Optimised versus standard dosing of vancomycin in infants with Gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trial

Hill, Leonard; Clements, Michelle N.; Turner, Mark A.; Donà, Daniele; Lutsar, Irja; Jacqz-Aigrain, Évelyne; Heath, Paul T.; Roilides, Emmanuel; Rawcliffe, Louise; Alonso-Díaz, Clara; Baraldi, Eugenio; Dotta, Andrea; Ilmoja, Mari‐Liis; Mahaveer, Ajit; Metsvaht, Tuuli; Mitsiakos, Georgıos; Papaevangelou, Vassiliki; Sarafidis, Kosmas; Walker, A Sarah; Bafadal, Basma; Al, Allen; Anatolitou, Fani; Vecchio, Antonio Del; Giuffrè, Mario; Karachristou, Korina; Manzoni, Paolo; Martinelli, Stefano; Moriarty, Paul; Nika, Angeliki; Papaevangelou, Vana; Roehr, Charles Christoph; Alcobendas, Laura Sanchez; Siahanidou, Tania; Tzialla, Chryssoula; Bonadies, Luca; Booth, Nicola; Morales-Betancourt, Paola Catalina; Cordeiro, Malaika; Romero, Concha de Alba; Cruz, Javier de la; Luca, Maia De; Farina, Daniele; Franco, Caterina; Gialamprinou, Dimitra; Hallik, Maarja; Ilardi, Laura; Insinga, Vincenzo; Iosifidis, Εlias; Kalamees, Riste; Kontou, Angeliki; Molnár, Zoltán; Nikaina, Eirini; Petropoulou, C.; Reyné, Mar; Tataropoulou, Kassandra; Triantafyllidou, Pinelopi; Vontzalidis, Adamantios; Sharland, Mike

doi:10.1016/s2352-4642(21)00305-9

Cited by 13 publications

(12 citation statements)

References 25 publications

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“…12 Dosing regimens as advised in the summary of product characteristics, or suggested by Lexicomp and Neofax Hi-Dose, resulted in excessive exposure within 24 h of vancomycin treatment (68% and 93%, respectively). [21][22][23] None of the simulated dosing regimens reached a target attainment of ≥90% due to the considerable IIV. A vancomycin loading dose of 10 mg/kg, followed by 24 mg/kg/ day in 4 doses, resulted in the highest percentage of appropriate exposure, both at the initiation and after 48 h of vancomycin treatment.…”

Section: Resultsmentioning

confidence: 99%

“…loading dose of 25 mg/kg, followed by 45 mg/kg/day in 3 doses), brings a large majority of neonates with perinatal asphyxia treated with TH above target within 24 h of treatment. 6,18,20,23 It is important to highlight that the absence of a definitive consensus on vancomycin dosing in neonates has resulted in a heterogeneous empirical dosing approach in clinical practice worldwide. 39 As more research emerges to explore the optimal vancomycin dosing strategy for neonates in general, there is a growing trend to disfavour regimens with low doses due to their inadequate exposure outcomes, and to adopt regimens with high loading and maintenance doses.…”

Section: Discussionmentioning

confidence: 99%

“…39 As more research emerges to explore the optimal vancomycin dosing strategy for neonates in general, there is a growing trend to disfavour regimens with low doses due to their inadequate exposure outcomes, and to adopt regimens with high loading and maintenance doses. 6,23 PPK studies that have provided the basis for the latter dosing regimens have also demonstrated their suitability for MIPD in neonates. 2 Nonetheless, it is crucial to exercise caution when applying these findings to neonates with perinatal asphyxia treated with TH.…”

Section: Discussionmentioning

confidence: 99%

“…Using Monte Carlo simulations (n = 5000) with the empirical Bayesian estimates from the final PPK model, existing dosing guidelines (summary of product characteristics, Lexicomp, Dutch paediatric formulary, Neofax Hi-Dose regimens) were evaluated for our patient population. 12,[20][21][22][23] If these guidelines resulted in suboptimal target attainment, alternative vancomycin dosing regimens were evaluated. A minimum of 90% of simulated neonates with a vancomycin AUC 0-24 / MIC ratio of 400-600 mg*h/L was used as a target.…”

