Comparison of Vancomycin Trough Concentrations in Pediatric Patients with and without Sickle Cell Disease: A Cohort Study in Saudi Children

Abstract

OBJECTIVE

Sickle cell disease (SCD) is associated with altered renal function, particularly glomerular hyperfiltration, which may increase vancomycin clearance and result in subtherapeutic drug exposure. Limited data exist on vancomycin pharmacokinetics in non-ICU pediatric SCD patients. The objective of this research is to compare vancomycin trough concentrations and dosing requirements between pediatric patients with and without SCD.

METHOD

A retrospective cohort study compared two groups—pediatric non-ICU patients with SCD (n=29) and without SCD (n=58)—assessing initial and repeated trough concentrations, dosing regimens, and renal function. The data was collected over 10-year (2014–2024).

RESULTS

Among the 87 included patients, 29 were SCD patients and 58 were without SCD Initial serum vancomycin trough concentrations were significantly lower in SCD patients compared to non-SCD patients (5.43 ± 2.61 vs. 10.62 ± 4.71 mg/L; p < 0.00001). Despite dose adjustments, troughs remained lower in SCD patients (10.30 ± 3.61 vs. 13.10 ± 3.73 mg/L; p = 0.0023). SCD patients required higher adjusted doses (64.2 ± 10.0 vs. 58.3 ± 12.0 mg/kg/day). Multiple regression confirmed SCD status as an independent predictor of lower trough concentrations (β = −4.40; p < 0.001).

CONCLUSION

Pediatric patients with SCD exhibit significantly lower serum vancomycin trough concentrations and require higher dosing to achieve therapeutic target concentrations. Early therapeutic drug monitoring and individualized dosing strategies are recommended to minimize subtherapeutic exposure and optimize antimicrobial efficacy in this high-risk population.

Introduction

Sickle cell disease (SCD) is a genetic disorder characterized by sickled red blood cells, anemia, chronic hemolysis, vaso-occlusion, and other complications.¹ Renal alterations, particularly glomerular hyperfiltration, are common in pediatric patients and can lead to increased clearance of renally excreted drugs like vancomycin, potentially leading to subtherapeutic blood concentrations with standard dosing.^2,3 Studies in adults have shown that SCD patients require higher vancomycin doses to achieve comparable serum trough concentrations due to enhanced clearance.⁴ In pediatrics, data are limited; however, one study on pediatric SCD patients with acute chest syndrome (ACS) found significantly lower serum vancomycin trough concentrations and delayed attainment of therapeutic concentrations compared to non-SCD controls in the ICU.⁵

Vancomycin is a glycopeptide antibiotic widely used to treat infections caused by gram-positive bacteria. It is the drug of choice for methicillin-resistant Staphylococcus aureus (MRSA) infections.^6,7 Therapeutic drug monitoring of vancomycin is crucial to ensure efficacy and minimize the risk of toxicity, which is most often performed through measuring the serum trough concentrations.⁸ Recommended vancomycin serum trough concentrations range from 10–15 mcg/ml for mild infections and 15–20 mcg/ml for more serious infections.⁹ The 2019 updated guideline for therapeutic vancomycin monitoring recommend using AUC-guided dosing. This study utilized trough data as it reflects real-world clinical practice at our institution during the study period (2014–2024) and allows for a direct comparison with prior literature. However, achieving optimal vancomycin exposure can be challenging in certain patient populations due to altered pharmacokinetics.¹⁰

Despite these findings, data on vancomycin pharmacokinetics in pediatric non-ICU SCD patients remain limited, and dosing recommendations in this population are not well established.¹¹ Understanding the differences in serum vancomycin trough concentrations between pediatric SCD and non-SCD patients is essential to optimize antimicrobial therapy and improve clinical outcomes in this vulnerable group.¹² In this study, we aimed to compare serum vancomycin trough concentrations between non-ICU pediatric patients with and without SCD, hypothesizing that SCD patients exhibit lower trough concentrations due to altered pharmacokinetics associated with this disease.

Methods

Study Design.

This was a retrospective cohort study at Dr Sulaiman Al Habib Hospital, Riyadh, including admissions from 1 January 2014 to 31 December 2024. The study compared vancomycin therapeutic drug monitoring outcomes in non-ICU paediatric inpatients with SCD to those without SCD.

Study Population.

The study population comprised paediatric inpatients aged 1–15 years who received intravenous vancomycin for common clinical indications, for example, pneumonia and osteomyelitis. Two groups were defined: all eligible non-ICU children with confirmed SCD who received vancomycin, and a comparison group of non-ICU children without SCD who received vancomycin for comparable indications. Because the eligible non-SCD pool was larger, random sampling was used to select a comparator cohort in an approximate 1:2 ratio (SCD:non-SCD) to improve precision.The comparator cohort was selected using simple random sampling from all eligible non-SCD patients.

