IDS A GUIDELINE S

Vancomycin Therapeutic Guidelines: A Summary

of Consensus Recommendations from the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society

of Infectious Diseases Pharmacists

Michael J. Rybak,1,2,3 Ben M. Lomaestro,4 John C. Rotschafer,5 Robert C. Moellering, Jr.,6,7,8 Willam A. Craig,9 Marianne Billeter,10 Joseph R. Dalovisio,11 and Donald P. Levine3

1Anti-Infective Research Laboratory, Department of Pharmacy Practice, College of Pharmacy & Health Sciences, and 2Department of Medicine, School of Medicine, Wayne State University, and 3Detroit Receiving Hospital & University Health Center, Detroit, Michigan; 4Albany Medical Center, Albany, New York; 5Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis; 6Shields Warren-Mallinckrodt Medical Research, 7Harvard Medical School, and 8Department of Medicine, Beth Israel Deaconess Medical Center,

Boston, Massachusetts; 9University of Wisconsin School of Medicine and Public Health, Madison; and 10Oshsner Medical Centers and 11Department of Infectious Diseases, Oschsner Health System, New Orleans, Louisiana

Practice guidelines for therapeutic monitoring of vancomycin treatment for Staphylococcus aureus infection in adult patients were reviewed by an expert panel of the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. A literature review of existing evidence regarding vancomycin dosing and monitoring of serum concentrations, in addition to patient outcomes combined with expert opinion regarding the drug’s pharmacokinetic, pharmacodynamic, and safety record, resulted in new recommendations for targeting and adjustment of vancomycin therapy.

EXECUTIVE SUMMARY

Adjustment and targeting of specific serum concentra- tions of vancomycin in patients have been the subject of debate for many years. The primary premise for monitoring and adjustment of serum vancomycin con- centrations is based on the perceived need to achieve serum concentrations at some multiple above the min- imum inhibitory concentration (MIC) for the offend- ing organisms and the avoidance of potential adverse effects, such as ototoxicity or nephrotoxicity. The lack

Received 9 April 2009; accepted 10 April 2009; electronically published 1 July

2009.

These guidelines were developed and issued on behalf of the Infectious Diseases Society of America.

Reprints or correspondence: Michael J. Rybak, Anti-Infective Research Laboratory, Wayne State University, 259 Mack Ave., Detroit, MI 48201 ([email protected]).

Clinical Infectious Diseases 2009; 49:325–7

© 2009 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2009/4903-0001$15.00

DOI: 10.1086/600877

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. Unfor- tunately, the controversy has resulted in variable clinical practice methods. In some cases, monitoring is infre- quent or avoided. In other cases, monitoring and dos- age adjustment is overly aggressive.

The relationship between serum concentrations and treatment success or failure in serious Staphylococcus aureus infections has recently been established. Failure rates exceeding 60% for S. aureus displaying a vanco- mycin MIC value of 4 mg/L prompted recommenda- tions in 2006 from the Clinical and Laboratory Stan- dards Institute to lower the breakpoint for susceptibil- ity from 4 to 2 mg/L and in 2008 from the US Food and Drug Administration. Recently, a number of stud- ies have established a relationship between vancomy- cin treatment failures and infections in patients with methicillin-resistant S. aureus displaying an MIC of

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2 mg/L. Vancomycin displays concentration-independent ac- tivity against S. aureus, with the area under the concentration curve (AUC) divided by the MIC as the primary predictive pharmacodynamic parameter for efficacy. On the basis of in vitro, animal, and limited human data, an AUC/MIC value of 400 has been established as the pharmacokinetic-pharmaco- dynamic target. To achieve this target, larger vancomycin doses and high trough serum concentrations are required. Although vancomycin administration is associated with some adverse ef- fects, the committee felt that the potential benefit of increased drug dosage was worth the risk of mostly reversible adverse events.

