Therapeutic Drug Monitoring of Vancomycin in Pediatric Patients: Defining a Therapeutic Drug Window

doi:10.21203/rs.3.rs-4213820/v1

Background

Methicillin-resistant Staphylococcus aureus (MRSA) infections among children are escalating annually. Vancomycin stands as the frontline therapeutic agent against MRSA infections. However, determining the therapeutic window for vancomycin in pediatric patients remains a challenge.

Methods

This retrospective study collected data from hospitalized children aged 1 month to 18 years, who underwent routine therapeutic drug monitoring for vancomycin. We analyzed the distribution patterns of vancomycin concentrations in these patients. Factors influencing clinical outcomes and adverse reaction (nephrotoxicity) were investigated. ROC analysis was used to establish the therapeutic window for vancomycin in pediatric patients.

Results

A comprehensive dataset encompassing 183 pediatric patients with 330 samples was analyzed. The mean trough concentration (C_min) of vancomycin was 7.6 ± 5.5 mg/L. 74.3% of patients exhibited concentrations below the conventionally recommended therapeutic window of 10–20 mg/L. Patients responding positively to treatment exhibited significantly higher C_min values (8.4 ± 5.7 mg/L) compared to those with treatment failure (5.9 ± 4.4 mg/L, P = 0.006). Similarly, patients who developed nephrotoxicity had significantly elevated C_min levels (17.8 ± 5.3 mg/L) compared to those without nephrotoxicity (6.4 ± 3.9 mg/L, P < 0.001). Both univariate and multivariate logistic regressions revealed that the C_min of vancomycin was the predictor of both clinical outcomes and adverse reaction. Furthermore, receiver operating characteristic curve analysis pinpointed that C_min of vancomycin with 5.9 mg/L and 14.8 mg/L associated with clinical effectiveness and safety, respectively.

Conclusion

Referring to the therapeutic window of adults, vancomycin underexposure in pediatrics is serious extremely. Based on our findings, we propose a revised therapeutic window of 5.9–14.8 mg/L for vancomycin in pediatric patients, which could aid in optimizing treatment outcomes and minimizing adverse effects.

vancomycin

pediatrics

therapeutic drug monitoring

therapeutic window

Vancomycin, a water-soluble glycopeptide antibacterial agent, has been approved for treating G⁺ bacterial infections in both adults and children. Although drugs like clindamycin, tetracycline, and trimethoprim-sulfamethoxazole are also utilized in infections by methicillin-resistant Staphylococcus aureus (MRSA), vancomycin remains the preferred choice, which has significant cost contribution among antibacterial drugs prescribed to children ^[1].

Vancomycin exhibits a narrow therapeutic index and significant inter-individual variations among individuals. The American Society of Health-System Pharmacists, Infectious Diseases Society of America (IDSA), and Society of Infectious Diseases Pharmacists advocate for monitoring the ratio of the 24 h area under the concentration-time curve and minimally inhibitory concentration (AUC₂₄/MIC) of vancomycin, aiming for a target value within the range of 400–600 mg·h/L ^[2]. However, monitoring vancomycin through pharmacokinetics/pharmacodynamics (PK/PD) exists significant challenges in clinical practice. A survey reveals that 93% of healthcare institutions still select trough concentration (C_min) as the primary indicator in therapeutic drug monitoring (TDM) ^[3].

