Exploring Real-World Vancomycin Target Attainment in Neonatal Intensive Care in the Context of Staphylococcal Infections: a Retrospective Observational Cohort Study

Dear Editor, We read with interest the article published by Gu and colleagues who report poor vancomycin target trough concentration attainment despite adequate institutional guideline adherence at a single UK centre.1Gu Q. Jones N. Drennan P. Peto T.E. Walker A.S. Eyre D.W. Assessment of an institutional guideline for vancomycin dosing and identification of predictive factors associated with dose and drug trough levels.J Infect. 2022; 85: 382-389https://doi.org/10.1016/j.jinf.2022.06.029Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar They propose altered guidelines using routinely available electronic health record data to improve trough concentration target compliance. An important question is whether achieving trough concentration correlates with clinical outcome. This is particularly important in high-risk populations, who are often under-represented in pharmacokinetic/pharmacodynamic (PK/PD) studies during development of antimicrobial dosing recommendations. Late onset neonatal sepsis (LOS) causes significant morbidity and mortality.2Hornik C.P. Fort P. Clark R.H. Watt K. Benjamin D.K. Smith P.B. et al.Early and late onset sepsis in very-low-birth-weight infants from a large group of neonatal intensive care units.Early Hum Dev. 2012; 88: S69-S74https://doi.org/10.1016/S0378-3782(12)70019-1Crossref PubMed Scopus (370) Google Scholar, 3Laurent F. Butin M. Staphylococcus capitis and NRCS-A clone: the story of an unrecognized pathogen in neonatal intensive care units.Clin Microbiol Infect. 2019; 25: 1081-1085https://doi.org/10.1016/j.cmi.2019.03.009Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar A recent call for research to support the management of Staphylococcus capitis (S.capitis) infections in neonatal intensive care units (NICUs) highlighted the need for greater understanding of optimal vancomycin dosing strategies.4Harvey E.J. Ashiru-Oredope D. Hill L.F. Demirjian A. Paranthaman K. Jauneikaite E. et al.Need for standardized vancomycin dosing for coagulase-negative staphylococci in hospitalized infants.Clin Microbiol Infect. 2023; 29: 10-12https://doi.org/10.1016/j.cmi.2022.09.016Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar S.capitis is a coagulase negative staphylococcus (CoNS) with documented resistance and heteroresistance to vancomycin.5Wan Y. Ganner M. Mumin Z. Ready D. Moore G. Potterill I. et al.Whole-genome sequencing reveals widespread presence of Staphylococcus capitis NRCS-A clone in neonatal units across the United Kingdom.J Infect. 2023; S0163445323003444https://doi.org/10.1016/j.jinf.2023.06.020Abstract Full Text Full Text PDF Scopus (0) Google Scholar, 6Rasigade J.-P. Raulin O. Picaud J.-C. Tellini C. Bes M. Grando J. et al.Methicillin-Resistant Staphylococcus capitis with Reduced Vancomycin Susceptibility Causes Late-Onset Sepsis in Intensive Care Neonates.PLoS ONE. 2012; 7e31548https://doi.org/10.1371/journal.pone.0031548Crossref Scopus (100) Google Scholar Concerns around appropriate dosing strategies of vancomycin in neonatal populations stem from issues with trough-based dosing as opposed to AUC-based dosing.7Frymoyer A. Hersh A.L. El-Komy M.H. Gaskari S. Su F. Drover D.R. et al.Association between vancomycin trough concentration and area under the concentration-time curve in neonates.Antimicrob Agents Chemother. 2014; 58: 6454-6461https://doi.org/10.1128/AAC.03620-14Crossref PubMed Scopus (106) Google Scholar We evaluated current trough-based vancomycin dosing strategies used in two tertiary NICUs in North West London, UK, between October 2022 and February 2023, and considered the likelihood of target attainment for the treatment of suspected and confirmed Gram-positive infections, in the context of concerns around the variant NRCS-A S.capitis. We explored the relationship between trough vancomycin concentrations and AUC:MIC ratios to better understand the extent that real-world practice supports attainment of desired PK/PD targets. We performed a retrospective observational cohort study of neonatal patients with LOS treated with intravenous vancomycin. Empirical local guidelines for LOS were vancomycin (intermittent infusion) and piperacillin-tazobactam. Dose adjustment at steady state was made using therapeutic drug monitoring (TDM), which targeted a trough concentration for vancomycin of 10-20 mg/L. Neonates were excluded from the analysis if: no drug concentrations were recorded, only one dose of vancomycin was given, or if there was significant heart disease or renal impairment requiring renal replacement therapy. If a patient received multiple treatment courses (for different episodes of LOS) with vancomycin during the study period, these were considered as independent treatment episodes if there was a minimum of 48-hours between vancomycin prescriptions. Data was extracted from the electronic patient records and vancomycin PK/PD parameters were calculated using the Bayesian NEOVANC model,8Frymoyer A. Stockmann C. Hersh A.L. Goswami S. Keizer R.J. Individualized Empiric Vancomycin Dosing in Neonates Using a Model-Based Approach.J Pediatr Infect Dis Soc. 2019; 8: 97-104https://doi.org/10.1093/jpids/pix109Crossref PubMed Scopus (35) Google Scholar with the ID-ODS software package (http://www.optimum-dosing-strategies.org). A MIC 1 mg/L was applied as default for AUC/MIC estimates. Vancomycin target AUC/MIC ratio for efficacy were defined as 400-600 based on previously reported PK/PD data. Risk of vancomycin toxicity was defined as AUC>600 mg·h/L. Data from 32 patients were included. 