieve target concentrations, facilitating prompt and effective sepsis treatment within the crucial golden hour.1-3 Nonetheless, within the neonatal cohort, the therapeutic merit of vancomycin loading doses remains contentious in the literature.4 This debate stems from concerns over potential toxicity, particularly ototoxicity in preterm neonates.5 To ensure both efficacy and safety, therapeutic drug monitoring (TDM) is indispensable for vancomycin dosing.6 Utilising Bayesian modelling approaches, we’ve leveraged its predictive capabilities to tailor vancomycin dosing for paediatric patients in South Africa.

Objectives: The objectives of this study were twofold: firstly, to assess the effectiveness of the current vancomycin loading dose practices at our hospital in achieving therapeutic target concentrations utilising a Bayesian modelling approach in neonates undergoing treatment for clinical sepsis. Secondly, to explore potential adverse events associated with vancomycin exposure in this population.

Methods: A retrospective cohort study and medical record review was conducted to compare vancomycin target attainment (specifically, area under the curve 0 – 24 hours (AUC0-24)/minimum inhibitory concentration (MIC) ³ 400)6 in neonates. This evaluation compared data before and after the implementation of revised vancomycin prescribing guidelines at a neonatal unit in Cape Town, South Africa. The revised prescribing practice entailed the administration of a 25 mg/kg loading dose followed by the customary 15 mg/kg maintenance dose which mirrored the prior approach. In line with standard practice, the Bayesian modelling software NextDose (https://www.nextdose.org/), was employed to compute the AUC from pre-dose trough concentrations during both periods, facilitating the comparison. Regression analyses were conducted, integrating multiple imputation techniques to account for missing data. Key variables including gestational age, creatinine levels, and sex were adjusted for in the analysis to mitigate potential confounding factors.

Results: A total of two hundred and ten neonates were enrolled in the study, providing 80% statistical power. Among them, seventy-five percent (157/210) were born preterm (<37 weeks gestation), with two-thirds (66%; 104/157) of these neonates born before 32 weeks gestation. Early target attainment (within 8 – 12 hours of treatment initiation) was significantly higher in the ‘loading dose’ group compared to the ‘no loading dose’ group (97 out of 105 [92.4%] vs 64 out of 105 [61.0%] respectively; p = <0.001). However, the overall proportion of neonates achieving target attainment at 24 hours did not exhibit significant differences between groups (73 out of 105 [69.5%] in the ‘loading dose’ group vs 62 out of 105 [59.0%] in the ‘no loading dose’ group; p = 0.110). Multivariable regression analysis revealed a twofold increase in the odds of target attainment among neonates receiving a loading dose of vancomycin. The incidence of nephrotoxicity was low, with 2 out of 105 (1.9%) neonates affected in both the ‘loading dose’ and ‘no loading dose’ groups.

Conclusions: Employing a Bayesian modelling approach enabled us to determine that loading doses of 25 mg/kg given to neonates, were effective in achieving target attainment earlier in the vancomycin treatment regimen. The inclusion of a vancomycin loading dose in neonatal treatment guidelines demonstrated a notable enhancement in the likelihood of achieving therapeutic targets within 24 hours. These findings highlight the potential clinical benefits associated with implementing vancomycin loading doses in neonatal care and could potentially improve treatment outcomes. Further research is warranted to comprehensively assess the effect of vancomycin loading doses on patient outcomes and the long-term efficacy and safety of this approach in the neonatal population.

References:

  1. Jacqz-Aigrain E, Leroux S, Thomson AH et al. Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young infants. J Antimicrob Chemother 2019; 74(8): 2128–2138.
  2. Ocampos-Martinez E, Penaccini L, Scolletta S et al. Determinants of early inadequate vancomycin concentrations during continuous infusion in septic patients. Int J Antimicrob Agents 2012; 39(4): 332-337.
  3. Mohammedi I, Descloux E, Argaud L et al. Loading dose of vancomycin in critically ill patients: 15 mg/kg is a better choice than 500 mg. Int J Antimicrob Agents 2006; 27(3): 259-262.
  4. Alrahahleh DA, Xu S, Luig M et al. Dosing of vancomycin and target attainment in neonates: a systematic review. Int J Antimicrob Agents 2022; 59(106515).
  5. Hill LF, Clements MN, Turner MA et al. Optimised versus standard dosing of vancomycin in infants with gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trial. Lancet Child Adolesc Health 2021; 6(1): 49–59.
  6. Rybak MJ, Le J, Lodise TP et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: A revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2020; 77(11): 835-864.

Reference: PAGE 32 (2024) Abstr 10863 [www.page-meeting.org/?abstract=10863]

Poster: Clinical Applications