The generally recommended vancomycin C_min range is 10–20 mg/L, with a narrower range of 10–15 mg/L for uncomplicated infections and 15–20 mg/L for severe infections, including endocarditis, meningitis, osteomyelitis, pneumonia, and septicemia ^[4]. Despite insufficient evidence, IDSA extrapolates the target ranges from adult patients to the pediatric population. Our research group has discovered that vancomycin C_min exhibits a strong correlation with PK/PD target ^[5]. Specifically, achieving a C_min within the ranges of 5.0-6.9 mg/L or 9.0-12.9 mg/L could meet the PK/PD target, depending on the MIC. In fact, the initial vancomycin C_min target range for most infections in pediatric patients was 5–10 mg/L, while for central nervous system infections, it was 10–15 mg/L ^[6]. The IDSA guidelines in 2011 advocated a higher C_min range, but the product insert did not introduce any new recommendations for the standard vancomycin dosing regimen accordingly ^[4]. Recent studies have revealed that with the current dosing of vancomycin, the rate of achieving the desired C_min in pediatric patients is unexpectedly low when using 10–15 mg/L as the standard for effective therapeutic concentration ^[7–11]. Sridharan et al. conducted TDM on 102 pediatric patients receiving vancomycin and discovered that only 25% of patients with normal renal function reached a concentration of 10–20 mg/L, while 22% of patients with renal insufficiency fell within the target range ^[7]. Similarly, Ringenberg reported that only 25.1% of concentrations fell within the range of 10–20 mg/L in the neonatal intensive care units ^[10].

Frankly, the IDSA recommended a vancomycin dosing of 60 mg/kg·d (15 mg/kg, q6 h) for pediatric patients with severe invasive MRSA infections. Nevertheless, several studies have indicated that even with higher dosing, it may still be inadequate to attain the desired C_min ^{[4, 11–14]}. The proportion is even lower in critically ill children, reaching only 20% ^[15]. Even when the target concentration is adjusted to 5–15 mg/L, the achievement rate rises to only 51% ^[15]. Surprisingly, a study reported a C_min achievement rate of just 4% despite the included pediatric patients receiving the recommended vancomycin dose of 40–60 mg/kg/day ^[16].

The clearance (CL) and volume of distribution of vancomycin vary significantly in pediatric patients compared to adults, rendering it particularly difficult to attain and sustain vancomycin concentrations within the desired range for pediatrics. This challenge is further exacerbated in patients with underlying conditions, such as congenital heart disease, renal impairment, sepsis, and those undergoing fluid resuscitation ^[17]. A number of studies have demonstrated that standard dosing regimens often fall short of achieving the current target concentration range, indicating that applying adult concentration ranges to pediatric patients directly may not be appropriate ^[7–11].

The aim of this study is to establish the therapeutic window of vancomycin specifically for pediatric patients, minimizing the risk of treatment failure due to insufficient exposure or toxicity.

2.1 Patient information and collection of clinical blood samples

This study retrospectively collected hospitalized pediatric patients from two hospitals: the First Affiliated Hospital of Xi'an Jiaotong University and the Affiliated Children's Hospital of Xi'an Jiaotong University. The period spanned from January 2017 to December 2018.

Inclusion criteria for the study comprised of: ① hospitalized patients aged 1 month to 18 years; ② those diagnosed or suspected with G⁺ bacterial infection and receiving vancomycin treatment; and ③ patients able to provide at least one TDM data point. The following patients were excluded from the study: ① those receiving vancomycin through non-intravenous routes; ② patients allergic to vancomycin; ③ and patients who died within 24 hours of vancomycin administration. The ethics committees of both medical institutions approved the research protocol.

Demographic data, medication details, and physiological and biochemical indicators (including age, gender, weight, serum creatinine [Scr], vancomycin dosing regimen, dosage, medication dates, and indications) were retrieved from the hospital's electronic medical record system. Blood concentration data of vancomycin in patients was collected from those undergoing routine TDM (samples taken 30 minutes prior to the next dose after reaching a steady state). The blood concentration of vancomycin was determined using the previously established HPLC-MS/MS method by our research team ^[18].

2.2 Therapeutic window of vancomycin in pediatric patients

A univariate logistic regression analysis was conducted to investigate the correlation between various factors and both clinical outcomes and adverse reactions. Subsequently, factors exhibiting a P value less than 0.1 in the univariate analysis were subjected to multivariate logistic analysis to further identify factors potentially linked to clinical efficacy and adverse reactions

Clinical outcomes were categorized into a four-level scale encompassing cured, improved, ineffective, and relapsed. For simplicity, cured and improved outcomes were jointly classified as treatment success, whereas ineffective and relapsed outcomes were grouped under treatment failure. The assessment of adverse reactions involved measuring Scr levels from the initiation of medication to 72 h post-medication. Acute kidney injury (AKI) was defined as either an elevation of Scr to 1.5 times the baseline level or a rise by 26.5 µmol/L. The therapeutic window refers to the spectrum of drug concentration levels that exhibit a significant correlation with clinical outcomes and the incidence of adverse reactions.