Section: Simulations To Evaluate Current and New Dosing Regimensmentioning

confidence: 99%

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Population pharmacokinetics of vancomycin in term neonates with perinatal asphyxia treated with therapeutic hypothermia

van der Veer,

de Haan,

Franken

et al. 2024

Brit J Clinical Pharma

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AimsLittle is known about the population pharmacokinetics (PPK) of vancomycin in neonates with perinatal asphyxia treated with therapeutic hypothermia (TH). We aimed to describe the PPK of vancomycin and propose an initial dosing regimen for the first 48 h of treatment with pharmacokinetic/pharmacodynamic target attainment.MethodsNeonates with perinatal asphyxia treated with TH were included from birth until Day 6 in a multicentre prospective cohort study. A vancomycin PPK model was constructed using nonlinear mixed‐effects modelling. The model was used to evaluate published dosing guidelines with regard to pharmacokinetic/pharmacodynamic target attainment. The area under the curve/minimal inhibitory concentration ratio of 400–600 mg*h/L was used as target range.ResultsSixteen patients received vancomycin (median gestational age: 41 [range: 38–42] weeks, postnatal age: 4.4 [2.5–5.5] days, birth weight: 3.5 [2.3–4.7] kg), and 112 vancomycin plasma concentrations were available. Most samples (79%) were collected during the rewarming and normothermic phase, as vancomycin was rarely initiated during the hypothermic phase due to its nonempirical use. An allometrically scaled 1‐compartment model showed the best fit. Vancomycin clearance was 0.17 L/h, lower than literature values for term neonates of 3.5 kg without perinatal asphyxia (range: 0.20–0.32 L/h). Volume of distribution was similar. Published dosing regimens led to overexposure within 24 h of treatment. A loading dose of 10 mg/kg followed by 24 mg/kg/day in 4 doses resulted in target attainment.ConclusionResults of this study suggest that vancomycin clearance is reduced in term neonates with perinatal asphyxia treated with TH. Lower dosing regimens should be considered followed by model‐informed precision dosing.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Simulations To Evaluate Current and New Dosing Regimensmentioning

confidence: 99%

See 2 more Smart Citations

Population pharmacokinetics of vancomycin in term neonates with perinatal asphyxia treated with therapeutic hypothermia

van der Veer,

de Haan,

Franken

et al. 2024

Brit J Clinical Pharma

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“…The phenotype is often unstable and can appear susceptible when not under antimicrobial selection pressure 14 . In a multi-centre study in NICUs in Greece, Italy, Estonia, Spain, and the UK, 101/116 (87%) of identi ed CoNS showed vancomycin heteroresistance 15 .…”

Section: Introductionmentioning

confidence: 99%

Exploring real-world vancomycin target attainment in neonatal intensive care in the context of Staphylococcal infections: a retrospective observational cohort study

Blank,

Wilson,

Wan

et al. 2023

Preprint

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Background: Vancomycin is commonly prescribed in late onset sepsis (LOS) in neonatal intensive care (NICU). Despite variation in vancomycin population pharmacokinetics, a paucity of evidence exists to support dose optimisation. This study explored the relationship between trough vancomycin concentrations and estimated area-under-the-concentration-time-curve (AUC) to minimum inhibitory concentration (MIC) ratios in real-world practice. Methods: Patients treated with vancomycin for LOS in two tertiary NICUs between October 2022 and February 2023 were included. Electronic patient record data on demographics, microbiology, dosing, therapeutic drug monitoring (TDM), and outcomes were extracted; these were used to estimate individual patient AUC and AUC:MIC ratios using Bayesian forecasting. Trough and AUC estimates were compared. Target attainment was estimated using an AUC:MIC>400, and toxicity using AUC>600 mg·h/L. Estimates for target attainment were evaluated at different MICs. Results: 32 patients, with 41 discrete treatment episodes, were analysed. Median gestational age at birth was 26.5 (IQR 25-30) weeks. Ten patients (31%) were female and median weight was 0.87 (IQR 0.7-1.4) kg. Trough concentrations correlated poorly with AUC estimates (r2=0.38). Dose adjustment using troughs did not improve AUC/MIC target attainment. Acute kidney injury (AKI) occurred in 4/41 (10%) treatment episodes; peak median AUC was 1170.4 (IQR 839.1-1493.7) mg·h/L compared to 582.1 (IQR 485.4-699.3) mg·h/L in those without AKI. For individual episodes, AUC/MIC targets at day 2 would be met for vancomycin in 30/41 (73%) for organisms with an MIC of 1 mg/L, 1/41 (2%) for MIC 2 mg/L, and 0/41 (0%) for MIC 4 mg/L. Conclusion: Using trough based TDM correlated poorly with AUC-based estimates for target attainment. Dose adjustment using trough-based TDM fails to improve drug-exposure, especially with MIC >1mg/L.

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Role of fluid status markers as risk factors for suboptimal vancomycin concentration during continuous infusion in neonates: an observational study

et al. 2022

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Optimised versus standard dosing of vancomycin in infants with Gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trial

Cited by 13 publications

References 25 publications

Population pharmacokinetics of vancomycin in term neonates with perinatal asphyxia treated with therapeutic hypothermia

Population pharmacokinetics of vancomycin in term neonates with perinatal asphyxia treated with therapeutic hypothermia

Exploring real-world vancomycin target attainment in neonatal intensive care in the context of Staphylococcal infections: a retrospective observational cohort study

Role of fluid status markers as risk factors for suboptimal vancomycin concentration during continuous infusion in neonates: an observational study

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