Vancomycin dosing and serum concentration monitoring in adults
- Richard H Drew, PharmD, MS, FCCP
Richard H Drew, PharmD, MS, FCCP
- Professor, Campbell University College of Pharmacy and Health Sciences
- Associate Professor and Clinical Pharmacist, Infectious Diseases
- Duke University Medical Center
Vancomycin is a glycopeptide antibiotic used for treatment of patients with suspected or proven invasive gram-positive infections, including methicillin-resistant Staphylococcus aureus (MRSA). Appropriate dosing requires consideration of the infection site, patient weight, renal function, and pathogen susceptibility [1,2]. Therefore, careful attention to individualizing therapy and prudent use of serum concentration monitoring (when indicated) will assist in selecting the appropriate dose [3-6].
Vancomycin pharmacokinetics, pharmacodynamics, dosing, use of serum concentration monitoring, and adverse effects will be reviewed here. Vancomycin hypersensitivity is discussed separately. (See "Vancomycin hypersensitivity".)
Vancomycin undergoes limited absorption when administered orally and is therefore restricted to parenteral administration for the treatment of systemic infections. It is distributed widely to various tissues and body fluids, with a volume of distribution ranging from 0.4 to 1 L/kg . Penetration of vancomycin may vary by site and concomitant disease states. For example, limited cerebrospinal fluid penetration may be enhanced by the presence of inflamed meninges. The favorable penetration of vancomycin into skin tissues may be significantly impaired in patients with diabetes . Vancomycin penetration into lung epithelial lining fluid is limited relative to that of simultaneous serum concentration (the ratio of lung tissue to serum concentration is about 0.25) . Vancomycin's primary route of elimination is via renal excretion of unchanged drug. The rate of elimination is directly related to creatinine clearance .
In vitro and animal model studies describing vancomycin pharmacodynamics indicate the rate of killing depends primarily upon time of concentration exceeding the organism's minimum inhibitory concentration (MIC). The area under the time concentration curve (AUC; AUC:MIC ratio) is the best predictor of efficacy in these models [2,10].
Data to characterize the pharmacodynamic properties of vancomycin against methicillin-resistant S. aureus (MRSA) in humans are limited. Some studies suggest that a ratio of AUC to MIC of ≥400 may be desirable, although this AUC/MIC target may not be reliably achieved with standard dosing in many patients who have serious S. aureus infections due to isolates with MIC value >1 mcg/mL [11-14]. The target exposure is affected by the time and method used to determine the AUC and the method utilized to determine the MIC of the causative pathogen .
- Barth RH, DeVincenzo N. Use of vancomycin in high-flux hemodialysis: experience with 130 courses of therapy. Kidney Int 1996; 50:929.
- Rybak MJ, Lomaestro BM, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adults summary of consensus recommendations from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Pharmacotherapy 2009; 29:1275.
- Matzke GR, McGory RW, Halstenson CE, Keane WF. Pharmacokinetics of vancomycin in patients with various degrees of renal function. Antimicrob Agents Chemother 1984; 25:433.
- Moellering RC Jr, Krogstad DJ, Greenblatt DJ. Vancomycin therapy in patients with impaired renal function: a nomogram for dosage. Ann Intern Med 1981; 94:343.
- Lake KD, Peterson CD. A simplified dosing method for initiating vancomycin therapy. Pharmacotherapy 1985; 5:340.
- Pryka RD, Rodvold KA, Erdman SM. An updated comparison of drug dosing methods. Part IV: Vancomycin. Clin Pharmacokinet 1991; 20:463.
- Rodvold KA, Blum RA, Fischer JH, et al. Vancomycin pharmacokinetics in patients with various degrees of renal function. Antimicrob Agents Chemother 1988; 32:848.
- Skhirtladze K, Hutschala D, Fleck T, et al. Impaired target site penetration of vancomycin in diabetic patients following cardiac surgery. Antimicrob Agents Chemother 2006; 50:1372.
- Cruciani M, Gatti G, Lazzarini L, et al. Penetration of vancomycin into human lung tissue. J Antimicrob Chemother 1996; 38:865.
- Rybak MJ. The pharmacokinetic and pharmacodynamic properties of vancomycin. Clin Infect Dis 2006; 42 Suppl 1:S35.
- Moise-Broder PA, Forrest A, Birmingham MC, Schentag JJ. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet 2004; 43:925.
