Alakeel et al. BMC Pediatrics(2024) 24:575
https://doi.org/10.1186/s12887-024-05048-8

BMC Pediatrics

RESEARCH

Open AccessAn evaluation of the empirical vancomycin
dosing guide in pediatric cardiology
Yousif S. Alakeel1,2,3,6*, Yazeed Alahmed3,4, Ghadah Alanazi2,3, Bushra Alawbathani2,3, Kadi Alshutwi2,3,
Meshary Almeshary1,3, Fahad Aldhahri1,2,3 and Meshal Alshakrah3,5
Abstract
Background Higher doses of vancomycin are currently prescribed due to the emergence of bacterial tolerance andresistance. This study aimed to evaluate the efficacy and safety of the currently adopted vancomycin dosing guide inpediatric cardiology.
Methods This was a single-center prospective cohort study with pediatric cardiac patients, younger than 14 years,
from June 2020 to March 2021. The patients received intravenous vancomycin (40 mg/kg/day divided every 6–8 h)according to the department’s vancomycin medication administration guide (MAG) for at least three days.
Results In total, 88 cardiac patients were included, with a median age of 0.82 years (IQR: 0.25–2.9), and 51 (58%)
received cardiopulmonary bypass surgery (CPB). The majority (71.6%, n = 61) achieved a serum vancomycin levelwithin the therapeutic range (7–20 mg/L). Infants, young children, and children exposed to CPB surgery had anincreased incidence of subtherapeutic vancomycin levels, [7 (29.2%); P = 0.033], [13 (54.2%); P = 0.01], and [21 (87.5%);
P = 0.009] respectively. After the treatment, 8 (10%) patients had an elevated Serum creatinine (SCr) and 2 (2.5%)
developed acute kidney injury (AKI). However, no significant difference was found between the patients developing
AKI or an elevated SCr and the group who did not, in terms of clinical, therapeutic, and demographic characteristics,
except for the decreased incidence of SCr elevation in patients receiving an ACE inhibitor, [4 (36.4%); P = 0.036].
Conclusion Our institution followed MAG recommendations; however, subtherapeutic serum concentrations were
evident in infants, young children, and CPB patients. Strategies to prevent AKI should be investigated, as the possible
causes have not been identified in this study.
Keywords Vancomycin, Pediatrics, Dosing protocol, Cardiology, Congenital heart disease, Cardiopulmonary bypass*Correspondence:
Yousif S. Alakeel
alakeely@gmail.com
1
Department Pharmaceutical Care Services, King Abdulaziz Medical City,
Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia
2
College of Pharmacy, King Saud bin Abdulaziz University for Health
Sciences, Riyadh, Saudi Arabia

3

King Abdullah International Medical Research Center, Riyadh, Saudi
Arabia4
Department of Pediatrics, College of Medicine, Qassim University,
Qassim, Saudi Arabia
5
Saudi Medication Safety Center, Ministry of the National Guard - Health
Affairs, Riyadh, Saudi Arabia
6
Department of Pharmaceutical Care Services, King Abdulaziz Medical
City, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you
give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified thelicensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to thematerial. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation
or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://
creativecommons.org/licenses/by-nc-nd/4.0/.