Inclusion criteria: age 1–15 years; receipt of vancomycin for at least 48 hours; at least one documented serum vancomycin trough concentration.

Exclusion criteria: admission to the Paediatric Intensive Care Unit (PICU) at any time during the vancomycin course; discharge within 48 hours of hospital admission. CKD patients were also excluded.

Vancomycin Monitoring Protocol.

Serum vancomycin trough concentrations were measured according to hospital therapeutic drug monitoring guidelines. The initial trough was obtained at steady state, typically immediately before the fourth dose. Based on this result, clinicians either continued the same regimen or adjusted the dose. Subsequent troughs were obtained either before the fourth adjusted dose or, if no adjustment was made, before the eighth dose. The therapeutic target range was 10–20 mg/L for both groups.

Data Collection.

Data were extracted from the electronic health record into a structured database. Variables included demographics (age, sex, weight, height), clinical indication, vancomycin dosing regimen and interval, timing and values of serum vancomycin trough concentrations, duration of therapy, serum creatinine, and estimated glomerular filtration rate (eGFR). The bedside Schwartz equation was used to calculate the eGFR.eGFR = (0.413 * Height [cm])/Serum Creatinine [mg/dL]

Data Analysis.

Analyses were performed using Microsoft Excel. Descriptive statistics (means and standard deviations, or counts and percentages) summarised baseline characteristics and outcomes. Independent-samples t tests compared mean trough concentrations between groups. Multiple linear regression was applied with the initial trough serum concentration as the dependent variable and SCD status, age, weight, initial dose, and eGFR as candidate predictors. Effect sizes were calculated as Hedges' g to provide a standardized measure of the difference between group means.

Results

Patient demographics and clinical characteristics.

Eighty-seven pediatric patients were included, 29 with SCD and 58 without SCD. SCD patients were older and had higher mean weight and height compared to non-SCD patients. Sex distribution was comparable between two groups. see Table 1.

Table 1.

Patient Characteristics

	SCD	Non-SCD
Number of patients	29	58
Male	15	28
Mean Age (SD)	7.41 (+/−3.46)	3.93 (+/− 2.54)
*Number of
Infants (1 month to 2 years)	2 (6.9%)	23 (39.6%)
Toddlers (3–5 years)	8 (27.5 %)	21 (36.2 %)
School-age (6–11 years)	14 (48.2 %)	14 (24.1 %)
Adolescents (12–18 years)	5 (17.2 %)	0
Height cm (Mean)	114.02 (+/− 22.07)	101.62 (+/− 20.26)
Weight Kg (Mean)	22.34 (+/− 12.41)	17.51 (+/− 8.09)

Data presented as Mean ± SD unless otherwise stated. *Age categories are presented as n (%)

Vancomycin serum trough concentrations and dose adjustments.

Despite comparable initial vancomycin doses, SCD patients had significantly lower serum trough concentrations than non-SCD patients, with larger effects size (Hedges g ≈ - 1.24; p < 0.00001). Following TDM-guided dose adjustment, serum trough concentrations improved in both groups but remained significantly lower in SCD patients (p= 0.0023). Higher adjusted vancomycin doses were required in the SCD group to reach the therapeutic level. (see Table 2).

Table 2.

Vancomycin serum trough concentrations and dosing parameters

Parameter	SCD (n=29)	Non-SCD (n=58)	p value
Initial serum trough (mg/L)	5.43 ± 2.61	10.62 ± 4.71	< 0.00001
Repeated serum trough value (mg/L)	10.30 ± 3.61	13.10 ± 3.73	0.0023
Initial vancomycin dose (mg/kg/day)	52.7 ± 9.2	55.9 ± 10.1	Not tested
Adjusted vancomycin dose (mg/kg/day)	64.2 ± 10.0	58.3 ± 12.0	Not tested
Duration of treatment (days)	9.3 ± 4.8	6.9 ± 4.8	Not tested
Serum creatinine (µmol/L)	24.3 ± 7.7	28.1 ± 9.3	Not tested
eGFR (mL/min/1.73 m²)	182 ± 52	140 ± 36	Not tested

The initial serum vancomycin trough concentration and serum creatinine (eGFR) were obtained before the 4th vancomycin dose. The mean time between the initial and repeated serum vancomycin trough concentration was 24 hours. Serum creatinine (eGFR) was obtained/calculated with the trough concentrations

Regression analysis.

Multiple linear regressions with the initial serum vancomycin trough concentration as the dependent variable, adjusting for age, weight, initial dose, and eGFR, were performed and identified SCD status as an independent predictor of lower initial troughs (coefficient −4.40; 95% CI −6.81 to −1.99; p < 0.001). No other covariates were statistically significant in the model. Since the p-value was not significant for age, subgroup analysis was not performed. The same was observed with eGFR and weight (see Table 3).

