Vancomycin Therapeutic Drug Monitoring
1-3Department of Pediatrics and Pediatric Infectious Diseases, Manipal Hospitals, Bengaluru, Karnataka, India
Corresponding Author: Bhaskar Shenoy, Department of Pediatrics and Pediatric infectious diseases, Manipal Hospitals, Bengaluru, Karnataka, India, Phone: +91 9845036174, e-mail: firstname.lastname@example.org
Received on: 12 December 2022; Accepted on: 14 January 2023; Published on: 15 April 2023
Introduction: Vancomycin is effective against gram-positive bacteria including staphylococcus aureus which are resistant to methicillin. Vancomycin has a narrow therapeutic range and is associated with adverse drug reactions related to iv infusion, nephrotoxicity and ototoxicity. Drug therapeutic level monitoring of this ambiguous drug is important, as a low therapeutic level will not be effective against multidrug-resistant bacteria and a higher drug level may lead to adverse drug reactions mainly renal damage. Hence therapeutic drug monitoring (TDM) of vancomycin becomes very crucial.
Objective: To discuss the TDM of vancomycin guidelines.
Discussion: This guideline includes indications of TDM, vancomycin target AUC/MIC (Area Under Curve over 24 hours/Minimum Inhibitory Concentration) ratio should be 400–600 mg/hour. In case of a MIC value of >1 mg/L, the guideline recommends changing the therapy. In critically ill patient loading dose can be considered. When conventional intermittent infusion fails to reach adequate therapeutic drug level continuous infusion of vancomycin is recommended. Children above the age of 3 months with suspected MRSA sepsis should receive vancomycin 60–80 mg/kg/day (should not increase >3600 mg/day) in three to four divided doses, considering they have normal renal function. Vancomycin dose should not increase >100 mg/kg/day which is more likely to surpass the threshold level. In the case of obese patients and patients on dialysis therapeutic monitoring and changing the dosage according to that is more important.
Conclusion: Vancomycin has a narrow therapeutic index. Low therapeutic levels can lead to treatment failure, and a higher level can lead to adverse effects. This article stresses the need for therapeutic monitoring of vancomycin, especially in children who are critically ill, who have compromised renal function, and those receiving other renal toxic drugs.
How to cite this article: Shenoy B, Joshi DN, Doddikoppad P. Vancomycin Therapeutic Drug Monitoring. Pediatr Inf Dis 2023;5(1):17-19.
Source of support: Nil
Conflict of interest: Dr Bhaskar Shenoy is associated as Journal Managing Editor of this journal and this manuscript was subjected to this journal’s standard review procedures, with this peer review handled independently of the Journal Managing Editor and his research group.
Keywords: Adverse drug effect, Therapeutic drug monitoring, Vancomycin.
Vancomycin is a glycopeptide that we have been using since the middle of the 20th century and is actually extracted from the organism Streptococcus orientalis. This is a bactericidal drug that acts by affecting bacterial cell wall synthesis by interfering in the polymerization of peptidoglycans.1,2 Vancomycin is effective against gram-positive organisms, including streptococci, enterococci, and Staphylococcus aureus, including MRSA infection as well.3 It is associated with adverse reactions like infusion-related events, nephrotoxicity, ototoxicity, neutropenia, and other adverse effects in the form of nausea, vomiting, chills, eosinophilia, and skin involvement in the form of exfoliative dermatitis, Stevens-Johnson syndrome, and vasculitis.
Vancomycin has a narrow therapeutic index.4 A higher drug level leads to significant adverse drug reactions, and a low level of the drug will not be effective against multi-drug resistance bacteria and might lead to the emergence of resistance against vancomycin as well. Because of this, TDM of vancomycin becomes very crucial.
In 2009 Infectious Disease Society of America issued the first guideline for vancomycin drug therapeutic dose monitoring.5 In this article, the need for TDM of vancomycin guidelines is discussed.
