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PHARMACOLOGY NOTES Recommendations for monitoring serum vancomycin concentrations CHRISTOPHER W. JAMES, PHARMD, AND CHERYLE GURK-TURNER, RPH V ancomycin is a glycopeptide antibiotic that has been used for the treatment of infections due to gram-positive microorganisms since 1956 (1). Shortly thereafter, Geraci et al described 2 cases of irreversible ototoxicity secondary to vancomycin therapy, with serum concentrations ranging from 80 to 100 mg/L (2). Based on this, the authors recommended therapeutic drug monitoring of vancomycin to reduce the risk of ototoxicity. The practice of routine therapeutic drug monitoring originated when the guidelines for monitoring peak and trough concentrations of aminoglycosides were applied to vancomycin therapy, based on similarities in pharmacokinetic and toxicity profiles (e.g., nephrotoxicity and ototoxicity) (3–5). However, the pharmacodynamics of vancomycin, which exhibits concentration-independent activity, are quite different from those of the aminoglycosides, which display concentration-dependent killing (5, 6). It is interesting to note that the manufacturer makes no recommendations regarding therapeutic drug monitoring (7). Therefore, the need for therapeutic drug monitoring in patients receiving vancomycin is controversial. This article examines the available evidence on the efficacy and toxicity of different concentrations of vancomycin and presents guidelines for therapeutic drug monitoring in patients receiving vancomycin therapy. EFFICACY Since vancomycin exhibits time-dependent killing of susceptible bacteria, the concentration of the drug must be maintained above the minimum inhibitory concentration (MIC) for the majority of the dosing interval (4). Researchers recommend keeping the peak value 5 to 8 times the MIC and the trough value 1 to 2 times the MIC (MIC for most bacteria is <5 µg/mL) (6, 8). Vancomycin regimens that are based on empiric pharmacokinetics (using a patient’s age, weight, and renal function) or adjusted based on serum levels have been shown to be equally effective in treating gram-positive infections (9). Zimmerman et al studied 273 patients receiving vancomycin and found that patients whose trough concentrations were ≥10 mg/L were more likely to become afebrile and have a normal white blood cell count within 72 hours (10). TOXICITY Serum drug monitoring of vancomycin therapy has traditionally been recommended to avoid the nephrotoxicity and ototoxicity documented in case reports (11). Confounding factors in these case reports include preexisting renal impairment and conBUMC PROCEEDINGS 2001;14:189–190 comitant therapy with other nephrotoxic or ototoxic agents, including aminoglycosides, amphotericin, and furosemide (12). Also complicating these early reports regarding nephrotoxicity and ototoxicity were the impurities contained in the older preparations of vancomycin, once referred to as “Mississippi mud.” These impurities may have been responsible for the toxicity (12, 13). The manufacturing process improved in the mid 1970s, resulting in fewer impurities and a decreased incidence of ototoxicity and infusion-related reactions (1). Ototoxicity secondary to vancomycin is manifested by vestibular damage and/or cochlear damage, which leads to sensory hearing loss and tinnitus (1). In 13 reports of vancomycin therapy leading to reversible ototoxicity, no confounding factors (concomitant medications or disease states) were present (9). Vancomycin concentrations in these patients ranged from 17 to 62 mg/L, with the vast majority occurring in the accepted therapeutic range (9). Reversible ototoxicity is generally associated with concentrations >40 mg/L. Irreversible damage is a rare complication of vancomycin therapy and is usually encountered in patients with concentrations >80 mg/L and preexisting renal impairment (14). The generally accepted incidence of nephrotoxicity secondary to vancomycin monotherapy is <5% but increases to 43% in patients receiving concomitant nephrotoxic medications (aminoglycosides, amphotericin) (1, 9, 14). Nephrotoxicity is generally reversible and is believed to result from the accumulation of the drug in renal cells (1). In reported cases of vancomycininduced nephrotoxicity, concentrations were generally higher than the accepted therapeutic range. However, given the drug’s dependence on renal elimination, vancomycin