2.3 Statistics and analysis

Continuous variables were described using mean ± standard deviation for normally distributed data and median for non-normal distributions. Categorical variables were characterized by frequencies and percentages. All statistical tests were two-sided with a significance level of α set at 0.05, and all analyses were conducted using SPSS (Version 19.0).

A total of 183 pediatric patients were included in this study and provided at least one vancomycin C_min sample. A comprehensive monitoring of 330 blood drug concentrations was undertaken. Boys comprised the majority, constituting 61.2% of the total patients. The mean age of the pediatric patients was 3.4 years, with a mean weight of 15.0 kg. Acute lymphoblastic leukemia emerged as the most prevalent underlying condition, representing 15.9% of the total cases. Furthermore, 24% of the patients were admitted to the intensive care unit (ICU). Of the indications for antimicrobial therapy, 67.8% were attributed to invasive infections, encompassing pneumonia, endocarditis, as well as bone and joint infections. Subsequently, central nervous system infections comprised 29.0% of the total cases. Only 53 patients had available pathogen culture results, which revealed the presence of 23 methicillin-susceptible Staphylococcus aureus (MSSA) and 7 MRSA strains. While undergoing vancomycin therapy, 37% of patients received at least one nephrotoxic drug. Diuretics were the most commonly prescribed nephrotoxic drugs, representing 30.6% of the total administered. Additionally, 45% of patients received concurrent therapy with meropenem, as part of their antimicrobial regimen. Baseline Scr levels were measured at 28.2 ± 19.0 µmol/L, whereas creatinine clearance was calculated as 134.3 ± 81.4 mL/min. A comprehensive overview of demographic and other information are presented in Table 1.

