
==== Front
BMC Pediatr
BMC Pediatr
BMC Pediatrics
1471-2431
BioMed Central London

5048
10.1186/s12887-024-05048-8
Research
An evaluation of the empirical vancomycin dosing guide in pediatric cardiology
Alakeel Yousif S. alakeely@gmail.com

1236
Alahmed Yazeed 34
Alanazi Ghadah 23
Alawbathani Bushra 23
Alshutwi Kadi 23
Almeshary Meshary 13
Aldhahri Fahad 123
Alshakrah Meshal 35
1 https://ror.org/009djsq06 grid.415254.3 0000 0004 1790 7311 Department Pharmaceutical Care Services, King Abdulaziz Medical City, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia
2 https://ror.org/0149jvn88 grid.412149.b 0000 0004 0608 0662 College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
3 https://ror.org/009p8zv69 grid.452607.2 0000 0004 0580 0891 King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
4 https://ror.org/01wsfe280 grid.412602.3 0000 0000 9421 8094 Department of Pediatrics, College of Medicine, Qassim University, Qassim, Saudi Arabia
5 grid.416641.0 0000 0004 0607 2419 Saudi Medication Safety Center, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia
6 https://ror.org/009djsq06 grid.415254.3 0000 0004 1790 7311 Department of Pharmaceutical Care Services, King Abdulaziz Medical City, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia
11 9 2024
11 9 2024
2024
24 57519 6 2023
2 9 2024
© The Author(s) 2024
2024
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Background

Higher doses of vancomycin are currently prescribed due to the emergence of bacterial tolerance and resistance. This study aimed to evaluate the efficacy and safety of the currently adopted vancomycin dosing guide in pediatric 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 level within the therapeutic range (7–20 mg/L). Infants, young children, and children exposed to CPB surgery had an increased 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
issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
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pmcIntroduction

Vancomycin is a bactericidal antibiotic used for the treatment 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 sufficient and safe for most pediatric patients. The serum blood level, obtained at a steady state just before the fourth dose, is used as a robust pharmacodynamic marker to ensure drug safety and efficacy [2]. A trough level ranging between 10 and 15 mg/L is often required for general indications, 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 and resistance, higher doses are currently prescribed to achieve the target vancomycin trough concentration (7–10 mg/L), a level desired for the majority of mild-moderate infections precipitated by MRSA [4–10]. Major organizations, such as the Infectious Disease Society of America (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 illness-induced stress responses (e.g., burns, major trauma), and certain therapeutic interventions (e.g., aggressive fluid resuscitation and diuresis) [20]. The presence of ARC is particularly impactful for time-dependent antibiotics primarily eliminated renally, such as vancomycin. Studies have linked ARC to subtherapeutic vancomycin trough levels in critically ill pediatric patients. Consequently, 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 attain higher trough levels, care should be taken to keep the serum levels below the nephrotoxic level. Although nephrotoxicity is not a direct effect of vancomycin therapy itself, other factors, for example baseline renal function, hydration status, and other nephrotoxic agents used, 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 and higher or if the therapy is continued for more than four days [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 of vancomycin to ensure its safety and efficacy [31]. The vancomycin medication administration guide (MAG) was developed by the pediatric clinical pharmacy team at 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 empirical vancomycin dosing included in the hospital MAG used in 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 if they were non-compliant with the MAG, if they had a pre-existing chronic or acute renal disease, or if they are receiving renal replacement therapy or extracorporeal membrane oxygenator (ECMO). Non-compliance included 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 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 is selected. The goal trough concentration for treatment of general 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 to q8h) for supratherapeutic trough levels. However, if the child has a subtherapeutic reading, the dose is increased by 2.5 mg/kg/dose (i.e., 10 mg/kg is changed to 12.5 mg/kg). According to the MAG, serum trough levels are usually obtained 15–30 min before the fourth dose for patients receiving the drug at an interval less than 24 h; otherwise, it is tested before the third dose if the dosing interval 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 for vancomycin orders. The baseline characteristics were sociodemographic 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 whenever available. The SCr and blood urea nitrogen (BUN) were monitored 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 dose and frequency, first trough level at steady state, number of dose adjustments, and duration of therapy) were also collected. The serum vancomycin concentrations were measured and analyzed at the main laboratory of our institution using the particle-enhanced turbidimetric inhibition immunoassay method (Siemens Dimension; Dade Behring, Deerfield, Illinois, PETINIA).

Primary and secondary outcomes

The primary outcomes were to assess the efficacy of the initial 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 vancomycin-associated AKI, defined as an absolute increase in SCr of ≥ 0.3 mg/dL, or a percentage increase in SCr of ≥ 50% (1.5-fold) from the baseline at day-3, day-6 and post-treatment [32]. The secondary outcome was the signs and symptoms 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 Student-t-test or Mann-Whitney test was used to compare the means between binomial variables. A Wilcoxon test was used to track the changes in the variables over time. The significance level was set as 5%.

