Population Pharmacokinetics and Pharmacodynamics of Vancomycin in Pediatric Patients With Various Degrees of Renal Function

Abstract

OBJECTIVE

Although vancomycin dosage recommendations in the pediatric setting for methicillin-resistant Staphylococcus aureus (MRSA) infection indicate that ≥60 mg/kg/day is correlated to a desired area under the vancomycin concentration time curve from 0 to 24 hours to minimum inhibitory concentration ratio (AUC_{0–24 hr}/MIC) ≥400, for some patients this dosage is inadequate or relates to toxicity. This study purposed to explore vancomycin dosing for pediatrics with various degrees of renal function.

METHODS

Routine monitoring data were retrospectively collected from patients, aged 1 month to 18 years. Population pharmacokinetic analysis was performed by using non-linear mixed-effect model with NONMEM software, and Monte Carlo simulation was conducted by using Crystal Ball software.

RESULTS

Two hundred twelve patients with 348 vancomycin serum concentrations were included. Median age was 3.5 years (IQR, 0.9–10.9), median weight was 14.0 kg (IQR, 7.2–30.4), with baseline estimated glomerular filtration rate (eGFR) ranging from 15.5 to 359.3 mL/min/1.73 m². A 1-compartment model with first-order elimination sufficiently described vancomycin PK. The dosing targeting AUC_0–24hr/MIC ≥400 and AUC_0–24hr <800 mg•h/L for pediatric patients with eGFRs of 15 to 29, 30 to 59, 60 to 89, 90 to 129, and 130 to 160 mL/min/1.73 m² was 12.5, 25, 40, 60, and 70 mg/kg/day, respectively. All vancomycin dosing obtained >85% of the cumulative fraction of response across the MIC distribution of MRSA.

CONCLUSIONS

Vancomycin dosing of 12.5, 25, 40, 60, and 70 mg/kg/day is suggested for pediatric patients with eGFRs of 15 to 29, 30 to 59, 60 to 89, 90 to 129, and 130 to 160 mL/min/1.73 m², respectively.

Introduction

Vancomycin, a glycopeptide antibiotic developed for inhibiting bacterial cell wall synthesis, is widely used for treatment of infections caused by Gram-positive bacterial infections including methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative Staphylococcus, Streptococcus spp, and Enterococcus spp.^1,2 Infections caused by MRSA are one of the major bacterial nosocomial infections resistant to antibiotics in Thailand.³ These infections cause an increase in mortality and morbidity including length of stay, and economic loss.^3,4

Consensus recommendations suggest that the area under the vancomycin serum concentration time curve from 0 to 24 hours to pathogen minimum inhibitory concentration ratio (AUC_{0–24 hr}/MIC) is the pharmacokinetic (PK) and pharmacodynamic (PD) parameter that best predicts vancomycin efficacy.^1,5,6 An AUC_{0–24 hr}/MIC of at least 400 was associated with superior clinical response, compared with lower AUC_{0–24 hr}/MIC ratios. Trough-only monitoring is no longer recommended. Instead, AUC-guided dosing should be implemented.⁵ Currently, data in children are limited and the same target AUC_{0–24 hr}/MIC ratios are generally applied for pediatric patients.¹ A recent meta-analysis study in pediatrics and the 2020 consensus guideline suggest that to achieve the target AUC_{0–24 hr}/MIC of ≥400, vancomycin doses of 60 to 80 mg/kg/day are required,^5,7 whereas vancomycin dosing data in augmented renal clearance are limited.⁸

Vancomycin has a narrow therapeutic window with potential for nephrotoxicity, particularly with aggressive dosing of vancomycin⁹ and with the concurrent use of nephrotoxins.^10–12 It is mainly eliminated via glomerular filtration. A reduction of glomerular filtration rate will reduce vancomycin clearance (CL), resulting in increased serum vancomycin concentrations, and make it difficult to determine a causal relationship between nephrotoxicity and serum vancomycin concentrations.⁵ Available adult data suggested that the risk of nephrotoxicity is associated with vancomycin AUC_{0–24 hr}, especially when the AUC_{0–24 hr} exceeds 600 to 700 mg•h/L.^13–15 One pediatric study¹⁶ suggested a toxicity threshold AUC_{0–24 hr} of 800 mg•h/L.

