Monitoring vancomycin for serious MRSA infections: Revised consensus guideline

These are the consensus statements and guideline of ASHP, IDSA, the Pediatric Infectious Diseases Society (PIDS), and SIDP. Guideline panel composition consisted of physicians, pharmacists, and a clinical pharmacologist with expertise in clinical practice and/or research with vancomycin. Committee members were assigned key topics regarding vancomycin dosing and monitoring. A draft document addressing these specific areas was reviewed by all committee members and made available for public comments for 30 days through ASHP, IDSA, PIDS, and SIDP. The committee then met to review and revise the document based on the submitted comments, suggestions, and recommendations. After careful discussion and consideration, the document was revised and circulated among the committee and supporting organizations prior to final approval and publication. A search of PubMed and Embase was conducted using the following search terms: vancomycin, pharmacokinetics, pharmacodynamics, efficacy, resistance, toxicity, obesity, and pediatrics. All relevant and available peer-reviewed studies in the English-language literature published from 1958 through 2019 were considered. Studies were rated by their quality of evidence, and the subsequent recommendations were graded using the classification schemata described in Table 1.

Following are the major recommendations:

• In patients with suspected or definitive serious MRSA infections, an individualized target of the AUC/MICBMDratio of 400 to 600 (assuming a vancomycin MICBMDof 1 mg/L) should be advocated to achieve clinical efficacy while improving patient safety(A-II). Doses of 15 to 20 mg/kg (based on actual body weight) administered every 8 to 12 hours as an intermittent infusion are recommended for most patients with normal renal function when assuming a MICBMDof 1 mg/L(A-II).In patients with normal renal function, these doses may not achieve the therapeutic AUC/MIC target when the MIC is 2 mg/L.
• Given the narrow vancomycin AUC range for therapeutic effect and minimal AKI risk, the most accurate and optimal way to manage vancomycin dosing should be through AUC-guided dosing and monitoring(A-II). We recommend to accomplish this in one of two ways.

• One approach relies on the collection of 2 concentrations (obtained near steady-state, postdistributional peak concentration [Cmax] at 1 to 2 hours after infusion and trough concentration [Cmin] at the end of the dosing interval), preferably but not required during the same dosing interval (if possible) and utilizing first-order PK equations to estimate the AUC(A-II).
• The preferred approach to monitor AUC involves the use of Bayesian software programs, embedded with a PK model 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 to obtain 2 PK samples (ie, at 1 to 2 hours post infusion and at 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 the viability of using trough-only data(B-II).
• When transitioning to AUC/MIC monitoring, clinicians should conservatively target AUC values for patients with suspected or documented serious infections due to MRSA assuming a vancomycin MICBMDof 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.

• Trough-only monitoring, with a target of 15 to 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.

• Vancomycin monitoring is recommended for patients receiving vancomycin for serious MRSA infections to achieve sustained targeted AUC values (assuming a MICBMDof 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 for 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, those with end-stage renal disease), with once-weekly monitoring for hemodynamically stable patients(B-II).

Vancomycin Susceptibility Testing

Based on current national vancomycin susceptibility surveillance data, under most circumstances of empiric dosing, the vancomycin MIC should be assumed to be 1 mg/L. When the MICBMDis >1 mg/L, the probability of achieving an AUC/MIC target of   ≥400 is low with conventional dosing; higher doses may risk unnecessary toxicity, and the decision to change therapy should be based on clinical judgment. In addition, when the MICBMDis <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 method used(B-II).

Continuous Infusion vs Intermittent Infusion

• The pharmacokinetics of CI suggest that such regimens may be a reasonable alternative to conventional II dosing when the AUC target cannot be achieved(B-II). Based on currently available data, a loading dose of 15 to 20 mg/kg, followed by daily maintenance CI of 30 to 40 mg/kg (up to 60 mg/kg) to achieve a target steady-state concentration of 20 to 25 mg/L may be considered for critically ill patients(B-II). AUC24can be simply calculated by multiplying the steady-state concentration (ie, the desired therapeutic range of 20 to 25 mg/L throughout the entire dosing interval) by a factor of 24. 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).
• The risk of developing nephrotoxicity with CI appears to be similar or lower than that with intermittent dosing when targeting a steady-state concentration of 15 to 25 mg/L and a trough concentration of 10 to 20 mg/L(B-II). Definitive studies are needed to compare drug exposure based on measured AUC24and factors that predispose to development of nephrotoxicity, such as receipt of concomitant nephrotoxins, diuretics, and/or vasopressor therapy in patients receiving CI vs II of vancomycin.
• Incompatibility of vancomycin with other drugs commonly coadministered in the ICU requires the use of independent lines or multiple catheters when vancomycin is being considered for CI(A-III).
  

Loading Doses

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 to 35 mg/kg can be considered for intermittent-infusion administration of vancomycin(B-II).1

Loading doses should be based on actual body weight and not exceed 3,000 mg (refer to Dosing in Obesity section). More intensive and early therapeutic monitoring should also be performed in obese patients(B-II).

