Continuous Intravenous Infusion of Vancomycin in Neonates: Case series from a Neonatal Intensive Care Unit

Continuous Intravenous Infusion of Vancomycin in Neonates: Case series from a Neonatal Intensive Care Unit | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Continuous Intravenous Infusion of Vancomycin in Neonates: Case series from a Neonatal Intensive Care Unit Kai Lun Tang, Khai Shing Chew, Jen Jen Leong, Catherine Tze Yinn Lim, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9381418/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 16 You are reading this latest preprint version Abstract Background There is no standard dosing guideline available for continuous intravenous infusion (cIVI) vancomycin in the neonatal population. Vancomycin administered as cIVI is the current practice in our neonatal intensive care unit. Data from this case series provided preliminary information on dosing range of cIVI vancomycin, serum vancomycin concentration (SVC), microbiological clearance, and incidence of vancomycin-related nephrotoxicity in neonates. Methods Clinical and laboratory data of this retrospective case series were extracted from patient’s medical record and therapeutic drug monitoring database. Results Of the total 36 steady-state SVCs from 15 records analysed, 64% (n = 23) were within a therapeutic range of 15–25 mg/L, approximating an area-under-the-curve (AUC 24 ) of 400–600 mg.hr/L. Initial SVCs were generally taken within 18–24 hours, however, only 20% (n = 3) were within therapeutic range. Loading dose given ranged between 10–15mg/kg, and the mean maintenance dose was 26 ± 6.58 mg/kg/day. Most of the cases (86.7%, n = 13) were targeted treatment for infections which involved Bacillus spp, Coagulase-negative Staphylococcus (CoNS) , and methicillin-resistant Staphylococcus aureus (MRSA). Microbiological clearance was achieved in all targeted cases, and no cases of vancomycin-induced acute kidney injury were reported. Conclusions This indicates vancomycin continuous infusion dosing regime in neonates seems practicable and was not associated with any incidence of nephrotoxicity. continuous intravenous infusion vancomycin premature neonates therapeutic drug monitoring nephrotoxicity Figures Figure 1 BACKGROUND Bacterial sepsis remains a leading cause of morbidity and mortality in the neonatal population, particularly among preterm neonates. 1 , 2 Methicillin-resistant coagulase-negative Staphylococci (CoNS) are frequently isolated in neonatal intensive care unit (NICU) cultures, though their definitive role as a cause of systemic disease can sometimes be debated. Vancomycin remains the main antibiotic prescribed for the treatment of late-onset sepsis caused by methicillin-resistant CoNS and Staphyloccocus aureus in NICU. 3 , 4 Local antibiogram showed that most of the pathogens isolated from the NICU, i.e. CoNS, Bacillus spp. , methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecium , maintain susceptibility to vancomycin. For treatment of systemic infections caused by susceptible pathogens, current available evidence is lacking to support routine implementation of continuous intravenous infusion (cIVI) over intermittent intravenous infusion (IIV) for both the pediatric and neonatal populations. 5 Measured vancomycin trough levels from the neonatal population showed significant interindividual variability and inconsistency. 6 Often, a series of blood sampling for therapeutic drug monitoring (TDM) and dosage adjustment were needed to achieve the desired therapeutic concentrations of 15–25 mg/L. Recently, cIVI of vancomycin has become the current standard of practice in our NICU since 2019. Target concentrations of vancomycin are obtained more rapidly when administered as continuous infusion and there is less variability in the daily dose. 7 , 8 Both adult and pediatric data suggested that administration of vancomycin by cIVI may facilitate easier dosage adjustment and potentially lower nephrotoxicity risks compared to IIV dosing. 5 , 8 – 11 Several therapeutic vancomycin concentration ranges have been recommended for cIVI (e.g. 10–15 mg/L, 15–20 mg/L, or 15–25 mg/L), 8, 10, 12–14 but little is known about the clinical and microbiological outcomes, and nephrotoxicity in neonates. Moreover, transitioning from trough-level monitoring to AUC 24 monitoring is notoriously difficult in neonates and pediatrics using IIV because it requires multiple blood draws and complex pharmacokinetic math. The math becomes very simple when we adopt the cIVI, where AUC 24 is just the steady-state concentration multiplied by 24. Dosage recommendations for neonates range from 10–20 mg/kg every 8 to 48 hours. These regimens aim to achieve a daily area-under-the-curve-to-minimum-inhibitory-concentration ratio (AUC 24 /MIC) of 400 (assuming a MIC of ≤ 1 mg/L, noting that CoNS MICs are often higher, i.e. ~ 2 mg/L); however, precise dosing depends heavily on postmenstrual age, weight, and serum creatinine (SCr). 13 Until recently, there is no consensus on specific dosing recommendations for cIVI in the premature neonatal population. Therefore, this compilation of case series aimed to provide real-world data on the dosing range of cIVI vancomycin, serum vancomycin concentration (SVC) measured, microbiological clearance, and incidence of vancomycin-related nephrotoxicity in neonates. METHODS Objectives This study aimed to provide simple and clinically practicable real-world data on the dosing range of cIVI vancomycin, serum vancomycin concentration achieved, microbiological clearance, and incidence of vancomycin-related nephrotoxicity in the neonatal population. Patient eligibility and data collection Neonatal patients who had been given cIVI of vancomycin during their hospital stay, who had at least one appropriately drawn vancomycin level (proper sampling time; AND peripheral blood; AND using red-cap plain tube; AND not drawn from the infusion line or arterial line) were included in the study. Relevant information was collected retrospectively from patients’ case notes in the NICU and from an existing clinical therapeutic drug monitoring (TDM) database. Data on gestational age (GA), post-menstrual age (PMA), post-natal age (PNA), birth weight (BW), current weight (CW) during vancomycin initiation, comorbidities, mode of ventilation, laboratory parameters, microbiological culture and sensitivity (C&S), indication of vancomycin therapy, duration of vancomycin use, concurrent nephrotoxicity medications, urine output rate (mL/kg/hour), vancomycin loading dose (LD) and maintenance dose (MD), serum vancomycin concentration (SVC) and its sampling time were recorded. The neonate was considered small-for-gestational-age (SGA) if the birth weight was below the 10th percentile according to the GA-specific percentile chart of fetal growth weight standard published by Fenton T.R et al. 15 Dosing and administration The loading dose (LD) and the initial maintenance dose (MD) of vancomycin were decided based on the total daily dose recommended by Micromedex® Neofax ( see Table 1 ). Table 1. Modified table showing total daily dose of vancomycin based on the original dosing table available on Micromedex ® Neofax Recommended dose Indications Central nervous system (i.e meningitis, ventriculitis) Other infections (sepsis, pneumonia etc) Loading dose, mg/kg/dose 15 10 Maintenance dose, mg/kg/day PMA (weeks) PNA (days) ≤ 29 0 - 14 20 13.33 >14 30 20 30 – 36 0 - 14 30 20 >14 45 30 37 – 44 0 - 7 30 20 >7 45 30 > 45 All 60 40 Abbreviations: PMA, post-menstrual age; PNA, post-natal age With reference to the Australasian Neonatal Medicines Formulary, standard preparation of vancomycin for cIVI was performed per institutional practice to a final infused concentration usually not exceeding 10mg/mL. 16 The LD required was diluted with compatible diluent to a final volume of 3–5 mL and infused over 1 hour using a syringe pump. As for MD, the prescribed dose is diluted up to a final volume of 12–24 mL and infused at a constant rate of 0.5–1 mL/hr via central line. Compatibility of Vancomycin with other medications co-infused through the same central line was routinely monitored by an in-house clinical pharmacist throughout the course of treatment. Dosage adjustments were made based on SVC and the recommendation provided by the TDM pharmacist. When SVC was within therapeutic range of 15-20 mg/L, the total daily dose (as in mg per kg) was maintained. If the SVC obtained did not fall within the therapeutic range, the daily dose was adjusted as shown in Equation 1: Potential technical issues addressed in TDM database Infrequently encountered technical issues with cIVI in the NICU are the proper preparation of vancomycin solution for 24-hour infusion by nursing staff, stability of vancomycin solution, and compatibility of vancomycin with other commonly co-administered medications. TDM pharmacist and clinical pharmacist in the NICU remained vigilant on the compatibility of vancomycin with parenteral nutrition and commonly administered medications in the NICU to prevent co-administration of incompatible medications. Compatibility charts, i.e drug–parenteral nutrition and drug–drug, were made available for clinicians and nursing staff in the NICU as a standard reference. Besides, extra care was adopted to prevent potential error whereby prescription of cIVI vancomycin clearly stated the dose, standard dilution and infusion rate intended, i.e. dose required diluted up to 12–24mL with normal saline and infused as 0.5–1 mL/hour. Assay of serum vancomycin concentration Peripheral blood was taken into clotting tubes and sera isolated by centrifugation. In vitro quantitative determination of serum vancomycin concentration was done using Cobas c system (Roche Diagnostics, Meylan, France). Serum vancomycin concentrations were determined through a homogenous microparticle agglutination immunoassay based on kinetic interaction of microparticles in a solution. The lowest limit of quantitation was 4.0 mg/L determined in accordance with the Clinical and Laboratory Standards Institute (CLSI) document EP17A2 requirement. 17 The precision was determined in accordance with the CLSI EP05-A3, with reported coefficients of variation (CV) 7.3% at 7.10 mg/L (TDM Control Set Level I), 2.4% at 21.2 mg/L (TDM Control Set Level II), and 2.0% at 34.3 mg/L (TDM Control Set Level III). 17 Therapeutic vancomycin concentration The first SVC was taken within 18–48 hours after the initiation of maintenance dose. Subsequently, the dose was adjusted based on SVC obtained and patient’s current weight to maintain a target concentration between 15–20 mg/L. Therapeutic SVC recommended by international standard was 15–25 mg/L, which has been correlated with an AUC within 400-600 mg.h/L. 13 However, current practice in our neonatal intensive care unit continued to be conservative, with the target concentration at the range of 15-20 mg/L. SVCs which exceeded 20mg/L led to a down-titration of the total daily dose of vancomycin. SVCs higher than 25mg/L were regarded as potentially toxic, requiring interruption of vancomycin infusion and later reinitiation at a lower total daily MD. Following the current guideline recommendations, if not otherwise specified, achievement of therapeutic concentration target mentioned in any section of this report refers to the range 15-25 mg/L. 13, 18 Validation of Clinical Outcomes Patient’s case notes and data collection form were reviewed by neonatologists. Neonatologists verified the patient’s clinical outcomes, i.e. resolution of nosocomial sepsis and meningitis, and reported adverse outcomes related to continuous intravenous infusion of vancomycin (if any), such as nephrotoxicity, transaminitis, or thrombophlebitis. For vancomycin-related nephrotoxicity, we adopted the definition and staging of acute kidney injury (AKI) proposed by neonatal modified Kidney Diseases: Improving Global Outcomes (KDIGO) study. 19, 20 First neonatal SCr was taken at least 36-48 hours after birth to reduce the interference by maternal SCr levels. Serum creatinine levels of premature neonates declined at different rates depending on gestational age. The validation of vancomycin-related nephrotoxicity was based on evaluation of SCr before, during and post-vancomycin treatment. Ethical Consideration and Consent to Participate The study protocol was designed to be a retrospective data collection and analysis, which involved the pre-existing clinical data of preterm neonates. The study was registered with the National Medical Research Register (NMRR) with the registration ID NMRR-17-3502-37577 (IIR), and it was subjected to review and approval by the Ministry of Health Medical Research and Ethics Committee (MREC Approval: Ref. KKM.NIHSEC. P18-2090(7)). We acknowledge the importance of ethical oversight when involving minors, as this was a non-interventional retrospective study utilising existing medical records and TDM database, and the nature of this study carries no more than minimal risk, the requirement for informed consent from parents or legal guardians was waived by the MREC. All data were handled in accordance with the Declaration of Helsinki to ensure participant anonymity and confidentiality. RESULTS A total of 31 neonates who received vancomycin as cIVI in the NICU within two years were screened. 14 premature neonates who met the inclusion criteria were included in the study. 