Therefore, we first aimed to characterize vancomycin PK behavior in pediatric patients aged 1 month to 18 years, from routine clinical data, and to investigate clinical factors affecting vancomycin PK. We also intended to recommend vancomycin dosing that provides a high possibility of achieving the desired target AUC_{0–24 h}/MIC of at least 400 and not exceed the proposed toxic AUC_{0–24 hr} threshold of 800 mg•h/L for pediatric patients with different levels of renal function.

Methods

Study Design. This retrospective study was conducted at King Chulalongkorn Memorial Hospital (KCMH), Bangkok, Thailand. All patients aged 1 month to 18 years who received intravenous vancomycin and had at least 1 measured vancomycin concentration between January 2012 and December 2017 were included. Patients with renal replacement therapy, chronic kidney disease stage 5, estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m², or insufficient data were excluded.

Data collection included age (years), sex, weight (kilograms), height (centimeters), serum creatinine (SCr) levels (milligrams per deciliter), chronic illness, vancomycin dose (milligrams), vancomycin serum concentrations (milligrams per liter), and concomitant drugs. Nephrotoxic drugs (acyclovir, aminoglycosides, amphotericin-B, cyclosporine, tacrolimus) and beta-lactams (piperacillin/tazobactam, cefoperazone/sulbactam) prescribed and continued along with vancomycin for at least 48 hours were considered as concomitant drugs, whereas vasopressors (epinephrine, norepinephrine, dopamine, dobutamine) were also included as concomitant drugs regardless of the duration of co-administration. If renal function changed during the study period, SCr concentration at the time or nearest time of collecting a vancomycin serum concentration was recorded. Blood samples were collected from routine therapeutic drug monitoring. Peak concentrations were drawn within 1 to 2 hours after the end of infusion (see below), and trough concentrations were drawn within 0 to 1 hour before the next dose. Both steady-state and non–steady-state vancomycin serum concentrations were included in this analysis.

Analytical Assay. Vancomycin serum concentrations were quantified at Center for Medical Diagnostic Laboratories, Faculty of Medicine, Chulalongkorn University, by using a validated chemiluminescent microparticle immunoassay (ARCHITECT i2000SR, Abbott Laboratories, Abbott Park, IL). The intraday and the interday coefficient of variations were less than 10%. The lower limit of quantitation of the assay was 3.0 mg/L, and the assay range was 3.0 to 100.0 mg/L.

Population PK Modeling. Population PK parameters were estimated by using non-linear mixed effect modeling approach with NONMEM version 7.4.3 and PDx-Pop version 5.2.1 (Icon Development Solutions, Ellicott City, MD). To find the appropriate structural model, 1- and 2-compartment models with first-order elimination were investigated by using subroutines from the NONMEM library. Interindividual variability was described by exponential model and residual unexplained variability was tested with additive, proportional, exponential, and combined (additive-proportional) models. First-order conditional estimation with interaction was used throughout the analysis.¹⁷ The model selection was considered by Akaike information criterion, objective function value (OFV), and goodness-of-fit plots.

Age, weight (actual body weight, ideal body weight [IBW]), lean body mass [LBM], fat-free mass [FFM]), body surface area, SCr, eGFR calculated by the Schwartz equation,¹⁸ and eGFR calculated by the full age spectrum (FAS) equation (eGFR_FAS)^19,20 were tested as continuous covariates by linear, power, exponential models. The Schwartz (1) and the FAS (2) equations are as follows, respectively:

where Ht represents height and Q values (milligrams per deciliter) are the fraction of SCr value based on age- and sex-specific pediatric population.^19,20 Cancer and concomitant drugs were tested as categorical covariates by a linear model. The covariate modeling was developed by using the stepwise approach. Based on a χ² test, if OFV was decreased by at least 3.84, a covariate was considered to be significant (p < 0.05) for stepwise forward addition. Covariates were retained in the model if a covariate removal increased OFV more than 10.83 (p < 0.001) for stepwise backward elimination.

