Vancomycin, a glycopeptide antibiotic, has been the mainstay antibiotic treatment for infections caused by gram-positive organisms, particularly for methicillin-resistant Staphylococcus aureus (MRSA) for nearly 60 years. Extensive pharmacokinetic (PK) and pharmacodynamic (PD) studies have been conducted in various patient populations to determine the optimal dosing of vancomycin.
The pharmacodynamic model best describes the predictor of successful treatment of MRSA as achieving an area under the curve (AUC24) over minimum inhibitory concentration (MIC) > to 4001,5. Currently vancomycin trough serum concentrations have been accepted as the most accurate and practical method for monitoring vancomycin therapy effectiveness. The 2009 guideline by Rybak et al.7 recommends achieving a total vancomycin serum trough concentration in the range of 15-20 mg/L and this trough would mostly achieve an AUC24/MIC > 400 in patients with complicated infections (e.g.. bacteremia, endocarditis, osteomyelitis, meningitis, and hospital acquired pneumonia caused by MRSA).
There has been chatter in the professional infectious disease community that an updated vancomycin guideline is in the making. What can we expect from this updated guideline? One of the age-old controversies related to vancomycin is whether the current recommended trough serum concentration target is a good predictor of clinical outcomes? In other words, is it necessary to aim for a trough of 15-20mg/L?
While the use of trough-only therapeutic monitoring for vancomycin has been integrated and widely accepted in clinical practice, recent studies have demonstrated that patients with adequate renal function can achieve AUC24/MIC > 400 with lower trough concentration.
- In a PK/PD stimulation study conducted by Neely et al.,6 vancomycin samples were collected from 47 adults with various levels of renal function (the median creatinine clearance was 56.8-78.0 mL/min). The trough-only and peak-trough monitoring underestimated the true AUCs by a mean of 23% (p=0.0001) and 14% (p<0.0001), respectively. In this simulation, for organisms with a vancomycin MIC of 1mg/L, approximately 60% of subject would be expected to have a trough concentration below the suggested minimum target of 15mg/L.
- In a single-centered retrospective cohort study conducted by Wong et al., similar study findings were observed. Investigators examined 131 critically-ill subjects with adequate renal function who were receiving intravenous vancomycin. Using a predicted vancomycin AUC24 equation5, investigators were able to determine whether subjects had achieved optimal AUC24/MIC > 400 during the course of therapy. Results showed that 87.5% of patients with serum trough of 10 - < 15mg/L achieved the optimal AUC24/MIC, versus 84.5% of patients with serum trough of 15-20mg/L (p=0.669). This study demonstrates that targeting a trough of 10 – 15 mg/L has approximately equal chance of achieving AUC24≥ 400 as compared to targeting trough of 15 – 20 mg/L.
- While a prospective randomized controlled trial is lacking in the literature, Prybylski et al.9 conducted a meta-analysis on 14 observational studies evaluating the strength of evidence for the use of vancomycin serum trough concentration as a predictor of clinical outcomes in patients with MRSA bacteremia. Whereas higher vancomycin trough levels of ≥ 15mg/L were not associated with significant reduction in treatment failure or mortality, higher AUC24/MIC values were associated with reduced treatment failure (OR 0.41; 95% CI 0.31-0.53) and mortality (OR 0.47, 95% CI 0.33-0.65). These authors concluded that the current recommended literature does not support the use of serum trough monitoring as a primary predictor for clinical outcomes.
It is likely that the updated vancomycin guideline will have new recommendations on the serum trough concentration target or support the use of AUC24/MIC values for the monitoring of vancomycin therapy.
- Holmes NE, Turnidge JD, Munckhof WJ, et al. Vancomycin AUC/MIC ratio and 30-day mortality in patienst with Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 2013;57(4):1654-1663.
- Kalil AC, Van Schooneveld TC, Fey PD, et al. Association between vancomycin minimum inhibitory concentration and mortality among pateinst with Staphylococcus aureus bloodstream infections: A systemic review and meta-analysis. JAMA. 2014; 312(15):1552-1564.
- Lodise TP, Lomaestro B, Graves J et al. Larger vancomycin doses (≥4 grams/day) are associated with an increased incidence of nephrotoxicity. Antimicrob Agents Chemother. 2008; 52:1330-6.
- Lomaestro BM. Vancomycin Dosing and Monitoring 2 years after the guidelines. Expert Rev Anti Infect Ther. 211;9(6):657-667.
- Moise-Broder PA, Forrest A, Birmingham MC, et al. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet. 2004;43(13):925-42.
- Neely MN, Youn G, Jones B, et al. Are vancomycin trough concentrations adequate for optimal dosing? Antimicrob Agents Chemother 2014;58(1):309–16.
- Pai MP, Neely M, Rodvold KA, Lodise TP. Innovative approaches to optimizing the delivery of vancomycin in individual patients. Adv Drug Deliv Rev 2014;77:50–7.
- Patel N, Pai MP, Rodvold KA, Lomaestro B, et al. Vancomycin: we can’t get there from here. Clin Infect Dis 2011;52(8):969–74.
- Prybylski JP. Vancomycin trough concentration as a predictor of clinical outcomes in patients with Staphylococcus aureus bacteremia: a meta-analysis of observation studies. Pharmacotherapy. 2015;35(10): 889-898.
- 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.
- Steinmetz T, Eliakim-Raz N, Goldberg E, et al. Association of vancomycin serum concentrations with efficacy in patients with MRSA infections: a systematic review and meta-analysis. Clin Micro and Infect. 2015 Jul.; 21(7):665-673
- van Hal SJ, Paterson DL, Lodise TP. Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. Antimicrob Agents Chemother. 2013 Feb;57(2):734-744.
- Wong Y, Lin H, Lopez N. Evaluation of vancomycin therapeutic drug monitoring: dosing practices, trough concentrations and predicted area under the curve. Poster presented at: 54th Interscience Conference on Antimicrobial Agents & Chemotherapy; Sep. 7, 2014; Washington, DC and 33rd Eastern States Annual Conference; May 5, 2014; Hershey, PA.