Veshni Pillay-fuentes Lorente 1, Rohan Benecke 1, Tim Cressey 2, Eric Decloedt 1, Adrie Bekker 3
1 Division of Clinical Pharmacology, Stellenbosch University (Cape Town, South Africa), 2 AMS-PHPT Research Collaboration, Faculty of Associated Medical Sciences, Chiang Mai University, (Chiang Mai, Thailand), 3 Department of Paediatrics and Child Health, Stellenbosch University (Cape Town, South Africa)
Background and Objectives: Gram-negative bacteria (GNB) is the most common cause of early onset sepsis (53%) and late onset neonatal sepsis (71%) in low-to-middle-income countries.(1) A large proportion of these GNB are resistant to first- and second line WHO-recommended antibiotic regimens as well as carbapenems.(2) Colistin is a polymyxin used as “salvage therapy” in patients with multi-drug resistant GNB infections. Colistin dosing guidelines are well established for adults (3), but dosing recommendations are lacking for children, particularly during the neonatal period. Colistin is administered as a prodrug, Colistimethate sodium (CMS). The PRECISION study is a prospective, observational trial aimed at investigating the pharmacokinetics (PK) and safety of CMS and colistin in neonates. A sparse PK sampling approach is required due to blood draw volume restrictions in neonates. Herein, we applied a pharmacometrics approach to identify the sparse PK sampling schedule that would provide the most accurate estimation of area under the concentration time curve (AUC) and good precision of clearance parameters for both CMS and colistin in neonates.
Methods: A 2-compartment CMS and 1-compartment colistin popPK model with linear elimination, developed with adult data (4), was optimized by adding a maturation model (5) to the clearance of CMS and allometrically scaled for weight on clearance and volume parameters, with fixed exponents, 0.75 and 1.0, respectively. Creatinine clearance (CrCl) was included as a covariate in the model. Patient characteristics including weight, gestational age (GA), postmenstrual age (PMA), postnatal age (PNA), CrCl and individual dosing from a prior study of neonates on colistin in South African centre was used to simulate a virtual cohort. The virtual cohort of 24 neonates was simulated with individualized CMS dosing, generating 10,000 Monte Carlo replicates per neonate to characterize PK variability and derive reference AUCs from intensive sampled profiles for both first dose (0–12 h) and steady-state (72–84 h) exposure. Eight sparse sampling strategies were assessed during the first dosing interval (AUC₀–₁₂) and again at steady state (AUCss). Sparse sampling strategies were assessed using a nested bootstrap of 1,000 trials of 24 resampled subjects, reflecting parameter uncertainty in the CMS/colistin model. AUC₀–₁₂ and AUCss estimated from the sparse sampling strategies were compared against true AUCs obtained from rich sampling. The best scenario for each sampling phases was also assessed using PopED (version0.7.0). The relative bias (%) for each sparse sampling strategy compared to the intensive reference was calculated. The optimal sampling design was implemented using R (version 4.4.3 (2025-02-28 ucrt)) and RStudio (version 2024.12.1.563).
Results: Median neonate body weight was 1.8 kg (range: 1.0 – 3.3), postmenstrual age 35.5 weeks (range: 29.3 – 44.0), postnatal age of 18 days (range: 6 – 83) and creatinine clearance was 48.25 mL/min/1.72m2 (range: 23.4 – 113.6). The best 3 sparse PK sampling strategies during the first dosing interval were: 2, 4 and 12 hours post loading dose (mean relative bias [MRB], -15.53%); 2 and 11-hours post loading dose (MRB -23.23%) and 1.5, 6 and 10 hours post loading dose (MRB -26.35%). At steady state, the 3 best sampling time points were: pre-dose, 6 and 12 hours post-dose (MRB -7.09%); pre-dose, 2 and 11 hours post-dose (MRB -8.86%) and pre-dose, 3 and 10 hours post-dose (MRB -17.87%). All 6 sampling strategies were evaluated using D-optimal design for a sample size of 24 patients and all strategies demonstrated good RSE (<30%) on the clearance parameters of both CMS and colistin. Conclusion: We identified 3-point sparse sampling strategies as the best approach following the first dose of CMS and at steady state in the neonatal population. A 2-point sparse sampling strategy could also be utilized if required within the first dosing interval. The sparse sampling scenarios identified provided precise estimates of CMS and colistin clearance parameters. These results will be applied as a practical and feasible sampling strategy when assessing CMS and colistin PK in neonates for the PRECISION study. References: References: 1. Harrison ML, Dickson BFR, Sharland M, Williams PCM. Beyond Early- and Late-onset Neonatal Sepsis Definitions: What are the Current Causes of Neonatal Sepsis Globally? A Systematic Review and Meta-analysis of the Evidence. Pediatr Infect Dis J. 2024 Dec 1;43(12):1182-1190. doi: 10.1097/INF.0000000000004485. Epub 2024 Nov 8. PMID: 39264197; PMCID: PMC11542974. 2. Russell NJ, Stöhr W, Plakkal N, Cook A, Berkley JA, Adhisivam B, et al. Patterns of antibiotic use, pathogens, and prediction of mortality in hospitalized neonates and young infants with sepsis: A global neonatal sepsis observational cohort study (NeoOBS). PLOS Medicine. 2023;20(6):e1004179 https://doi.org/10.1371/journal.pmed.1004179.10.1371/journal.pmed.1004179 3. Tsuji BT, Pogue JM, Zavascki AP, Paul M, Daikos GL, Forrest A, Giacobbe DR, Viscoli C, Giamarellou H, Karaiskos I, Kaye D, Mouton JW, Tam VH, Thamlikitkul V, Wunderink RG, Li J, Nation RL, Kaye KS. International Consensus Guidelines for the Optimal Use of the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). Pharmacotherapy. 2019 Jan;39(1):10-39. doi: 10.1002/phar.2209. PMID: 30710469; PMCID: PMC7437259. 4. Pillay-Fuentes Lorente VA-O, Abulfathi AA, Marais JA-O, De Jong J, Kellermann TA-O, Mashishi D, et al. Pharmacokinetics of colistin in adult critically ill patients in South Africa. LID - dkag011 [pii] LID - 10.1093/jac/dkag011 [doi]. (1460-2091 (Electronic)) 5. Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, et al. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatric Nephrology. 2009;24(1):67-76 https://doi.org/10.1007/s00467-008-0997-5.10.1007/s00467-008-0997-5
Reference: PAGE 34 (2026) Abstr 12165 [www.page-meeting.org/?abstract=12165]
Poster: Methodology - Study Design