The final model was evaluated by the bootstrap analysis (n = 1000 runs). Prediction-corrected visual predictive check (1000 simulated replicates) was performed by using Perl-speaks-NONMEM version 5.0 (Uppsala University, Uppsala, Sweden). Goodness-of-fit plots of observed concentrations vs population-predicted concentrations (PREDs) and individual-predicted concentrations (IPREDs), conditional weighted residuals (CWRES) vs PRED and time after dose were assessed.

PD Analysis Using Monte Carlo Simulation. The PK parameter estimates from the final model were used to perform Monte Carlo simulation (n = 10,000) using Crystal Ball software (Decisioneering Inc, Denver, CO) to determine probability of target attainment (PTA) of AUC_{0–24 hr}/MIC ≥400 and AUC_{0–24 hr} <800 mg•h/L^16,21 for a variety of MICs (0.5–4 μg/mL). Simulated patients were created in 5 different renal function groups as follows: G1a (high; eGFR 130–160 mL/min/1.73 m²), G1b (normal; 90–129 mL/min/1.73 m²), G2 (mildly decreased; 60–89 mL/min/1.73 m²), G3a/b (mildly to severely decreased; 30–59 mL/min/1.73 m²), and G4 (severely decreased; 15–29 mL/min/1.73 m²).

For G1a/b and G2, 5 dosage regimens were examined: 40 mg/kg/day,²² 50 mg/kg/day,²¹ 60 mg/kg/day, 70 mg/kg/day, and 80 mg/kg/day. Four dosage regimens—20 mg/kg/day,²² 25 mg/kg/day, 30 mg/kg/day, and 35 mg/kg/day—were investigated in G3a/b. Four dosage regimens—10 mg/kg/day,²² 12.5 mg/kg/day, 15 mg/kg/day, and 17.5 mg/kg/day—were studied in G4.

The MIC distributions of MRSA from the European Committee for Antimicrobial Susceptibility and Testing (EUCAST) database were used to determine the cumulative fraction of response (CFR).²³ The calculation was done by multiplying the PTA at each MIC by the fraction of organisms susceptible at each MIC. Then the summation of those results was the CFR for the respective MIC distribution. A CFR of at least 85% was considered to be acceptable.

Results

In total, this study enrolled 212 pediatric patients. The median age was 3.5 years (IQR, 0.9–10.9) with a median weight of 14 kg (IQR, 7.2–30.4). Of 87 children younger than 2 years, 11 (12.6%) were overweight but not obese.²⁴ Among 125 patients between the ages of 2 to 18 years, 12 (9.6%) were overweight and 16 (12.8%) were obese.²⁵ Patient demographic characteristics and vancomycin use are summarized in Table 1 and Supplemental Table S1. Approximately 40% of the patients had augmented renal clearance (ARC) (eGFR calculated by the Schwartz equation ≥130 mL/min/1.73 m²)^8,18 and had concomitant cancer. Sixty percent of the cases received vancomycin empirically. The median initial vancomycin dose was 54.2 mg/kg/day, ranging from 9.7 to 131.1 mg/kg/day. All patients were receiving vancomycin therapy with intermittent administration. Time of infusion ranged from 1 hour to 3 hours with a median of 1 hour (66.2% of the patients). The dosing intervals were every 6 hours (41.5%), 8 hours (45.3%), 12 hours (8.5%), 18 hours (0.9%), and 24 hours (3.8%). The median duration of empirical and targeted therapy was 6.8 days (IQR, 3.3–12.5) and 12.7 days (IQR, 8.0–15.4), respectively. Four concentrations were below the limit of quantification for our assay and were treated as missing data.

