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Keywords:

  • Nomogram;
  • Pediatric;
  • Vancomycin

With widespread emergence of community-acquired methicillin-resistant Staphylococcus aureus (MRSA), empiric and therapeutic use of vancomycin is common among hospitalized children.[1] Concerns of creeping vancomycin minimum inhibitory concentrations (MICs) among susceptible MRSA strains encourage the use of higher dosages to achieve targeted serum concentrations.[2] Current guidelines from the Infectious Diseases Society of America, the American Society of Health-System Pharmacists and the Society of Infectious Diseases Pharmacists recommend targeting vancomycin serum trough concentrations of ≥10 mcg/ml.[3] Higher targeted serum concentrations, 15–20 mcg/ml, are recommended for patients with more serious infections such as osteomyelitis, meningitis, and pneumonia.[3, 4] The standard recommended dosing regimen to achieve these concentrations in children is 15 mg/kg given every 6 hours (60 mg/kg/day).[3] The preferred recommend regimen for adult patients is 15–20 mg/kg given every 8–12 hours.[3, 4] While a dosing regimen of 15 mg/kg every 6 hours is appropriate for young children with normal renal function, the safety and tolerability among teenagers has not been studied. Although much is known about the impact of growth and development and ontogeny of drug elimination in infancy and early childhood, pharmacokinetic differences between teens and young adults remain poorly understood.[5] Size models, using weight, height, and body surface area, are widely used in determining pediatric pharmacokinetic parameters, but may or may not predict drug clearance in teenagers.[6] These limitations pose a challenge when deciding appropriate vancomycin dose regimens targeting therapeutic troughs in this patient population.

Numerous nomograms have been developed and validated for adult patients in order to streamline vancomycin dosing for patients of varying weights and renal function.[7-9] These nomograms use the patient's weight and creatinine clearance (CrCl) to determine an empiric starting dose. The dose is then adjusted based on trough concentrations. Institutions utilizing nomograms have noted an increase in the number of patients with therapeutic drug concentrations with the first dosing regimen. Following puberty, where adult height and muscle mass are achieved, the similarities between adolescent and adult body mass and creatinine clearance would allow the use of adult vancomycin nomogram in older teens. To the best of our knowledge, vancomycin nomograms have not been evaluated in the older pediatric population. The aim of this study was to determine if adult nomograms applied to pediatric patients 10 years of age and older, with a minimum weight of 40 kg could provide optimal vancomycin trough concentrations while minimizing the risk of reaching supratherapeutic drug concentrations.

Methods

  1. Top of page
  2. Methods
  3. Results
  4. Discussion
  5. References
  6. Supporting Information

The study was conducted at Monroe Carell, Jr. Children's Hospital at Vanderbilt, Nashville, TN, a 271-bed tertiary pediatric teaching hospital with 78 pediatric residents and 31 fellows rotating through the year. The inpatient units average 8,500 admissions per year.

Patients were eligible for inclusion if they received vancomycin from 2/1/2011 through 7/31/2012 and had at least one vancomycin concentration drawn. Patients 10 years of age and older, with normal CrCl, weight ≥40 kg, and a therapeutic vancomycin concentration were included in the study. Patients were excluded if they were admitted to the neonatal intensive care unit, the pediatric intensive care unit, the operating room, or the emergency department at the initiation of vancomycin therapy. Children transferred to the pediatric intensive care unit while on vancomycin therapy were not excluded if their renal function remained normal.

Therapeutic trough concentrations were defined as vancomycin serum concentrations between 10 and 20 µg/mL. Serum vancomycin trough values <10 and >20 µg/mL were considered sub-therapeutic and supratherapeutic, respectively.

Vancomycin assays were determined utilizing COBAS INTEGRA 800® analyzer (Roche Diagnostics GmbH, Mannheim, Germany) with a reference range of 2–80 µg/mL, and the ability to extend to 400 µg/mL with dilution. BioRad controls are stabilized specimens treated like patient specimens to monitor the performance of the assay. Vanderbilt Medical Center Clinical Laboratory performance is accredited by the College of American Pathologists Proficiency Survey Program. Vancomycin trough concentrations were considered drawn appropriately if they were collected within 1 hour before or 1 hour after the dose was due in order to coincide with our institutional policy for drug administration.