17 neonates were excluded due to incomplete information or non-fulfilment of inclusion criteria. One of them was treated with two courses of cIVI vancomycin a week apart due to a reinfection with the same pathogen sensitive to vancomycin. A total of 58 random SVCs were recorded. From the 58 random SVCs evaluated, 8 SVCs were excluded due to either interruption in cIVI vancomycin following a toxic level (n=3), non-steady-state sampling (n=2) or suspected sampling error (n=3). Characteristics of the premature neonates were summarised in Table 2. All the 14 premature neonates included in our case series were aged between PMA 28.9 – 36.7 weeks. Table 2 Patient characteristics Characteristic of premature neonates No. (%) Median (IQR) Gestational age (n=14), weeks 28.9 (27.6 to 30.9) Post-menstrual age (n=15*), weeks 31.9 (29.3 to 34.0) Post-natal age (n=15*), days 13 (11 to 15) Birth weight (n=14), kg 1.125 (1.019 to 1.441) Weight (at vancomycin initiation), kg 1.315 (1.035 to 1.490) Initial status of renal function Mean (SD) Serum creatinine, µmol/L 44.0 (± 14.36) Growth weight standard, Small for gestational age, SGA 5 (35.7) Appropriate for gestational age, AGA 9 (64.3) Gender Male 10 (71.4) Female 4 (28.6) PMA (weeks) PNA (days) Current weight range, kg ≤ 29 0 – 14 4 (21.1) 0.740 – 1.07 30 – 36 0 – 14 5 (26.3) 1.175 – 1.47 > 14 5 (26.3) 0.835 – 1.80 Indication of vancomycin for each case ( n=15 ) Nosocomial sepsis 14 (93.3) Sepsis with concern for meningitis 1 (6.7) Targeted treatment ( n=13 ) Bacillus spp bacteraemia 8 (53.3) MRCoNS bacteraemia 3 (20.0) MRSA bacteraemia 1 (6.7) VISA bacteraemia (MIC 4mg/L) 1 (6.7) Empirical treatment 1 (6.7) Inappropriate indication ( A. baumanii ) 1 (6.7) Abbreviations: PMA, post-menstrual age; PNA, post-natal age; IQR, interquartile range; NEC, necrotizing enterocolitis; MRCoNS, methicillin-resistance coagulase negative staphylococcus ; MRSA, methicillin-resistant staphylococcus aureus ; VISA, vancomycin-intermediate sensitive staphylococcus aureus; E. meningoseptica, Elizabethkingia meningoseptica ; A. baumanii, Acinetobacter baumanii. *One of the premature neonates was treated with two courses of cIVI vancomycin a week apart. The PMA and PNA of the premature neonate were recorded twice when cIVI was initiated at different time periods. In most of the cases (86.7%, n=13) of cIVI, vancomycin was initiated as targeted treatment. Bacillus spp bacteraemia was the commonest cause encountered, followed by CoNS bacteraemia . Only 1 case was started on vancomycin empirically without a positive culture. The neonate who had a positive blood culture with vancomycin intermediate-sensitive Staphylococcus aureus (VISA, with MIC of 4mg/L) was maintained at a targeted vancomycin concentration between 15-20mg/L. Repeated blood culture for this neonate showed no growth of Staphylococcus aureus . However, his antibiotic was later upgraded to intravenous linezolid based on clinical impression of unresolving nosocomial sepsis. All 50 SVCs obtained were tabulated as shown in Figure 1 . Approximately half (52%, n=26) of the SVCs lay within the therapeutic range of 15–25 mg/L (area-under-curve, AUC 400–600mg.hr/L). Unexpectedly, there were 6 SVCs recorded higher than 25 mg/L with 5 of the supratherapeutic SVCs recorded at the initial phase of maintenance dose. Based on the investigation findings recorded in the TDM database, only 1 out of the 5 unexpectedly high initial SVCs was suspected to be possibly the result of pre-analytical sampling error. The unexpectedly high initial SVC plummeted from an abnormally high potentially toxic level (77.8 mg/L) down to a low level (6.4 mg/L) within 16 hours after interruption of vancomycin infusion, significantly faster than the general neonatal population’s renal clearance and physiological half-life ( see Table 3 ). Hence, the subsequent lower level probably represented the patient's true systemic concentration. Among the pool of 5 premature neonates who were born SGA, 60% (n=3) of them had their initial SVC recorded above 25 mg/L, which was potentially toxic. The majority (89%, n=8) of the premature neonates who were born appropriate-for-gestation-age had recorded an initial SVC lower than 20 mg/L. Out of 14 courses of cIVI vancomycin, dosing (LD and MD) deviated from the exact Micromedex ® Neofax recommendations in 9 of the 14 courses. Only a few of the premature neonates (21.4%, n=3) had their initial SVC recorded within the therapeutic range of 15–25 mg/L, whereas majority (57.1%, n=8) had an initial SVC lower than 15 mg/L. The median time-to-first-random-sample (TTS) after starting on the initial maintenance dose was 20 hours (IQR 16.5–24). Demographic data, vancomycin dosing, and initial SVC data for individual neonates are presented in Table 3 . Table 3 Demographic data of each neonate, vancomycin initial dosing data, initial serum vancomycin concentration achieved and pre-vancomycin serum creatinine. ID PMA, wks+days PNA, days Cw, kg Other Comorbid-ities Nephro-toxic meds† LD, mg/kg iMD, mg/kg TTS, hrs iSVC, mg/L MD range, mg/kg/D SVC ss , mg/L No. of sample Total Days of Tx SCr, µmol/L AKI ‡ 1 31 + 0 14 1.195 PDA, RDS, h/o RI No 10 (=) 30.0 (=) 17* 26.1 (>) 17.2–19.7 7.9–33.5 5 10 61 No 2 30 + 5 8 1.365 PDA, RDS, IVH No 15 (∧) 29.3 (∧) 41 45.8 (>) 23.4–25.0 13.3–18.2 8 17 33 No 3 28 + 6 13 1.035 PDA, RDS No 10 (=) 15.0 (∨) 16.5* 6.1 (<) 25.0 10.1 3 5 57 No 4 31 + 6 15 1.315 PDA, RDS Yes 10 (=) 27.4 (∨) 20 15.0 (<>) 25.6–31.1 15.1–16.6 4 23 33 No 5 30 + 5 15 0.835 RDS No 19.2 a (∧) 30.2 (=) 19 12.5 (<) 30.2 12.5 1 2 c 37 No 6 29 + 0 13 1.070 PDA, RDS, PH, h/o RI, IVH Yes 10 (=) 18.7 (∨) 32 9.6 (<) 29.1–32.7 23.3–24.2 4 15 41 No 7 32 + 5 10 1.470 - No 10 (=) 18.0 (∨) 22 12.5 () 19.6 10.0b 3 14 50 No 9 32 + 3 8 1.410 RDS Yes 10 (=) 20 (=) 22 12.5 (<) 27.1–33.9 15.3–18.5 4 10 53 No 10 29 + 2 12 0.985 PDA, RDS, PH Yes 10 (=) 20 (=) 16.5* 8.1 () 13.5–22.0 10.2–22.2 8 22 69 No 12 36 + 3 59 1.740 PDA, RDS, NEC No 10 (=) 28.7 (∨) 20 8.9 (<) 34.5–36.5 13.7–15.2 3 11 27 No 13 36 + 5 56 1.490 PDA, RDS, h/o RI Yes 15 (∧) 28.7 (∨) 24 10 (<) 40.0–45.0 13.5–18.5 3 21 17 No 14A 34 + 0 11 1.700 RDS, hydrop fetalis, ascites No 10 (=) 29.4 (∧) 12* 15.7 (<>) 29.4 16.3–16.7 3 11 51 No 14B 36 + 0 25 1.800 RDS, hydrop fetalis, ascites No 10 (=) 30.5 (=) 12* 15.3 (<>) 30.5 16.4–25.5 3 14 30 No † Presence of concurrent nephrotoxic medications, e.g diuretics, paracetamol, aminoglycosides. ‡ No reported case of vancomycin-induced AKI among the neonates treated with cIVI * First blood draw was earlier than recommended (at least 18-24 hours after initiation of vancomycin) a Higher than recommended LD was due to inappropriate dose calculation using the patient’s best weight instead of the current weight when vancomycin treatment was planned. b Recheck of SVC at 16 hours after interruption of vancomycin infusion reported as 6.4mg/l, dropped significantly faster than reasonable renal clearance for the neonate, which highly suggestive of pre-analytical sampling error. Hence ID-8 was excluded from analysis of initial serum vancomycin concentration. c Vancomycin was off on 2 nd day when blood culture and sensitivity results showed Acinetobacter baumanii. Abbreviations: AKI, acute kidney injury; CW, current weight; h/o RI, history of renal impairment; ID, patient identity; iMD, initial maintenance dose; iSVC, initial serum vancomycin concentration; IVH, intraventricular hemorrhage; LD, loading dose; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus; PH, pulmonary hemorrhage; PMA, post-menstrual age; PNA, post-natal age; RDS, respiratory distress syndrome; SCr, serum creatinine; SVC ss , steady-state serum vancomycin concentration; TTS, time to sampling; Tx, treatment; wks+days, weeks & days; Symbols: =, same as Neofax recommendation; ∧, higher than Neofax recommendation; ∨, lower than Neofax recommendation; <>, within therapeutic range (15-25 mg/L); , higher than therapeutic range. As for practice of cIVI vancomycin in the premature neonate population, we did not notice the trend of higher number of blood samples for SVC monitoring in cases with longer duration of treatment. Average frequency of SVC monitoring for each premature neonate was 3 times per week, and if vancomycin duration of treatment extended into second and third week, the frequency of blood taking for SVC monitoring eventually reduced to 1 time per week. Details on dosing range and SVC monitoring are summarised in Table 4 . Table 4 Dosing pattern of continuous intravenous infusion of vancomycin, serum vancomycin concentrations Parameters related to vancomycin Range Mean ± SD / Median (IQR) Loading dose given, mg/kg Average maintenance dose (MD), mg/kg/day Initial serum vancomycin concentration (iSVC), mg/L Average serum vancomycin concentration (SVC), mg/L Duration of treatment, days No. of blood sample taken for measurement of SVC No. of blood sample taken on 1 st week (Day 1–7) No. of blood sample taken on 2 nd week (Day 8–14) b No. of blood sample taken on 3 rd week (Day 15–21) c 10 – 19.2 a 13.5 – 45.0 6.1 – 45.8 7.9 – 33.5 5 – 23 3 – 8 2 – 5 0 – 4 0 – 1 - Mean 26.0 ± 6.6 Median 12.5 (9.4 – 18.3) Median 15.9 (13.8 – 18.5) Median 14 (11 – 18) Median 3 (3 – 4) Mean 3 ± 1 Median 1 (0 – 1) a A higher than recommended LD (i.e 19.2mg/kg, n=1) was due to inappropriate dose calculation using patient’s best weight instead of current weight when vancomycin treatment was planned. b Accounted to vancomycin treatment which exceeded one(1) week, n = 13 c Accounted to vancomycin treatment which exceeded two(2) weeks, n = 5 Abbreviations: SD, standard deviation; IQR, interquartile range; iMD, initial maintenance dose; MD, maintenance dose; iSVC, initial serum vancomycin concentration; SVC, serum vancomycin concentration. Maintenance dose (MD) adjustments were proposed by pharmacist from the therapeutic drug monitoring (TDM) unit after the initial SVC and current renal profile were reviewed. All the initial SVCs or repeated SVCs which were noted to be higher than 25 mg/L led to a temporary interruption in cIVI vancomycin until a recheck SVC confirmed clearance of the SVC to a concentration lower than 20 mg/L. After adjustment of MD by the TDM pharmacist, the percentage of subsequent SVCs achieving the therapeutic range of 15-25 mg/L was 53% (n=8), and 40% (n=6) were within the range of 10-15 mg/L, all iSVCs that were below 10 mg/L (27%, n=4) increased to be above 10 mg/L without exceeding toxic level. All cases with a positive blood culture (n=13) were validated as achieving microbiologic clearance, and all patients (except for the patient with VISA, for whom vancomycin was changed to linezolid) were documented as having responded to vancomycin treatment. None of our premature neonates experienced any central-line-related complications with vancomycin (solution concentration of 5–7.5 mg/mL) infused at a constant rate of 1 mL/hour. No cases of vancomycin-induced acute kidney injury were reported, and all cases had recorded good urine output rate throughout the whole treatment course of vancomycin, with a mean urine output rate of 5.1 ± 1.5 mL/kg/hour. Our study did not assess the risk of ototoxicity and did not record the outcome in term of pathological ototoxicity. DISCUSSION Continuous intravenous infusion of vancomycin: Dosing and therapeutic range Based on Micromedex ® Neofax, the expected therapeutic trough concentration for intermittent dosing ranged from 10 to 20 mg/L, which is inherently lower than the steady-state therapeutic concentration range of 15-25 mg/L often recommended for cIVI. 7, 13, 21 Adopting the practice of cIVI vancomycin enabled us to easily estimate the AUC 24 by multiplying the steady-state SVC (i.e. targeted therapeutic concentration range of 15–25 mg/L) by 24 hours.In our case series, we have expected that many of the initial SVCs recorded may not fall within the therapeutic concentration range of 15–25mg/L, and that merely 21.4% (n=3) of the iSVCs were satisfactory. It was also expected that more than half (57.1%, n=8) of the iSVCs were lower than 15mg/L because our dosing was based primarily on Neofax recommendations. Findings from population kinetic dosing modelling done by Li et al suggested that the current recommended doses of vancomycin from FDA labelling, Red Book, Pediatric & Neonatal Dosage Handbook, and Neofax may be inadequate to meet a treatment target of AUC 24h / MIC ≥ 400 mg.h/L in neonatal patients with a greater renal clearance status, especially SCr < 15 µmol/L. 22 Hence, a specific dosing guide for cIVI of vancomycin in the neonatal population should be developed; use of a TDM service is necessary along with this dosing guidance, to ensure optimisation of the dosing regimen and achievement of therapeutic concentration. It is recommended that dosages to achieve an AUC 24 of 400 mg.hr/L (assuming a MIC of 1 mg/L) in neonates ranged from 10 to 20 mg/kg every 8 to 48 hours, depending on postmenstrual age, weight, and SCr. 13 The clinical utility of this dosing recommendation remained less relevant to our current practice setting as we did not fully adopt AUC 24 as a guide for dosage adjustment. Our study with small sample size lacked in-depth details on dosing and SVC data (i.e. specific time point), hence impactful inference could not be derived from this case series. Our TDM research team continued with more in-depth data collection for cIVI use in both premature and term neonates. More cases are being recruited currently to provide a bigger database sufficient to provide inferences about pharmacokinetics and pharmacodynamics for cIVI of vancomycin in this vulnerable population, and ultimately a database with the capacity to facilitate modelling and simulation. Clinical utility of cIVI vancomycin with a targeted SVC of 15–25mg/L requires further evaluation prior to adoption into practice among neonatologists, as the most common pathogen cultured and treated in our setting was Bacillus spp (53.3%) instead of Staphylococcus aureus, followed by methicillin-resistant coagulase-negative Staphylococcus spp. (20%). Because the 15-25 mg/L therapeutic range is specifically correlated with outcomes for MRSA, it cannot necessarily be extrapolated to other organisms. All of our cases with positive blood culture were validated as having achieved microbiologic clearance, although not all the SVCs recorded were within the therapeutic concentration range of 15-25 mg/L. It seems possible that a lower target SVC may be sufficient for the elimination of non- Staphylococcus aureus pathogens, but more robust data are needed to support this recommendation. Moving forward, the TDM and clinical pharmacy team would remain cautious and may propose a higher vancomycin LD at 15mg/kg for treatment targeting all MRSA infections and any infection which involve the central nervous system, followed by the MD as per Micromedex ® Neofax recommendation for the reason that a high percentage of the iSVCs obtained were lower than recommended therapeutic range of 15–25mg/L. Furthermore, the decision to propose higher vancomycin doses to rapidly achieve therapeutic targets must always be weighed against the compounding risks of AKI, particularly when nephrotoxic comorbidities are present. A good example to highlight was case ID-11, where the neonate was extremely premature, SGA with very low birth weight, had hemodynamically significant PDA, and had previously and concurrently been on nephrotoxic medication. The case was diagnosed with sepsis, likely meningitis, and treated with 3 weeks of vancomycin. A decision was made to only use lower iLD and iMD, and draw blood earlier than 18 hours to ensure no vancomycin accumulation. The iSVC at 12 hours turned out to be higher than 28.8 mg/L. The role of TDM in support of the current practice of cIVI remained relevant as the percentage of SVCs within the therapeutic concentration range of 15-25 mg/L increased from 21% to 53% after dosage adjustment recommended by TDM pharmacist. Changes in body weight and kidney function of the patient are known factors that affect the drug distribution and the clearance of vancomycin, of which the compounding effect will be reflected in SVC throughout the course of treatment. For neonates with stable renal function, vancomycin dose should be adjusted based on the latest body weight to prevent the patient from having subtherapeutic or supratherapeutic SVC. From every case with SVC above 25mg/l, we investigated and concluded several possibilities, i.e initiated on higher than recommended MD, maintaining existing dose despite a drop in body weight, deteriorating kidney function (increasing SCr and reducing urine output), and adjusting to a higher maintenance dose based on initial SVC taken less than 16 hours. From cases with SVC below 10mg/l, most of the cases (75%) were initiated on lower than recommended MD. Reduced the number of blood samples needed for TDM and lower risk of sampling time error One of the reasons cIVI vancomycin was the preferred method of administration in the NICU was the benefit of having fewer blood draws. In our case series, it was interesting to find that the mean frequency of blood draws for SVC monitoring in this group of neonates was 3 times per week for the 1 st week, and subsequently, when the duration of vancomycin treatment was extended to a 2 nd or 3 rd week, the frequency of blood draws for SVC monitoring reduced to once a week. After further investigation into each case with more than 3 times blood draws per week, we found that it was mainly due to initial unexpected high SVCs which raised suspicion of sampling or administration error, leading to interruption of cIVI vancomycin and requirement of a repeated SVC level to confirm a normalisation of vancomycin concentration to below 20mg/L. Otherwise, for those cases where SVCs appeared stable within the 1 st week, the maintenance dose (in term of mg/kg/day) was continued and the total daily dose was kept in check i.e. adjusted according to latest body weight. This finding was consistent with study finding by Hong LT et al which proved that continuous infusion of vancomycin reduced number of blood samples needed for SVC monitoring in intensive care unit patients. 