Table 2.

Primary Recommendations for Vancomycin Dosing and Therapeutic Drug Monitoring

A. Adults and pediatric patients
1. In patients with suspected or definitive serious MRSA infections, an individualized target of the AUC/MICBMD ratio of 400 to 600 (assuming a vancomycin MICBMD of 1 mg/L) should be advocated to achieve clinical efficacy while improving patient safety (A-II).
2. When transitioning to AUC/MIC monitoring, clinicians should conservatively target AUCs for patients with suspected or documented serious infections due to MRSA assuming a vancomycin MICBMD of 1 mg/L or less at most institutions. Given the importance of early, appropriate therapy, vancomycin-targeted exposure should be achieved early during the course of therapy, preferably within the first 24 to 48 hours (A-II). As such, the use of Bayesian-derived AUC monitoring may be prudent in these cases since it does not require steady-state serum vancomycin concentrations to allow for early assessment of AUC target attainment.
3. Trough-only monitoring, with a target between 15 and 20 mg/L, is no longer recommended based on efficacy and nephrotoxicity data in patients with serious infections due to MRSA (A-II). There is insufficient evidence to provide recommendations on whether trough-only or AUC-guided vancomycin monitoring should be used among patients with noninvasive MRSA or other infections.
4. Vancomycin monitoring is recommended for patients receiving vancomycin for serious MRSA infections to achieve a sustained targeted AUC (assuming a MICBMD of 1 mg/L, unless it is known to be greater or less than 1 mg/L by BMD). Independent of MRSA infection, vancomycin monitoring is also recommended for all patients at high risk of nephrotoxicity (eg, critically ill patients receiving concurrent nephrotoxins), patients with unstable (ie, deteriorating or significantly improving) renal function, and those receiving prolonged courses of therapy (more than 3 to 5 days). We suggest the frequency of monitoring be based on clinical judgment; frequent or daily monitoring may be prudent for hemodynamically unstable patients (eg, end stage renal disease) and once-weekly monitoring for hemodynamically stable patients (B-II).
5. Based on current national vancomycin susceptibility surveillance data, under most circumstances for empiric dosing, the vancomycin MIC should be assumed to be 1 mg/L. When the MICBMD is >1 mg/L, the probability of achieving an AUC/MIC ≥400 target is unlikely with conventional dosing. Higher doses may risk unnecessary toxicity, and the decision to change therapy should be based on clinical judgment. In addition, when MICBMD is <1 mg/L, we do not recommend decreasing the dose to achieve the AUC/MIC target. It is important to note the limitations in automated susceptibility testing methods, including the lack of precision and variability in MIC results depending on the method used (B-II).
6. The PK of continuous infusion suggest that such regimens may be a reasonable alternative to conventional intermittent infusion dosing when the AUC target cannot be achieved (B-II).
7. Incompatibility with vancomycin and other drugs commonly coadministered in the intensive care unit requires the use of independent lines or multiple catheters when vancomycin is being considered for continuous infusion (A-III).
B. Adults
8. Given the narrow vancomycin AUC range for therapeutic effect and minimal AKI, the most accurate and optimal way to manage vancomycin dosing should be through AUC-guided dosing and monitoring (A-II). We recommend that this be accomplished in 1 of 2 ways: a. One approach relies on the collection of 2 concentrations (obtained near steady-state, post-distributional peak concentration at 1–2 hours after infusion and trough at end of dosing interval) preferably, but not required, during the same dosing interval (if possible) and using first-order PK equations to estimate the AUC (A-II). b. The preferred approach for monitoring the AUC involves the use of Bayesian software programs embedded with a PK model that is based on richly sampled vancomycin data as the Bayesian prior, to optimize the delivery of vancomycin based on the collection of 1 or 2 vancomycin concentrations, with at least 1 trough. It is preferred that 2 PK samples be obtained (ie, 1–2 hours post-infusion and at the end of the dosing interval) to estimate the AUC with the Bayesian approach (A-II). A trough concentration alone may be sufficient to estimate the AUC with the Bayesian approach in some patients, but more data are needed across different patient populations to confirm viability of using trough-only data (B-II).
