MONITORING VANCOMYCIN LEVELS IN BLOOD IN PEDIATRIC PATIENTS
I. The necessity of monitoring vancomycin levels in the blood
Vancomycin is the first-line antibiotic for treating Gram-positive bacteria resistant to betalactam, typically methicillin-resistant Staphylococcus aureus (MRSA). However, it is also an antibiotic with a narrow therapeutic range, with a high risk of nephrotoxicity and ototoxicity. In children, due to physiological changes during growth, the pharmacokinetics of vancomycin exhibit significant individual variability and differ from adults. Especially in critically ill pediatric patients, the complex progression of the disease and the active interventions performed further cause the values of pharmacokinetic parameters of vancomycin to fluctuate significantly and be difficult to predict.
Therapeutic drug monitoring (TDM) is defined as the activity of quantifying drug concentrations in the blood at specified intervals to maintain levels within a certain range, in order to optimize dosing regimens for each individual. For vancomycin, this approach has garnered significant attention in recent decades due to the following criteria:
– Clinical demand: it is the first-line choice in the treatment of MRSA
– Clear correlation between drug concentration in the blood with efficacy and toxicity
– Significant variability in blood drug concentrations when using the same dose among individuals
– Narrow therapeutic range
– Drug concentrations are easily quantifiable in routine practice using biochemical kits
– Treatment efficacy and safety are difficult to monitor and assess based on clinical signs and are easily confounded by many factors, especially in critically ill patients.
A systematic review shows that TDM of vancomycin helps improve clinical efficacy by 2.62 times and reduces the rate of nephrotoxicity by up to 75%. Evidence over the years has demonstrated the necessity and benefits of TDM for vancomycin.
II. Pharmacokinetic – Pharmacodynamic parameters predicting efficacy and safety
The antibacterial effect of vancomycin depends on both concentration and time, and the pharmacokinetic/pharmacodynamic parameter that best reflects antibacterial efficacy is the area under the curve (Area Under the Curve – AUC)/minimum inhibitory concentration (minimum inhibitory concentration – MIC). Recent studies have shown that vancomycin needs to achieve an AUC/MIC of 400 to 600 mg.h/L to demonstrate effect, with AUC levels > 700 – 800 mg.h/L increasing the risk of nephrotoxicity in patients.
Due to the difficulty in calculating AUC, studies have been conducted to identify drug concentration parameters at a specific time that correlate well with AUC values. In the first consensus guideline on TDM of vancomycin for adult patients in the United States in 2009, the Ctrough value, determined by measuring the drug concentration in the patient’s serum within 30 minutes before the next dose is administered, was selected. The guidelines were developed in collaboration with the American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), and the Society of Infectious Diseases Pharmacists (SIDP). Key recommendations include eliminating peak concentration monitoring, determining (AUC/MIC) ≥400 as a primary predictive factor; and a target trough concentration of 15 to 20 mg/L can substitute for the optimal AUC/MIC value if MIC ≤ 1 mg/L in patients with normal renal function. The guidelines also recommend vancomycin dosing and loading doses for severe infections in critically ill patients based on actual body weight. However, the 2009 guidelines still have some unclear issues due to limited data and a lack of recommendations for pediatric patients.
Subsequent studies have shown that the relationship between trough concentration and AUC depends on many factors. Therefore, the 2020 modified consensus published on an updated basis, evaluating the existing scientific data related to the use of vancomycin and monitoring drug levels in patients with severe MRSA infections (including bacteremia, infective endocarditis, pneumonia, osteomyelitis, and meningitis) recommended the use of the AUC index calculated by the Bayesian method in clinical practice, including pediatric patients.