23 Furthermore, if compared to IIV, cIVI offers simplified TDM with less dependence on strict sampling time, eliminating the need to time the draw exactly 30 minutes before the next dose. 24 IIV dosing’s reliance on exact timing makes it highly vulnerable to errors in a busy NICU setting. 25 On the contrary, 6 out of 15 iSVCs were drawn earlier than the recommended time of 18-24 hours after initiation of vancomycin infusion. There was no specific justification recorded in the TDM database. By assessing individual case details, we concluded several possible explanations to the early blood draw: premature neonates at risk of AKI requiring early level to ensure that no vancomycin accumulation, to coincide with other blood investigations due to difficult peripheral blood draw, or use of vancomycin dosing regimen deviated from standard recommendations (i.e. higher dose used, TDM blood earlier to ensure no drug accumulation; lower dose used, TDM blood earlier to facilitate dosage up-titration if noted subtherapeutic SVC). Vancomycin-related nephrotoxicity and ototoxicity The known risk factors for AKI in neonates who received vancomycin include higher vancomycin trough concentrations, concurrent use of nephrotoxic medications, low birth weight, and patent ductus arteriosus. 20, 26, 27 The wide varying estimates of incidence of vancomycin-related nephrotoxicity among neonates reported, ranging from 2% to 20%, have led to confusion and controversy regarding the safety of vancomycin among neonates. 28 Several studies have shown that cases of vancomycin-related nephrotoxicity in neonates were infrequently reported. 8, 26, 28 There were no reported cases of vancomycin-induced AKI among the neonates treated with cIVI in our cohort, with more than half of the measured SVCs were within higher therapeutic concentration range of 15–25 mg/L (AUC 400–600 mg.h/L) while a few SVCs above 25 mg/L. Additionally, a few of our cases involved neonates with prior or concomitant use of nephrotoxic medications (e.g., aminoglycosides, frusemide, hydrochlorothiazide, paracetamol), underlying PDA, or SGA. Current evidence showed a mixed safety profile of vancomycin in both neonates and paediatric patients, suggesting an incidence of 1% up to 18.2% vancomycin-associated AKI, especially when the trough concentration was more than 15 mg/L. 29-31 A large cohort study revealed that vancomycin exposure in very-low-birth-weight infants is associated with an increased risk of pathological hearing test, in a dose-dependent manner. 32 This warrants us to remain cautious as long-term safety data (including ototoxicity) for early exposure of premature neonates to vancomycin is not readily available locally. Hence, treatment with cIVI vancomycin in premature neonates must be practised with care, with appropriate periodic steady-state SVC monitoring to prevent unexpected drug accumulation, routine renal function monitoring to detect early AKI, and to schedule the infants for appropriate follow-up hearing tests. CONCLUSION The case series provided us with good insight into the practicability of cIVI of vancomycin in treating premature neonates in the neonatal intensive care unit. The percentage of measured SVCs that were within the therapeutic concentration range was 72%. Microbiological clearance and clinical resolution of nosocomial sepsis for cases with correct indication was 100%. This indicates vancomycin continuous infusion dosing regimen in neonates seems simple and clinically practicable, and was not associated with any incidence of nephrotoxicity. Abbreviations acute kidney injury, AKI; area-under-the-curve, AUC 24 ; birth weight, BW; Coagulase-negative Staphylococcus, CoNS; continuous intravenous infusion, cIVI; culture and sensitivity, C&S; current weight, CW; gestational age, GA; intermittent intravenous infusion, IIV; interquartile range, IQR; intraventricular hemorrhage, IVH; loading dose, LD; maintenance dose, MD; methicillin-resistant Staphylococcus aureus, MRSA; minimum inhibitory concentration, MIC; necrotizing enterocolitis, NEC; neonatal intensive care unit, NICU; patent ductus arteriosus, PDA; post-menstrual age, PMA; post-natal age, PNA; pulmonary hemorrhage, PH; serum creatinine, SCr; serum vancomycin concentration, SVC; small for gestation age, SGA; standard deviation, SD; therapeutic drug monitoring, TDM Declarations Funding Source : No funding was secured for this study Conflict of Interest : All authors have no conflicts of interest to disclose Content Summary : Continuous infusion of vancomycin has been instituted as a standard practice in our centre, and through this case series, we provided preliminary information on the dosing range of vancomycin, serum vancomycin concentration achieved, microbiological clearance, and incidence of vancomycin-related nephrotoxicity in neonates. Registration of Research, NMRR ID: NMRR-17-3502-37577 (IIR) Ethical Approval, MREC : KKM.NIHSEC. P18-2090(7) COMPETING INTERESTS . There is no conflict of interest to disclose. FUNDING No funding was secured for this study AUTHORS’ CONTRIBUTIONS TKL and CKS contributed to the conceptualisation and design of the study. CKS was responsible for study registration. Data acquisition was carried out by CKS, LTY, and ASR. Data analysis and interpretation were performed by CKS, LTY, and TKL. The manuscript was drafted by CKS, TKL, LTY, and ASR. Critical revision of the manuscript was conducted by TKL and CKS. Statistical analysis was performed by CKS and LTY. LJJ, LCH, and LCM provided resources and support. Supervision was provided by TKL and LCM. All authors read and approved the final manuscript. ACKNOWLEDGEMENT We would like to express our sincere appreciation to the Director-General of Health, Malaysia, for permission to publish this work. We also extend our gratitude to the Head of the Pediatric Department, Dato’ Dr Angeline Yeoh Aing Chiee, for her support leading to the completion of this study. Furthermore, we are deeply grateful to Dr Yeap Li Ling from the School of Pharmacy, Monash University Malaysia, for her expert review and feedback on this manuscript. Human Ethics and Consent to Participate Declarations: The study was registered with the National Medical Research Register (NMRR) with the registration ID NMRR-17-3502-37577 (IIR), and it was subjected to review and approval by the Ministry of Health Medical Research and Ethics Committee (MREC Approval: Ref. KKM.NIHSEC. P18-2090(7)). We acknowledge the importance of ethical oversight when involving minors, as this was a non-interventional retrospective study utilising existing medical records and TDM database, and the nature of this study carries no more than minimal risk, the requirement for informed consent from parents or legal guardians was waived by the MREC. All data were handled in accordance with the Declaration of Helsinki to ensure participant anonymity and confidentiality. Clinical trial number Not applicable Consent for Publication All authors reviewed and approved the final manuscript and consent to its publication. AI use statement During the preparation of this work, the author used ChatGPT (free version) for brainstorming and Grammarly (free version) to refine and verify the grammar of the original manuscript. After using these tools, the author reviewed and edited the content as needed and takes full responsibility for the content of the published article. Consent to Participate Not applicable. Availability of Data and Materials Data are available from the corresponding author upon reasonable request, subject to a data sharing agreement References Marchant EA, Boyce GK, Sadarangani M, Lavoie PM. Neonatal sepsis due to coagulase-negative staphylococci. Clin Dev Immunol. 2013;2013:586076. 10.1155/2013/586076 . Epub 2013 May 22. Greenberg RG, Kandefer S, Do BT, Smith PB, Stoll BJ, Bell EF, et al. Late-onset Sepsis in Extremely Premature Infants: 2000–2011. Pediatr Infect Dis J. 2017;36(8):774–9. Li J-y, Chen S-q, Yan Y-y, Hu Y-y, Wei J, Wu Q-p, et al. Identification and antimicrobial resistance of pathogens in neonatal septicemia in China—A meta-analysis. Int J Infect Dis. 2018;71:89–93. Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics. 2002;110(2 Pt 1):285–91. Girand HL. Continuous Infusion Vancomycin in Pediatric Patients: A Critical Review of the Evidence. J Pediatr Pharmacol Ther. 2020;25(3):198–214. Kim J, Walker SA, Iaboni DC, Walker SE, Elligsen M, Dunn MS, et al. Determination of vancomycin pharmacokinetics in neonates to develop practical initial dosing recommendations. Antimicrob Agents Chemother. 2014;58(5):2830–40. Zhao W, Lopez E, Biran V, Durrmeyer X, Fakhoury M, Jacqz-Aigrain E. Vancomycin continuous infusion in neonates: dosing optimisation and therapeutic drug monitoring. Arch Dis Child. 2013;98(6):449–53. 10.1136/archdischild-2012-302765 . Epub 2012 Dec 19. Gwee A, Cranswick N, McMullan B, Perkins E, Bolisetty S, Gardiner K, et al. Continuous Versus Intermittent Vancomycin Infusions in Infants: A Randomized Controlled Trial. Pediatrics. 2019;143(2):e20182179. Cataldo MA, Tacconelli E, Grilli E, Pea F, Petrosillo N. Continuous versus intermittent infusion of vancomycin for the treatment of Gram-positive infections: systematic review and meta-analysis. J Antimicrob Chemother. 2012;67(1):17–24. 10.1093/jac/dkr442 . Epub 2011 Oct 25. Wysocki M, Delatour F, Faurisson F, Rauss A, Pean Y, Misset B, et al. Continuous versus Intermittent Infusion of Vancomycin in Severe Staphylococcal Infections: Prospective Multicenter Randomized Study. Antimicrob Agents Chemother. 2001;45(9):2460–7. 10.1128/AAC.45.9.2460-7.001 . Junker A, Howe Z, Schneider JG, Bhumbra S, Kussin ML. Continuous Infusion Vancomycin Dosing and Area Under the Curve Target Attainment in a Freestanding Children’s Hospital. J Pediatr Infect Dis Soc. 2024;13(Supplement3):S12–3. Lo YL, van Hasselt JG, Heng SC, Lim CT, Lee TC, Charles BG. Population pharmacokinetics of vancomycin in premature Malaysian neonates: identification of predictors for dosing determination. Antimicrob Agents Chemother. 2010;54(6):2626–32. 10.1128/AAC.01370-09 . Epub 2010 Apr 12. Rybak MJ, Le J, Lodise TP, Levine DP, Bradley JS, Liu C, 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. American Journal of Health-System Pharmacy; 2020. Leroux S, Zhao W, Betremieux P, Pladys P, Saliba E, Jacqz-Aigrain E. Therapeutic guidelines for prescribing antibiotics in neonates should be evidence-based: a French national survey. Arch Dis Child. 2015;100(4):394–8. 10.1136/archdischild-2014-306873 . Epub 2015 Jan 27. Fenton TR, Elmrayed S, Alshaikh BN. Fenton Third-Generation Growth Charts of Preterm Infants Without Abnormal Fetal Growth: A Systematic Review and Meta-Analysis. Paediatr Perinat Epidemiol. 2025;39(6):543–55. Australasian Neonatal Medicines Formulary. Vancomycin-continuous infusion (Newborn Use Only) Date of publication 29/01/2026 [Available from: https://www.anmfonline.org/ Test VANC (Vancomycin), editor. test ID 0-459. Mannheim, Germany: Roche Diagnostics GmbH; 2022. He N, Su S, Ye Z, Du G, He B, Li D, et al. Evidence-based Guideline for Therapeutic Drug Monitoring of Vancomycin: 2020 Update by the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society. Clin Infect Dis. 2020;71(Suppl 4):S363–71. Jetton JG, Askenazi DJ. Update on acute kidney injury in the neonate. Curr Opin Pediatr. 2012;24(2):191–6. Hanna MH, Askenazi DJ, Selewski DT. Drug-induced acute kidney injury in neonates. Curr Opin Pediatr. 2016;28(2):180–7. Vancomycin. (2018). In IBM Micromedex Neofax Drug Reference for Android iOS (Version v1.3b252) [Mobile application software]. Li Z-l, Liu Y-x, Jiao Z, Qiu G, Huang J-q, Xiao Y-b et al. Population Pharmacokinetics of Vancomycin in Chinese ICU Neonates: Initial Dosage Recommendations. Front Pharmacol. 2018;9(603). Hong LT, Goolsby TA, Sherman DS, Mueller SW, Reynolds P, Cava L, et al. Continuous infusion vs intermittent vancomycin in neurosurgical intensive care unit patients. J Crit Care. 2015;30(5):e11531–6. Flannery AH, Bissell BD, Bastin MT, Morris PE, Neyra JA. Continuous Versus Intermittent Infusion of Vancomycin and the Risk of Acute Kidney Injury in Critically Ill Adults: A Systematic Review and Meta-Analysis. Crit Care Med. 2020;48(6):912–8. Nguyen TA, Kirubakaran R, Schultz HB, Wong S, Reuter SE, McMullan B, et al. Analytical and Non-Analytical Variation May Lead to Inappropriate Antimicrobial Dosing in Neonates: An In Silico Study. Clin Chem. 2023;69(6):637–48. Bhatt-Mehta V, Schumacher R, Faix R, Leady M, Brenner T. Lack of Vancomycin-associated Nephrotoxicity in Newborn Infants: A Case-Control Study. Pediatrics. 