Results

Sample characteristics

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

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

Table 1 Baseline data (N=88)

Variable		n (%)/ Mean±SD/ Median (IQR)	
Demographic			
Age (years)		0.82 (0.25, 2.9)	
Age category	Neonates	6 (6.8)	
Infants	42 (47.7)	
Young Child (1 – 6 y)	29 (33)	
Old child (7-14 years)	11 (12.5)	
Gender	Female	37 (42)	
Male	51 (58)	
Weight (kg)		5.9 (3.6 – 11.95)	
Weight category*	Underweight	51 (58)	
Healthy weight	34 (38.6)	
Overweight	1 (1.1)	
Obese	2 (2.3)	
Baseline Clinical data			
Cardiac lesion	Cyanotic	36 (40.9)	
CPB exposure		58 (65.9)	
Setting	ICU	36 (40.9)	
Non-ICU	52 (59.1)	
Fever		52 (59.1)	
Culture	Negative	41 (46.6)	
Positive	14 (15.9)	
Not available	33 (37.5)	
Baseline lab	WBC ×109/L	12.75 ± 5.99	
Platelet ×109/L	325.9 ± 209.9	
ESR (mm/hr)	10 (4 – 30)	
CRP (mg/dL)	2.0 (0.875 – 6.9)	
SCr (mg/dL)	0.44 ± 0.078	
BUN (mg/dL)	12.3 ± 6.1	
Concomitant Nephrotoxic Medication	Piperacillin/tazobactam	4 (4.5)	
Meropenem	16 (18.2)	
Aminoglycosides	10 (11.4)	
Ceftazidime	55 (62.5)	
Angiotensin converting enzyme inhibitors (ACEI)	59 (67)	
Furosemide	81 (92)	
Spironolactone	29 (33)	
Other	2 (2.2)	
Vancomycin therapy			
Indication**	Therapeutic	15 (17)	
Empirical	71 (80.7)	
Prophylaxis	2 (2.3)	
Infection type	Fever (no identified infection)	32 (36.4)	
Endocarditis	6 (6.8)	
Bacteremia	9 (10.2)	
Sepsis	16 (18.2)	
Wound infection	5 (5.7)	
Clinical deterioration	16 (18.2)	
Others	3 (3.4)	
Culture	No positive culture	66 (75)	
MSSA	3 (3.4)	
MRSA	5 (5.7)	
S. Epidermidis	9 (10.2)	
Enterococcus	3 (3.4)	
Streptococcus	2 (2.3)	
Frequency Category	Every 6 h	82 (93.2)	
Every 8 h	6 (6.8)	
Initial trough level (mg/L)		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

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 were taking 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 was mostly 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 of therapy 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 level within 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 a supratherapeutic initial level (> 20 mg/L), and 24 (27.2%) initially had a subtherapeutic trough level (< 7 mg/L).

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

The sociodemographic and clinical characteristics of the 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 of subtherapeutic 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 the group who did not.

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

	Subtherapeutic level (n = 24)	Supratherapeutic level (n = 3)	
Variable	Frequency (%)	p-value	Frequency (%)	p-value	
Age group	Neonates (n = 6)	1 (4.2)	0.47	0	0.8	
Infants (n = 42)	7 (29.2)	0.033	2 (66.7)	0.604	
Young Children (n = 29)	13 (54.2)	0.01	0	0.54	
Old children (n = 11)	3 (12.5)	0.65	1 (33.3)	0.33	
Weight category*	Underweight (n = 51)	13 (54.2)	0.65	1 (33.3)	0.57	
Normal weight (n = 34)	11 (45.8)	0.39	1 (33.3)	0.67	
Overweight/ obese (n = 3)	0	0.55	1 (33.3)	0.1	
Cardiac lesion	Cyanotic (n = 36)	11 (45.8)	0.56	0	0.26	
Acyanotic (n = 52)	13 (54.2)	3 (100)	
CPB exposure	Exposed (n = 58)	21 (87.5)	0.009	2 (66.7)	0.73	
Non-exposed (n = 30)	3 (12.5)	1 (33.3)	
Care setting	ICU (n = 36)	8 (33.3)	0.37	2 (66.7)	0.56	
Non-ICU (n = 52)	16 (66.7)	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 displays the safety of the recommended dosing in the medication administration guide. At baseline, only patients with a normal renal function were included in the study. On day 3, only 2 (3.8%) patients had an elevated SCr. On day 6, 2 (5.9%) patients had an elevated SCr and 2 (5.9%) others developed AKI. After the treatment, however, 8 (10%) had an elevated SCr and 2 (2.5%) children had AKI.