Table 1

Patient demographics, clinical characteristics and vancomycin dose.
Variable	All Patients n = 183 (%)	Treatment Outcomes			Adverse Effects
Variable	All Patients n = 183 (%)	Treatment Success n = 132 (%)	Treatment Failure or Death n = 51 (%)	P	Nephrotoxicity n = 21 (%)	No Nephrotoxicity n = 162 (%)	P
Gender, male	112 (61.2)	84 (63.6)	28 (54.9)	0.277	14 (66.7)	98 (60.5)	0.474
Age, year ^a	3.4 ± 3.4	3.3 ± 3.4	3.6 ± 3.6	0.707	4.7 ± 3.6	3.2 ± 3.4	0.074
weight, kg ^a	15.0 ± 9.6	14.1 ± 9.8	16.4 ± 8.8	0.213	14.1 (10.3)	15.1 (9.5)	0.671
Body mass index, kg/m²	0.6 ± 0.3	0.6 ± 0.3	0.7 ± 0.3	0.067	0.6 ± 0.3	0.6 ± 0.3	0.595
Comorbid conditions
Acute lymphoblastic leukemia	29 (15.9)	21 (15.9)	8 (15.7)	0.970	6 (28.6)	23 (14.2)	0.168
Other malignant solid tumor	9 (4.9)	8 (6.1)	1 (2)	0.442	0	9 (5.6)	-
Liver disease	20 (10.9)	14 (10.6)	6 (11.8)	0.822	0	20 (12.3)	-
Anemia	22 (12.0)	16 (12.1)	6 (11.8)	0.947	1 (4.8)	21 (13.0)	0.465
Sepsis/severe sepsis/septic shock	54 (29.5)	54 (29.5)	10 (19.6)	0.068	10 (47.6)	44 (27.2)	0.053
Intensive care unit stay ^b	44 (24.0)	30 (22.7)	14 (27.5)	0.503	7 (33.3)	37 (22.8)	0.290
Mechanical ventilation ^b	40 (21.9)	27 (20.5)	13 (25.5)	0.460	7 (33.3)	33 (20.4)	0.284
Median white blood cell count, ×10^{9 b}	10.8 (5.9 ~ 16.4)	10.9 (6.5 ~ 16.5)	10.8 (4.0 ~ 15.3)	0.978	11.5 (2.9 ~ 14.5)	10.8 (6.3 ~ 16.7)	0.354
Blood urea nitrogen, mmol/L^a	4.1 ± 4.2	4.2 ± 4.6	4.0 ± 3.0	0.742	5.3 ± 5.2	3.9 ± 3.8	0.103
Baseline creatinine, µmol/L^a	28.2 ± 19.0	28.9 ± 21.4	26.5 ± 10.5	0.463	36.4 ± 37.6	27.1 ± 14.9	0.036
Baseline creatinine clearance, mL/min^a*	134.3 ± 81.36	126.3 ± 55.0	154.9 ± 124.8	0.033	124.5 ± 76.7	135.6 ± 82.1	0.561
Infection type and diagnosis
Skin/soft tissue infection	16 (8.7)	16 (8.7)	3 (5.9)	0.576	1 (4.8)	15 (9.3)	0.783
Bone/joint infection	23 (12.6)	23 (12.6)	6 (11.8)	0.838	1 (4.8)	22 (13.6)	0.425
Bacteremia	34 (18.6)	34 (18.6)	9 (17.6)	0.840	5 (23.8)	29 (17.9)	0.721
CNS infection	53 (29.0)	53 (29.0)	9 (17.6)	0.036	11 (52.4)	42 (25.9)	0.012
Other/unknown	19 (10.4)	19 (10.4)	5 (9.8)	0.873	1 (4.8)	18 (11.1)	0.605
Invasive infection ^c	124 (67.8)	129 (70.5)	33 (64.7)	0.286	14 (66.7)	115 (71.0)	0.683
Pathogens
Methicillin-resistant Staphylococcus aureus	7 (3.8)	5 (3.8)	2 (3.9)	1.000	1 (4.8)	6 (3.7)	1.000
Methicillin-susceptible Staphylococcus aureus	23 (12.6)	18 (13.6)	5 (9.8)	0.483	7 (33.3)	16 (9.9)	0.007
Other Gram-positive bacteria	23 (12.6)	17 (12.9)	6 (11.8)	0.838	4 (19.0)	19 (11.7)	0.547
Concomitant nephrotoxins
Diuretics	56 (30.6)	41 (31.1)	15 (29.4)	0.828	8 (37.1)	48 (29.6)	0.428
Acyclovir	10 (5.5)	10 (5.5)	1 (2.0)	0.351	1 (4.8)	9 (5.6)	1.000
Amphotericin B	6 (3.3)	2 (1.5)	4 (7.8)	0.091	1 (4.8)	5 (3.1)	1.000
No. of concomitant nephrotoxins
0	114 (62.2)	82 (62.1)	32 (62.7)	0.938	12 (57.1)	102 (63.0)	0.605
1-2	69 (37.8)	50 (37.9)	19 (37.3)		9 (42.9)	60 (37.0)
Concomitant other antibiotics
Meropenem	82 (44.8)	63 (47.7)	19 (37.3)	0.202	13 (61.9)	69 (42.6)	0.094
Vancomycin dose, mg/kg ^a	38.6 ± 5.4	38.7 ± 4.9	38.2 ± 6.6	0.539	39.0 ± 3.0	38.5 ± 5.6	0.694
Vancomycin trough concentration, mg/L ^a	7.6 ± 5.5	8.4 ± 5.7	5.9 ± 4.4	0.006	17.8 ± 5.3	6.4 ± 3.9	< 0.001
Treatment duration, day ^a	15.0 (9.0 ~ 21.0)	15.0 (10.0 ~ 21.8)	13.0 (9.0 ~ 20.0)	0.944	14 (8.8 ~ 16.8)	15.0 (10.0 ~ 22.0)	0.319

Statistically significant values are shown in bold.