1999;103:e48. McKamy S, Hernandez E, Jahng M, Moriwaki T, Deveikis A, Le J. Incidence and risk factors influencing the development of vancomycin nephrotoxicity in children. J Pediatr. 2011;158(3):422–6. Constance JE, Balch AH, Stockmann C, Linakis MW, Korgenski EK, Roberts JK, et al. A propensity-matched cohort study of vancomycin-associated nephrotoxicity in neonates. Archives disease Child Fetal neonatal Ed. 2016;101(3):F236–43. Bhargava V, Malloy M, Fonseca R. The association between vancomycin trough concentrations and acute kidney injury in the neonatal intensive care unit. BMC Pediatr. 2017;17(1):50. Ashkenazi-Hoffnung L, Schiller O, Krubiner M, Dagan O, Haskin O, Manor-Shulman O, et al. Vancomycin Dosing and Its Association With Acute Kidney Injury in Pediatric Cardiac Intensive Care Patients Under 3 Months of Age. Pediatr Infect Dis J. 2024;43(10):963–9. Knoderer CA, Nichols KR, Lyon KC, Veverka MM, Wilson AC. Are Elevated Vancomycin Serum Trough Concentrations Achieved Within the First 7 Days of Therapy Associated With Acute Kidney Injury in Children? J Pediatr Infect Dis Soc. 2014;3(2):127–31. Marissen J, Fortmann I, Humberg A, Rausch TK, Simon A, Stein A, et al. Vancomycin-induced ototoxicity in very-low-birthweight infants. J Antimicrob Chemother. 2020;75(8):2291–8. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9381418","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":629348783,"identity":"befa3ca0-5489-4801-8993-0cb499b5d6b5","order_by":0,"name":"Kai Lun Tang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIiWNgGAWjYJACxgYGCRkGBuZjYB4bOwHlPFAtQJotjYEhAUgxE6cFRPOYgbUwENJiz3728MsZNRY8Brd7vj34+GObPB8zA+OHjzl4bOHJS7PccEyCx+DO2e2GMxJuG7YxMzBLztyGz2E5ZoYP2IBabuRuk+ZJuM0I1MLGzItPC/8boJZ/IC05z0Ba7AlrkcgxfrixDayFDaQlkbCWG2/MGGf2SfBI3kgzk5yRdju5jZmxGa9f2PtzjD/2fKuT47uR/Ezig81t2/ntzQc/fMSjBQjYJNAEQPGEHzB/IKRiFIyCUTAKRjgAAJKcSpEGZS6eAAAAAElFTkSuQmCC","orcid":"","institution":"Hospital Seberang Jaya","correspondingAuthor":true,"prefix":"","firstName":"Kai","middleName":"Lun","lastName":"Tang","suffix":""},{"id":629348784,"identity":"6232ebc3-4cb2-4e7b-a542-282a9202751a","order_by":1,"name":"Khai Shing Chew","email":"","orcid":"","institution":"Hospital Bukit Mertajam","correspondingAuthor":false,"prefix":"","firstName":"Khai","middleName":"Shing","lastName":"Chew","suffix":""},{"id":629348787,"identity":"1048ec96-0f6a-4ae2-9c60-edf3136b792f","order_by":2,"name":"Jen Jen Leong","email":"","orcid":"","institution":"Sunway Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Jen","middleName":"Jen","lastName":"Leong","suffix":""},{"id":629348790,"identity":"1fbf504e-931e-4956-be87-89941d8064a5","order_by":3,"name":"Catherine Tze Yinn Lim","email":"","orcid":"","institution":"Bandar Perda Health Clinic","correspondingAuthor":false,"prefix":"","firstName":"Catherine","middleName":"Tze Yinn","lastName":"Lim","suffix":""},{"id":629348792,"identity":"4a094c18-0187-4a4f-857a-ddb34b7b0917","order_by":4,"name":"Amiza Suriani Ramli","email":"","orcid":"","institution":"Hospital Seberang Jaya","correspondingAuthor":false,"prefix":"","firstName":"Amiza","middleName":"Suriani","lastName":"Ramli","suffix":""},{"id":629348794,"identity":"708c78b4-131c-4dec-aab1-ed1e98465762","order_by":5,"name":"Choo Hau Lim","email":"","orcid":"","institution":"Hospital Seberang Jaya","correspondingAuthor":false,"prefix":"","firstName":"Choo","middleName":"Hau","lastName":"Lim","suffix":""},{"id":629348799,"identity":"1221f254-773c-4719-9574-1b5f69aa5f8d","order_by":6,"name":"Chiau Ming Long","email":"","orcid":"","institution":"Sir Jeffery Cheah Sunway Medical School","correspondingAuthor":false,"prefix":"","firstName":"Chiau","middleName":"Ming","lastName":"Long","suffix":""}],"badges":[],"createdAt":"2026-04-10 15:55:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9381418/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9381418/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107948591,"identity":"75f99862-c670-44af-8d36-6542d684d7d1","added_by":"auto","created_at":"2026-04-28 00:22:24","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":15788,"visible":true,"origin":"","legend":"\u003cp\u003eScattered plot illustrated the overall distribution of SVCs, which consisted\u003c/p\u003e\n\u003cp\u003eOf initial SVCs (n=14) and steady-state SVCs (n=36).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9381418/v1/9ec5cd619449bb895648f046.png"},{"id":108007047,"identity":"42be044e-eac4-41db-9804-1dbcc0b9c8a2","added_by":"auto","created_at":"2026-04-28 12:58:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":547571,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9381418/v1/237a95f3-1bf8-4bb5-a508-0d1f1a4c45d9.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Continuous Intravenous Infusion of Vancomycin in Neonates: Case series from a Neonatal Intensive Care Unit","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eBacterial sepsis remains a leading cause of morbidity and mortality in the neonatal population, particularly among preterm neonates.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Methicillin-resistant \u003cem\u003ecoagulase-negative Staphylococci\u003c/em\u003e (CoNS) are frequently isolated in neonatal intensive care unit (NICU) cultures, though their definitive role as a cause of systemic disease can sometimes be debated. Vancomycin remains the main antibiotic prescribed for the treatment of late-onset sepsis caused by methicillin-resistant CoNS and \u003cem\u003eStaphyloccocus aureus\u003c/em\u003e in NICU.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Local antibiogram showed that most of the pathogens isolated from the NICU, i.e. CoNS, \u003cem\u003eBacillus spp.\u003c/em\u003e, methicillin-resistant \u003cem\u003eStaphylococcus aureus\u003c/em\u003e (MRSA) and \u003cem\u003eEnterococcus faecium\u003c/em\u003e, maintain susceptibility to vancomycin. For treatment of systemic infections caused by susceptible pathogens, current available evidence is lacking to support routine implementation of continuous intravenous infusion (cIVI) over intermittent intravenous infusion (IIV) for both the pediatric and neonatal populations.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Measured vancomycin trough levels from the neonatal population showed significant interindividual variability and inconsistency.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Often, a series of blood sampling for therapeutic drug monitoring (TDM) and dosage adjustment were needed to achieve the desired therapeutic concentrations of 15\u0026ndash;25 mg/L.\u003c/p\u003e \u003cp\u003eRecently, cIVI of vancomycin has become the current standard of practice in our NICU since 2019. Target concentrations of vancomycin are obtained more rapidly when administered as continuous infusion and there is less variability in the daily dose.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Both adult and pediatric data suggested that administration of vancomycin by cIVI may facilitate easier dosage adjustment and potentially lower nephrotoxicity risks compared to IIV dosing.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Several therapeutic vancomycin concentration ranges have been recommended for cIVI (e.g. 10\u0026ndash;15 mg/L, 15\u0026ndash;20 mg/L, or 15\u0026ndash;25 mg/L),\u003csup\u003e8, 10, 12\u0026ndash;14\u003c/sup\u003e but little is known about the clinical and microbiological outcomes, and nephrotoxicity in neonates. Moreover, transitioning from trough-level monitoring to AUC\u003csub\u003e24\u003c/sub\u003e monitoring is notoriously difficult in neonates and pediatrics using IIV because it requires multiple blood draws and complex pharmacokinetic math. The math becomes very simple when we adopt the cIVI, where AUC\u003csub\u003e24\u003c/sub\u003e is just the steady-state concentration multiplied by 24.\u003c/p\u003e \u003cp\u003eDosage recommendations for neonates range from 10\u0026ndash;20 mg/kg every 8 to 48 hours. These regimens aim to achieve a daily area-under-the-curve-to-minimum-inhibitory-concentration ratio (AUC\u003csub\u003e24\u003c/sub\u003e/MIC) of 400 (assuming a MIC of \u0026le;\u0026thinsp;1 mg/L, noting that CoNS MICs are often higher, i.e. ~ 2 mg/L); however, precise dosing depends heavily on postmenstrual age, weight, and serum creatinine (SCr).\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Until recently, there is no consensus on specific dosing recommendations for cIVI in the premature neonatal population. Therefore, this compilation of case series aimed to provide real-world data on the dosing range of cIVI vancomycin, serum vancomycin concentration (SVC) measured, microbiological clearance, and incidence of vancomycin-related nephrotoxicity in neonates.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cem\u003eObjectives\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis study aimed to provide simple and clinically practicable real-world data on the dosing range of cIVI vancomycin, serum vancomycin concentration achieved, microbiological clearance, and incidence of vancomycin-related nephrotoxicity in the neonatal population.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePatient eligibility and data collection\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e Neonatal patients who had been given cIVI of vancomycin during their hospital stay, who had at least one appropriately drawn vancomycin level (proper sampling time; AND peripheral blood; AND using red-cap plain tube; AND not drawn from the infusion line or arterial line) were included in the study. Relevant information was collected retrospectively from patients\u0026rsquo; case notes in the NICU and from an existing clinical therapeutic drug monitoring (TDM) database. Data on gestational age (GA), post-menstrual age (PMA), post-natal age (PNA), birth weight (BW), current weight (CW) during vancomycin initiation, comorbidities, mode of ventilation, laboratory parameters, microbiological culture and sensitivity (C\u0026amp;S), indication of vancomycin therapy, duration of vancomycin use, concurrent nephrotoxicity medications, urine output rate (mL/kg/hour), vancomycin loading dose (LD) and maintenance dose (MD), serum vancomycin concentration (SVC) and its sampling time were recorded. The neonate was considered small-for-gestational-age (SGA) if the birth weight was below the 10th percentile according to the GA-specific percentile chart of fetal growth weight standard published by Fenton T.R et al.\u003csup\u003e15\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDosing and administration\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e The loading dose (LD) and the initial maintenance dose (MD) of vancomycin were decided based on the total daily dose recommended by Micromedex\u0026reg; Neofax (\u003cem\u003esee Table 1\u003c/em\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 1. \u0026nbsp;Modified table showing total daily dose of vancomycin based on the original dosing table available on Micromedex\u003csup\u003e\u0026reg;\u003c/sup\u003e Neofax\u003c/p\u003e\n\u003ctable\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eRecommended dose\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eIndications\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCentral nervous system\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(i.e meningitis, ventriculitis)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eOther infections\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(sepsis, pneumonia etc)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eLoading dose, mg/kg/dose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eMaintenance dose, mg/kg/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePMA (weeks)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePNA (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e\u0026le; 29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0 - 14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13.33\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026gt;14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e30 \u0026ndash; 36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0 - 14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026gt;14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e37 \u0026ndash; 44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0 - 7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026gt;7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026gt; 45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAll\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e Abbreviations: PMA, post-menstrual age; PNA, post-natal age\u003c/p\u003e\n\u003cp\u003e With reference to the Australasian Neonatal Medicines Formulary, standard preparation of vancomycin for cIVI was performed per institutional practice to a final infused concentration usually not exceeding 10mg/mL.\u003csup\u003e16\u003c/sup\u003e The LD required was diluted with compatible diluent to a final volume of 3\u0026ndash;5 mL and infused over 1 hour using a syringe pump. As for MD, the prescribed dose is diluted up to a final volume of 12\u0026ndash;24 mL and infused at a constant rate of 0.5\u0026ndash;1 mL/hr via central line. Compatibility of Vancomycin with other medications co-infused through the same central line was routinely monitored by an in-house clinical pharmacist throughout the course of treatment. Dosage adjustments were made based on SVC and the recommendation provided by the TDM pharmacist. When SVC was within therapeutic range of 15-20 mg/L, the total daily dose (as in mg per kg) was maintained. If the SVC obtained did not fall within the therapeutic range, the daily dose was adjusted as shown in Equation 1:\u003c/p\u003e\n\u003cp\u003e\u003cimg 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\"\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePotential technical issues addressed in TDM database\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eInfrequently encountered technical issues with cIVI in the NICU are the proper preparation of vancomycin solution for 24-hour infusion by nursing staff, stability of vancomycin solution, and compatibility of vancomycin with other commonly co-administered medications. TDM pharmacist and clinical pharmacist in the NICU remained vigilant on the compatibility of vancomycin with parenteral nutrition and commonly administered medications in the NICU to prevent co-administration of incompatible medications. Compatibility charts, i.e drug\u0026ndash;parenteral nutrition and drug\u0026ndash;drug, were made available for clinicians and nursing staff in the NICU as a standard reference. Besides, extra care was adopted to prevent potential error whereby prescription of cIVI vancomycin clearly stated the dose, standard dilution and infusion rate intended, i.e. dose required diluted up to 12\u0026ndash;24mL with normal saline and infused as 0.5\u0026ndash;1 mL/hour.