Vancomycin is a rapidly acting drug and gets eliminated from the body by glomerular filtration in the kidney. Measuring vancomycin serum level is useful in deciding the drug efficacy, clearance, and dosing regimen in an individual patient.
Vancomycin is a time-dependent antibiotic.6 For time-dependent antibiotics, optimal bactericidal effect obtains when drug concentration is maintained above the MIC. Hence time period during which AUC was more than MIC is more important than peak drug concentration (Fig. 1).7
As mentioned, the vancomycin AUC range has a narrow therapeutic effect. The AUC-guided dosing regimen is more appropriate for vancomycin monitoring. The Bayesian software program-based approach to monitoring AUC is the preferred one. This software is based on the pharmacokinetic (PK) model, which works on the bases of the huge data of vancomycin concentration as the Bayesian prior. It optimizes the vancomycin delivery based on one or two samples of vancomycin concentration. Two samples are preferred; among them, one should be collected after 1–2 hours of vancomycin infusion and the second at the end of the dosing interval. When the trough level is measured, a sample should be collected within 30 minutes before the next dose administration.
In 2013 meta-analysis done by Ye et al. found that TDM—the vancomycin cohort had very good clinical efficacy with low renal toxicity. Although the difference in duration of therapy or hospital stay was not there among this cohort.8
Tsutsuura et al. published a meta-analysis on monitoring of vancomycin in February 2021 in BMC infectious diseases journal, where they found patients with MRSA infection have reduced treatment failure significantly if vancomycin trough concentrations ≥15 μg/mL. On the other hand, trough concentrations of >20 μg/mL are associated with a higher incidence of acute renal injury as compared to trough levels of 15–20 μg/mL. They concluded that AUC-guided monitoring leads to reducing the incidence of acute kidney injury (AKI) as compared to trough-guided therapeutic monitoring; however, the difference in mortality was not statistically significant.9
In May 2022, Al-Maqbali et al. published their study in the Journal of Infection and Public Health, where they studied around 101 patients in Muscat regarding vancomycin TDM and their clinical outcomes. They found around 16.8% of the patients hadn’t achieved therapeutic levels, and 47.5% of patients had a high level of vancomycin. Those patients with low therapeutic levels of vancomycin were associated with poor outcomes. This study was concluded with the recommendation of appropriate TDM to improve the efficacy of therapy and reduce the serious toxicity of vancomycin.10 Aljefri et al., in February 2019, published their study “Vancomycin AUC and AKI: A Meta-analysis,” where they studied eight observation studies which included 2,491 patients and found that there is a decreased incidence of renal injury in patients whose first 24–48 hours AUCs were lower than 650 mg/L. Hence, they concluded that vancomycin AUC monitoring is associated with reduced incidence of vancomycin-associated AKI.11
There are very few prospective comparative data on the value of vancomycin therapeutic monitoring in the adult population for a better outcome and reduced adverse reaction. Whereas in the pediatric age group, there is virtually no prospective data at all. Apart from this, the case of neonates (particularly preterm babies) who has immature kidneys and a relatively higher vancomycin dose by body weight cause further complications in the drug dosing regimen.
In 2009 Infectious Disease Society of America came up with the first guideline for the vancomycin TDM in which some of the important issues were not discussed because of a lack of study and data. In March 2020, they released a new guideline in which important problems like drug dosing and monitoring in the pediatric age group, drug dose adjustment in morbidly obese and renal failure patients, and recommendations on continuous infusion of vancomycin therapy have been discussed. In this article, salient points and their clinical applications of the same are discussed below.
Vancomycin Drug Therapeutic Level Monitoring12
Vancomycin drug level monitoring is indicated in the following situations:
Patients with serious infection by MRSA who are critically ill.
Patients who are at high risk for renal toxicity.
Patients who have an unstable renal function.
Patients who required a longer duration of therapy (>3–5 days).