Two nomograms designed to provide optimal dosing guidelines for adult patients ≥18 years of age were used to determine the correlation between the dose prescribed in patients with therapeutic troughs and the regimens noted in the nomogram.[7, 9] Nomogram A (Supplemental Table S1) was developed for patients with a weight range of 40–110 kg and a CrCl of 30–110 mL/min with a goal target trough concentration of 15–20 µg/mL.

Nomogram B (Supplemental Table S2) was developed for patients ≥18 years and ≥40 kg, modifying the dose and dosing interval according to the actual body weight and the estimated CrCl in mL/min (modified Cockcroft–Gault).[9]

To determine possible differences between CrCl using the Schwartz equation, the standard formula used in pediatrics, and the modified Cockcroft–Gault equation, used for adult patients, we determine CrCl using both calculations.[10-12]

Descriptive statistics were used to determine the end points. The relationship between CrCl calculated by Schwartz and the modified Cockcroft–Gault equations, and the prescribed and predicted doses were determined by Pearson correlation coefficient. Paired t-test was used to compare mean differences between prescribed and predicted doses. All tests were 2-tailed at the level of significance of 0.05. Analyses were performed using IBM SPSS software (Version 20; IBM Corp). Vanderbilt University Institutional Review Board reviewed and approved this protocol.

Results

  1. Top of page
  2. Methods
  3. Results
  4. Discussion
  5. References
  6. Supporting Information

One hundred sixty-five trough concentrations from 120 patients were reviewed for inclusion. Fifty-three vancomycin trough concentrations of 10–20 mcg/mL were identified from patients ≥40 kg with normal renal function and a therapeutic trough concentration resulting from the empiric regimen. Two vancomycin trough concentrations were excluded due to the blood level being drawn after a single vancomycin dose. One trough concentration was excluded because the patient's height was not recorded in the electronic medical record, and CrCl could not be calculated. Two patients were excluded because the blood sample was drawn outside of the appropriate time frame. Forty-eight vancomycin dosing regimens were included in the final analysis from 38 individual patients drawn at different hospitalizations. The median age of the patients was 16 years (range, 10–21 years), median weight 54 kg (range, 40–138 kg), and median baseline serum creatinine 0.60 mg/dL (range, 0.33–1 mg/dL). There were an equal number of males and females (24 of 48; 50%). The median serum vancomycin trough concentration was 14 µg/mL (range, 10–20 µg/mL) drawn at a median time of 14.4 minutes prior to the next scheduled vancomycin dose (range, −45 to 60 minutes). Of these, 33% (16 of 48) of vancomycin regimens were prescribed to children without underlying conditions, 46% (22 of 48) to children with cystic fibrosis (CF) and 21% (10 of 48) to oncology patients.

The mean CrCl using the Schwartz and the modified Cockcroft–Gault equation was 169 mL/min (range, 97–303 mL/min) and 139 mL/min (range, 88–273 mL/min), respectively. Based on the strong correlation (r = 0.9; P < .001) found between both calculations, the Schwartz equation was used to estimate CrCl in the final analysis.

Table 1 depicts the mean dose and range of the dose prescribed to achieve a therapeutic vancomycin trough concentration and the predicted dose and range by both nomograms. Nomogram A predicted lower dosing regimens than those used to achieved therapeutic trough concentrations. The mean daily dose predicted was statistically different from the average daily dose prescribed (t(47) = 4.5, P < .001, 95% confidence interval [CI], 399–1,051; Table 1). The average dose predicted by nomogram B differed significantly from the prescribed daily dose (t(47) = −8.5, P < .001, 95% CI, −1,545 to −952). On average, the daily vancomycin dose predicted by nomogram B was 4,214 mg, a dose that could lead to supratherapeutic trough concentrations if applied to this patient population (Table 1).

Table 1. Prescribed and Predicted Vancomycin Dosing
 Mean Dose (Std. Deviation)Range
 mg/kg/daymg/daymg/kg/daymg/day
Dose prescribed53 (13)2,965 (595)15–721,500–4,000
Nomogram A136 (5.8)2,240 (1,159)27–471,500–5,250
Nomogram B273 (11)4,214 (969)47–932,750–6,750

Based on actual body weight, the prescribed average daily dose was significantly different from those predicted by nomogram A (t(47) = 7.4 mg/kg/day, P < .001, 95% CI, 13–22 mg/kg/day) and nomogram B (t(47) = −12 mg/kg/day, P < .001, 95% CI, −23 to −17 mg/kg/day). A weak correlation was found between the daily dose prescribed and the predicted daily dose by nomogram A (r = 0.317; P = .03), but not with nomogram B (r = 0.216; P = .14).