Alakeel et al. BMC Pediatrics(2024) 24:575

Introduction
Vancomycin is a bactericidal antibiotic used for thetreatment of infections caused by gram-positive bacteria, including methicillin-resistant Staphylococcus
aureus (MRSA) [1]. An initial dose ranging between 40
and 60 mg/kg/day divided q6-8 h is usually sufficientand safe for most pediatric patients. The serum bloodlevel, obtained at a steady state just before the fourthdose, is used as a robust pharmacodynamic marker toensure drug safety and efficacy [2]. A trough level ranging between 10 and 15 mg/L is often required for generalindications, while a higher level ranging between 15 and
20 mg/L is recommended for more complicated infections [1, 3].
Due to the emergence of bacterial tolerance andresistance, higher doses are currently prescribed toachieve the target vancomycin trough concentration(7–10 mg/L), a level desired for the majority of mildmoderate infections precipitated by MRSA [4–10]. Major
organizations, such as the Infectious Disease Society ofAmerica (IDSA) guidelines, endorses a total daily dose(TDD) of 60–80 mg/kg for children younger than 12
years old, and 60–70 mg/kg for children older than 12
years for MRSA strains with a MIC ≤ 1 mg/L [11].
Similarly, variable dosing regimens have been suggested for different patient subgroups. Higher doses per
body weight have been suggested for younger children
compared to other pediatric age groups; though limited
data are currently available to support an exact dosing
requirement [4, 6, 9, 12]. Certain clinical characteristics
or disease states (e.g., burn, cancer, and critical illness)
can affect the pharmacokinetics of vancomycin, which
will affect the achieved trough level [13–17]. The physiological functions of the body, including renal perfusion,
cardiac output, the volume of distribution, and clearance
may be changed following cardiac surgery, which may
affect the pharmacokinetics of drugs. Such patients usually need lower dosing requirements (between 20 and
40 mg/kg/day), as suggested by two retrospective studies[2, 18].
On the other hand, augmented renal clearance (ARC),a well-described phenomenon in critically ill children,
leads to a pathophysiologic increase in kidney filtration
capacity. This manifests as creatinine clearance exceeding 130 mL/min/1.73 m² [19]. ARC affects up to 65%
of ICU patients and is thought to be mediated by the
inflammatory response to infections, critical illnessinduced stress responses (e.g., burns, major trauma), andcertain therapeutic interventions (e.g., aggressive fluid
resuscitation and diuresis) [20]. The presence of ARC isparticularly impactful for time-dependent antibiotics primarily eliminated renally, such as vancomycin. Studies
have linked ARC to subtherapeutic vancomycin troughlevels in critically ill pediatric patients. Consequently,

Page 2 of 10

higher vancomycin doses (at least 70 mg/kg/day) are recommended for this patient group compared to standard
pediatric regimens [21, 22].
While higher doses are routinely prescribed to attainhigher trough levels, care should be taken to keep theserum levels below the nephrotoxic level. Althoughnephrotoxicity is not a direct effect of vancomycin therapy itself, other factors, for example baseline renal function, hydration status, and other nephrotoxic agentsused, may increase the incidence of this adverse effect [3,
23–30]. Nephrotoxicity is more frequently experienced
as the trough concentration increases above 15 mg/L andhigher or if the therapy is continued for more than fourdays [11].
Due to the lack of solid evidence regarding the preferred dosing requirements for pediatric cardiac patients,
many pediatric care centers developed their own prescribing guidelines for the initiation and monitoring ofvancomycin to ensure its safety and efficacy [31]. The
vancomycin medication administration guide (MAG)was developed by the pediatric clinical pharmacy teamat King Abdulaziz Medical City, Riyadh (KAMC-R). We
conducted this prospective study to evaluate the efficacy
and safety of the empirical vancomycin doses endorsed in
the currently adopted MAG in pediatric cardiology.

Materials and methods
Design and settings

This was a single-center prospective cohort study conducted to evaluate the efficacy and safety of the empiricalvancomycin dosing included in the hospital MAG usedin children with cardiac disease. The study received ethical approval from King Abdullah International Medical
Research Center (KAIMRC) and conducted at KAMC-R,
Cardiac Center, Section of Pediatric Cardiology, which
provides tertiary care for children with complex congenital and acquired heart diseases.
Patient selection

All the children prescribed intravenous vancomycin from
June 2020 to March 2021, at the pediatric cardiac intensive care unit (PCICU) or pediatric cardiac ward (PCW)
were initially screened. Only the patients aged 14 years
or below, who received intravenous vancomycin according to the departmental MAG for at least three days
were included in the analysis. Patients were excluded ifthey were non-compliant with the MAG, if they had apre-existing chronic or acute renal disease, or if they
are receiving renal replacement therapy or extracorporeal membrane oxygenator (ECMO). Non-complianceincluded a vancomycin prescription in a dose or a dosing interval that is different from the recommendation,
or a serum level that was not measured at the proposed
timing intervals. Each patient was included only onceAlakeel et al. BMC Pediatrics(2024) 24:575

during the study period irrespective of the time duration
between both administrations.
Vancomycin MAG