Patients with serious infection: AUC-guided vancomycin monitoring is preferable (with an AUC/MIC ratio within the range of 400–600 mg*hour/L) over trough-only monitoring (within the range of 15–20 mg/L).
AUC—guided dosing and monitoring are done either utilizing first-order PK equations or using a Bayesian software program.
In the case of Bayesian software, when the values are provided, the software only predicts a dosing regimen that has the maximum chance of reaching the optimum target of the AUC/MIC ratio.13,14
As the Bayesian AUC—guided dosing strategy incorporates variables like age, weight, and renal function, it is considered the best approach for the pediatric population.
In case of a MIC value of >1 mg/L, high doses of vancomycin will be needed to achieve a targeted AUC/MIC ratio of ≥400. These higher doses might lead to unnecessary toxicity, so it is advisable to change the therapy in this situation.
Loading dose—in the case of a critical patient with a suspected or confirmed case of MRSA infection, loading a dose of vancomycin is advisable to achieve the target concentration of the drug rapidly. The loading dose is 25–30 mg per actual body weight with a maximum limit of 3000 mg.15
Continuous infusion: Continuous infusion can increase the drug efficacy and reduce toxicity.
Loading dose of 15–20 mg/kg should be followed by maintenance of 30–40 mg/kg/day (up to 60 mg/kg/day) given as continuous infusion with a targeted serum level of 20–25 mg/L.
In intensive care unit patients, when a continuous infusion of vancomycin is required, it should be given from an independent line or from a multiple catheter line.
When compared to conventional intermittent infusion, continuous infusion is associated with the same or lower renal toxicity.16-18
How frequently monitoring is required? Depending on the clinical situation frequency of monitoring should be decided.
In the case of hemodynamically unstable patients, daily monitoring will be required.
In the case of the hemodynamically stable patient, once-a-week monitoring is enough.
Pediatric—for pediatric patients with normal kidneys, the vancomycin dose is 60–80 mg/kg/day, which is given in three to four divided doses. The maximum dose should not increase to >3600 mg/day.
Vancomycin exposure should be optimally maintained lower than the thresholds for AUC of 800 mg*hour/L. No clear data is available regarding the safety of vancomycin doses of >80 mg/kg/day. It is advisable to avoid vancomycin doses above 100 mg/kg/day.
Therapeutic monitoring can be initiated within 24–48 hours of the start of the therapy in case of serious MRSA infections in children.
Dosing adjustments require in the following situations:
Patients with renal insufficiency.
Patients who are on other nephrotoxic drugs.
When dose adjustment is required for acute renal insufficiency, and the patient has subsequent improvement in renal function, needs to do readjustment in the drug doses regimen according to the improvement in renal functions.
In the case of obese patients and patients on dialysis, therapeutic monitoring and changing the dosage according to that is more important.
Neonates—10–20 mg/kg dose is recommended for every 8–48 hours to achieve a target AUC of 400 mg*hour/L.
Frequency depends on the newborn’s weight, gestation age, and renal function.
Vancomycin has a very narrow therapeutic index. Low therapeutic levels can lead to treatment failure, and a higher level can lead to adverse effects. This article stresses the need for therapeutic monitoring of vancomycin, especially in children who are critically ill, who have compromised renal function, and those receiving other renal toxic drugs. For the successful treatment of MRSA infection and to achieve a targeted vancomycin level, Bayesian estimated AUC-guided therapeutic dosing and monitoring is the best approach. It will also help in reducing vancomycin-associated renal impairment in critically ill patients.
1. Gardete S, Tomasz A. Mechanisms of vancomycin resistance in Staphylococcus aureus. J Clin Invest 2014;124(7):2836–2840. DOI: 10.1172/JCI68834
2. Carreno JJ, Kenney RM, Lomaestro B. Vancomycin-associated renal dysfunction: where are we now? Pharmacotherapy 2014;34(12):1259–1268. DOI: 10.1002/phar.1488
3. “Goodman and Gilman’s THE PHARMACOLOGICAL BASIS OF THERAPEUTICS”. THIRTEENTH EDITION, Brunton Laurence L., et al. Volume 1. p. 1059.