Assessing patient categories separately, the mean daily dose required to achieve a therapeutic trough concentration among healthy children was 50 mg/kg/day. Oncology patients required a lower dose, 43 mg/kg/day, while children with CF needed on average 59 mg/kg/day (Figure 1).

image

Figure 1. Distribution of vancomycin dosing regimens prescribed and predicted by both nomograms among healthy, oncology, and cystic fibrosis patients. Box-plots depicting the differences between vancomycin dosing regimens prescribed and predicted by nomogram A and nomogram B by patient category, expressed as mg/kg/day. The lowest, second lowest, middle, second highest, and highest box point represents the 10%, 25%, median, 75%, and 90%, respectively. Means are represented by the black square symbol. N A, nomogram A; N B, nomogram B.

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After applying both nomograms, vancomycin regimens were most closely related for oncology patients (Figure 1). The mean total daily dose prescribed (2,840 mg/day) and the mean daily dose prescribed per kilogram (44 mg/kg/day) did not differ significantly from the mean daily dose (2,900 mg) and the mean daily dose per kilogram (37 mg/kg/day) calculated using nomogram A (respectively) (t(9) = −0.114, P = .9, 95% CI, −1,254 to 1,134; and (t(9) = 1, P = .3, 95% CI, −9 to 22, respectively).

Discussion

  1. Top of page
  2. Methods
  3. Results
  4. Discussion
  5. References
  6. Supporting Information

In our experience, vancomycin nomograms did not predict appropriate dosing regimens in older children with the same accuracy reported in adults. Variability of pharmacokinetic parameters and drug clearance could explain the differences noted between drug regimens utilized and the regimens predicted by the nomograms. Renal clearance and tubular secretion reach adult values around 1 year of age, however, GFR continues to increase until prepubescent age.[5, 13] Following puberty, where adult height and muscle mass are achieved, similarities between adolescent and adult drug elimination would allow using an adult vancomycin nomogram in older teens. Whereas the pharmacokinetics of vancomycin has been described for the pediatric population, manuscripts describing vancomycin pharmacokinetic parameters in adolescents and their differences with adult parameters have not been published. A recent meta-analysis reported an increased risk of nephrotoxicity associated with vancomycin trough concentrations > 15 µg/mL (odds ratio [OR], 2.67; 95% CI, 1.95–3.65). This association was maintained even after accounting for variables known to increase the risk of nephrotoxicity. Despite the risks of renal toxicity associated with higher vancomycin trough concentrations, adult nomograms can accurately predict the most appropriate dose required to achieve these targets. Pediatric studies focusing on dosing regimens required to achieve an AUC/MIC ratio ≥400 mg/kg/L with MRSA isolates expressing an MIC ≥1 µg/mL recommend using higher vancomycin dosing regimens, 60 mg/kg/day, as stated in IDSA clinical practice guidelines.[2, 3]

The use of more aggressive vancomycin dosing regimens to achieve and maintain an AUC/MIC ratio ≥400 mg/kg/L have been found to pose an increased risk of nephrotoxicity.[12] Applying trough-nephrotoxicity logistic regression function, Patel et al reported that the use of ≥3 g of vancomycin daily is associated with unacceptable risks of renal toxicity.[12] If we extrapolate these conclusions to older children using PK/PD calculations and current clinical practice guidelines, an average healthy 40–50 kg teen, receiving 0.8–1 g every 6 hours, has a median probability of a nephrotoxic event between 5 and 7 during each vancomycin course.[2, 3, 14]

Based on the variability of pharmacokinetic parameters and drug clearance, the two vancomycin nomograms developed to predict therapeutic vancomycin trough concentrations in healthy adults did not accurately estimate dosage regimens in older children regardless of weight or age, and therefore should not be used to aid in empiric dosing. Nomogram A provided dosing recommendations that would underdose patients potentially providing inadequate treatment for serious infections, while nomogram B provided dosing recommendations which could overdose patients leading to increased nephrotoxicity. Current recommendations to use high vancomycin dosing regimens of 60 mg/kg/day are placing this patient population at significant risks of nephrotoxicity, despite the limited data on clinical outcomes associated with vancomycin MICs ≥1 mg/L and shifts toward higher MICs in children. We strongly recommend close monitoring of vancomycin trough concentrations and CrCl when using vancomycin doses above 3 g/day, and caution clinical pharmacists and clinicians to balance the need to use these higher vancomycin regimens for empiric therapy in otherwise clinically stable teens.