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAssay of serum vancomycin concentration\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e Peripheral blood was taken into clotting tubes and sera isolated by centrifugation. In vitro quantitative determination of serum vancomycin concentration was done using Cobas c system (Roche Diagnostics, Meylan, France). Serum vancomycin concentrations were determined through a homogenous microparticle agglutination immunoassay based on kinetic interaction of microparticles in a solution. The lowest limit of quantitation was 4.0 mg/L determined in accordance with the Clinical and Laboratory Standards Institute (CLSI) document EP17A2 requirement.\u003csup\u003e17\u003c/sup\u003e The precision was determined in accordance with the CLSI EP05-A3, with reported coefficients of variation (CV) 7.3% at 7.10 mg/L (TDM Control Set Level I), 2.4% at 21.2 mg/L (TDM Control Set Level II), and 2.0% at 34.3 mg/L (TDM Control Set Level III).\u003csup\u003e17\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTherapeutic vancomycin concentration\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e The first SVC was taken within 18\u0026ndash;48 hours after the initiation of maintenance dose. Subsequently, the dose was adjusted based on SVC obtained and patient\u0026rsquo;s current weight to maintain a target concentration between 15\u0026ndash;20 mg/L. Therapeutic SVC recommended by international standard was 15\u0026ndash;25 mg/L, which has been correlated with an AUC within 400-600 mg.h/L.\u003csup\u003e13\u003c/sup\u003e However, current practice in our neonatal intensive care unit continued to be conservative, with the target concentration at the range of 15-20 mg/L. SVCs which exceeded 20mg/L led to a down-titration of the total daily dose of vancomycin. SVCs higher than 25mg/L were regarded as potentially toxic, requiring interruption of vancomycin infusion and later reinitiation at a lower total daily MD. Following the current guideline recommendations, if not otherwise specified, achievement of therapeutic concentration target mentioned in any section of this report refers to the range 15-25 mg/L.\u003csup\u003e13, 18\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eValidation of Clinical Outcomes\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e Patient\u0026rsquo;s case notes and data collection form were reviewed by neonatologists. Neonatologists verified the patient\u0026rsquo;s clinical outcomes, i.e. resolution of nosocomial sepsis and meningitis, and reported adverse outcomes related to continuous intravenous infusion of vancomycin (if any), such as nephrotoxicity, transaminitis, or thrombophlebitis. For vancomycin-related nephrotoxicity, we adopted the definition and staging of acute kidney injury (AKI) proposed by neonatal modified Kidney Diseases: Improving Global Outcomes (KDIGO) study.\u003csup\u003e19, 20\u003c/sup\u003e First neonatal SCr was taken at least 36-48 hours after birth to reduce the interference by maternal SCr levels. Serum creatinine levels of premature neonates declined at different rates depending on gestational age. The validation of vancomycin-related nephrotoxicity was based on evaluation of SCr before, during and post-vancomycin treatment.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEthical Consideration and Consent to Participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e The study protocol was designed to be a retrospective data collection and analysis, which involved the pre-existing clinical data of preterm neonates. The study was registered with the National Medical Research Register (NMRR) with the registration ID NMRR-17-3502-37577 (IIR), and it was subjected to review and approval by the Ministry of Health Medical Research and Ethics Committee (MREC Approval: Ref. KKM.NIHSEC. P18-2090(7)). We acknowledge the importance of ethical oversight when involving minors, as this was a non-interventional retrospective study utilising existing medical records and TDM database, and the nature of this study carries no more than minimal risk, the requirement for informed consent from parents or legal guardians was waived by the MREC. All data were handled in accordance with the Declaration of Helsinki to ensure participant anonymity and confidentiality.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 31 neonates who received vancomycin as cIVI in the NICU within two years were screened. 14 premature neonates who met the inclusion criteria were included in the study. 17 neonates were excluded due to incomplete information or non-fulfilment of inclusion criteria. One of them was treated with two courses of cIVI vancomycin a week apart due to a reinfection with the same pathogen sensitive to vancomycin. A total of 58 random SVCs were recorded. From the 58 random SVCs evaluated, 8 SVCs were excluded due to either interruption in cIVI vancomycin following a toxic level (n=3), non-steady-state sampling (n=2) or suspected sampling error (n=3). Characteristics of the premature neonates were summarised in Table 2. All the 14 premature neonates included in our case series were aged between PMA 28.9 \u0026ndash; 36.7 weeks.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2 \u0026nbsp;Patient characteristics\u003c/p\u003e\n\u003ctable style=\"width: 100%;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eCharacteristic of premature neonates\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMedian \u0026nbsp;(IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eGestational age (n=14), weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28.9 \u0026nbsp; \u0026nbsp;(27.6 to 30.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003ePost-menstrual age (n=15*), weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e31.9 \u0026nbsp; \u0026nbsp;(29.3 to 34.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003ePost-natal age (n=15*), days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13 \u0026nbsp; \u0026nbsp; \u0026nbsp; (11 to 15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eBirth weight (n=14), kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.125 \u0026nbsp;(1.019 to 1.441)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eWeight (at vancomycin initiation), kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.315 \u0026nbsp;(1.035 to 1.490)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eInitial status of renal function\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eSerum creatinine,\u0026nbsp;\u0026micro;mol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e44.0 \u0026nbsp; \u0026nbsp;(\u0026plusmn; 14.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eGrowth weight standard,\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eSmall for gestational age, SGA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5 \u0026nbsp;(35.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eAppropriate for gestational age, AGA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9 \u0026nbsp;(64.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eGender \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10 \u0026nbsp;(71.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4 \u0026nbsp;(28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePMA (weeks)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePNA (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eCurrent weight range, kg\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026le; 29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0 \u0026ndash; 14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4 \u0026nbsp;(21.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.740 \u0026ndash; 1.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e30 \u0026ndash; 36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0 \u0026ndash; 14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5 \u0026nbsp;(26.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.175 \u0026ndash; 1.47\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026gt; 14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5 \u0026nbsp;(26.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.835 \u0026ndash; 1.80\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003e\n \u003cp\u003eIndication of vancomycin for each case (\u003cem\u003en=15\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u003cem\u003eNosocomial sepsis\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14 \u0026nbsp;(93.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u003cem\u003eSepsis with concern for meningitis\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 \u0026nbsp;(6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eTargeted treatment (\u003cem\u003en=13\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u003cem\u003eBacillus spp bacteraemia\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8 \u0026nbsp;(53.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u003cem\u003eMRCoNS bacteraemia\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3 \u0026nbsp;(20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u003cem\u003eMRSA bacteraemia\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 \u0026nbsp;(6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u003cem\u003eVISA bacteraemia (MIC 4mg/L)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 \u0026nbsp;(6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eEmpirical treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 \u0026nbsp;(6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eInappropriate indication (\u003cem\u003eA. baumanii\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 \u0026nbsp;(6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: \u0026nbsp; \u0026nbsp; PMA, post-menstrual age; PNA, post-natal age; IQR, interquartile range; NEC, necrotizing enterocolitis; MRCoNS, methicillin-resistance coagulase negative \u003cem\u003estaphylococcus\u003c/em\u003e; MRSA, methicillin-resistant \u003cem\u003estaphylococcus aureus\u003c/em\u003e; VISA, vancomycin-intermediate sensitive staphylococcus aureus; \u003cem\u003eE. meningoseptica, Elizabethkingia meningoseptica\u003c/em\u003e; \u003cem\u003eA. baumanii,\u003c/em\u003e \u003cem\u003eAcinetobacter baumanii.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e*One of the premature neonates was treated with two courses of cIVI vancomycin a week apart. The PMA and PNA of the premature neonate were recorded twice when cIVI was initiated at different time periods.\u003c/p\u003e\n\u003cp\u003eIn most of the cases (86.7%, n=13) of cIVI, vancomycin was initiated as targeted treatment. \u003cem\u003eBacillus spp\u0026nbsp;\u003c/em\u003ebacteraemia was the commonest cause encountered, followed by \u003cem\u003eCoNS\u003c/em\u003e bacteraemia\u003cem\u003e.\u003c/em\u003e Only 1 case was started on vancomycin empirically without a positive culture. The neonate who had a positive blood culture with vancomycin intermediate-sensitive \u003cem\u003eStaphylococcus aureus\u003c/em\u003e (VISA, with MIC of 4mg/L) was maintained at a targeted vancomycin concentration between 15-20mg/L. Repeated blood culture for this neonate showed no growth of \u003cem\u003eStaphylococcus aureus\u003c/em\u003e. However, his antibiotic was later upgraded to intravenous linezolid based on clinical impression of unresolving nosocomial sepsis.\u003c/p\u003e\n\u003cp\u003eAll 50 SVCs obtained were tabulated as shown in \u003cem\u003eFigure 1\u003c/em\u003e. Approximately half (52%, n=26) of the SVCs lay within the therapeutic range of 15\u0026ndash;25 mg/L (area-under-curve, AUC 400\u0026ndash;600mg.hr/L). Unexpectedly, there were 6 SVCs recorded higher than 25 mg/L with 5 of the supratherapeutic SVCs recorded at the initial phase of maintenance dose. Based on the investigation findings recorded in the TDM database, only 1 out of the 5 unexpectedly high initial SVCs was suspected to be possibly the result of pre-analytical sampling error. The unexpectedly high initial SVC plummeted from an abnormally high potentially toxic level (77.8 mg/L) down to a low level (6.4 mg/L) within 16 hours after interruption of vancomycin infusion, significantly faster than the general neonatal population\u0026rsquo;s renal clearance and physiological half-life (\u003cem\u003esee Table 3\u003c/em\u003e). Hence, the subsequent lower level probably represented the patient\u0026apos;s true systemic concentration. Among the pool of 5 premature neonates who were born SGA, 60% (n=3) of them had their initial SVC recorded above 25 mg/L, which was potentially toxic. The majority (89%, n=8) of the premature neonates who were born appropriate-for-gestation-age had recorded an initial SVC lower than 20 mg/L.\u003c/p\u003e\n\u003cp\u003eOut of 14 courses of cIVI vancomycin, dosing (LD and MD) deviated from the exact Micromedex\u003csup\u003e\u0026reg;\u003c/sup\u003e Neofax recommendations in 9 of the 14 courses. Only a few of the premature neonates (21.4%, n=3) had their initial SVC recorded within the therapeutic range of 15\u0026ndash;25 mg/L, whereas majority (57.1%, n=8) had an initial SVC lower than 15 mg/L. The median time-to-first-random-sample (TTS) after starting on the initial maintenance dose was 20 hours (IQR 16.5\u0026ndash;24). Demographic data, vancomycin dosing, and initial SVC data for individual neonates are presented in \u003cem\u003eTable 3\u003c/em\u003e.\u003c/p\u003e\n\u003cp\u003eTable 3 Demographic data of each neonate, vancomycin initial dosing data, initial serum vancomycin concentration achieved and pre-vancomycin serum creatinine.\u003c/p\u003e\n\u003ctable style=\"width:100%;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePMA, wks+days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePNA, days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eCw,\u003c/p\u003e\n \u003cp\u003ekg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eOther\u003c/p\u003e\n \u003cp\u003eComorbid-ities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNephro-toxic meds\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eLD, mg/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eiMD, mg/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eTTS,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ehrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eiSVC, mg/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMD range,\u003c/p\u003e\n \u003cp\u003emg/kg/D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eSVC\u003csub\u003ess\u003c/sub\u003e, mg/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo. of sample\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003cp\u003eDays of Tx\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eSCr,\u003c/p\u003e\n \u003cp\u003e\u0026micro;mol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAKI\u003csub\u003e\u0026Dagger;\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e31 + 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.195\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePDA, RDS, h/o RI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e(=)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30.0 (=)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e17*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e26.1\u003c/p\u003e\n \u003cp\u003e(\u0026gt;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e17.2\u0026ndash;19.