- Moise PA, Sakoulas G, Forrest A, Schentag JJ. Vancomycin in vitro bactericidal activity and its relationship to efficacy in clearance of methicillin-resistant Staphylococcus aureus bacteremia. Antimicrob Agents Chemother 2007; 51:2582.
- Patel N, Pai MP, Rodvold KA, et al. Vancomycin: we can't get there from here. Clin Infect Dis 2011; 52:969.
- Kullar R, Davis SL, Levine DP, Rybak MJ. Impact of vancomycin exposure on outcomes in patients with methicillin-resistant Staphylococcus aureus bacteremia: support for consensus guidelines suggested targets. Clin Infect Dis 2011; 52:975.
- Lodise TP, Drusano GL, Zasowski E, et al. Vancomycin exposure in patients with methicillin-resistant Staphylococcus aureus bloodstream infections: how much is enough? Clin Infect Dis 2014; 59:666.
- Sakoulas G, Moise-Broder PA, Schentag J, et al. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia. J Clin Microbiol 2004; 42:2398.
- Hidayat LK, Hsu DI, Quist R, et al. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med 2006; 166:2138.
- Lodise TP, Graves J, Evans A, et al. Relationship between vancomycin MIC and failure among patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin. Antimicrob Agents Chemother 2008; 52:3315.
- Sakoulas G, Gold HS, Cohen RA, et al. Effects of prolonged vancomycin administration on methicillin-resistant Staphylococcus aureus (MRSA) in a patient with recurrent bacteraemia. J Antimicrob Chemother 2006; 57:699.
- Howden BP, Ward PB, Charles PG, et al. Treatment outcomes for serious infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility. Clin Infect Dis 2004; 38:521.
- Mohr JF, Murray BE. Point: Vancomycin is not obsolete for the treatment of infection caused by methicillin-resistant Staphylococcus aureus. Clin Infect Dis 2007; 44:1536.
- Kuti JL, Kiffer CR, Mendes CM, Nicolau DP. Pharmacodynamic comparison of linezolid, teicoplanin and vancomycin against clinical isolates of Staphylococcus aureus and coagulase-negative staphylococci collected from hospitals in Brazil. Clin Microbiol Infect 2008; 14:116.
- Osawa R, Kaka AS. Maculopapular rash induced by oral vancomycin. Clin Infect Dis 2008; 47:860.
- Polk RE, Israel D, Wang J, et al. Vancomycin skin tests and prediction of "red man syndrome" in healthy volunteers. Antimicrob Agents Chemother 1993; 37:2139.
- Appel GB, Given DB, Levine LR, Cooper GL. Vancomycin and the kidney. Am J Kidney Dis 1986; 8:75.
- Bailie GR, Neal D. Vancomycin ototoxicity and nephrotoxicity. A review. Med Toxicol Adverse Drug Exp 1988; 3:376.
- Downs NJ, Neihart RE, Dolezal JM, Hodges GR. Mild nephrotoxicity associated with vancomycin use. Arch Intern Med 1989; 149:1777.
- Rybak MJ, Albrecht LM, Boike SC, Chandrasekar PH. Nephrotoxicity of vancomycin, alone and with an aminoglycoside. J Antimicrob Chemother 1990; 25:679.
- Jeffres MN, Isakow W, Doherty JA, et al. A retrospective analysis of possible renal toxicity associated with vancomycin in patients with health care-associated methicillin-resistant Staphylococcus aureus pneumonia. Clin Ther 2007; 29:1107.
- Lodise TP, Lomaestro B, Graves J, Drusano GL. Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrob Agents Chemother 2008; 52:1330.
- Lodise TP, Patel N, Lomaestro BM, et al. Relationship between initial vancomycin concentration-time profile and nephrotoxicity among hospitalized patients. Clin Infect Dis 2009; 49:507.
- Rybak MJ, Abate BJ, Kang SL, et al. Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents Chemother 1999; 43:1549.
- Burgess LD, Drew RH. Comparison of the incidence of vancomycin-induced nephrotoxicity in hospitalized patients with and without concomitant piperacillin-tazobactam. Pharmacotherapy 2014; 34:670.
- Gomes DM, Smotherman C, Birch A, et al. Comparison of acute kidney injury during treatment with vancomycin in combination with piperacillin-tazobactam or cefepime. Pharmacotherapy 2014; 34:662.
- Meaney CJ, Hynicka LM, Tsoukleris MG. Vancomycin-associated nephrotoxicity in adult medicine patients: incidence, outcomes, and risk factors. Pharmacotherapy 2014; 34:653.