Table 1.

Patient Demographics and Clinical Data

Characteristic	Value, N = 212
Male, n (%)	119 (43.7)
Age, yr	3.5 (0.9–10.9)*
0.1–2 yr, n (%)	87 (41.1)
2.1–12 yr, n (%)	80 (37.7)
12.1–18 yr, n (%)	45 (21.2)
Weight, kg	14.0 (7.2–30.4)*
Height, cm	95.5 (65–136)*
Body surface area, m2	0.62 (0.35–1.08)*
Serum creatinine, mg/dL	0.38 (0.25–0.59)*
eGFR†, mL/min/1.73 m2	108.9 (70.9–151.3)*
≥130, n (%)	82 (38.7)
90–129, n (%)	55 (25.9)
60–89, n (%)	35 (16.5)
30–59, n (%)	31 (14.6)
15–29, n (%)	9 (4.2)
Chronic illness, n (%)
Cancer	82 (38.7)
Congenital/chronic heart disease	23 (10.8)
Gastrointestinal disorders	33 (15.6)
Congenital/chronicpulmonary disease	11 (5.2)
Epilepsy	9 (4.2)
Others	27 (12.7)
None	27 (12.7)

eGFR, estimated glomerular filtration rate

^* Data expressed in median (quartile 1–quartile 3).

^† Estimated glomerular filtration rate calculated with the Schwartz equation¹⁸.

A total of 348 serum vancomycin concentrations were analyzed (see supplemental Figure S1). Thirteen (3.7%) vancomycin samples were measured as peak concentrations and 335 (96.3%) were trough concentrations. Median peak and trough concentrations were 35.3 mg/L (IQR, 20.0–44.2) and 11.7 mg/L (IQR, 7.1–18.4), respectively. According to clinical practice, vancomycin dosages for pediatric patients were adjusted on the basis of renal function and therapeutic drug monitoring results. Among 85 patients (40.1%) with positive microbiologic cultures, MIC results were examined for 27 (31.8%) patients. There were 12 MRSA infections; only 3 MICs to vancomycin were reported as 0.38, 1.5, and 2 mg/L.

Population PK Modeling. One-compartment model with first-order elimination provided a better fit than the 2-compartment model. A combined proportional and additive model was used to explain residual variability. Body-size scaling with IBW, FFM, and lean body weight did not improve model fit as well as weight. Allometric weight scaling with a fixed exponent of 0.75 for CL and 1 for volume of distribution (Vd) was used as the basis for further covariate modeling (see supplemental Table S2). All covariates were tested into the base model as an influential covariate to CL and Vd of vancomycin. In stepwise forward addition, eGFR, vasopressors, and age on CL produced significant decreases in OFV when compared with the base model (p < 0.05). In the backward elimination, only eGFR on CL was retained in the final model (see supplemental Table S3).

As shown in Supplemental Figure S2, model evaluation presented proper goodness-of-fit plots. Observations vs PRED and IPRED were agreeable. The CWRES were included in ±3 at all points and well distributed symmetrically with respect to zero. The 1000-bootstrap results are presented in Table 2. The final estimates were within 95% CI of bootstrap results, and 100% of replicates were successful. Prediction-corrected visual predictive check (pcVPC) is demonstrated in Figure 1 and pcVPC with age stratifications in Supplemental Figure S3.

Table 2.