Abbreviations: CNS, central nervous system.

^aData are presented as mean ± standard deviation.

^b Data are presented as median, interquartile range.

^*Estimated using Schwartz formula.

Table 2

Multivariate logistic regression analysis of factors influencing the effectiveness and safety of vancomycin.
Variable	Treatment Outcomes		Adverse Effects
Variable	OR (95% CI)	P	OR (95% CI)	P
Age, year	-	-	1.000 (1.000 ~ 1.001)	0.115
BMI, kg/m²	0.638 (0.174 ~ 2.331)	0.496	-	-
Sepsis/severe sepsis/septic shock	0.663 (0.288 ~ 1.524)	0.333	0.401 (0.124 ~ 1.301)	0.128
Baseline creatinine clearance, mL/min^*	0.997 (0.993 ~ 1.002)	0.232	-	-
CNS infection	0.185 (0.227 ~ 1.332)	0.550	0.402 (0.137 ~ 1.177)	0.096
Baseline creatinine, µmol/L	-	-	0.999 (0.984 ~ 1.014)	0.888
MSSA	-	-	1.222 (0.322 ~ 4.638)	0.769
Concomitant amphotericin B	5.118 (0.836 ~ 31.314)	0.077	-	-
Concomitant meropenem	-	-	0.531 (0.203 ~ 1.389)	0.197
Vancomycin trough concentration, mg/L	1.090 (1.007 ~ 1.179)	0.032	1.320 (1.197 ~ 1.456)	< 0.001
Statistically significant values are shown in bold.
Abbreviations: OR, odds ratio; CI, confidence interval; BMI, body mass index; CNS, central nervous system; MSSA, methicillin-susceptible Staphylococcus aureus.
^*Estimated using Schwartz formula.
Additional analysis of the receiver operating characteristic (ROC) curve demonstrated that a C_min concentration of 5.9 mg/L serves as a predictor for therapeutic effect, exhibiting an area under the curve (AUC) of 0.643, with a sensitivity of 70.1% and a specificity of 64.1% (Fig. 3A). A C_min level of 14.8 mg/L effectively anticipated the emergence of nephrotoxicity, displaying an AUC of 0.960, accompanied by a sensitivity of 95.2% and a specificity of 85.0% (Fig. 3B). Taking into account the temporal influence on nephrotoxicity risk, patients were stratified into two groups based on their C_min levels (< 14.8 and ≥ 14.8 mg/L) for subsequent Kaplan-Meier survival analysis. As depicted in Fig. 4, a significant difference in the incidence of nephrotoxicity was observed between the two groups over the course of vancomycin treatment.

Vancomycin has been clinically utilized for more than 60 years, yet the precise therapeutic window for pediatric patients remains elusive. CL serves as a crucial PK parameter, exerting a significant influence on drug exposure levels. Nevertheless, the vancomycin CL in pediatric patients is typically much faster compared to adults, approximately 2.5 times greater ^{[7, 16, 19]}. Limited available data indicate that the vancomycin CL in Chinese pediatric patients ranges from 0.11 to 0.17 L/h·kg, which is notably higher than that observed in adults ^{[20, 21]}. This may be attributed to physiological characteristics in pediatric patients, such as higher water content and renal clearance, which influence PK parameters and subsequently lead to lower drug concentration attainment rates ^[22]. Therefore, acknowledging the PK disparities between pediatric and adult populations, this study reassessed the therapeutic window of vancomycin in pediatric patients and advocated for adjusting it to a range of 5.9-14.8 mg/L, which is similar to the findings reported previously by our research team ^[5].

