Vancomycin Therapeutic Monitoring: Review and Recommendations from the ASHP, IDSA and SIDP Task Force



Vancomycin is a glycopeptide antibiotic that has been in clinical use for nearly 50 years as a penicillin alternative to treat penicillinase-producing strains of Staphlococcus aureus. It is one of the most widely used antibiotics in the United States for the treatment of serious gram-positive infections involving methicillin-resistant S. aureus (MRSA).
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Summary: Based on these study results, an AUC/MIC ratio of 400 has been advocated as a target to achieve clinical effectiveness with vancomycin. Animal studies and limited human data appear to demonstrate that vancomycin is not concentration dependent and that the AUC/MIC is a predictive pharmacokinetic parameter for vancomycin.
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Summary and recommendations:Vancomycin dosages should be calculated on ABW. For obese patients, initial dosing can be based on ABW and then adjusted based on serum vancomycin concentrations to achieve therapeutic levels. Continuous infusion regimens are unlikely to substantially improve patient outcome when compared with intermittent dosing. (Level of evidence = II, grade of recommendation = A.)
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Summary and recommendation: Trough serum vancomycin concentrations are the most accurate and practical method for monitoring vancomycin effectiveness. Trough concentrations should be obtained just before the next dose at steady-state conditions. (Level of evidence = II, grade of recommendation = B.) (Note: Steady-state achievement is variable but occurs approximately after the fourth dose.)
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Summary and recommendation: Based on evidence suggesting that S. aureus exposure to trough serum vancomycin concentrations of <10 mg/L can produce strains with VISA-like characteristics, it is recommended that trough serum vancomycin concentrations always be maintained above 10 mg/L to avoid development of resistance. (Level of evidence = III, grade of recommendation = B.)
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Summary and recommendations: Based on the potential to improve penetration, increase the probability of optimal target serum vancomycin concentrations, and improve clinical outcomes for complicated infections such as bacteremia, endocarditis, osteomyelitis, meningitis, and hospital- acquired pneumonia caused by S. aureus, total trough serum vancomycin concentrations of 15–20 mg/L are recommended. Trough serum vancomycin concentrations in that range should achieve an AUC/MIC of 400 in most patients if the MIC is 1 mg/L. (Level of evidence = III, grade of recommendation = B.)

In order to achieve rapid attainment of this target concentration for seriously ill patients, a loading dose of 25–30 mg/kg (based on ABW) can be considered. (Level of evidence = III, grade of recommendation = B.)

A targeted AUC/MIC of 400 is not achievable with conventional dosing methods if the vancomycin MIC is 2 mg/L in a patient with normal renal function (i.e., CLcr of 70–100 mL/min). Therefore, alternative therapies should be considered.

Vancomycin dosages of 15–20 mg/kg (based on ABW) given every 8–12 hours are required for most patients with normal renal function to achieve the suggested serum concentrations when the MIC is 1 mg/L. It should be noted that currently available nomograms were not developed to achieve these targeted endpoints. Individual pharmacokinetic adjustments and verification of serum target achievement are recommended. When individual doses exceed 1 g (i.e., 1.5 and 2 g), the infusion period should be extended to 1.5–2 hours. (Level of evidence = III, grade of recommendation = B.)
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Summary and recommendation: There are limited data suggesting a direct causal relationship between toxicity and specific serum vancomycin concentrations. In addition, data are conflicting and characterized by the presence of confounding nephrotoxic agents, inconsistent and highly variable definitions of toxicity, and the inability to examine the time sequence of events surrounding changes in renal function secondary to vancomycin exposure.

A patient should be identified as having experienced vancomycin-induced nephrotoxicity if multiple (at least two or three consecutive) high serum creatinine concentrations (increase of 0.5 mg/dL or 50% increase from baseline, whichever is greater) are documented after several days of vancomycin therapy in the absence of an alternative explanation. (Level of evidence = II, grade of recommendation = B.)
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Summary and recommendations: Available evidence does not support monitoring peak serum vancomycin concentrations to decrease the frequency of nephrotoxicity. (Level of evidence = I, grade of recommendation = A.)

Monitoring of trough serum vancomycin concentrations to reduce nephrotoxicity is best suited to patients receiving aggressive dosing targeted to produce sustained trough drug concentrations of 15–20 mg/L or who are at high risk of toxicity, such as patients receiving concurrent nephrotoxins. (Level of evidence = III, grade of recommendation = B.)

Monitoring is also recommended for patients with unstable renal function (either deteriorating or significantly improving) and those receiving prolonged courses of therapy (over three to five days). (Level of evidence = II, grade of recommendation = B.)

All patients receiving prolonged courses of vancomycin should have at least one steady-state trough concentration obtained (approximately after the fourth dose). Frequent monitoring (more than a single trough concentration before the fourth dose) for short-course therapy (less than five days) or for lower-intensity dosing (targeted to attain trough serum vancomycin concentrations below 15 mg/L) is not recommended. (Level of evidence = II, grade of recommendation = B.)

There are limited data to support the safety of sustained trough serum vancomycin concentrations of 15–20 mg/L. When this target range is desired, obtaining once-weekly trough concentrations in hemodynamically stable patients is recommended. Frequent (in some instances daily) trough concentration monitoring is advisable to prevent toxicity in hemodynamically unstable patients. The exact frequency of monitoring is often a matter of clinical judgment. (Level of evidence = III, grade of recommendation = B.)

Data on comparative vancomycin toxicity using continuous versus intermittent administration are conflicting and no recommendation can be made.
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Summary and recommendation: Monitoring serum vancomycin levels to prevent ototoxicity is not recommended because this toxicity is rarely associated with monotherapy and does not correlate with serum vancomycin concentrations. Monitoring may be more important when other ototoxic agents, such as aminoglycosides, are administered. (Level of evidence = III, grade of recommendation = B.)

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