Population Pharmacokinetic Parameter Estimates of the Vancomycin Final Model and Bootstrap Parameters

	Base Model	Final Model	Bootstrap (n = 1000)
	Estimate (%RSE)	Estimate (%RSE)	Estimate (%RSE)	95% CI
CL (L/h) = θ1 × (weight/14)0.75 × (eGFR/108.9)
θ1	1.68 (8.7)	1.66 (4.0)	1.65 (4.2)	1.52–1.79
Vd (L) = θ2 × (weight/14)
θ2	20.8 (27.3)	12.7 (11.1)	12.5 (12.4)	9.65–15.5
IIV of CL (%CV)	104.0 (16.2)	34.8 (14.5)	34.8 (15.3)	29.4–39.6
IIV of Vd (%CV)	90.1 (34.8)	39.6 (33.1)	37.1 (43.8)	14.5–50.4
RV: Additive (SD)	1.54 (35.9)	1.4 (29.1)	1.4 (30.6)	0.94–1.81
RV: Proportional (%CV)	19.0 (21.1)	17.8 (18.8)	17.9 (21.0)	14.2–21.5

CL, vancomycin clearance; eGFR, estimated glomerular filtration rate calculated from the bedside Schwartz equation; IIV, interindividual variability; RV, residual unexplained variability; Vd, volume of distribution; %CV, percent coefficient of variation; %RSE, percent relative standard error of estimate

Figure 1.

Prediction-corrected visual predictive check (VPC) with binning analysis achieved from1000 simulation data when using the vancomycin final model. The circles symbolize observed vancomycin serum concentrations. The solid line and dashed lines represent the median and the 2.5th and 97.5th percentiles of the observed data. Shaded area represents the 95% CIs of the corresponding model predicted percentiles. The vancomycin serum concentrations between 24 and 50 hours are not shown in this VPC.

PD Analysis Using Monte Carlo Simulation. The PTA of AUC_{0–24 hr}/MIC ≥400 and AUC_{0–24 hr} <800 mg•h/L and CFR at different levels of renal function for the MIC ranges of 0.5 to 4 mg/L of selected regimens are shown in Figure 2 and Supplemental Table S4. Assuming a body weight of 14 kg, the optimal vancomycin doses (achieving a CFR ≥85%) for G1a, G1b, G2, G3a/b, and G4 would be a vancomycindose of 70, 60, 40, 25, and 12.5 mg/kg/day, respectively.

Figure 2.

Probability of Target Attainment of Vancomycin Dosage Regimens for the 5 Renal Function Groups.

To be more comprehensive, the suggested vancomycin daily doses for other body weights in each renal function group are shown in Figure 3 and Supplemental Table S5. Daily dose (mg/kg/day) must be decreased when body weight increases at the same eGFR to achieve the AUC target.

Figure 3.

Suggested vancomycin dosing (mg/kg/day) targeting vancomycin AUC of 400 to 800 mg•h/L for each renal function group at different body weights.

Discussion

This population PK study characterized vancomycin PK in patients between 1 month and 18 years of age and investigated factors influencing its PK parameters from routine clinical data. One-compartment model with first-order elimination adequately described the drug kinetic behavior, similar to previous studies.^26–30 Weight and eGFR significantly influenced vancomycin PK parameters. We studied vancomycin dosing in pediatric patients with different renal function, targeting AUC_{0–24 hr}/MIC ≥400 and AUC_0–24hr < 800 mg•h/L. The population mean vancomycin CL was 0.13 ± 0.06 L/h/kg and Vd was 0.88 ± 0.15 L/kg. Vancomycin CL was within the previously reported range for Asian pediatric patients (0.11–0.17 L/h/kg)^29,30 and similar to that of White children (0.12 L/h/kg),²⁶ while Vd was slightly greater than reported in the literature (0.52–0.78 L/kg).^26,29,30 Allometric scaling of 0.75 for vancomycin CL and 1 for Vd with IBW, FFM, and LBM significantly decreased OFV from the base model analysis (p < 0.05); however, allometric scaling with actual body weight was the most significant covariate (ΔOFV −196.069, p < 0.05). This finding agrees with the results of previous studies^8,26,30,31 and implies that vancomycin doses should be based on actual body weight. However, Moffett et al³² found that the FFM model with allometric scaling (0.75 for CL, 1 for Vd) had significantly lower OFV than other allometric weight scaling in the vancomycin PK model of pediatric patients weighing ≥70 kg. Optimal vancomycin dosing in obese pediatric patients requires further research.