LITERATURE REVIEW, ANALYSIS, AND CONSENSUS

The expert panel reviewed the literature on pharmacokinetics, pharmacodynamics, efficacy, resistance, and toxicity of van- comycin.[1] A computerized literature search of PubMed for all relevant data published in the English language from 1958 through 2008 was conducted and forms the basis of these rec- ommendations. The quality of the studies was rated, and con- sensus recommendations were graded using the classification scheme of the Canadian Medical Association (table 1). It should be noted that the majority of the published vancomycin-mon- itoring studies were not randomized but consisted of obser- vational data. In addition, data from pediatric studies were not included; therefore, the recommendations are only for adult patients. The committee members were assigned specific topic areas and met via several teleconferences and in person to re- view the draft guidelines. The draft monitoring guidelines were circulated among committee members and were reviewed by each participating professional society for comments and re-

visions. The final guidelines were reviewed and approved by the 3 supporting organizations.

SUMMARY OF RECOMMENDATIONS

Therapeutic Vancomycin Dose Adjustment and Drug Monitoring Dosage. Initial vancomycin dosages should be calculated on the basis of actual body weight, including for obese patients. Subsequent dosage adjustments should be based on actual se- rum concentrations, to achieve targeted therapeutic concentra- tions. Continuous infusion regimens are unlikely to substantially improve patient outcome, compared with intermittent dosing. (Level of evidence, II; grade of recommendation, A.)

Peak versus trough concentrations. Trough serum van- comycin concentrations are the most accurate and practical method of monitoring the effectiveness of vancomycin. Trough serum concentrations should be obtained just before the fourth dose, at steady-state conditions. (Note that steady-state achieve- ment is variable but occurs approximately just before the fourth dose.) (Level of evidence, II; grade of recommendation, B.)

Avoidance of development of resistance. On the basis of the evidence suggesting that S. aureus exposure to trough serum concentrations of !10 mg/L can produce strains with vanco- mycin–intermediately susceptible S. aureus (VISA)–like char- acteristics, it is recommended that trough serum vancomycin concentrations always be maintained at 110 mg/L to avoid the development of resistance. (Level of evidence, III; grade of rec- ommendation, B.)

Recommended trough serum concentrations and dosage adjustments. On the basis of the potential to improve pen- etration, to increase the probability of optimal target serum concentrations, and to improve clinical outcomes of compli- cated infections, such as bacteremia, endocarditis, osteomyelitis,

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Table 1. Definition of quality of evidence and strength of recommendation.

Assessment Type of evidence

Quality of evidence

Level I Evidence from at least 1 properly designed randomized, controlled trial

Level II

Evidence from at least 1 well-designed clinical trial, with- out randomization; from cohort or case-controlled ana- lytic studies (preferably from 11 center); from multiple time series; or from dramatic results of uncontrolled experiments

Level III Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

Strength of recommendation

Grade A Good evidence to support a recommendation for use

Grade B Moderate evidence to support a recommendation for use

Grade C Poor evidence to support a recommendation

NOTE. Adapted from the Canadian Task Force on the Periodic Health Examination [2].

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meningitis, and hospital-acquired pneumonia caused by S. au- reus, trough serum vancomycin concentrations of 15–20 mg/ L are recommended. Trough serum vancomycin concentrations in that range should achieve an AUC/MIC of 1400 for most patients if the MIC is !1 mg/L. (Level of evidence, III; grade of recommendation, B.) To achieve rapid attainment of this target concentration for seriously ill patients, a loading dose of 25–30 mg/kg (based on actual body weight) can be considered. (Level of evidence, III; grade of recommendation, B.) A targeted AUC/MIC of 1400 is not achievable with conventional dosing methods if the vancomycin MIC is “2 mg/L for a patient with normal renal function (i.e., creatinine clearance, 70–100 mL/ min). Therefore, alternative therapies should be considered. Vancomycin dosages of 15–20 mg/kg (based on actual body weight) given every 8–12 h are required for most patients with normal renal function to achieve the suggested trough serum concentrations when the MIC is !1 mg/L. It should be noted that currently available nomograms were not developed to achieve these targeted end points. Individual pharmacokinetic adjustments and verification of achievement of target serum concentrations are recommended. When individual doses ex- ceed 1 g (e.g., 1.5 and 2 g), the infusion period should be extended to 1.5–2 h. (Level of evidence, III; grade of recom- mendation, B.)

