Mississippi Mud No More: Cost-Effectiveness of Pharmacokinetic Dosage Adjustment of Vancomycin to Prevent Nephrotoxicity

William Darko, Pharm.D., Joseph J. Medicis, Pharm.D., Adrienne Smith, Pharm.D., Roy Guharoy, Pharm.D., David F. Lehmann, M.D., Pharm.D.


Pharmacotherapy. 2003;23(5) 

In This Article

Abstract and Introduction

Objective: To determine the cost-effectiveness of pharmacokinetic dosage adjustment of vancomycin to prevent nephrotoxicity. An analysis was performed for subpopulations of patients receiving nephrotoxic agents (aminoglycosides, amphotericin, and acyclovir), those in the intensive care unit, and those on the oncology service.
Methods: Decision analysis was used to model the cost-effectiveness of pharmacokinetic dosage adjustment of vancomycin. The reference case was determined, in part, by a retrospective review of 200 patients randomly selected from our clinical pharmacology consultation service. Patients were aged 18 years or older and had received intravenous vancomycin for at least 48 hours, with at least two -- one peak and one trough -- vancomycin serum concentrations obtained during therapy. Results of published clinical trials were used to determine the probability of vancomycin-induced nephrotoxicity.
Results: The mean cost of treating nephrotoxicity was $11,233 at our institution. The mean cost for all patients was $25,166 (sensitivity analysis $15,000-27,500)/nephrotoxic episode prevented. The subgroup analysis revealed a cost of $8363 (sensitivity analysis $4368-10,500)/nephrotoxic episode prevented in intensive care patients, $5000 (sensitivity analysis $1687-13,250) in oncology patients, and a dominant strategy showing a cost savings of $5564 (sensitivity analysis $2724-12,428) in those receiving concomitant nephrotoxins.
Conclusion: Although pharmacokinetic monitoring and dosage adjustment are effective methods for reducing the toxicity of many drugs, controversy exists regarding the necessity of such monitoring with vancomycin. Evaluation by decision analysis over a range of assumptions, varying probabilities, and costs reveals that pharmacokinetic monitoring and vancomycin dosage adjustment to prevent nephrotoxicity are not cost-effective for all patients. However, such dosage adjustment demonstrates cost-effectiveness for patients receiving concomitant nephrotoxins, intensive care patients, and probably oncology patients.

Vancomycin was isolated in 1956 and was administered initially as a reserve drug for treatment of gram-positive infections. However, over the past 2 decades its administration has increased as resistant organisms have become more prevalent. It is the drug of choice for treatment of severe systemic infections, such as those caused by methicillin-resistant Staphylococcus aureus strains.[1,2,3] In the treatment of febrile neutropenia, vancomycin frequently is administered with other nephrotoxic agents, such as amphotericin B, aminoglycosides, and acyclovir.[4] The most common side effects associated with vancomycin are fever, chills, and phlebitis. These symptoms occur less often if the drug is infused slowly in a large volume of fluid. Tingling and flushing of the face and thorax, commonly known as the red man syndrome, often occur when large doses are infused rapidly. This is related to histamine release secondary to local hyperosmolarity.

Another important adverse reaction to vancomycin is nephrotoxicity, which occurred relatively often with impure preparations of vancomycin, especially when given at high doses.[1] Since the introduction of vancomycin and through the mid-1980s, early lots of vancomycin contained large amounts of fermentation broth impurities. The preparation was brown and thus was dubbed Mississippi mud because of its appearance. Before purification methods improved, vancomycin was a highly toxic antibiotic; however, the modern formulation, if administered at appropriate dosages, has an excellent safety profile. Still, reports of dose-dependent toxicity related to serum concentrations and wide interpatient variability of its pharmacokinetic profile have led many clinicians to monitor vancomycin serum concentrations routinely and adjust dosage accordingly.[5,6,7,8,9]

The main goal of such pharmacokinetic monitoring and dosage adjustment is to optimize serum drug concentrations for patients receiving drugs that have a narrow therapeutic range. Because the frequency of nephrotoxicity associated with vancomycin administration alone is low,[10,11,12] investigators have raised the question regarding the necessity of monitoring vancomycin serum concentrations.[10,11,12,13] In addition, efficacy does not correlate with serum levels, and earlier reports of the correlation of nephro-toxicity with serum levels have been challenged. Therefore, controversy remains regarding when vancomycin monitoring is appropriate or whether it is even necessary.[10,11,12,13] These considerations have led many clinicians to abandon routine pharmacokinetic monitoring as a guide for vancomycin dosage adjustments.[5,11,12,13,14,15]

An intermediary stance has been taken against routine monitoring of vancomycin serum levels in most patients, with the suggestion that monitoring be restricted to patients at risk for nephrotoxicity. Such patients are those receiving dialysis with unconventional high-flux filter membranes, those receiving concomitant aminoglycoside antibiotics, those receiving higher than normal doses to treat infections in the cerebrospinal fluid or infections caused by more resistant organisms, those with changing renal function, or those for whom the risk of possible legal repercussions is great.[16,17] Given the lack of evidence elucidating patients in whom aggressive monitoring of vancomycin serum concentration should be performed, our objective was to determine the cost-effectiveness of monitoring vancomycin serum concentrations to prevent nephrotoxicity. We also performed an analysis for subpopulations defined as patients receiving concomitant nephrotoxins (aminoglycosides, amphotericin, and acyclovir), patients in the intensive care unit, and patients on the oncology service.