Vancomycin is primarily eliminated by glomerular filtration. As the indicators of kidney function, SCr, eGFR, and eGFR_FAS^19,20 were tested in order to quantify the effect on vancomycin CL in pediatrics. Although the FAS equation has previously better performed than the Schwartz equation in estimating the GFR in children and adolescents,¹⁹ our finding indicates that eGFR calculated by the bedside Schwartz equation is the best predictor of CL.

Age was not a significant covariate in our findings, which differs from previous studies reporting significant effects of age on CL.^21,26,31,33 Le et al^21,26,33 consistently reported allometric-scaled weight, SCr, and log(age) as important covariates for vancomycin CL in various groups of children. Our patients had a mean ± SD and median age of 5.8 ± 5.6 and 3.5 years, respectively, suggesting right-skewed data. Although we found positive correlation between CL and age (either normal [ΔOFV +4.179, p > 0.001] or log-transformed data [ΔOFV +5.405, p > 0.001], the effects were not statistically significant enough to be retained in the final model. As illustrated in Supplemental Table S3, we attempted to add postnatal age into the model in stepwise forward addition. A sigmoidal maturation function of age could decrease OFV (−8.313 for postnatal age in weeks), but the 95% CI of parameter estimates includes zero. Age maturation with the Hill coefficient equation did not show any significant influence and was therefore not further considered. Instead, we found that allometric-scaled weight and eGFR and incorporating height and SCr were significant factors affecting CL variability in children (p < 0.001). The effect of postmenstrual age on CL was also previously reported^31,34; however, insufficient postmenstrual age data were available for the present study.

The PK and PD target of this study was AUC_{0–24 hr}/MIC ≥400 and AUC_{0–24 hr} <800 mg•h/L. When considering MIC ≤1 mg/L, current recommended doses in pediatric patients with normal renal function are vancomycin 10 to 15 mg/kg every 6 hours.²² This study found that 10 and 12.5 mg/kg vancomycin every 6 hours (40 and 50 mg/kg/day, respectively) presented a PTA of 6% and 69%, respectively, while 15 mg/kg vancomycin every 6 hours (60 mg/kg/day) provided a PTA of 100%. Consistently, a study of pediatric patients with median eGFR of 84 mL/min/1.73 m² found that 15 mg/kg vancomycin every 6 hours could attain PTA of 97.2%.³⁵ To be more comprehensive, integrating EUCAST MIC distribution is crucial; the CFR for the dosing of 15 mg/kg vancomycin every 6 hours was 90%, shown to be acceptable for treatment of MRSA infections.

Augmented renal clearance is the enhanced elimination of drugs by the kidneys, and currently there is no standard definition of ARC in pediatrics (≥130 or ≥160 mL/min/1.73 m²).³⁶ We used eGFR ≥130 mL/min/1.73 m2 as the ARC group in this study. ARC often occurs in patients with malignancy, febrile neutropenia, severe inflammation, or in critically ill pediatric patients^36–38 and increases the risk of vancomycin subtherapeutic serum concentrations.^38–40 In this study, 48.8% (40/82) and 40.2% (33/82) of patients with ARC presented with malignancy and stayed in the intensive care unit. Similar to beta-lactams and amikacin, the standard dosing regimens did not provide adequate drug exposure.^36,37 Regarding patients with ARC, this study found that the dosing of 60 mg/kg/day vancomycin achieved the target for only 29% of simulated patients, while the higher doses of 70 and 80 mg/kg/day could provide a PTA of 100%. Similarly, a study of pediatric patients with a median eGFR of 191 mL/min reported that PTA of vancomycin 60 mg/kg/day was 24%, while 80 mg/kg/day increased the probability of attaining the target (AUC_{0–24 hr}/MIC ≥ 400).²⁷ Consistent with our findings, Lv and colleagues⁸ also found that the recommended vancomycin doses to achieve a target of AUC_0–24hr/MIC ≥400 were 50 to 75 mg/kg/day and the suggested dosage increased with decreasing weight in pediatric patients with hematologic malignancy and ARC. Using the EUCAST MIC distribution in our Monte Carlo simulation, the dosing of 70 and 80 mg/kg/day vancomycin could provide a CFR of 90%. Consistently, a previous study²⁶ also found that the dosing of 70 mg/kg/day provided a CFR of 75% and 85% in 2 different hospitals. In addition, this work found that the vancomycin AUC_{0–24 hr} ≥800 mg•h/L associated with nephrotoxicity was not observed when providing doses ≤80 mg/kg/day in patients with ARC. However, dosing above 80 mg/kg/day should be of concern. Le et al¹⁶ reported that mean vancomycin AUC_{0–24 hr} for the dosing of 90 and 100 mg/kg/day was about 800 mg•h/L, with mean trough concentrations of about 20 mg/L for each of these dosings. Recent evidence suggested that the risk of nephrotoxicity increases when vancomycin AUC_{0–24 hr} ≥ 800 mg•h/L or trough ≥ 15 mg/L.¹⁶ In conditions requiring doses >80 mg/kg/day, alternative antibiotics against MRSA, including linezolid and daptomycin, should be considered.²⁶