Vancomycin toxicity. There are limited data suggesting a

direct causal relationship between toxicity and specific serum vancomycin concentrations. There are also conflicting data characterized by 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 considered to have vancomycin-induced nephrotox- icity if multiple (at least 2 or 3 consecutive) high serum cre- atinine concentrations (increase of 0.5 mg/dL or 150% increase from baseline, whichever is greater) are documented after sev- eral days of vancomycin therapy in the absence of an alterna- tive explanation. (Level of evidence, II; grade of recommen- dation, B.)

Monitoring of serum concentrations to reduce toxicity.

Available evidence does not support monitoring of peak serum vancomycin concentrations to decrease the frequency of ne- phrotoxicity. (Level of evidence, I; grade of recommendation, A.) Monitoring of trough serum vancomycin concentrations to reduce nephrotoxicity is best suited for patients receiving aggressive dose targeting to produce sustained trough serum concentrations of 15–20 mg/L or who are at risk of toxicity, such as patients receiving concurrent treatment with nephro- toxins. (Level of evidence, III; grade of recommendation, B.) Monitoring is also recommended for patients with unstable renal function (either deteriorating or significantly improving

function) and for patients receiving prolonged courses of ther- apy (13–5 days). (Level of evidence, II; grade of recommen- dation, B.) All patients receiving prolonged courses of vanco- mycin treatment should have at least 1 steady-state trough serum concentration measured just before the fourth dose. Fre- quent monitoring (11 measurement of trough concentration before the fourth dose) for short-course therapy (!5 days) or for lower-intensity dosing (targeted to attain trough serum van- comycin concentrations of !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, once-weekly measurements of trough concen- trations for hemodynamically stable patients is recommended. Frequent (in some instances, daily) monitoring of trough con- centrations 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 for continuous versus intermittent administration are conflict- ing, and no recommendation can be made. Monitoring of se- rum vancomycin concentrations 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 adminis- tered. (Level of evidence, III; grade of recommendation, B.)

Acknowledgments

Potential conflicts of interest. M.J.R. received research grants from Astellas, Cubist, Forest, and Pfizer; consulted for Astellas, Cubist, Forest, Ortho-McNeil, and Targanta; and has served on speakers’ bureaus for Cubist, Wyeth, Pfizer, and Targanta. J.C.R. has received research grants from Ortho-McNeil and Astra-Zeneca; has been a consultant for Ortho- McNeil, Schering, Cubist, Wyeth, Pfizer, Theravance, Optimer, and Bayer; and has served on speakers’ bureaus for Ortho-McNeil, Schering, Pfizer, Wyeth, and Cubist. R.C.M. was a former consultant for Eli Lilly. W.A.C. has received research funding from Johnson & Johnson and Astra-Zeneca and has been a consultant for Bristol-Myers Squibb and Forest Pharma- ceuticals. M.B. has received research funding from Cubist and has served on speakers’ bureaus for Sanofi-Pasteur, Pfizer, and Ortho-McNeil. J.R.D. has received a consulting fee to testify on Capitol Hill regarding the clinical impact of the methicillin-resistant S. aureus outbreak in the United States; no product-specific data were discussed. B.M.L. and D.P.L.: no conflicts.

References

1. 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; 66:82–98. Available at: http://www.ashp.org/ DocLibrary/BestPractices/BPVancoAJHP.aspx. Accessed 25 June 2009.
2. Canadian Task Force on the Periodic Health Examination. The periodic health examination. Can Med Assoc J 1979; 121:1193–254.

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