Children with normal renal function are usually started
on an initial dose of 40 mg/kg divided q6-8 hourly for
mild to moderate infections. The guide involves no loading dose for any patient. Based on the estimated creatinine clearance (CrCl), using the bedside Schwartz
equation, the interval of daily vancomycin dosing isselected. The goal trough concentration for treatment ofgeneral infection is 7–15 mg/L, and for severe infection is> 15–20 mg/dL. The guide also proposes a dosage adjustment based on the serum trough level and the dosage
interval is extended by two hours (i.e., q6h is changed toq8h) for supratherapeutic trough levels. However, if thechild has a subtherapeutic reading, the dose is increasedby 2.5 mg/kg/dose (i.e., 10 mg/kg is changed to 12.5 mg/kg). According to the MAG, serum trough levels areusually obtained 15–30 min before the fourth dose forpatients receiving the drug at an interval less than 24 h;otherwise, it is tested before the third dose if the dosinginterval is 24 h or longer. The level is repeated every 5–7
days after achieving the target level.
Data collection

Data were collected using the hospital’s electronic database where all patient records were checked daily forPage 3 of 10

vancomycin orders. The baseline characteristics weresociodemographic variables, including weight, height,
and gender. The clinical variables were comorbidities,
type of cardiac lesion, concomitant nephrotoxic medications, the presence of fever, and laboratory values (i.e.,WBC, platelets, ESR, CRP, culture, SCr, BUN). These
values were recorded at baseline and daily wheneveravailable. The SCr and blood urea nitrogen (BUN) weremonitored at baseline then every three to five days providing that the kidney function was stable, and no concomitant nephrotoxic medication was administered,otherwise, more frequent monitoring was required. The
Jaffé method, specifically through the kinetic Alkaline
Picrate reaction, is used in our hospital for the measurement of serum creatinine levels. Information related
to the vancomycin therapy (i.e., indication, initial doseand frequency, first trough level at steady state, numberof dose adjustments, and duration of therapy) were alsocollected. The serum vancomycin concentrations were
measured and analyzed at the main laboratory of ourinstitution using the particle-enhanced turbidimetricinhibition immunoassay method (Siemens Dimension;
Dade Behring, Deerfield, Illinois, PETINIA).
Primary and secondary outcomes

The primary outcomes were to assess the efficacy of theinitial dosing regimen (40 mg/kg/day administered every
6–8 h), endorsed by the MAG, in achieving the therapeutic vancomycin levels, and the incidence of vancomycinassociated AKI, defined as an absolute increase in SCrof ≥ 0.3 mg/dL, or a percentage increase in SCr of ≥ 50%(1.5-fold) from the baseline at day-3, day-6 and posttreatment [32]. The secondary outcome was the signs andsymptoms of the resolution of the infection (fever, WBC,
Platelet, ESR, CRP) by days 3 and 6.
Statistical analysis

The data were analyzed using the Statistical Package for
the Social Sciences (SPSS; version 25.0). Nominal variables are represented as frequency, and the scale variables are reported as mean ± SD or median (Interquartile
range: IQR) based on the normality of the data. A correlational analysis was done using the Chi-squared test or
Fisher’s exact test for the nominal variables. The Studentt-test or Mann-Whitney test was used to compare themeans between binomial variables. A Wilcoxon test wasused to track the changes in the variables over time. The
significance level was set as 5%.

Results
Sample characteristics
Fig. 1 The study flow diagram. *MAG: medication administration guide,**ECMO: extracorporeal membrane oxygenator

Figure 1 illustrates the patient enrollment. Eventually,
88 congenital heart disease (CHD) pediatric patientswere included in the study, with a median age of 0.82