Concerning patients with renal impairment (eGFR <90 mL/min/1.73 m²), this study found that the dosing of 40 and 50 mg/kg/day provided a PTA of 100% for patients with mildly decreased GFR. However, the recommended vancomycin dosing in patients with moderately and severely decreased GFR—20 mg/kg/day and 10 mg/kg/day, respectively²¹—could not provide a PTA ≥85%; however, the larger doses of 25 mg/kg/day and 12.5 mg/kg/day could provide a PTA of 96% and 99%, respectively, consistent with the results of CFR. In addition, our simulation found that approximately 20% to 40% of patients would have an vancomycin AUC >800 mg•h/L when using ≥60, 30, and 15 mg/kg/day for patients with mild, moderately decreased, and severely decreased GFR, respectively.

The current study has some limitations. First, most of the data were trough concentrations (335/348, 96.3%), which may not adequately describe the distribution phase. Second, we did not include patients <1 month of age and we did not validate our final model externally. For this reason, we suggest that further research be performed to externally validate these findings.

Conclusion

In summary, mean vancomycin CL and Vd values in our pediatric patients were 0.13 L/h/kg and 0.88 L/kg, respectively. Allometric-scaled weight and eGFR calculated by the bedside Schwartz equation were the best predictors of vancomycin CL. To target vancomycin AUC_{0–24 hr}/MIC ≥400 (efficacy target) and AUC_{0–24 hr} <800 mg•h/L (toxic threshold) for pediatric patients with eGFR of 15 to 29, 30 to 59, 60 to 89, 90 to 129, and 130 to 160 mL/min/1.73 m², the suggested initial dosing for vancomycin is 12.5, 25, 40, 60, and 70 mg/kg/day, respectively. All vancomycin dosage regimens obtained >85% of the CFR across the MIC distribution of MRSA; however, therapeutic drug monitoring after using the dosing is recommended.

ABBREVIATIONS

ARC

augmented renal clearance

AUC_{0–24 hr}

area under the serum concentration-time curve from 0 to 24 hours

CFR

cumulative fraction of response

CL

clearance

CWRES

conditional weighted residuals

eGFR

estimated glomerular filtration rate

EUCAST

European Committee for Antimicrobial Susceptibility and Testing

FAS

full age spectrum

FFM

fat-free mass

IBW

ideal body weight

IPRED

individual-predicted concentration

LBM

lean body mass

MIC

minimum inhibitory concentration

MRSA

methicillin-resistant Staphylococcus aureus

OFV

objective function value

pcVPC

prediction-corrected visual predictive check

PD

pharmacodynamic

PK

pharmacokinetic

PRED

population-predicted concentration

PTA

probability of target attainment

Vd

volume of distribution