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 mcg/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 concomitant 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 vancomycin-induced 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, 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 higher-than-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
  • 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.

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