Alakeel et al. BMC Pediatrics(2024) 24:575

years (IQR: 0.25–2.9). Approximately half were infants(Table 1). A slightly higher proportion of males (58%,n = 51) was included, and the majority were underweight(58%, n = 51), exposed to CPB surgery (65.9%, n = 58),
admitted to non-ICU (59.1%, n = 52), and had an acyanotic cardiac lesion (59.1%, n = 52).
At baseline, the majority of the patients (59.1%, n = 52)
had a fever; 41 (46.6%) had a negative culture, slightly elevated mean WBC, 12.75 ± 5.99 × 109/L, elevated CRP and
ESR, and a normal renal function. Most patients weretaking at least one nephrotoxic medication concurrently
with vancomycin. Furosemide was received by 81 (92%)
patients, ACE inhibitors by 59 (67%), ceftazidime by 55(62.5%), spironolactone by 29 (33%), and meropenem by
16 (18.2%).
Vancomycin therapy was mainly administered empirically (80.7%, n = 71). Fever was the main indication
for prescribing vancomycin (36.4%, n = 32), followed
by clinical deterioration (18.2%, n = 18), sepsis (18.2%,
n = 16), and bacteremia (10.2%, n = 9). The culture wasmostly positive for S. epidermidis (10.2%, n = 9), MRSA
(5.7%, n = 5), methicillin-sensitive Staphylococcus aureus(MSSA) (3.4%, n = 3) and enterococcus (3.4%, n = 3).
Patients were mostly receiving the 40 mg/kg in four
divided doses (93.2%, n = 82), and the mean duration oftherapy was 6.92 ± 5.2 days.
Primary outcomes

Figure 2 demonstrates the efficacy of the MAG recommended initial dose (40 mg/kg/day q6-8 h). The majority (71.6%, n = 61) achieved a serum vancomycin levelwithin the therapeutic range 7–20 mg/L “wide-range”,
46 (52.3%) had a serum level between 7 and 15 mg/L
“low-range” and 15 (17%) had a serum level between> 15–20 mg/L “high-range”. Only 3 (3.4%) children had asupratherapeutic initial level (> 20 mg/L), and 24 (27.2%)
initially had a subtherapeutic trough level (< 7 mg/L).
The sociodemographic and clinical characteristics ofthe sample with a serum vancomycin level below or above
the therapeutic trough level are presented in Table 2. The
infants and young children had an increased incidence ofsubtherapeutic vancomycin levels, [7 (29.2%); P = 0.033]
and [13 (54.2%); P = 0.01] respectively. The CPB group
had more subtherapeutic levels [21 (87.5%); P = 0.009)].
No significant difference was found between the group
who obtained a subtherapeutic trough level and thegroup who did not.
Table 3 displays the safety of the recommended dosing in the medication administration guide. At baseline,
only patients with a normal renal function were includedin the study. On day 3, only 2 (3.8%) patients had anelevated SCr. On day 6, 2 (5.9%) patients had an elevated SCr and 2 (5.9%) others developed AKI. After the

Page 4 of 10

treatment, however, 8 (10%) had an elevated SCr and 2(2.5%) children had AKI.
As shown in Table 4, no significant difference wasfound between the patients developing AKI or an elevated SCr and the group who did not in terms of theclinical, therapeutic, and demographic characteristics.
However, a decreased incidence of SCr elevation wasobserved in patients prescribed an ACE inhibitor [4(36.4%); P = 0.036].
The resolution of the infection signs (WBC, platelet count, CRP, and ESR) were not significant on day 3
or day 6 compared to baseline (P = 0.2 and 0.76, P = 0.57
and 0.76, P = 0.72 and 0.103, P = 0.36 and 0.14, respectively). However, the incidence of fever was significantly
decreased (P < 0.001).

Discussion
All the pediatric patients enrolled in this study received
vancomycin according to the MAG of KAMC-R. The
majority of the sample achieved a therapeutic troughlevel from the initial dose administered (40 mg/kg
divided q6-8 h), with significantly resolved signs of infection and a preserved kidney function, although 27.2%
attained an initial subtherapeutic trough level, which
necessitated dosage adjustment.
Vancomycin was mainly prescribed for patients developing fever (36.4%), clinical deterioration (18.2%), sepsis(18.2%), and bacteremia (10.2%). The fever was significantly decreased (P < 0.001), but no other significant
changes were observed in the other inflammatory markers WBC, CRP, ESR, and platelets, compared to baseline.
The MAG recommends that the patient receive an
initial dose of 10 mg/kg every six hours. This dose represents the cutline border between the generally recommended dose (40–60 mg/kg/day divided q6-8 h) andthe dosing suggested by two studies with pediatric cardiac patients (20 and 40 mg/kg/day) [2, 18]. This dose is,however, notably higher than that endorsed by a study(20 mg/kg/day divided every 12 h) for “low range” troughlevels: 7–15 mg in pediatric cardiology [18].
Nephrogenesis is considered complete anatomicallywhen each kidney contains approximately 1,000,000
nephrons, typically around gestation week 36. Following birth, there is rapid maturation of the glomerular
filtration rate during the neonatal period, which continues to increase steadily over the next 9 weeks of life [33,34]. This maturation process, along with gestational age,relies on adequate oxygenation and blood flow to thekidneys, which receive approximately 25% of the cardiac output [35]. The presence of cyanotic heart lesions
was noted in almost 41% of our study cohort. This, combined with potential reductions in cardiac output, canlead to decreased oxygen levels and renal blood flow in
the kidneys. Consequently, this could result in delayed