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.9\u0026ndash;33.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30 + 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.365\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePDA, RDS, IVH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003cp\u003e(\u0026and;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29.3 (\u0026and;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e45.8\u003c/p\u003e\n \u003cp\u003e(\u0026gt;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e23.4\u0026ndash;25.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13.3\u0026ndash;18.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28 + 6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.035\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePDA, RDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e(=)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15.0 (\u0026or;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16.5*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6.1\u003c/p\u003e\n \u003cp\u003e(\u0026lt;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e25.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e31 + 6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.315\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePDA, RDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e(=)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e27.4 (\u0026or;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15.0\u003c/p\u003e\n \u003cp\u003e(\u0026lt;\u0026gt;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e25.6\u0026ndash;31.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15.1\u0026ndash;16.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30 + 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.835\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19.2\u003cstrong\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(\u0026and;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30.2 (=)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12.5\u003c/p\u003e\n \u003cp\u003e(\u0026lt;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2\u003cstrong\u003e\u003csup\u003ec\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29 + 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.070\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePDA, RDS, PH, h/o RI, IVH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e(=)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e18.7 (\u0026or;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9.6\u003c/p\u003e\n \u003cp\u003e(\u0026lt;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29.1\u0026ndash;32.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e23.3\u0026ndash;24.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e32 + 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.470\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e(=)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e18.0 (\u0026or;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12.5\u003c/p\u003e\n \u003cp\u003e(\u0026lt;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e26.7\u0026ndash;28.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15.7\u0026ndash;17.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e32 + 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.150\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e(=)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003cp\u003e(=)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e77.8\u003cstrong\u003e\u003csup\u003eb\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(\u0026gt;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10.0b\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e32 + 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.410\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e(=)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003cp\u003e(=)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12.5\u003c/p\u003e\n \u003cp\u003e(\u0026lt;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e27.1\u0026ndash;33.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15.3\u0026ndash;18.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29 + 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.985\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePDA, RDS, PH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e(=)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003cp\u003e(=)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16.5*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8.1\u003c/p\u003e\n \u003cp\u003e(\u0026lt;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20.0\u0026ndash;25.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e21.1\u0026ndash;21.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29 + 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.740\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePDA, RDS, IVH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e(\u0026or;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28.3 (\u0026or;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28.8\u003c/p\u003e\n \u003cp\u003e(\u0026gt;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13.5\u0026ndash;22.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10.2\u0026ndash;22.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e36 + 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.740\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePDA, RDS, NEC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e(=)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28.7 (\u0026or;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8.9\u003c/p\u003e\n \u003cp\u003e(\u0026lt;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e34.5\u0026ndash;36.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13.7\u0026ndash;15.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e36 + 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.490\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePDA, RDS, h/o RI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003cp\u003e(\u0026and;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28.7 (\u0026or;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e(\u0026lt;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e40.0\u0026ndash;45.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13.5\u0026ndash;18.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e14A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e34 + 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.700\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRDS, hydrop fetalis, ascites\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e(=)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29.4 (\u0026and;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15.7\u003c/p\u003e\n \u003cp\u003e(\u0026lt;\u0026gt;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16.3\u0026ndash;16.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e14B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e36 + 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.800\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRDS, hydrop fetalis, ascites\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e(=)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30.5 (=)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15.3\u003c/p\u003e\n \u003cp\u003e(\u0026lt;\u0026gt;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16.4\u0026ndash;25.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/strong\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003ePresence of concurrent nephrotoxic medications, e.g diuretics, paracetamol, aminoglycosides.\u003c/p\u003e\n\u003cp\u003e\u0026Dagger;\u0026nbsp;No reported case of vancomycin-induced AKI among the neonates treated with cIVI\u003c/p\u003e\n\u003cp\u003e* First blood draw was earlier than recommended (at least 18-24 hours after initiation of vancomycin) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea\u003c/strong\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003eHigher than recommended LD was due to inappropriate dose calculation using the patient\u0026rsquo;s best weight instead of the current weight when vancomycin treatment was planned. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eb\u003c/strong\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003eRecheck of SVC at 16 hours after interruption of vancomycin infusion reported as 6.4mg/l, dropped significantly faster than reasonable renal clearance for the neonate, which highly suggestive of pre-analytical sampling error. Hence ID-8 was excluded from analysis of initial serum vancomycin concentration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ec\u0026nbsp;\u003c/strong\u003eVancomycin was off on 2\u003csup\u003end\u003c/sup\u003e day when blood culture and sensitivity results showed Acinetobacter baumanii.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAbbreviations: AKI, acute kidney injury; CW, current weight; h/o RI, history of renal impairment; ID, patient identity; iMD, initial maintenance dose; iSVC, initial serum vancomycin concentration; IVH, intraventricular hemorrhage; LD, loading dose; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus; PH, pulmonary hemorrhage; PMA, post-menstrual age; PNA, post-natal age; RDS, respiratory distress syndrome; SCr, serum creatinine; SVC\u003csub\u003ess\u003c/sub\u003e, steady-state serum vancomycin concentration; TTS, time to sampling; Tx, treatment; wks+days, weeks \u0026amp; days;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSymbols: =, same as Neofax recommendation; \u0026and;, higher than Neofax recommendation; \u0026or;, lower than Neofax recommendation; \u0026lt;\u0026gt;, within therapeutic range (15-25 mg/L); \u0026lt;, lower than therapeutic range; \u0026gt;, higher than therapeutic range.\u003c/p\u003e\n\u003cp\u003eAs for practice of cIVI vancomycin in the premature neonate population, we did not notice the trend of higher number of blood samples for SVC monitoring in cases with longer duration of treatment. Average frequency of SVC monitoring for each premature neonate was 3 times per week, and if vancomycin duration of treatment extended into second and third week, the frequency of blood taking for SVC monitoring eventually reduced to 1 time per week. Details on dosing range and SVC monitoring are summarised in \u003cem\u003eTable 4\u003c/em\u003e.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 4 Dosing pattern of continuous intravenous infusion of vancomycin, serum vancomycin concentrations\u003c/p\u003e\n\u003ctable style=\"width:100%;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eParameters related to vancomycin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRange\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMean \u0026plusmn; SD / Median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eLoading dose given, mg/kg\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eAverage maintenance dose (MD), mg/kg/day\u003c/p\u003e\n \u003cp\u003eInitial serum vancomycin concentration (iSVC), mg/L\u003c/p\u003e\n \u003cp\u003eAverage serum vancomycin concentration (SVC), mg/L\u003c/p\u003e\n \u003cp\u003eDuration of treatment, days\u003c/p\u003e\n \u003cp\u003eNo. of blood sample taken for measurement of SVC\u003c/p\u003e\n \u003cp\u003eNo. of blood sample taken on 1\u003csup\u003est\u003c/sup\u003e week (Day 1\u0026ndash;7)\u003c/p\u003e\n \u003cp\u003eNo. of blood sample taken on 2\u003csup\u003end\u003c/sup\u003e week (Day 8\u0026ndash;14)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eNo. of blood sample taken on 3\u003csup\u003erd\u003c/sup\u003e week (Day 15\u0026ndash;21)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10 \u0026ndash; 19.2\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e13.5 \u0026ndash; 45.0\u003c/p\u003e\n \u003cp\u003e6.1 \u0026ndash; 45.8\u003c/p\u003e\n \u003cp\u003e7.9 \u0026ndash; 33.5\u003c/p\u003e\n \u003cp\u003e5 \u0026ndash; 23\u003c/p\u003e\n \u003cp\u003e3 \u0026ndash; 8\u003c/p\u003e\n \u003cp\u003e2 \u0026ndash; 5\u003c/p\u003e\n \u003cp\u003e0 \u0026ndash; 4\u003c/p\u003e\n \u003cp\u003e0 \u0026ndash; 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; -\u003c/p\u003e\n \u003cp\u003eMean 26.0 \u0026plusmn; 6.6\u003c/p\u003e\n \u003cp\u003eMedian 12.5 (9.4 \u0026ndash; 18.3)\u003c/p\u003e\n \u003cp\u003eMedian 15.9 (13.8 \u0026ndash; 18.5)\u003c/p\u003e\n \u003cp\u003eMedian 14 (11 \u0026ndash; 18)\u003c/p\u003e\n \u003cp\u003eMedian 3 (3 \u0026ndash; 4)\u003c/p\u003e\n \u003cp\u003eMean 3 \u0026plusmn; 1\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eMedian 1 (0 \u0026ndash; 1)\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003eA higher than recommended LD (i.e 19.2mg/kg, n=1) was due to inappropriate dose calculation using patient\u0026rsquo;s best weight instead of current weight when vancomycin treatment was planned.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e Accounted to vancomycin treatment which exceeded one(1) week, n = 13\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ec\u003c/sup\u003e Accounted to vancomycin treatment which exceeded two(2) weeks, n = 5\u003c/p\u003e\n\u003cp\u003eAbbreviations: \u0026nbsp;SD, standard deviation; IQR, interquartile range; iMD, initial maintenance dose; MD, maintenance dose; iSVC, initial serum vancomycin concentration; SVC, serum vancomycin concentration.\u003c/p\u003e\n\u003cp\u003eMaintenance dose (MD) adjustments were proposed by pharmacist from the therapeutic drug monitoring (TDM) unit after the initial SVC and current renal profile were reviewed. All the initial SVCs or repeated SVCs which were noted to be higher than 25 mg/L led to a temporary interruption in cIVI vancomycin until a recheck SVC confirmed clearance of the SVC to a concentration lower than 20 mg/L. After adjustment of MD by the TDM pharmacist, the percentage of subsequent SVCs achieving the therapeutic range of 15-25 mg/L was 53% (n=8), and 40% (n=6) were within the range of 10-15 mg/L, all iSVCs that were below 10 mg/L (27%, n=4) increased to be above 10 mg/L without exceeding toxic level.