concentrations would be expected to be elevated in patients with renal dysfunction (15). Zimmerman et al found that in patients receiving vancomycin alone, nephrotoxicity did not occur until the trough concentrations exceeded 20 mg/L (10). OTHER CONSIDERATIONS Significant costs are associated with vancomycin therapeutic drug monitoring. In addition to the cost of the assay itself, the cost of monitoring includes the time and effort of nurses, From the Department of Pharmacy Services, Baylor University Medical Center, Dallas, Texas. Corresponding author: Cheryle Gurk-Turner, RPh, Department of Pharmacy Services, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, Texas 75246 (e-mail: [email protected]). 189 pharmacists, laboratory personnel, and physicians (9). The cost for a vancomycin serum level at our institution is $97.50. Phlebotomy associated with monitoring vancomycin levels also contributes to increased morbidity from venipuncture and lowered hemoglobin from blood loss (15). DISCUSSION For vancomycin therapy to be optimal, adequate trough concentrations must be maintained and elevated peak concentrations avoided. It can generally be assumed that trough concentrations maintained below 15 mg/L would not provide peak concentrations that exceed 40 mg/L, except in patients with smaller volumes of distribution (13). Therefore, in most instances, optimal vancomycin therapy can be assured with trough concentrations alone. Some authors have recommended that vancomycin monitoring is not necessary at all, arguing that empiric dosing based on nomograms almost always results in trough levels that exceed the MIC of susceptible bacteria (9). However, therapeutic drug monitoring is recommended in several instances: a) patients receiving concomitant aminoglycosides, b) anephric patients receiving hemodialysis, especially high-flux dialysis such as continuous venovenous hemofiltration, c) patients receiving higherthan-normal doses of vancomycin (i.e., for meningitis), and d) patients with rapidly changing renal function (12). Patients receiving hemodialysis should have vancomycin concentrations drawn periodically (every 4 to 7 days) to ensure that therapeutic levels are maintained. Therapeutic drug monitoring is also recommended in patients with high volumes of distribution, such as burn patients and intravenous drug abusers (11). Based on this information, the Pharmacy and Therapeutics Committee at Baylor University Medical Center has adopted the following guidelines: • Routine monitoring of vancomycin peak and trough concentrations in all adult patients receiving vancomycin therapy is not recommended unless therapy is longer than 5 days. • Measurement of a single trough concentration at steady state is recommended for the following patients: – Patients receiving concomitant aminoglycosides 190 – Patients receiving higher-than-normal doses of vancomycin (i.e., for meningitis) – Patients with rapidly changing renal function – Patients with altered volumes of distribution (burn patients, trauma patients, intravenous drug abusers) – Patients in whom treatment is failing • Anephric patients receiving hemodialysis should have vancomycin concentrations drawn periodically (approximately every 4 to 7 days) to ensure that therapeutic levels are maintained. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 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Therapeutic monitoring of vancomycin. Arch Pathol Lab Med 2000;124:322–323. Cantu TG, Yamanaka-Yuen NA, Lietman PS. Serum vancomycin concentrations: reappraisal of their clinical value. Clin Infect Dis 1994;18:533–543. Zimmermann AE, Katona BG, Plaisance KI. Association of vancomycin serum concentrations with outcomes in patients with gram-positive bacteremia. Pharmacotherapy 1995;15:85–91. MacGowan AP. Pharmacodynamics, pharmacokinetics, and therapeutic drug monitoring of glycopeptides. Ther Drug Monit 1998;20:473–477. Freeman CD, Quintiliani R, Nightingale CH. Vancomycin therapeutic drug monitoring: is it necessary? Ann Pharmacother 1993;27:594–598. Moellering RC Jr. Monitoring serum vancomycin levels: climbing the mountain because it is there? Clin Infect Dis 1994;18:544–546. Saunders NJ. Why monitor peak vancomycin concentrations? Lancet 1994; 344:1748–1750. Creekmore F. Vancomycin levels: to draw or not to draw. S D J Med 1998; 51:195–196. BAYLOR UNIVERSITY MEDICAL CENTER PROCEEDINGS VOLUME 14, NUMBER 2