Alakeel et al. BMC Pediatrics(2024) 24:575

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Table 1 Baseline data (N=88)
Variable
Demographic
Age (years)
Age category

Gender
Weight (kg)Weight category*Baseline Clinical data
Cardiac lesion
CPB exposure
Setting
Fever
CultureBaseline lab

Concomitant Nephrotoxic Medication

Vancomycin therapy
Indication**

Infection type

Culturen (%)/ Mean±SD/ Median (IQR)

Neonates
Infants
Young Child (1 – 6 y)
Old child (7-14 years)
FemaleMale
Underweight
Healthy weight
Overweight
Obese
Cyanotic

0.82 (0.25, 2.9)
6 (6.8)42 (47.7)
29 (33)
11 (12.5)
37 (42)51 (58)5.9 (3.6 – 11.95)
51 (58)34 (38.6)
1 (1.1)2 (2.3)

Negative
Positive
Not available
WBC ×109/L
Platelet ×109/L
ESR (mm/hr)
CRP (mg/dL)
SCr (mg/dL)
BUN (mg/dL)
Piperacillin/tazobactam
Meropenem
Aminoglycosides
Ceftazidime
Angiotensin converting enzyme inhibitors (ACEI)
Furosemide
Spironolactone
Other

36 (40.9)
58 (65.9)
36 (40.9)
52 (59.1)
52 (59.1)
41 (46.6)
14 (15.9)
33 (37.5)
12.75 ± 5.99
325.9 ± 209.9
10 (4 – 30)
2.0 (0.875 – 6.9)
0.44 ± 0.078
12.3 ± 6.1
4 (4.5)16 (18.2)
10 (11.4)
55 (62.5)
59 (67)81 (92)29 (33)2 (2.2)

Therapeutic
Empirical
Prophylaxis
Fever (no identified infection)
Endocarditis
Bacteremia
SepsisWound infection
Clinical deterioration
OthersNo positive culture
MSSA
MRSA
S. Epidermidis
Enterococcus
Streptococcus

15 (17)71 (80.7)
2 (2.3)32 (36.4)
6 (6.8)9 (10.2)
16 (18.2)
5 (5.7)16 (18.2)
3 (3.4)66 (75)3 (3.4)5 (5.7)9 (10.2)
3 (3.4)2 (2.3)ICU
Non-ICU

Alakeel et al. BMC Pediatrics(2024) 24:575

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Table 1 (continued)
Variable
Frequency Category

Every 6 hEvery 8 h

Initial trough level (mg/L)

n (%)/ Mean±SD/ Median (IQR)
82 (93.2)
6 (6.8)10.6 ± 4.4* Weight category is based on the Centers for Disease Control and Prevention (CDC) chart: Weight-for-length percentiles for children ≤ 24 months (<5th: underweight,
5th to < 95th: Healthy weight, ≥95th: overweight), and BMI percentiles for children > 24 months (<5th: underweight, 5th to <85th: healthy weight, ≥85th to < 95th:
overweight, ≥95th: obese)** Most of the treated patients were diagnosed clinically without positive cultures