\u003c/p\u003e\n\u003cp\u003eAll cases with a positive blood culture (n=13) were validated as achieving microbiologic clearance, and all patients (except for the patient with VISA, for whom vancomycin was changed to linezolid) were documented as having responded to vancomycin treatment. None of our premature neonates experienced any central-line-related complications with vancomycin (solution concentration of 5\u0026ndash;7.5 mg/mL) infused at a constant rate of 1 mL/hour. No cases of vancomycin-induced acute kidney injury were reported, and all cases had recorded good urine output rate throughout the whole treatment course of vancomycin, with a mean urine output rate of 5.1 \u0026plusmn; 1.5 mL/kg/hour. Our study did not assess the risk of ototoxicity and did not record the outcome in term of pathological ototoxicity.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003e\u003cem\u003eContinuous intravenous infusion of vancomycin: Dosing and therapeutic range\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eBased on Micromedex\u003csup\u003e®\u003c/sup\u003e Neofax, the expected therapeutic trough concentration for intermittent dosing ranged from 10 to 20 mg/L, which is inherently lower than the steady-state therapeutic concentration range of 15-25 mg/L often recommended for cIVI.\u003csup\u003e7, 13, 21\u003c/sup\u003e Adopting the practice of cIVI vancomycin enabled us to easily estimate the AUC\u003csub\u003e24\u003c/sub\u003e by multiplying the steady-state SVC (i.e. targeted therapeutic concentration range of 15–25 mg/L) by 24 hours.In our case series, we have expected that many of the initial SVCs recorded may not fall within the therapeutic concentration range of 15–25mg/L, and that merely 21.4% (n=3) of the iSVCs were satisfactory. \u0026nbsp;It was also expected that more than half (57.1%, n=8) of the iSVCs were lower than 15mg/L because our dosing was based primarily on Neofax recommendations. Findings from population kinetic dosing modelling done by Li et al suggested that the current recommended doses of vancomycin from FDA labelling, Red Book, Pediatric \u0026amp; Neonatal Dosage Handbook, and Neofax may be inadequate to meet a treatment target of AUC\u003csub\u003e24h\u0026nbsp;\u003c/sub\u003e/ MIC ≥ 400 mg.h/L in neonatal patients with a greater renal clearance status, especially SCr \u0026lt; 15 µmol/L.\u003csup\u003e22\u003c/sup\u003e Hence, a specific dosing guide for cIVI of vancomycin in the neonatal population should be developed; use of a TDM service is necessary along with this dosing guidance, to ensure optimisation of the dosing regimen and achievement of therapeutic concentration.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIt is recommended that dosages to achieve an AUC\u003csub\u003e24\u003c/sub\u003e of 400 mg.hr/L (assuming a MIC of 1 mg/L) in neonates ranged from 10 to 20 mg/kg every 8 to 48 hours, depending on postmenstrual age, weight, and SCr.\u003csup\u003e13\u003c/sup\u003e The clinical utility of this dosing recommendation remained less relevant to our current practice setting as we did not fully adopt AUC\u003csub\u003e24\u003c/sub\u003e as a guide for dosage adjustment. Our study with small sample size lacked in-depth details on dosing and SVC data (i.e. specific time point), hence impactful inference could not be derived from this case series. Our TDM research team continued with more in-depth data collection for cIVI use in both premature and term neonates. More cases are being recruited currently to provide a bigger database sufficient to provide inferences about pharmacokinetics and pharmacodynamics for cIVI of vancomycin in this vulnerable population, and ultimately a database with the capacity to facilitate modelling and simulation.\u003c/p\u003e\n\u003cp\u003eClinical utility of cIVI vancomycin with a targeted SVC of 15–25mg/L requires further evaluation prior to adoption into practice among neonatologists, as the most common pathogen cultured and treated in our setting was \u003cem\u003eBacillus spp\u003c/em\u003e (53.3%) instead of \u003cem\u003eStaphylococcus aureus,\u0026nbsp;\u003c/em\u003efollowed by methicillin-resistant coagulase-negative \u003cem\u003eStaphylococcus spp.\u0026nbsp;\u003c/em\u003e(20%). Because the 15-25 mg/L therapeutic range is specifically correlated with outcomes for MRSA, it cannot necessarily be extrapolated to other organisms. All of our cases with positive blood culture were validated as having achieved microbiologic clearance, although not all the SVCs recorded were within the therapeutic concentration range of 15-25 mg/L. It seems possible that a lower target SVC may be sufficient for the elimination of non-\u003cem\u003eStaphylococcus aureus\u003c/em\u003e pathogens, but more robust data are needed to support this recommendation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMoving forward, the TDM and clinical pharmacy team would remain cautious and may propose a higher vancomycin LD at 15mg/kg for treatment targeting all MRSA infections and any infection which involve the central nervous system, followed by the MD as per Micromedex\u003csup\u003e®\u003c/sup\u003e Neofax recommendation for the reason that a high percentage of the iSVCs obtained were lower than recommended therapeutic range of 15–25mg/L. Furthermore, the decision to propose higher vancomycin doses to rapidly achieve therapeutic targets must always be weighed against the compounding risks of AKI, particularly when nephrotoxic comorbidities are present. A good example to highlight was case ID-11, where the neonate was extremely premature, SGA with very low birth weight, had hemodynamically significant PDA, and had previously and concurrently been on nephrotoxic medication. The case was diagnosed with sepsis, likely meningitis, and treated with 3 weeks of vancomycin. A decision was made to only use lower iLD and iMD, and draw blood earlier than 18 hours to ensure no vancomycin accumulation. The iSVC at 12 hours turned out to be higher than 28.8 mg/L. The role of TDM in support of the current practice of cIVI remained relevant as the percentage of SVCs within the therapeutic concentration range of 15-25 mg/L increased from 21% to 53% after dosage adjustment recommended by TDM pharmacist.\u003c/p\u003e\n\u003cp\u003eChanges in body weight and kidney function of the patient are known factors that affect the drug distribution and the clearance of vancomycin, of which the compounding effect will be reflected in SVC throughout the course of treatment. For neonates with stable renal function, vancomycin dose should be adjusted based on the latest body weight to prevent the patient from having subtherapeutic or supratherapeutic SVC. From every case with SVC above 25mg/l, we investigated and concluded several possibilities, i.e initiated on higher than recommended MD, maintaining existing dose despite a drop in body weight, deteriorating kidney function (increasing SCr and reducing urine output), and adjusting to a higher maintenance dose based on initial SVC taken less than 16 hours. From cases with SVC below 10mg/l, most of the cases (75%) were initiated on lower than recommended MD.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eReduced the number of blood samples needed for TDM and lower risk of sampling time error\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOne of the reasons cIVI vancomycin was the preferred method of administration in the NICU was the benefit of having fewer blood draws. In our case series, it was interesting to find that the mean frequency of blood draws for SVC monitoring in this group of neonates was 3 times per week for the 1\u003csup\u003est\u003c/sup\u003e week, and subsequently, when the duration of vancomycin treatment was extended to a 2\u003csup\u003end\u003c/sup\u003e or 3\u003csup\u003erd\u003c/sup\u003e week, the frequency of blood draws for SVC monitoring reduced to once a week. After further investigation into each case with more than 3 times blood draws per week, we found that it was mainly due to initial unexpected high SVCs which raised suspicion of sampling or administration error, leading to interruption of cIVI vancomycin and requirement of a repeated SVC level to confirm a normalisation of vancomycin concentration to below 20mg/L. Otherwise, for those cases where SVCs appeared stable within the 1\u003csup\u003est\u003c/sup\u003e week, the maintenance dose (in term of mg/kg/day) was continued and the total daily dose was kept in check i.e. adjusted according to latest body weight. This finding was consistent with study finding by Hong LT et al which proved that continuous infusion of vancomycin\u0026nbsp;reduced number of blood samples needed for SVC monitoring in intensive care unit patients.\u003csup\u003e23\u003c/sup\u003e Furthermore, if compared to IIV, cIVI offers simplified TDM with less dependence on strict sampling time, eliminating the need to time the draw exactly 30 minutes before the next dose.\u003csup\u003e24\u003c/sup\u003e IIV dosing’s reliance on exact timing makes it highly vulnerable to errors in a busy NICU setting.\u003csup\u003e25\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eOn the contrary, 6 out of 15 iSVCs were drawn earlier than the recommended time of 18-24 hours after initiation of vancomycin infusion. There was no specific justification recorded in the TDM database. By assessing individual case details, we concluded several possible explanations to the early blood draw: premature neonates at risk of AKI requiring early level to ensure that no vancomycin accumulation, to coincide with other blood investigations due to difficult peripheral blood draw, or use of vancomycin dosing regimen deviated from standard recommendations (i.e. higher dose used, TDM blood earlier to ensure no drug accumulation; lower dose used, TDM blood earlier to facilitate dosage up-titration if noted subtherapeutic SVC).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eVancomycin-related nephrotoxicity and ototoxicity\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe known risk factors for AKI in neonates who received vancomycin include higher vancomycin trough concentrations, concurrent use of nephrotoxic medications, low birth weight, and patent ductus arteriosus.\u003csup\u003e20, 26, 27\u003c/sup\u003e The wide varying estimates of incidence of vancomycin-related nephrotoxicity among neonates reported, ranging from 2% to 20%, have led to confusion and controversy regarding the safety of vancomycin among neonates.\u003csup\u003e28\u003c/sup\u003e Several studies have shown that cases of vancomycin-related nephrotoxicity in neonates were infrequently reported.\u003csup\u003e8, 26, 28\u003c/sup\u003e\u0026nbsp; There were no reported cases of vancomycin-induced AKI among the neonates treated with cIVI in our cohort, with more than half of the measured SVCs were within higher therapeutic concentration range of 15–25 mg/L (AUC 400–600 mg.h/L) while a few SVCs above 25 mg/L. Additionally, a few of our cases involved neonates with prior or concomitant use of nephrotoxic medications (e.g., aminoglycosides, frusemide, hydrochlorothiazide, paracetamol), underlying PDA, or SGA. Current evidence showed a mixed safety profile of\u0026nbsp;vancomycin in both neonates and paediatric patients, suggesting an incidence of 1% up to 18.2% vancomycin-associated AKI, especially when the trough concentration was more than 15 mg/L.\u003csup\u003e29-31\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eA large cohort study revealed that vancomycin exposure in very-low-birth-weight infants is associated with an increased risk of pathological hearing test, in a dose-dependent manner.\u003csup\u003e32\u003c/sup\u003e This warrants us to remain cautious as long-term safety data (including ototoxicity) for early exposure of premature neonates to vancomycin is not readily available locally. Hence, treatment with cIVI vancomycin in premature neonates must be practised with care, with appropriate periodic steady-state SVC monitoring to prevent unexpected drug accumulation, routine renal function monitoring to detect early AKI, and to schedule the infants for appropriate follow-up hearing tests.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThe case series provided us with good insight into the practicability of cIVI of vancomycin in treating premature neonates in the neonatal intensive care unit. The percentage of measured SVCs that were within the therapeutic concentration range was 72%. Microbiological clearance and clinical resolution of nosocomial sepsis for cases with correct indication was 100%. This indicates vancomycin continuous infusion dosing regimen in neonates seems simple and clinically practicable, and was not associated with any incidence of nephrotoxicity.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eacute kidney injury, AKI; area-under-the-curve, AUC\u003csub\u003e24\u003c/sub\u003e;\u0026nbsp;birth weight, BW; \u003cem\u003eCoagulase-negative Staphylococcus, CoNS;\u0026nbsp;\u003c/em\u003econtinuous intravenous infusion, cIVI; culture and sensitivity, C\u0026amp;S; current weight, CW; gestational age, GA; intermittent intravenous infusion, IIV; interquartile range, IQR; intraventricular hemorrhage, IVH;\u0026nbsp;loading dose, LD; maintenance dose, MD; methicillin-resistant\u003cem\u003e\u0026nbsp;Staphylococcus aureus, MRSA;\u0026nbsp;\u003c/em\u003eminimum inhibitory concentration, MIC; necrotizing enterocolitis, NEC; neonatal intensive care unit, NICU; patent ductus arteriosus, PDA; post-menstrual age, PMA; post-natal age, PNA; pulmonary hemorrhage, PH;\u0026nbsp;serum creatinine, SCr; serum vancomycin concentration, SVC; small for gestation age, SGA; standard deviation, SD; therapeutic drug monitoring, TDM\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding Source \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;:\u0026nbsp;\u003c/strong\u003eNo funding was secured for this study\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest \u0026nbsp; \u0026nbsp;:\u0026nbsp;\u003c/strong\u003eAll authors have no conflicts of interest to disclose\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContent Summary\u003c/strong\u003e : Continuous infusion of vancomycin has been instituted as a standard practice in our centre, and through this case series, we provided preliminary information on the dosing range of vancomycin, serum vancomycin concentration achieved, microbiological clearance, and incidence of vancomycin-related nephrotoxicity in neonates.