III. Summary of Recommendations in the Updated 2020 Consensus Guidelines on Vancomycin TDM in Children
1. Based on the target AUC of 400 mg.h/L (but can be up to 600 mg.h/L, assuming a vancomycin MIC of 1 mg/L for MRSA), the recommended initial vancomycin dose for children with normal renal function and suspected severe MRSA infections (including pneumonia, pyelonephritis, osteomyelitis, complicated bacteremia, necrotizing fasciitis) is:
– 60 to 80 mg/kg/day, divided every 6 hours, for children aged 3 months to under 12 years
– 60 to 70 mg/kg/day, divided every 6 to 8 hours, for children ≥12 years (A-II).
The maximum empiric dose is usually 3600 mg/day in children with appropriate renal function (C-III). Most children typically do not require more than 3000 mg/day and should have their doses adjusted based on measured concentrations to achieve the target AUC/MIC. Early monitoring of concentrations is recommended when doses exceed 2000 to 3000 mg/day (A-III). Close monitoring of drug levels and renal function is necessary in patients with poor renal clearance or increased clearance due to potential reversible renal function abnormalities within the first 5 days of treatment.
2. Monitoring vancomycin therapy based on AUC, preferably via Bayesian methods, is recommended for children.established in all age groups, based on the changes in vancomycin clearance observed from neonates to adolescents. Both serum concentrations of vancomycin and renal function should be monitored as vancomycin clearance and creatinine clearance in children may correlate closely with each other.
3. Drug concentration monitoring may begin within 24 to 48 hours of treatment with vancomycin for severe MRSA infections in children, similar to adults (B-III). Delaying TDM should be based on the severity of the infection and clinical assessment. Dose adjustments should be made for patients with renal impairment, obesity, and children receiving concurrent nephrotoxic medications. After the initial dose, dose adjustment is crucial for those with acute renal failure, but dose adjustments should also continue (especially during the first 5 days of treatment) for patients with recovering renal function. A dose reduction may be needed later, particularly for those with chronic renal failure and those receiving concurrent nephrotoxic medications (B-III).
4. Vancomycin can be optimally maintained below an AUC threshold of 800 mg.h/L and a trough concentration threshold of 15 mg/L to minimize AKI (B-II). The safety of vancomycin doses above 80 mg/kg/day has not beenevaluation. Avoid using vancomycin doses ≥100 mg/kg/day due to the risk of exceeding safety thresholds (B-III).
5. Currently, there is insufficient data to make recommendations for loading doses in children. Loading doses from studies in adults may be considered, but further research is needed to establish appropriate doses for different pediatric groups from infants to adolescents (C-III).
6. Data suggest that obese children may have a statistically higher exposure to vancomycin compared to normal-weight children when doses are calculated per mg/kg, but these differences are not clinically significant enough to recommend different vancomycin (mg/kg) dosing in obese children at this time. Similar to non-obese children, obese children <12 years may require higher mg/kg doses than those over 12 years (B-II).
7. Treatment monitoring may be particularly significant in obese children, both in terms of treatment response and risk of nephrotoxicity. Specific recommendations for monitoring treatment in non-obese children may also apply to obese children (B-II).
8. A loading dose of 20 mg/kg based on total body weight should be used in obese children (A-III).
9. The recommended dose to achieve an AUC of 400 mg.h/L (assuming MIC is 1 mg/L) in infants and young children up to 3 months old is from 10 to 20.mg/kg every 8 to 48 hours, depending on postmenstrual age, weight, and serum creatinine concentration (A-II). Monitoring and adjusting the dose based on the target AUC (prioritizing the Bayesian estimation method) can help achieve the therapeutic target of vancomycin for successfully treating MRSA infections in all neonates, regardless of gestational age. Specific recommendations for monitoring drug levels based on AUC in children should also apply to neonates (see recommendation 2, A-III).
References:
- Rybak M. J., Le J., et al. (2020), “Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: A revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists”, Am J Health Syst Pharm, 77(11), pp. 835-863
- Micromedex online, Vancomycin, accessed at https://www.micromedexsolutions.com/micromedex2/librarian/ on 10/10/2024
- Uptodate online, vancomycin, accessed at https://www.uptodate.com/login on 10/10/2024
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