9. Doses of 15–20 mg/kg (based on actual body weight) administered every 8–12 hours as an intermittent infusion are recommended for most patients with normal renal function when assuming an MICBMD of 1 mg/L (A-II). In patients with normal renal function, these doses may not achieve a therapeutic AUC/MIC target when the MIC is 2 mg/L.
10. Continuous infusion: Based on current available data, a loading dose of 15–20 mg/kg followed by daily maintenance clearance of 30–40 mg/kg up to 60 mg/kg to achieve a target steady-state concentration of 20–25 mg/L may be considered for critically ill patients (B-II). AUC24 can be simply calculated when multiplying steady-state concentration (ie, desired therapeutic range of 20–25 mg/L throughout entire dosing interval) by a factor of 24 (B-II). Attaining the desired drug exposure may be more readily accomplished given the ease of sampling time and dosage adjustment by changing the rate of infusion, which is a highly desirable feature in critically ill patients (B-II).
11. The risk of developing nephrotoxicity with continuous infusion appears to be similar or lower compared with intermittent dosing when targeting the steady-state concentration of 15–25 mg/L and trough of 10–20 mg/L, respectively (B-II). Definitive studies are needed to compare drug exposure based on measured AUC24 and factors that predispose to development of nephrotoxicity, such as receipt of concomitant nephrotoxins, diuretics, and/or vasopressor therapy in patients receiving continuous infusion vs intermittent infusion of vancomycin.
12. In order to achieve rapid attainment of targeted concentrations in critically ill patients with suspected or documented serious MRSA infections, a loading dose of 20–35 mg/kg can be considered for intermittent administration of vancomycin (B-II). Loading doses should be based on actual body weight and should not exceed 3000 mg. More intensive and early therapeutic monitoring should also be performed in obese patients (B-II).
13. Adult obesity: A vancomycin loading dose of 20–25 mg/kg using actual body weight with a maximum of 3000 mg may be considered in obese adult patients with serious infections (B-II). Empiric maintenance doses for most obese patients usually do not exceed 4500 mg/day, depending on their renal function (B-II). Early and frequent monitoring of AUC exposure is recommended for dose adjustment, especially when empiric doses exceed 4000 mg/day (A-II).
14. Intermittent hemodialysis: Since efficacy data are unavailable for AUC <400 mg × h/L, monitoring based on pre-dialysis serum concentrations and extrapolating these values to estimate AUC is most practical. Maintaining pre-dialysis concentrations between 15 and 20 mg/L is likely to achieve the AUC of 400–600 mg × h/L in the previous 24 hours (C-III). Pre-dialysis serum concentration monitoring should be performed not less than weekly and should drive subsequent dosing rather than a strict weight-based recommendation, although these recommended doses provide a useful starting point until serum concentrations have been determined (B-II).
15. Hybrid dialysis therapies (eg, slow-low efficiency dialysis): Loading doses of 20–25 mg/kg actual body weight should be used, recognizing that these hybrid dialysis therapies efficiently remove vancomycin (B-III). Initial doses should not be delayed until the completion of dialysis treatment. Maintenance doses of 15 mg/kg should be given after hybrid hemodialysis ends or during the final 60–90 minutes of dialysis, as is done with standard hemodialysis (B-III). Concentration monitoring should guide further maintenance doses.
16. CRRT: Loading doses of 20–25 mg/kg by actual body weight should be used in patients receiving CRRT at conventional, Kidney Disease Improving Global Outcomes-recommended effluent rates of 20–25 mL/kg/h (B-II). Initial maintenance dosing for CRRT with effluent rates of 20–25 mL/kg/h should be 7.5–10 mg/kg every 12 hours (B-II). The maintenance dose and dosing interval should be based on serum concentration monitoring, which should be conducted within the first 24 hours to ensure AUC/MIC targets are met. In fluid-overloaded patients, doses may be reduced as patients become euvolemic and drug volume of distribution decreases. The use of continuous infusion vancomycin in patients receiving CRRT appears to be growing and could be used in place of intermittent vancomycin dosing, especially when high CRRT ultrafiltrate/dialysate flow rates are used (B-II).