In our Institution's computerized provider order entry (CPOE), the starting vancomycin dosing recommended for patients <18 years of age and <60 kg is 15 mg/kg/dose every 6 hours, with the exception of oncology patients who receive 20 mg/kg/dose every 8 hours.[3] In the absence of literature providing safety and pharmacokinetic data specific for adolescents, we recommend close monitoring of renal function and vancomycin serum concentrations for patients receiving more than 3 g/day. For children ≥11 years of age, in addition to baseline creatinine and trough following the third dose, our CPOE vancomycin drug monitoring advisor recommends checking creatinine and troughs every 48 hours, or sooner for patients who develop hypotension or fluid loss. Further prospective studies are warranted for teens between 10 and 18 years of age to determine the most appropriate vancomycin dosing to maximize drug efficacy and reduce the risk of vancomycin induced-renal toxicity.

References

  1. Top of page
  2. Methods
  3. Results
  4. Discussion
  5. References
  6. Supporting Information
  • 1
    Di Pentima MC, Chan S. Impact of antimicrobial stewardship program on vancomycin use in a pediatric teaching hospital. Pediatr Infect Dis J. 2010; 29:707711.
  • 2
    Frymoyer A, Hersh AL, Benet LZ, Guglielmo BJ. Current recommended dosing of vancomycin for children with invasive methicillin-resistant Staphylococcus aureus infections is inadequate. Pediatr Infect Dis J. 2009; 28:398402.
  • 3
    Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary. Clin Infect Dis. 2011; 52:285292.
  • 4
    Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm. 2009; 66:8298.
  • 5
    Chen N, Aleksa K, Woodland C, Rieder M, Koren G. Ontogeny of drug elimination by the human kidney. Pediatr Nephrol. 2006; 21:160168.
  • 6
    Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008; 48:303332.
  • 7
    Kullar R, Leonard SN, Davis SL, et al. Validation of the effectiveness of a vancomycin nomogram in achieving target trough concentrations of 15–20 mg/L suggested by the vancomycin consensus guidelines. Pharmacotherapy. 2011; 31:441448.
  • 8
    McCluggage L, Lee K, Potter T, Dugger R, Pakyz A. Implementation and evaluation of vancomycin nomogram guidelines in a computerized prescriber-order-entry system. Am J Health Syst Pharm. 2010; 67:7075.
  • 9
    Mason W, Nelsen C, Talbot T, Wright P. Evaluation and validation of a vancomycin nomogram advisor utilized in a computerized provider order entry system. Nashville: Vanderbilt University Medical Center; 2005.
  • 10
    Schwartz GJ, Haycock GB, Edelmann CM, Jr., Spitzer A. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics. 1976; 58:259263.
  • 11
    Schwartz GJ, Gauthier B. A simple estimate of glomerular filtration rate in adolescent boys. J Pediatr. 1985; 106:522526.
  • 12
    Filler G, Foster J, Acker A, Lepage N, Akbari A, Ehrich JH. The Cockcroft–Gault formula should not be used in children. Kidney Int. 2005; 67:23212324.
  • 13
    Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology—Drug disposition, action, and therapy in infants and children. N Engl J Med. 2003; 349:11571167.
  • 14
    Patel N, Pai MP, Rodvold KA, Lomaestro B, Drusano GL, Lodise TP. Vancomycin: we can't get there from here. Clin Infect Dis. 2011; 52:969974.

Supporting Information

  1. Top of page
  2. Methods
  3. Results
  4. Discussion
  5. References
  6. Supporting Information

Additional supporting information may be found in the online version of this article at the publisher's web-site.

FilenameFormatSizeDescription
jcph173-sm-0001-SupTab-S1.doc34KSupplementary Table S1.
jcph173-sm-0002-SupTab-S2.doc35KSupplementary Table S2.
jcph173-sm-0003-SupInfo-S1.doc86KSupporting Information.

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