Fig. 2 Efficacy of the recommended initial dosing (40 mg/kg/day q6-8 h) endorsed in the medication administration guide (n = 88)

maturation and impaired renal vancomycin clearance.
Shimamoto et al. described this phenomenon in children
with CHD, recommending a lower dose of vancomycin
compared to standard pediatric doses [36], which aligns
with the initial doses outlined in our hospital guidelines.
The majority of the sample (69.3%, n = 61) treatedwith the initial MAG recommended vancomycin dose
(40 mg/kg/day q6-8 h) had a trough level within the wide
therapeutic range (7–20 mg/L), the majority of which(75.4%, 46) had a low range trough level (7–15 mg/L).
Contrarily, in the study by Hoang et al., only 39% of thepatients receiving the empiric dose (40–60 mg/kg daily)
achieved a therapeutic trough level (10–20 mg/L) [4].
The correlation between the desired vancomycin troughconcentrations and the clinical efficacy has not been
proved in pediatric patients, especially CHD patients[9]. A proportion of the group receiving this dose (24%),
had trough levels outside the therapeutic range. It is
worth mentioning that more subtherapeutic readings(< 7 mg/L) were observed (27.2%) than supratherapeuticlevels (> 20 mg/L) (3.4%). In our study, 15 patients (17%)
achieved the high-range trough level (15–20 mg/L), while
Hwang et al. reported a lower achievement rate of 5.6%
(5/90) for this target level in a general pediatric population using the same dose [8]. This difference may be

explained by the changes in cardiac output, renal perfusion, volume of distribution, and ultimately vancomycin
clearance following cardiac surgery.
Infants and young children in this study were especially susceptible to below target readings (P = 0.033)
and (P = 0.01) respectively. The cardiopulmonary bypass
surgery patients were more likely to have subtherapeutic levels (P = 0.009). This dosing (40 mg/kg/day divided
q6-8 h) may not be supported for patients who underwent cardiopulmonary bypass surgery or infants/ young
children. This may be explained by the increased vancomycin systemic clearance in patients exposed to CPB surgery, as noted in the Gracia et al. study [37]. However, inthe study by Thomas et al., patient exposure to CPB did
not affect the vancomycin TDD requirements [2]. Similar
to our study, Thomas et al. reported in their study thatdifferent dosing requirements were recommended for thedifferent age groups, with increased dosing requirementsfor pediatric patients [2]. Although fewer subtherapeutic
readings were observed in the ICU patients, the difference was non-significant. The care setting did not affectthe out-of-therapeutic range readings. According to a
study conducted by Glover et al., however, higher vancomycin doses were required by PICU patients to achieve
acceptable therapeutic levels [10].

Alakeel et al. BMC Pediatrics(2024) 24:575

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Table 2 Characteristics of patients experiencing a
supratherapeutic or subtherapeutic initial level

VariableAge group

Neonates(n = 6)
Infants(n = 42)
Young Children (n = 29)
Old children(n = 11)WeightUnderweightcategory*(n = 51)
Normalweight(n = 34)
Overweight/
obese (n = 3)
CardiacCyanotic
lesion(n = 36)
Acyanotic(n = 52)
CPB
Exposedexposure(n = 58)
Non-exposed(n = 30)
Care setting ICU (n = 36)
Non-ICU(n = 52)

Subtherapeuticlevel (n = 24)
Frep-value
quency(%)
1 (4.2)0.47

Supratherapeutic level (n = 3)
Frep-value
quency (%)
00.8

7 (29.2)

2 (66.7) 0.604

0.033

13 (54.2) 0.01

03 (12.5)

0.65

1 (33.3) 0.33

13 (54.2) 0.65

1 (33.3) 0.57

11 (45.8) 0.39

1 (33.3) 0.67

01 (33.3) 0.1

0.55

0.54

11 (45.8) 0.56

0

0.26

13 (54.2)

3 (100)21 (87.5) 0.009

2 (66.7) 0.73

3 (12.5)

1 (33.3)

8 (33.3) 0.37
16 (66.7)

2 (66.7) 0.56
1 (33.3)* Weight category is based on the Centers for Disease Control and Prevention(CDC) chart: Weight-for-length percentiles for children ≤ 24 months, and BMI
percentiles for children > 24 months

Table 3 Safety of the recommended dosing in the medication
administration guide (MAG) N(%)
Baseline

Day 3(n = 53)Day 6(n = 34)

Normal SCr

Reference> 25 to 50% increase in SCr(elevated SCr)
≥ 50% increase in SCr (AKI)

Reference

Post
Treatment(n = 80)
51 (96.2) 30 (88.2) 70(87.5)
2 (3.8)2 (5.9) 8 (10)Reference0

2 (5.9) 2 (2.5)