24/32 (75%) had one treatment episode with vancomycin (75%), seven (22%) had two episodes, and one (3%) had three episodes. Baseline characteristics of individual patients are summarised in Table 1. The median duration of vancomycin treatment was 4.22 (IQR 2.0-6.0) days and 5.0 (IQR 4.0-14.0) doses were prescribed per treatment episode.Table 1Patient characteristics (n=32, who had 41 episodes of vancomycin exposure altogether). IQR=interquartile range,.CharacteristicValueGestational age at birth (median [IQR]) (weeks)26.5 [25-30]Gestational age (n[%])<28 weeks20 [62.5%]28-36 weeks9 [28.1%]≥37 weeks3 [9.4%]Female Sex (n, [%])10 [31.3%]Weight (median [IQR]) (kg)0.87 [0.7-1.4]Postmenstrual age (median [IQR])aThis median includes multiple treatment episodes for some people (seven had two episodes, and one had three episodes) (weeks)29 [27-32]Postnatal age (median [IQR]) (days)15 [8.8-22.3]Serum creatinine level (median [IQR]) (umol/L)50 [43-65]a This median includes multiple treatment episodes for some people (seven had two episodes, and one had three episodes) Open table in a new tab Most patients (32/41; 78.0%) had no causative organism identified. S.capitis was the most commonly isolated in 6/41 (15%) treatment episodes. At 30 days post individual treatment episode, 33/41 (81%) patients were still inpatients, 6/41 (15%) had been discharged, and 2 patient (5%) had died. During treatment episodes there were 4/41 (13%) cases of AKI observed. Current trough-based vancomycin dosing strategy in the NICU achieved initial trough targets in 32/41 (78.0%) of patients at day 2. Median day 2 trough concentration was 16.5 mg/L (IQR 10.7-20.8 mg/L). Dose adjustment occurred in 10/41 (24%) treatment episodes. This led to trough target attainment in 6/10 (60%) of cases. Correlation between trough and estimated AUC is represented in Fig. 1 and had an r2 of 0.38. Using Bayesian NEOVANC forecasting, day 2 AUCs were estimated as above 400 mg·h/L in 30/41 (73%) of treatment episodes. On day 2, 10/41 (24%) patients had an estimated AUC>600 mg·h/L. Estimated AUC on the final day of treatment demonstrated that 26/41 (63%) achieved an AUC above 400 mg·h/L (8/26 or 31% had a dose adjustment performed) with 10/41 (24%) episodes achieing an AUC above 600 mg·h/L. Of the 10 episodes in which a dose adjustment was made based on trough-based TDM, 4/10 (40%) dose adjustments achieved the target AUC >400 mg·h/L, 2/10 (20%) still did not achieve the target, and 4/10 (40%) had already achieved the target before the adjustment was made. Dose adjustment achieved an AUC>600 mg·h/L in 4/10 (40%). Of the 4/41 (10%) episodes who developed an AKI during a treatment episode, the peak median AUC was 1170.4 (IQR 839.1-1493.7) mg·h/L, compared to a peak median AUC for those without an AKI of 582.1 (IQR 485.4-699.3) mg·h/L. For individual infection episodes, AUC/MIC targets at day 2 would be met for vancomycin in 30/41 (73%) cases for an organism with an MIC of 1 mg/L, 1/41 (2%) for an MIC of 2 mg/L, and 0/41 (0%) for an MIC of 4 mg/L. This real-world evaluation of trough-based TDM using Bayesian forecasting to estimate vancomycin target attainment using AUC in neonates with LOS suggests that there is a poor correlation between trough concentration and AUC at steady state. For Gram-positive isolates with an MIC of ≤1 mg/L, almost three-quarters of patients achieved a target AUC/MIC of >400 mg·h/L. For isolates with higher MICs, as is often observed with NRCS-A S. capitis, current vancomycin dosing appears to be inadequate. Dose adjustment using trough concentrations during treatment did not improve target attainment by the end of therapy. This may be due to the lack of correlation between trough concentration and AUC. This study has several limitations. Current AUC targets' correlation with clinical outcomes in neonates requires further characterisation. We evaluated AUC on day 2 and the final day of treatment, but it is unclear whether these timepoints are optimal.9Lodise T.P. Rosenkranz S.L. Finnemeyer M. Evans S. Sims M. Zervos M.J. et al.The Emperor's New Clothes: PRospective Observational Evaluation of the Association Between Initial VancomycIn Exposure and Failure Rates Among ADult HospitalizEd Patients With Methicillin-resistant Staphylococcus aureus Bloodstream Infections (PROVIDE).Clin Infect Dis. 2020; 70: 1536-1545https://doi.org/10.1093/cid/ciz460Crossref PubMed Scopus (108) Google Scholar Current PK/PD targets are extrapolated from S.aureus infection, and may not be relevant for S.capitis.10Chen Q. Wan J. Shen W. Lin W. Lin X. Huang Z. et al.Optimal exposure targets for vancomycin in the treatment of neonatal coagulase-negative Staphylococcus infection: A retrospective study based on electronic medical records.Pediatr Neonatol. 2022; 63: 247-254https://doi.org/10.1016/j.pedneo.2021.11.010Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Additionally, the NEOVANC model has not been validated in our local neonatal population, which differs from the original trial population. The data from the electronic health records may also lack some reliability due to how the data has been inputed. We conclude that antimicrobial optimisation in neonates is challenging. Trough-based dose adjustments do not appear adequate to improve target attainment in this population. Future work should explore the clinical effectiveness of alternative PK/PD targets in non-complicated infections, investigate the viability of using minimally invasive and low volume sampling methods for TDM linked to artificial intelligence supported dose optimisation, and consider the role of alternative drugs that may deliver more robust target attainment in high risk populations. This research was funded by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at Imperial College London in partnership with the UK Health Security Agency (previously PHE), in collaboration with, Imperial Healthcare Partners, University of Cambridge and University of Warwick.