4. Duffull SB, Begg EJ. Vancomycin toxicity: what is the evidence for dose dependency? Adverse Drug React Toxicol Rev 1994;13(2):103–114. PMID: 7918897.
5. 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(1):82–98. DOI: 10.2146/ajhp080434
6. Kishk OA, Lardieri AB, Heil EL, et al. Vancomycin AUC/MIC and corresponding troughs in a pediatric population. J Pediatr Pharmacol Ther 2017;22(1):41–47. DOI: 10.5863/1551-6776-22.1.41
7. Eyler RF, Shvets K. Clinical pharmacology of antibiotics. Clin J Am Soc Nephrol 2019;14(7):1080–1090. DOI: 10.2215/CJN.08140718
8. Ye ZK, Tang HL, Zhai SD. Benefits of therapeutic drug monitoring of vancomycin: a systematic review and meta-analysis. PloS One 2013;8(10):e77169. DOI: 10.1371/journal.pone.0077169
9. Tsutsuura M, Moriyama H, Kojima N, et al. The monitoring of vancomycin: a systematic review and meta-analyses of area under the concentration-time curve-guided dosing and trough-guided dosing. BMC Infect Dis 2021;21(1):153. DOI: 10.1186/s12879-021-05858-6
10. Al-Maqbali JS, Shukri ZA, Sabahi NA, et al. Vancomycin therapeutic drug monitoring (TDM) and its association with clinical outcomes: a retrospective cohort. JInfect Public Health 2022;15(5):589–593. DOI: 10.1016/j.jiph.2022.04.007
11. Aljefri DM, Avedissian SN, Rhodes NJ, et al. Vancomycin area under the curve and acute kidney injury: a meta-analysis. Clin Infect Dis 2019;69(11):1881–1887. DOI: 10.1093/cid/ciz051
12. Rybak MJ, Le J, Lodise TP, et al. 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 2020;77(11):835–864. DOI: 10.1093/ajhp/zxaa036
13. Matsumoto K, Oda K, Shoji K, et al. Clinical practice guidelines for therapeutic drug monitoring of vancomycin in the framework of model-informed precision dosing: a consensus review by the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring. Pharmaceutics 2022;14(3):489. DOI: 10.3390/pharmaceutics14030489
14. Elyasi S, Khalili H, Dashti-Khavidaki S, et al. Vancomycin-induced nephrotoxicity: mechanism, incidence, risk factors and special populations. A literature review. Eur J Clin Pharmacol 2012;68(9):1243–1255. DOI: 10.1007/s00228-012-1259-9
15. Crass RL, Dunn R, Hong J, et al. Dosing vancomycin in the super obese: less is more. J Antimicrob Chemother 2018;73(11):3081–3086. DOI: 10.1093/jac/dky310
16. Schmelzer TM, Christmas AB, Norton HJ, et al. Vancomycin intermittent dosing versus continuous infusion for treatment of ventilator-associated pneumonia in trauma patients. Am Surg 2013;79(11):1185–1190. DOI: 10.1177/000313481307901123
17. Tafelski S, Nachtigall I, Troeger U, et al. Observational clinical study on the effects of different dosing regimens on vancomycin target levels in critically ill patients: continuous versus intermittent application. J Infect Public Health 2015;8(4):355–363. DOI: 10.1016/j.jiph.2015.01.011
18. Hutschala D, Kinstner C, Skhirdladze K, et al. Influence of vancomycin on renal function in critically ill patients after cardiac surgery: continuous versus intermittent infusion. Anesthesiology 2009;111(2):356–365. DOI: 10.1097/ALN.0b013e3181a97272
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