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRegistration of Research, NMRR ID:\u003c/strong\u003e NMRR-17-3502-37577 (IIR)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval, MREC \u0026nbsp; \u0026nbsp; \u0026nbsp; :\u0026nbsp;\u003c/strong\u003eKKM.NIHSEC. P18-2090(7)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPETING INTERESTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e. There is no conflict of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was secured for this study\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHORS’ CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTKL and CKS contributed to the conceptualisation and design of the study. CKS was responsible for study registration. Data acquisition was carried out by CKS, LTY, and ASR. Data analysis and interpretation were performed by CKS, LTY, and TKL. The manuscript was drafted by CKS, TKL, LTY, and ASR. Critical revision of the manuscript was conducted by TKL and CKS. Statistical analysis was performed by CKS and LTY. LJJ, LCH, and LCM provided resources and support. Supervision was provided by TKL and LCM. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to express our sincere appreciation to the Director-General of Health, Malaysia, for permission to publish this work. We also extend our gratitude to the Head of the Pediatric Department, Dato’ Dr Angeline Yeoh Aing Chiee, for her support leading to the completion of this study. Furthermore, we are deeply grateful to Dr Yeap Li Ling from the School of Pharmacy, Monash University Malaysia, for her expert review and feedback on this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman Ethics and Consent to Participate Declarations:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study was registered with the National Medical Research Register (NMRR) with the registration ID NMRR-17-3502-37577 (IIR), and it was subjected to review and approval by the Ministry of Health Medical Research and Ethics Committee (MREC Approval: Ref. KKM.NIHSEC. P18-2090(7)). We acknowledge the importance of ethical oversight when involving minors, as this was a non-interventional retrospective study utilising existing medical records and TDM database, and the nature of this study carries no more than minimal risk, the requirement for informed consent from parents or legal guardians was waived by the MREC. All data were handled in accordance with the Declaration of Helsinki to ensure participant anonymity and confidentiality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors reviewed and approved the final manuscript and consent to its publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAI use statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the preparation of this work, the author used ChatGPT (free version) for brainstorming and Grammarly (free version) to refine and verify the grammar of the original manuscript. After using these tools, the author reviewed and edited the content as needed and takes full responsibility for the content of the published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData are available from the corresponding author upon reasonable request, subject to a data sharing agreement\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMarchant EA, Boyce GK, Sadarangani M, Lavoie PM. Neonatal sepsis due to coagulase-negative staphylococci. Clin Dev Immunol. 2013;2013:586076. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1155/2013/586076\u003c/span\u003e\u003cspan address=\"10.1155/2013/586076\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. 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Epub 2012 Dec 19.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGwee A, Cranswick N, McMullan B, Perkins E, Bolisetty S, Gardiner K, et al. Continuous Versus Intermittent Vancomycin Infusions in Infants: A Randomized Controlled Trial. Pediatrics. 2019;143(2):e20182179.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCataldo MA, Tacconelli E, Grilli E, Pea F, Petrosillo N. Continuous versus intermittent infusion of vancomycin for the treatment of Gram-positive infections: systematic review and meta-analysis. J Antimicrob Chemother. 2012;67(1):17\u0026ndash;24. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/jac/dkr442\u003c/span\u003e\u003cspan address=\"10.1093/jac/dkr442\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2011 Oct 25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWysocki M, Delatour F, Faurisson F, Rauss A, Pean Y, Misset B, et al. Continuous versus Intermittent Infusion of Vancomycin in Severe Staphylococcal Infections: Prospective Multicenter Randomized Study. Antimicrob Agents Chemother. 2001;45(9):2460\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1128/AAC.45.9.2460-7.001\u003c/span\u003e\u003cspan address=\"10.1128/AAC.45.9.2460-7.001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJunker A, Howe Z, Schneider JG, Bhumbra S, Kussin ML. Continuous Infusion Vancomycin Dosing and Area Under the Curve Target Attainment in a Freestanding Children\u0026rsquo;s Hospital. J Pediatr Infect Dis Soc. 2024;13(Supplement3):S12\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLo YL, van Hasselt JG, Heng SC, Lim CT, Lee TC, Charles BG. 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American Journal of Health-System Pharmacy; 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeroux S, Zhao W, Betremieux P, Pladys P, Saliba E, Jacqz-Aigrain E. Therapeutic guidelines for prescribing antibiotics in neonates should be evidence-based: a French national survey. Arch Dis Child. 2015;100(4):394\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/archdischild-2014-306873\u003c/span\u003e\u003cspan address=\"10.1136/archdischild-2014-306873\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2015 Jan 27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFenton TR, Elmrayed S, Alshaikh BN. Fenton Third-Generation Growth Charts of Preterm Infants Without Abnormal Fetal Growth: A Systematic Review and Meta-Analysis. Paediatr Perinat Epidemiol. 2025;39(6):543\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAustralasian Neonatal Medicines Formulary. Vancomycin-continuous infusion (Newborn Use Only) Date of publication 29/01/2026 [Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.anmfonline.org/\u003c/span\u003e\u003cspan address=\"https://www.anmfonline.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTest VANC (Vancomycin), editor. test ID 0-459. Mannheim, Germany: Roche Diagnostics GmbH; 2022.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHe N, Su S, Ye Z, Du G, He B, Li D, et al. Evidence-based Guideline for Therapeutic Drug Monitoring of Vancomycin: 2020 Update by the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society. Clin Infect Dis. 2020;71(Suppl 4):S363\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJetton JG, Askenazi DJ. Update on acute kidney injury in the neonate. Curr Opin Pediatr. 2012;24(2):191\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHanna MH, Askenazi DJ, Selewski DT. Drug-induced acute kidney injury in neonates. Curr Opin Pediatr. 2016;28(2):180\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVancomycin. (2018). In IBM Micromedex Neofax Drug Reference for Android iOS (Version v1.3b252) [Mobile application software].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi Z-l, Liu Y-x, Jiao Z, Qiu G, Huang J-q, Xiao Y-b et al. Population Pharmacokinetics of Vancomycin in Chinese ICU Neonates: Initial Dosage Recommendations. Front Pharmacol. 2018;9(603).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHong LT, Goolsby TA, Sherman DS, Mueller SW, Reynolds P, Cava L, et al. Continuous infusion vs intermittent vancomycin in neurosurgical intensive care unit patients. J Crit Care. 2015;30(5):e11531\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFlannery AH, Bissell BD, Bastin MT, Morris PE, Neyra JA. Continuous Versus Intermittent Infusion of Vancomycin and the Risk of Acute Kidney Injury in Critically Ill Adults: A Systematic Review and Meta-Analysis. Crit Care Med. 2020;48(6):912\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNguyen TA, Kirubakaran R, Schultz HB, Wong S, Reuter SE, McMullan B, et al. Analytical and Non-Analytical Variation May Lead to Inappropriate Antimicrobial Dosing in Neonates: An In Silico Study. Clin Chem. 2023;69(6):637\u0026ndash;48.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBhatt-Mehta V, Schumacher R, Faix R, Leady M, Brenner T. Lack of Vancomycin-associated Nephrotoxicity in Newborn Infants: A Case-Control Study. Pediatrics. 1999;103:e48.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcKamy S, Hernandez E, Jahng M, Moriwaki T, Deveikis A, Le J. Incidence and risk factors influencing the development of vancomycin nephrotoxicity in children. J Pediatr. 2011;158(3):422\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eConstance JE, Balch AH, Stockmann C, Linakis MW, Korgenski EK, Roberts JK, et al. A propensity-matched cohort study of vancomycin-associated nephrotoxicity in neonates. Archives disease Child Fetal neonatal Ed. 2016;101(3):F236\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBhargava V, Malloy M, Fonseca R. The association between vancomycin trough concentrations and acute kidney injury in the neonatal intensive care unit. BMC Pediatr. 2017;17(1):50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAshkenazi-Hoffnung L, Schiller O, Krubiner M, Dagan O, Haskin O, Manor-Shulman O, et al. Vancomycin Dosing and Its Association With Acute Kidney Injury in Pediatric Cardiac Intensive Care Patients Under 3 Months of Age. Pediatr Infect Dis J. 2024;43(10):963\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKnoderer CA, Nichols KR, Lyon KC, Veverka MM, Wilson AC. Are Elevated Vancomycin Serum Trough Concentrations Achieved Within the First 7 Days of Therapy Associated With Acute Kidney Injury in Children? J Pediatr Infect Dis Soc. 2014;3(2):127\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarissen J, Fortmann I, Humberg A, Rausch TK, Simon A, Stein A, et al. Vancomycin-induced ototoxicity in very-low-birthweight infants. J Antimicrob Chemother. 2020;75(8):2291\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"continuous intravenous infusion, vancomycin, premature neonates, therapeutic drug monitoring, nephrotoxicity","lastPublishedDoi":"10.21203/rs.3.rs-9381418/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9381418/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThere is no standard dosing guideline available for continuous intravenous infusion (cIVI) vancomycin in the neonatal population. Vancomycin administered as cIVI is the current practice in our neonatal intensive care unit. Data from this case series provided preliminary information on dosing range of cIVI vancomycin, serum vancomycin concentration (SVC), microbiological clearance, and incidence of vancomycin-related nephrotoxicity in neonates.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eClinical and laboratory data of this retrospective case series were extracted from patient\u0026rsquo;s medical record and therapeutic drug monitoring database.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOf the total 36 steady-state SVCs from 15 records analysed, 64% (n\u0026thinsp;=\u0026thinsp;23) were within a therapeutic range of 15\u0026ndash;25 mg/L, approximating an area-under-the-curve (AUC\u003csub\u003e24\u003c/sub\u003e) of 400\u0026ndash;600 mg.hr/L. Initial SVCs were generally taken within 18\u0026ndash;24 hours, however, only 20% (n\u0026thinsp;=\u0026thinsp;3) were within therapeutic range. Loading dose given ranged between 10\u0026ndash;15mg/kg, and the mean maintenance dose was 26\u0026thinsp;\u0026plusmn;\u0026thinsp;6.58 mg/kg/day. Most of the cases (86.7%, n\u0026thinsp;=\u0026thinsp;13) were targeted treatment for infections which involved \u003cem\u003eBacillus spp, Coagulase-negative Staphylococcus (CoNS)\u003c/em\u003e, and methicillin-resistant \u003cem\u003eStaphylococcus aureus (MRSA).\u003c/em\u003e Microbiological clearance was achieved in all targeted cases, and no cases of vancomycin-induced acute kidney injury were reported.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis indicates vancomycin continuous infusion dosing regime in neonates seems practicable and was not associated with any incidence of nephrotoxicity.\u003c/p\u003e","manuscriptTitle":"Continuous Intravenous Infusion of Vancomycin in Neonates: Case series from a Neonatal Intensive Care Unit","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-28 00:22:20","doi":"10.21203/rs.3.rs-9381418/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-04T06:44:29+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-01T00:35:29+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-30T10:07:23+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-29T09:08:02+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-25T06:57:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"91939717145825712538645385294834730003","date":"2026-04-24T13:24:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"36880763568232301823291305996689112920","date":"2026-04-21T12:55:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"131391236098876982465862293452673952422","date":"2026-04-21T04:02:00+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-21T01:30:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"222511048618839419080545247318430328758","date":"2026-04-20T02:57:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"167294847707267385978065451379927575653","date":"2026-04-19T13:31:59+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-19T12:22:31+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-04-16T20:22:58+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-14T01:59:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-14T01:59:22+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2026-04-10T15:37:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9a7e98db-9ff2-428d-8563-d8527a567f02","owner":[],"postedDate":"April 28th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-04T06:44:29+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-01T00:35:29+00:00","index":44,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-30T10:07:23+00:00","index":43,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T06:55:34+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-28 00:22:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9381418","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9381418","identity":"rs-9381418","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}