Dosing in Obesity

A vancomycin loading dose of 20 to 25 mg/kg using actual body weight, with a maximum dose of 3,000 mg, may be considered in obese adult patients with serious infections(B-II). Initial maintenance doses of vancomycin can be computed using a population PK estimate of vancomycin clearance and the target AUC in obese patients. Empiric maintenance doses for most obese patients usually do not exceed 4,500 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 4,000 mg/day(A-II). Measurement of peak and trough concentrations is recommended to improve the accuracy of vancomycin AUC estimation and maintenance dose optimization in obese patients, aligning with recommendations 2 and 5 for nonobese adults.

Renal Disease and Renal Replacement Therapies

Intermittent  hemodialysis.

The following tabulation outlines recommended vancomycin loading and maintenance doses for patients receiving hemodialysis, with accounting for permeability of the dialyzer and whether the dose is administered intradialytically or after dialysis ends(B-II).

Since efficacy data are unavailable for AUC values of <400 mg·h/L, monitoring based on predialysis serum concentrations and extrapolating these values to estimate AUC is most practical. Maintaining predialysis concentrations between 15 and 20 mg/L is likely to achieve the AUC of 400 to 600 mg·h/L in the previous 24 hours(C-III). Predialysis serum concentration monitoring should be performed not less than weekly and should drive subsequent dosing, as opposed to a strict weight-based recommendation, although these recommended doses provide a useful starting point until serum concentrations have been determined(B-II).

Hybrid hemodialysis therapies.

Loading doses of 20 to 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 to wait for a dialysis treatment to end. Maintenance doses of 15 mg/kg should be given after hybrid hemodialysis ends or during the final 60 to 90 minutes of dialysis, as is done with standard hemodialysis(B-III).130 Concentration monitoring should guide further maintenance doses.

Continuous renal replacement therapies.

Loading doses of 20 to 25 mg/kg by actual body weight should be used in patients receiving CRRT at conventional, KDIGO-recommended effluent rates of 20 to 25 mL/kg/h(B-II).153 Initial maintenance dosing for CRRT with effluent rates of 20 to 25 mL/kg/h should be 7.5 to 10 mg/kg every 12 hours(B-II). 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.154 In fluid overloaded patients, doses may be reduced as patients become euvolemic and drug Vddecreases. The use of CI of vancomycin in patients receiving CRRT appears to begrowing,84 ,105 and this method could be used in place of intermittent vancomycin dosing, especially when high CRRT ultrafiltrate/dialysate flow rates are employed(B-II).

Pediatric Patients

• Based on an AUC target of 400 mg·h/L (but potentially up to 600 mg·hr/L, assuming a vancomycin MIC of ≤1 mg/L for MRSA) from adult data, the initial recommended vancomycin dosage for children with normal renal function and suspected serious MRSA infections (including pneumonia, pyomyositis, multifocal osteomyelitis, complicated bacteremia, and necrotizing fasciitis) is:

• 60 to 80 mg/kg/day, in divided doses given every 6 hours, for children ages 3 months to less than 12 years or
• 60 to 70 mg/kg/day, in divided doses given every 6 to 8 hours, for those ≥12 years old(A-II).

The maximum empiric daily dose is usually 3,600 mg in children with adequate renal function(C-III). Most children generally should not require more than 3,000 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 2,000 to 3,000 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 abnormalities may occur within the first 5 days of therapy.

• 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 from the newborn to the adolescent. Based on current available data, the suggestion for AUC-guided monitoring in pediatrics aligns with the approach for adults, including the application of Bayesian estimation for 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 pediatrics since it can incorporate varying ages, weights, and renal function. Both serum concentrations of vancomycin and renal function should be monitored since vancomycin CL and CLcrare not always well correlated in pediatrics. Furthermore, aggressive dosing to maintain target AUC exposure and decrease the risk of potential AKI in treatment of MRSA infection necessitates drug monitoring.
• Therapeutic monitoring may begin within 24 to 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 severity of infection and clinical judgment. Dosing adjustment should be made for those with renal insufficiency, those with obesity (see Pediatric Obesity), and 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).
• Vancomycin exposure may be optimally maintained below the thresholds for AUC of 800 mg·h/L and for trough concentrations of 15 mg/L to minimize AKI(B-II). The safety of vancomycin dosages above 80 mg/kg/day has not been prospectively evaluated. Avoiding vancomycin dosages of ≥100 mg/kg/day is suggested since they are likely to surpass these thresholds(B-III).
• 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 further studies are needed to elucidate the appropriate dose for the various pediatric populations from the neonate to adolescent(C-III).

Pediatric obesity

• Data suggest that obese children are likely to have vancomycin exposures that may be statistically greater than those in normal-weight children when doses are calculated on a mg/kg basis, but these differences are not known to be of sufficient clinical importance to suggest different mg/kg empiric vancomycin dosages in obese children at this time. Similar to nonobese children, obese children < 12 years old, compared with those ≥ 12 years, may require a higher mg/kg dose(B-II).
• 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).

Neonates

• Doses recommended to achieve an AUC of 400 mg·h/L (assuming a MIC of 1 mg/L) in neonates and infants up to 3 months old range from 10 to 20 mg/kg every 8 to 48 hours, depending on postmenstrual age, weight, and SCr(A-II). AUC-guided therapeutic dosing and monitoring, preferably with Bayesian estimation, can best achieve the target vancomycin exposure likely to be required for a successful outcome of treatment for a MRSA infection for all neonates, regardless of gestational and chronologic age. The specific recommendations for AUC-guided therapeutic monitoring in children should also apply for neonates (see recommendation 18,A-III).