vancomycin treatment

Guidelines Issued for Monitoring of Vancomycin Treatment of S aureus Infection

Laurie Barclay, MD

Authors and Disclosures

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July 23, 2009 — The Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists have issued therapeutic guidelines for monitoring of vancomycin treatment for Staphylococcus aureus infection. The summary of consensus recommendations is published in the August 1 issue of Clinical Infectious Disease.
"Adjustment and targeting of specific serum concentrations of vancomycin in patients have been the subject of debate for many years," write Michael J. Rybak, PharmD, from the College of Pharmacy and Health Sciences, School of Medicine, Wayne State University, Detroit, Michigan, and colleagues.
"The primary premise for monitoring and adjustment of serum vancomycin concentrations is based on the perceived need to achieve serum concentrations at some multiple above the minimum inhibitory concentration (MIC) for the offending organisms and the avoidance of potential adverse effects, such as ototoxicity or nephrotoxicity. The lack of well-designed randomized clinical evaluations or data to support a clear relationship between specific serum concentrations and patient outcome has been the overriding contributor to this controversy."
A panel of experts from the authoring societies reviewed practice guidelines for therapeutic monitoring of vancomycin treatment for S aureus infection in adults and performed a literature search of existing evidence concerning vancomycin dosing and monitoring of serum concentrations and their relationship to patient outcomes. This review, as well as expert consensus opinion regarding the pharmacokinetic, pharmacodynamic, and safety record for vancomycin, led to new recommendations for targeting and adjustment of treatment.
Recommendations for Treatment
Specific clinical recommendations, and their accompanying level of evidence rating, are as follows:

• Even for obese patients, initial vancomycin dosages should be calculated based on actual body weight. To achieve targeted therapeutic concentrations, further dosage adjustments should be based on actual serum concentrations. Compared with intermittent dosing, continuous infusion is not likely to significantly improve patient outcome (level of evidence, 2; grade of recommendation, A).
• The most accurate and practical way to monitor vancomycin effectiveness is by using trough serum vancomycin concentrations, which should be measured just before the fourth dose, at steady-state conditions (level of evidence, 2; grade of recommendation, B).
• To avoid the development of resistance, trough serum vancomycin concentrations should always be maintained at greater than 10 mg/L, based on evidence suggesting that exposure of S aureus to trough serum concentrations of less than 10 mg/L can produce strains with vancomycin–intermediately susceptible S aureus–like characteristics (level of evidence, 3; grade of recommendation, B).
• Trough serum vancomycin concentrations of 15 to 20 mg/L are recommended because of the potential of these concentrations to improve penetration, to increase the likelihood of optimal target serum concentrations, and to improve clinical outcomes of complicated infections caused by S aureus, such as bacteremia, endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia. If the MIC is less than 1 mg/L, trough serum vancomycin concentrations of 15 to 20 mg/L should achieve an area under the curve/MIC of 1400 for most patients (level of evidence, 3; grade of recommendation, B). For seriously ill patients, a loading dose of 25 to 30 mg/kg (based on actual body weight) can be considered to rapidly reach this target concentration (level of evidence, 3; grade of recommendation, B).
• For patients with normal renal function, defined as creatinine clearance 70 to 100 mL/minute, a targeted area under the curve/MIC of more than 400 is not achievable with conventional dosing methods if the vancomycin MIC is 2 mg/L or higher, and alternative treatments should therefore be considered. To achieve the recommended trough serum concentrations when the MIC is less than 1 mg/L, most patients with normal renal function should receive vancomycin dosages of 15 to 20 mg/kg (based on actual body weight) given every 8 to 12 hours. The guidelines authors note that because currently available nomograms were not developed to achieve these targeted end points, individual pharmacokinetic adjustments and confirmation that target serum concentrations have been reached are recommended. The infusion period should be increased to 1.5 to 2 hours when individual doses greater than 1 g (eg, 1.5 and 2 g) are used (level of evidence, 3; grade of recommendation, B).
• Evidence to date for a direct causal relationship between toxicity and specific serum vancomycin concentrations is limited, and data are inconclusive because of confounding nephrotoxic agents, inconsistent and highly variable definitions of toxicity, and difficulty in assessing the time sequence of events regarding changes in renal function secondary to vancomycin exposure. In the absence of an alternative explanation, a patient should be considered to have vancomycin-induced nephrotoxicity if there are multiple (at least 2 or 3 consecutive) high serum creatinine concentrations (increase of 0.5 mg/dL or 150% increase from baseline, whichever is greater) after several days of vancomycin therapy (level of evidence, 2; grade of recommendation, B).
• Evidence to date does not suggest that monitoring of peak serum vancomycin concentrations will reduce the incidence of nephrotoxicity (level of evidence, 1; grade of recommendation, A). In patients receiving aggressive dose targeting to achieve sustained trough serum concentrations of 15 to 20 mg/L, or those at risk for toxicity (eg, because of concurrent treatment with nephrotoxins), monitoring of trough serum vancomycin concentrations to decrease nephrotoxicity is most appropriate (level of evidence, 3; grade of recommendation, B).
• In addition, patients with unstable renal function and those being treated for more than 3 to 5 days should also undergo monitoring (level of evidence, 2; grade of recommendation, B). All patients treated with vancomycin for 5 days or more should have at least 1 steady-state trough serum concentration measured just before the fourth dose. Frequent monitoring with more than 1 measurement of trough concentration before the fourth dose is not recommended for treatment lasting less than 5 days or for lower-intensity dosing targeted to achieve trough serum vancomycin concentrations of less than 15 mg/L (level of evidence, 2; grade of recommendation, B).
• Because evidence is limited to support the safety of sustained trough serum vancomycin concentrations of 15 to 20 mg/L, once-weekly measurements of trough concentrations are recommended for hemodynamically stable patients in whom this target range is desired. To prevent toxicity in hemodynamically unstable patients, frequent or even daily monitoring of trough concentrations is recommended, although clinical judgment should guide the exact frequency of monitoring (level of evidence, 3; grade of recommendation, B).
• Because of conflicting evidence regarding comparative vancomycin toxicity for continuous vs intermittent administration, no recommendation can be made. The guidelines do not recommend monitoring serum vancomycin concentrations to prevent ototoxicity, because monotherapy seldom results in ototoxicity and there is no apparent correlation with serum vancomycin concentrations. However, monitoring may be more important during coadministration of aminoglycosides or other ototoxic agents (level of evidence, 3; grade of recommendation, B).

"On the basis of in vitro, animal, and limited human data, an [area under the curve]/MIC value of 400 has been established as the pharmacokinetic-pharmacodynamic target," the guidelines authors conclude. "To achieve this target, larger vancomycin doses and high trough serum concentrations are required. Although vancomycin administration is associated with some adverse effects, the committee felt that the potential benefit of increased drug dosage was worth the risk of mostly reversible adverse events."
Some of the guidelines authors have disclosed financial relationships with Astellas, Cubist, Forest, Pfizer, Ortho-McNeil, Targanta, Astra-Zeneca, Schering, Wyeth, Theravance, Optimer, Bayer, Eli Lilly, Johnson & Johnson, Bristol-Myers Squibb, and/or Sanofi-Pasteur.