Table 3.

Multiple linear regressions predicting initial serum vancomycin troughs

Variable	Coefficient	Standard error	p value	95% CI lower	95% CI upper
Intercept	11.30	3.11	0.0005	5.12	17.49
SCD status (1 = SCD)	−4.40	1.21	< 0.001	−6.81	−1.99
Age (years)	−0.05	0.24	0.83	−0.53	0.43
Weight (kg)	0.06	0.07	0.41	−0.08	0.20
Initial dose (mg/kg/day)	0.02	0.05	0.65	−0.07	0.11
eGFR (mL/min/1.73 m²)	−0.02	0.01	0.08	−0.04	0

Discussion

This retrospective cohort study indicates that paediatric patients with SCD require higher vancomycin dosing to reach therapeutic serum trough concentrations than non-SCD inpatients, even outside intensive care. The risk of subtherapeutic vancomycin exposure in SCD persisted despite dose optimisation, which is consistent with augmented renal clearance associated with glomerular hyperfiltration.

As shown in Table 2, initial serum vancomycin trough concentrations were substantially lower in SCD than non-SCD despite comparable starting doses (5.43 vs 10.62 mg/L, p < 0.00001). After therapeutic drug monitoring, the gap narrowed but remained significant (10.30 vs 13.10 mg/L, p = 0.0023). Adjusted doses were higher in SCD, supporting the need for individualised, rather than standard, empirical regimens in this group. Patients with SCD in our study required a longer duration of therapy (9.3 ± 4.8 days) compared with non-SCD patients (6.9 ± 4.8 days). This prolonged treatment course may be attributed to their immunocompromised status, which can predispose them to slower infection resolution and an increased risk of complication. In multivariable analysis, SCD status independently predicted lower initial troughs (β = −4.40, p < 0.001), whereas age, weight, initial dose, and creatinine-based eGFR were not significant. This pattern suggests disease-related alterations in renal physiology that are not fully captured by enzymatic eGFR estimation; however, causality cannot be inferred, and residual confounding remains possible.

Clinical implications.

Early, routine therapeutic drug monitoring (TDM) should be standard in SCD when prescribing vancomycin, with consideration of higher empirical doses or reduced intervals from the outset.

Limitations

This single-centre, retrospective design is vulnerable to selection bias and unmeasured confounding, for example hydration status, concomitant nephrotoxins, and indication severity. Baseline imbalances between groups may also influence vancomycin pharmacokinetics. Trough-based monitoring, variable sampling accuracy, and creatinine-derived eGFR further limit inference. Clinical outcomes, for example infection resolution or nephrotoxicity, were not assessed. The total number of dose adjustments required and time to reach therapeutic serum concentrations (hours or days) were not collected because the primary objective was to understand the trough concentration (pharmacokinetics) rather than efficacy. Also, the number of adjustments per patient, and the time from initiation to the first therapeutic trough were not systematically collected. Dose adjustments were made at the discretion of the treating clinician based on the institutional TDM protocol.

Future research.

Prospective, multicentre studies using population pharmacokinetic–pharmacodynamic modelling, direct or gold-standard measures of renal clearance, and linkage to clinical outcomes are warranted to refine dosing strategies and improve care for children with SCD.

While trough-guided monitoring has been historically common, contemporary 2019 guidelines from the American Society of Health-System Pharmacists (ASHP) and the Infectious Diseases Society of America (IDSA) now recommend area under the curve (AUC)-guided monitoring as the preferred method for its superior correlation with efficacy and nephrotoxicity. This study utilized trough data as it reflects real-world clinical practice at our institution during the study period (2014-2024) and allows for a direct comparison with prior literature.

Conclusion

In this retrospective cohort of non-ICU paediatric inpatients, children with SCD had markedly lower initial serum vancomycin trough concentrations than non-SCD peers despite similar starting doses, consistent with augmented renal clearance associated with glomerular hyperfiltration. Dose optimisation narrowed but did not eliminate this exposure gap, and higher adjusted doses were required in SCD. These findings support early therapeutic drug monitoring and individualised dosing, including consideration of higher empirical doses or reduced dosing intervals, to minimise subtherapeutic exposure in SCD. While the study provides useful real-world evidence, its single-centre retrospective design and absence of linked clinical outcomes limit causal inference and preclude definitive dosing recommendations. Prospective multicentre studies, incorporating pharmacokinetic–pharmacodynamic modelling and outcome assessment, are warranted to establish clear dosing guidance for paediatric SCD populations.

ABBREVIATIONS

ACS

acute chest syndrome

AUC

area under curve

eGFR

estimated glomerular filtration rate

MRSA

methicillin resistant staphylococcus aureus

PICU

Pediatric intensive care unit

SCD

sickle cell disease

SD

standard deviation

TDM

therapeutic drug monitoring