SCr: serum Creatinine, AKI: acute Kidney Injury

Although present, elevated SCr (10%) and AKI (2.5%)
were experienced by a small proportion of the sample
receiving this vancomycin dose. This is lower than theincidence of AKI (19.9%) reported for the general pediatric population who received vancomycin for more than
three days [27, 30]. It is noteworthy that vancomycin
by itself is not an independent factor for nephrotoxicity. Other factors may increase the odds of the development. The majority of patients were taking at least one

nephrotoxic medication concurrently with vancomycin,
including Furosemide 81 (92%) patients, ACE inhibitors 59 (67%), ceftazidime 55 (62.5%), spironolactone
29 (33%), and meropenem 16 (18.2%). However, none ofthese drugs significantly affected the AKI incidence. A
decreased incidence of SCr elevation was observed in thepatients receiving ACE inhibitors (P = 0.036) which may
be related to their prevention of unfavorable intrarenal
effects of angiotensin II such as increased glomerular
capillary pressure and stimulation of growth hormone
leading to vascular smooth muscle hypertrophy. No
other significant difference was found between the AKI
or elevated SCr group and the control group, in termsof clinical and therapeutic characteristics. The patient
demographics, including age and weight, did not significantly affect the incidence of vancomycin-associated AKI,
compared to literature suggesting an increased incidenceof AKI in obese patients due to increased exposure [27,38]. However, a limited number of overweight or obese
patients were examined in this study which may haveaffected the association. The vancomycin trough level
was not an independent factor for the development of
AKI in this study. The mean trough level associated with
AKI (10.7 ± 6.3 mg/L) was even lower than that obtainedfor patients with an elevated SCr (12.7 ± 4.9 mg/L). Theselevels were lower than the cut-point limit set for the prevention of vancomycin-associated AKI (15 mg/L) whichcause safety concerns [24, 39, 40]. In this regard, thereduction of the serum concentration would not offer any
added benefit to prevent AKI, though therapeutic failure
is possible. Moffett et al. found that the administrationof vancomycin in an ICU setting or concomitantly withother nephrotoxic medications (e.g., nafcillin, clindamycin, and acetazolamide) significant predictors for vancomycin associated AKI (P < 0.05) [27]. Previous cardiac
surgery or the use of an ACE inhibitor did not affect theincidence of AKI in the latter study [27].
The improvement of the inflammatory markers at any
time were not observed in our study. This finding may
be related to several factors. First, most patients (71, or
80.7%) received vancomycin empirically without abnormal baseline laboratory values; fever and clinical deterioration were the primary reasons for treatment initiation.
Additionally, the elevation of these markers could be due
to other chronic inflammatory conditions, common inpediatric cardiac patients, besides infection. Even if due
to infection, it may take weeks for these markers to show
significant decline, which could be beyond our study’s
follow-up period.

Limitations of the study
This was a prospective single-center study that included
patients treated according to the center guideline, as
other centers may have adopted different treatment

Alakeel et al. BMC Pediatrics(2024) 24:575

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Table 4 Risk factors associated with AKI and SCr elevation
Variable
Vancomycin dose (mg/kg/day)Trough Levels (mg/L)
Duration of therapy
Frequency
Concomitant nephrotoxic medications

Age group

Weight category*

Cardiac lesion type
CPB surgery exposure
Care Setting

Every 6 h (n = 82)
Every 8 h (n = 6)
Piperacillin/Tazobactam (n = 4)
Meropenem (n = 16)
Aminoglycoside (n = 10)
Ceftazidime (n = 55)
Furosemide (n = 81)
ACE I (n = 59)
Spironolactone (n = 29)
Neonate (n = 6)
Infant (n = 42)
Young Child (n = 29)
Old child (n = 11)
Underweight (n = 51)
Normal (n = 34)
Overweight/ obese (n = 3)
Cyanotic (n = 36)
Exposed (n = 58)
ICU (n = 36)

AKI (n = 3)n (%)/Mean±SD4010.7 ± 6.3
9 ± 2.6
2 (66.7)
1 (33.3)
0
1 (33.3)
1 (33.3)
2 (66.7)
3 (100)1 (33.3)
1 (33.3)
1 (33.3)
1 (33.3)
1 (33.3)
02 (66.7)
1 (33.3)
0
1 (33.3)
2 (66.7)
1 (33.3)

p-value
0.94
0.95
0.092
0.19
0.86
0.45
0.307
0.68
0.78
0.25
0.704
0.19
0.53
0.704
0.66
0.62
0.67
0.9
0.63
0.73
0.56