C. Pediatric patients
17. Based on an AUC target of 400 mg × h/L (but potentially up to 600 mg × h/L assuming an MIC of ≤1 mg/L) from adult data, the initial recommended vancomycin dosage for children with normal renal function and suspected serious MRSA infections is 60–80 mg/kg/day, divided every 6–8 hour, for children aged ≥3 months (A-II).
18. The maximum empiric daily dose is usually 3600 mg/day in children with adequate renal function (C-III). Most children generally should not require more than 3000 mg/day, and doses should be adjusted based on observed concentrations to achieve the AUC/MIC target. Early monitoring of observed concentrations is recommended when doses exceed 2000–3000 mg/day (A-III). Furthermore, close monitoring of observed concentrations and renal function is prudent in patients with poor or augmented renal clearance as resolution of their renal function may occur within the first 5 days of therapy.
19. AUC-guided therapeutic monitoring for vancomycin, preferably with Bayesian estimation, is suggested for all pediatric age groups, based on developmental changes of vancomycin CL documented in the newborn to the adolescent. Based on current available data, the suggestion for AUC-guided monitoring in pediatric patients aligns with the approach for adults, including the application of Bayesian estimation with 1 trough concentration or first-order PK equations with 2 concentrations (B-II). The Bayesian AUC-guided dosing strategy may be an optimal approach to individualize vancomycin therapy in pediatric patients since it can incorporate varying ages, weights, and renal function. Both vancomycin serum concentration and renal function should be monitored since vancomycin CL and creatinine CL are not always well correlated in pediatric patients. Furthermore, aggressive dosing to maintain target AUC exposure and decrease the risk of potential AKI in treatment of MRSA infections necessitates drug monitoring.
20. Therapeutic monitoring may begin within 24–48 hours of vancomycin therapy for serious MRSA infections in children, as in adults (B-III). Any delay in therapeutic monitoring should be based on the severity of infection and clinical judgment. Dosing adjustment should be made for those with renal insufficiency, obesity, or for those receiving concurrent nephrotoxic drug therapy. Following the initial dose, dosing adjustment is important for those with acute renal insufficiency, but subsequent adjustment (particularly within the first 5 days of therapy) may be necessary for those experiencing recovery of renal function. Sustained or subsequent decreases in dosage may be needed, particularly for those with chronic renal insufficiency and those receiving concurrent nephrotoxic drug therapy (B-III).
21. Vancomycin exposure may be optimally maintained below the thresholds for AUC of 800 mg × h/L and a trough concentration of 15 mg/L to minimize AKI (B-II). The safety of vancomycin above 80 mg/kg/day has not been prospectively evaluated. Avoiding vancomycin doses ≥100 mg/kg/day is suggested since they are likely to surpass these thresholds (B-III).
22. Insufficient data exist on which to base a recommendation for a loading dose among the nonobese pediatric population. Loading doses from adult studies may be considered, but additional studies are needed to elucidate the appropriate dose for the various pediatric populations from the neonate to adolescent (C-III).
23. Pediatric obesity: Data suggest that obese children are likely to have vancomycin exposures that may be statistically greater than those of normal-weight children when doses are calculated on a milligram per kilogram basis. However, these differences are not known to be of sufficient clinical importance to suggest different milligram per kilogram empiric vancomycin dosages in obese children at this time. Similar to nonobese children, obese children aged <12 years, compared with those aged ≥12 years, may require a higher milligram per kilogram dose (B-II).
24. Pediatric obesity: Therapeutic monitoring is likely to be of particular value in obese children, both for therapeutic response and the risk of AKI. The specific recommendations for therapeutic monitoring in nonobese children may also apply for obese children (B-II). A loading dose of 20 mg/kg by total body weight is recommended in obese children (A-III).
25. Neonates: Doses recommended to achieve an AUC of 400 mg × h/L (assuming an MIC of 1 mg/L) in neonates and infants aged ≤3 months are 10–20 mg/kg every 8–48 hours, depending on post-menstrual age, weight, and serum creatinine (A-II).

Abbreviations: AKI, acute kidney injury; AUC, area under the curve; BMD, broth Micro Dilution, clearance; CL, CRRT, continuous renal replacement therapy; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; PK, pharmacokinetic.