According to the latest international guidelines, monitoring the AUC₂₄/MIC for vancomycin is recommended, with a target range of 400-600 ^[2]. Nevertheless, the practicality of monitoring AUC₂₄/MIC in clinical settings is limited due to various factors, including the necessity for secondary sampling, the scarcity of specialized personnel, and the ambiguity surrounding PK/PD standards for pediatric patients ^[23]. Consequently, monitoring C_min remains a widely adopted practice, even in most large tertiary medical institutions, emphasizing the crucial importance of further exploring the rational use of vancomycin through C_min monitoring ^[24]. Owing to the lack of clinical data, the reference range for target concentrations of vancomycin in special populations, including children, has historically aligned with that established for adults. When administered standard dosing regimens, only 28.9% of pediatric patients attain a vancomycin C_min within the range of 10-20 mg/L, while a mere 6.9% achieve a C_min of 15-20 mg/L ^[25]. Consistent with our findings, Tatjana et al. observed a mere 24% achievement rate of C_min in pediatric patients during TDM ^[26]. Data indicate that pediatric patients with normal renal function need 70 mg/kg·d to attain a target C_min of 10 mg/L, while younger patients aged 1-6 years may require 80-85 mg/kg·d to achieve a target C_min ranging from 15-20 mg/L ^{[9, 11]}. To investigate the reasons for the low vancomycin blood concentration attainment rate in pediatric patients, we assess the appropriateness of extrapolating the therapeutic window from adults to the pediatric population.

Our findings reveal that satisfactory clinical outcomes could be attained in pediatric patients when C_min exceeds 5.9 mg/L, which aligns with the lower limit of the initial vancomycin therapeutic window ^[6]. Hamdy and Yoo et al. drew a similar conclusion, stating that a vancomycin C_min below 10 mg/L is insufficient to predict treatment failure ^{[27, 28]}. A recent meta-analysis suggests that a vancomycin C_min ranging from 10-15 mg/L in pediatric patients is associated with clinical efficacy, and exceeding 15 mg/L is not necessary ^[29]. The Chinese guidelines for TDM of vancomycin (2020) also recommend maintaining a vancomycin C_min of 5-15 mg/L for pediatric patients. However, this recommendation is solely based on a retrospective study with a limited sample size of 100 cases ^[30]. By employing a nearly doubled sample size, we achieved comparable outcomes, thus offering robust evidence to support the recommended scope outlined in the guidelines.

The IDSA published vancomycin TDM guidelines from 2009 to 2011, consecutively for three years, advocating a monitoring threshold of 10 mg/L to mitigate drug resistance. However, despite the persistent and significant shortfall in achieving the target C_min, no change in the resistance of MRSA isolates to vancomycin has been noted ^{[31, 32]}. Over a four-year period, Faiqa et al. gathered 352 MRSA isolates and discovered no alterations in MIC₅₀ or MIC₉₀ values. ^[33]. Another study examining the MIC changes of 736 MRSA isolates against vancomycin revealed that all MIC values were below 2 mg/L, with the majority falling below 1 mg/L ^[34]. Wang et al. also conducted an analysis of 879 MRSA isolates collected from pediatric patients with bloodstream infections in China over a four-year period (2015-2018) and reported no vancomycin-resistant strains ^[35]. Additionally, our institution also conducted a statistical analysis spanning from 2013 to 2019, focusing on the MIC changes of MRSA isolates against vancomycin. The proportion of MRSA strains with MIC of 1 mg/L exhibited a steady decline, decreasing from 81% in 2013 to 30% in 2019. Conversely, the proportion of MRSA strains with MIC of ≤ 0.5 mg/L increased from 19% in 2013 to 70% during the same period. No vancomycin-resistant MRSA strains have been detected. Actually, since the establishment of the China Antimicrobial Resistance Surveillance Network in 2005, domestic drug resistance surveillance data indicate no reported cases of vancomycin-resistant MRSA strains. The findings from these studies suggest that while vancomycin TDM guidelines recommend specific monitoring thresholds to prevent drug resistance, the actual resistance patterns of MRSA isolates to vancomycin may not be as straightforward as initially anticipated. In other words, vancomycin has maintained a consistently low exposure level in pediatric patients for decades, without causing any significant shifts in the MIC of MRSA against vancomycin. Certainly, it is crucial to continue monitoring and evaluating these isolates to gain a deeper understanding of their resistance patterns and to ensure effective treatment strategies.