- Klibanov OM, Filicko JE, DeSimone JA Jr, Tice DS. Sensorineural hearing loss associated with intrathecal vancomycin. Ann Pharmacother 2003; 37:61.
- Cohen E, Dadashev A, Drucker M, et al. Once-daily versus twice-daily intravenous administration of vancomycin for infections in hospitalized patients. J Antimicrob Chemother 2002; 49:155.
- Forouzesh A, Moise PA, Sakoulas G. Vancomycin ototoxicity: a reevaluation in an era of increasing doses. Antimicrob Agents Chemother 2009; 53:483.
- de Hoog M, van Zanten BA, Hop WC, et al. Newborn hearing screening: tobramycin and vancomycin are not risk factors for hearing loss. J Pediatr 2003; 142:41.
- Brummett RE. Ototoxicity of vancomycin and analogues. Otolaryngol Clin North Am 1993; 26:821.
- Brummett RE, Fox KE, Jacobs F, et al. Augmented gentamicin ototoxicity induced by vancomycin in guinea pigs. Arch Otolaryngol Head Neck Surg 1990; 116:61.
- Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011; 52:e18.
- Pea F, Viale P. The antimicrobial therapy puzzle: could pharmacokinetic-pharmacodynamic relationships be helpful in addressing the issue of appropriate pneumonia treatment in critically ill patients? Clin Infect Dis 2006; 42:1764.
- Cataldo MA, Tacconelli E, Grilli E, et al. Continuous versus intermittent infusion of vancomycin for the treatment of Gram-positive infections: systematic review and meta-analysis. J Antimicrob Chemother 2012; 67:17.
- Hall RG 2nd, Payne KD, Bain AM, et al. Multicenter evaluation of vancomycin dosing: emphasis on obesity. Am J Med 2008; 121:515.
- Blouin RA, Bauer LA, Miller DD, et al. Vancomycin pharmacokinetics in normal and morbidly obese subjects. Antimicrob Agents Chemother 1982; 21:575.
- Cantú TG, Yamanaka-Yuen NA, Lietman PS. Serum vancomycin concentrations: reappraisal of their clinical value. Clin Infect Dis 1994; 18:533.
- Freeman CD, Quintiliani R, Nightingale CH. Vancomycin therapeutic drug monitoring: is it necessary? Ann Pharmacother 1993; 27:594.
- 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.
- 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.
- Tsuji BT, Rybak MJ, Lau KL, Sakoulas G. Evaluation of accessory gene regulator (agr) group and function in the proclivity towards vancomycin intermediate resistance in Staphylococcus aureus. Antimicrob Agents Chemother 2007; 51:1089.
- Sakoulas G, Eliopoulos GM, Moellering RC Jr, et al. Staphylococcus aureus accessory gene regulator (agr) group II: is there a relationship to the development of intermediate-level glycopeptide resistance? J Infect Dis 2003; 187:929.
- Moellering RC Jr. Monitoring serum vancomycin levels: climbing the mountain because it is there? Clin Infect Dis 1994; 18:544.
- Vandecasteele SJ, De Bacquer D, De Vriese AS. Implementation of a dose calculator for vancomycin to achieve target trough levels of 15-20 microg/mL in persons undergoing hemodialysis. Clin Infect Dis 2011; 53:124.
- Brown M, Polisetty R, Gracely EJ, et al. Weight-based loading of vancomycin in patients on hemodialysis. Clin Infect Dis 2011; 53:164.
- Quale JM, O'Halloran JJ, DeVincenzo N, Barth RH. Removal of vancomycin by high-flux hemodialysis membranes. Antimicrob Agents Chemother 1992; 36:1424.
- Zelenitsky SA, Ariano RE, McCrae ML, Vercaigne LM. Initial vancomycin dosing protocol to achieve therapeutic serum concentrations in patients undergoing hemodialysis. Clin Infect Dis 2012; 55:527.
- Pai AB, Pai MP. Vancomycin dosing in high flux hemodialysis: a limited-sampling algorithm. Am J Health Syst Pharm 2004; 61:1812.
- ADVERSE EFFECTS
- Red man syndrome
- INITIAL DOSING
- Routine administration
- Impaired renal function
- SERUM CONCENTRATION MONITORING
- Troughs versus peaks
- Clinical approach
- - Target troughs
- - Whom to monitor
- - Timing of concentrations
- - Dose adjustments
- - Subsequent management
- SUMMARY AND RECOMMENDATIONS