Elevated SCr (n = 11)n (%)/Mean±SDp-value40
0.75
12.7 ± 4.9
0.108
6.27 ± 1.5
0.36
11 (100)
0.43
0
0
0.58
3 (27.3)
0.41
1 (9)
0.63
7 (63.6)
0.6
10 (90.9)
0.62
4 (36.4)
0.036
2 (18.2)
0.326
0
0.43
7 (63.6)
0.25
3 (27.3)
0.47
1 (9)
0.58
5 (45.5)
0.52
5 (45.5)
0.74
1 (9)
0.33
5 (45.5)
0.75
7 (63.6)
0.56
6 (54.5)
0.75*Weight category is based on the Centers for Disease Control and Prevention (CDC) chart: Weight-for-length percentiles for children ≤ 24 months, and BMI percentiles
for children > 24 months
AKI: acute Kidney injury, SCr: serum creatinine

approaches. The sample was representative and divided
by age and other attributes that may affect the drug
pharmacokinetics. However, important subgroups had
a limited sample size, which may have undermined thestatistical power to identify significant associations.
In addition, important clinical values (SCr and troughlevel) were sometimes missing. Lastly, the SCr was the
only marker used to identify patients developing AKI
as per the Kidney Disease Improving Global Outcomes(KDIGO) definition of AKI [32]. A different method of
identification may have affected the AKI incidence [41].
There was no control group (patients not taking vancomycin), which may have the possibility of confoundingby indication. We believe that our analysis may offer thebasis for future studies to be conducted for an increased
period.

Conclusions
Evaluation of the optimal dosing regimen in pediatriccardiology patients is critical in determining the drug
safety and efficacy. This should be evaluated regularly, as
higher doses are required over time. Our institution follows the MAG recommendations; however, subtherapeutic serum concentrations were evident, especially in theinfants, young children, and cardiopulmonary surgery
patients. It would be interesting to determine the optimaldose in these subgroups in future. Strategies to prevent
AKI should be investigated, as the possible causes havenot been identified in this study. It is noteworthy however, that AKI was independent of the trough concentration, and may even occur at normal therapeutic levels.
Abbreviations
MAG	Medication administration guide
ARC	Augmented renal clearance
CPB	Cardiopulmonary bypass surgery
SCr	Serum creatinine
AKI	Acute kidney injury
MRSA	Methicillin-resistant Staphylococcus aureus
MSSA	Methicillin-sensitive Staphylococcus aureus
IDSA	Infectious Disease Society of America
TDD	Total daily dose
KAMC-R	King Abdulaziz Medical City, Riyadh
KAIMRC	King Abdullah International Medical Research Center
PCICU	Pediatric cardiac intensive care unit
PCW	Pediatric cardiac ward
ECMO	Extracorporeal membrane oxygenator
CrCl	Creatinine clearanceWBC	White blood count
BUN	Blood urea nitrogen
ESR	Erythrocyte sedimentation rate
CRP	C-reactive protein
CHD	Congenital heart disease
KDIGO	Kidney Disease Improving Global Outcomes
KSAU-HS	King Saud bin Abdulaziz University for Health Sciences
Acknowledgements
We acknowledge the assistance of the Research Unit at the College of
Pharmacy, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS).

Alakeel et al. BMC Pediatrics(2024) 24:575

Author contributions
YA designed the research study. YA and YS sorted and compiled the relevant
information and wrote the draft. MF, GA, BA, KA, FA, MA and YA collected
and analyzed the data, and helped with the data interpretation. All authors
contributed to editorial changes in the manuscript. All authors read andapproved the final manuscript.
Funding
Not applicable.
Data availability
All data generated or analyzed during this study are included in this publishedarticle and its supplementary information files.

Declarations
Ethics approval and consent to participate
This study was approved by the Institutional Review Board (study number
SP18/197/R) at the King Abdullah International Medical Research Center(KAIMRC). Informed consent was waived off by the KAIMRC institutional
review board. All methods were carried out in accordance with relevant
guidelines and regulations.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Received: 19 June 2023 / Accepted: 2 September 2024

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