A high concentration of vancomycin C_min is strongly associated with the occurrence of nephrotoxicity ^[36]. Our findings indicate a significant increase in the risk of AKI in pediatric patients when vancomycin C_min exceeds 14.8 mg/L. A large retrospective study of 859 pediatric patients found a significant association between vancomycin C_min concentrations exceeding 15 mg/L and AKI (odds ratio, 2.18; 95% confidence interval, 1.21-3.92), corroborating our own observations ^[37]. Furthermore, a recent meta-analysis encompassing eight pediatric studies revealed that vancomycin C_min concentrations exceeding 15 mg/L could elevate the risk of nephrotoxicity by a factor of 2.7 ^[29]. These findings highlight the need for careful monitoring of vancomycin levels in pediatric patients to mitigate the risk of nephrotoxicity. Clinicians prioritize the potential adverse effects of vancomycin over therapeutic outcomes, making it challenging to justify aiming for high-level vancomycin C_min levels in pediatric patients, especially when high concentrations lack clear clinical benefits ^[38]. Notably, children with sepsis frequently have a history of multiple hospitalizations and underlying diseases, potentially increasing AKI risk.

This study is not without limitations. First, our study solely established a correlation between C_min and AKI risk, and our assessment focused solely on the concurrent use of nephrotoxic drugs, neglecting the effects of pretreatment medications prior to hospitalization and the cumulative effects of other nephrotoxic agents. It is imperative to point out that children with sepsis frequently have a history of multiple hospitalizations and underlying diseases, and obese children might receive higher dosing regimen based on actual weight, potentially increasing AKI risk ^{[39, 40]}. Second, measuring the free concentration of vancomycin holds greater significance than measuring the total concentration, particularly in neonatal and pediatric intensive care units ^{[41, 42]}. However, there remains a lack of consensus regarding the optimal concentration range of free vancomycin, necessitating further exploration in future research. Last but not least, the absence of microbial culture results for most patients precluded the comprehensive analysis of microbial susceptibility in the final analysis. In fact, given the low proportion of positive cultures, the clinical application of vancomycin is primarily empirical. Considering acceptable therapeutic outcomes of vancomycin and the concordance of previous reports with our findings, we maintain that our study holds significant guiding value, to a certain extent. Although there are limited evidences supporting specific vancomycin therapeutic windows for pediatric patients, further research with larger sample sizes and more robust methodologies is still needed to establish more definitive therapeutic windows for this vulnerable population.

Based on the correlation between vancomycin C_min and both clinical effectiveness and safety, a therapeutic window of 5.9-14.8 mg/L for vancomycin in pediatric patients is proposed, aiming to facilitate its rational use within this specific population.

Funding

This study is unfunded.

Availability of data and materials

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Acknowledgements

The authors would like to acknowledge Zhenyu Pan, Yuan Li, Ziyun Duan and Jie Mi for their attribution in samples collecting and useful insights to the results.

Authors’ contributions

Conceived and designed the protocol: Yalin Dong, Tao Zhang. Determination of samples: Xinyan Han, Yan Wang, Jiao Xie, Qianting Yang, Sasa Hu. Statistical analyses: Hua Cheng, Tao Zhang. Drafting manuscript: Yalin Dong, Jingjing Yi, Tao Zhang. All authors contributed to the interpretation of data and critical revisions of the manuscript for important intellectual content. Tao Zhang had final responsibility for the decision to submit for publication.

Ethical approval statement and consent to participate

The ethics has been approved by the Ethics Committee of the First Affiliated Hospital of Xi’an Jiaotong University. Informed consent for the use of routinely collected data has been waived according to local requirements. All associated procedures were conducted in accordance with the approved guidelines.

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No competing interests reported.

Therapeutic Drug Monitoring of Vancomycin in Pediatric Patients: Defining a Therapeutic Drug Window

Status:

Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

1. Introduction

2. Methods

2.1 Patient information and collection of clinical blood samples

2.2 Therapeutic window of vancomycin in pediatric patients

2.3 Statistics and analysis

3. Results

Discussion

Conclusions

Declarations

References

Additional Declarations

Status:

Version 1