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

	Baseline	Day 3 (n = 53)	Day 6 (n = 34)	Post Treatment (n = 80)	
Normal SCr	Reference	51 (96.2)	30 (88.2)	70 (87.5)	
> 25 to 50% increase in SCr (elevated SCr)	Reference	2 (3.8)	2 (5.9)	8 (10)	
≥ 50% increase in SCr (AKI)	Reference	0	2 (5.9)	2 (2.5)	
SCr: serum Creatinine, AKI: acute Kidney Injury

As shown in Table 4, no significant difference was found between the patients developing AKI or an elevated SCr and the group who did not in terms of the clinical, therapeutic, and demographic characteristics. However, a decreased incidence of SCr elevation was observed 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).

Table 4 Risk factors associated with AKI and SCr elevation

Variable	AKI (n = 3)	Elevated SCr (n = 11)	
n (%)/Mean±SD	p-value	n (%)/Mean±SD	p-value	
Vancomycin dose (mg/kg/day)		40	0.94	40	0.75	
Trough Levels (mg/L)		10.7 ± 6.3	0.95	12.7 ± 4.9	0.108	
Duration of therapy		9 ± 2.6	0.092	6.27 ± 1.5	0.36	
Frequency	Every 6 h (n = 82)	2 (66.7)	0.19	11 (100)	0.43	
Every 8 h (n = 6)	1 (33.3)	0	
Concomitant nephrotoxic medications	Piperacillin/Tazobactam (n = 4)	0	0.86	0	0.58	
Meropenem (n = 16)	1 (33.3)	0.45	3 (27.3)	0.41	
Aminoglycoside (n = 10)	1 (33.3)	0.307	1 (9)	0.63	
Ceftazidime (n = 55)	2 (66.7)	0.68	7 (63.6)	0.6	
Furosemide (n = 81)	3 (100)	0.78	10 (90.9)	0.62	
ACE I (n = 59)	1 (33.3)	0.25	4 (36.4)	0.036	
Spironolactone (n = 29)	1 (33.3)	0.704	2 (18.2)	0.326	
Age group	Neonate (n = 6)	1 (33.3)	0.19	0	0.43	
Infant (n = 42)	1 (33.3)	0.53	7 (63.6)	0.25	
Young Child (n = 29)	1 (33.3)	0.704	3 (27.3)	0.47	
Old child (n = 11)	0	0.66	1 (9)	0.58	
Weight category*	Underweight (n = 51)	2 (66.7)	0.62	5 (45.5)	0.52	
Normal (n = 34)	1 (33.3)	0.67	5 (45.5)	0.74	
Overweight/ obese (n = 3)	0	0.9	1 (9)	0.33	
Cardiac lesion type	Cyanotic (n = 36)	1 (33.3)	0.63	5 (45.5)	0.75	
CPB surgery exposure	Exposed (n = 58)	2 (66.7)	0.73	7 (63.6)	0.56	
Care Setting	ICU (n = 36)	1 (33.3)	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

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 trough level 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) and the 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” trough levels: 7–15 mg in pediatric cardiology [18].

Nephrogenesis is considered complete anatomically when 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 the kidneys, 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, can lead to decreased oxygen levels and renal blood flow in the kidneys. Consequently, this could result in delayed 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) treated with 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 the patients 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 trough concentrations 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 supratherapeutic levels (> 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, in the 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 that different dosing requirements were recommended for the different age groups, with increased dosing requirements for pediatric patients [2]. Although fewer subtherapeutic readings were observed in the ICU patients, the difference was non-significant. The care setting did not affect the 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].

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 the incidence 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 of these drugs significantly affected the AKI incidence. A decreased incidence of SCr elevation was observed in the patients 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 terms of 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 incidence of 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 have affected 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 obtained for patients with an elevated SCr (12.7 ± 4.9 mg/L). These levels were lower than the cut-point limit set for the prevention of vancomycin-associated AKI (15 mg/L) which cause safety concerns [24, 39, 40]. In this regard, the reduction of the serum concentration would not offer any added benefit to prevent AKI, though therapeutic failure is possible. Moffett et al. found that the administration of vancomycin in an ICU setting or concomitantly with other 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 the incidence 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 in pediatric 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 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 the statistical power to identify significant associations. In addition, important clinical values (SCr and trough level) 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 confounding by indication. We believe that our analysis may offer the basis for future studies to be conducted for an increased period.

Conclusions

Evaluation of the optimal dosing regimen in pediatric cardiology 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 the infants, young children, and cardiopulmonary surgery patients. It would be interesting to determine the optimal dose in these subgroups in future. Strategies to prevent AKI should be investigated, as the possible causes have not 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 clearance

WBC 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).

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 and approved the final manuscript.

Funding

Not applicable.

Data availability

All data generated or analyzed during this study are included in this published article 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.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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