Previous Article | Next Article ![]()
Journal of Clinical Microbiology, June 2007, p. 1884-1888, Vol. 45, No. 6
0095-1137/07/$08.00+0 doi:10.1128/JCM.00192-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Susan L. Salo,2 and
Duane W. Newton2
Departments of Pharmacy Services,1 Pathology, University of Michigan Health System, Ann Arbor, Michigan 481092
Received 25 January 2007/ Returned for modification 14 March 2007/ Accepted 22 March 2007
|
|
|---|
|
|
|---|
First, prior to the azole antifungal agents, amphotericin B was the only reliable agent available to treat systemic infection. As such, susceptibility testing would have offered no true benefit to clinicians. However, since that time the azoles and triazoles have been introduced, expanding the antifungal armamentarium. Most recently, the echinocandins, displaying superb activity against most Candida spp., have come into routine use (6). This increased use is not without a financial impact on health systems, as echinocandins have a substantially greater acquisition cost than fluconazole.
Second, a shift has taken place in the composition of Candida spp. causing infections over the past decade. Infections due to Candida spp. other than C. albicans have increased and now comprise approximately 50% of all Candida bloodstream isolates (4). Some of these non-C. albicans isolates, such as Candida parapsilosis and C. tropicalis, are traditionally very sensitive to fluconazole. Candida krusei, however, is intrinsically resistant to fluconazole. Isolation of Candida glabrata, which comprises about 20% of all Candida isolates in the United States, presents a conundrum to clinicians, since the organism displays a variable susceptibility pattern to fluconazole (23). Table 1 showcases the institution-to-institution variability in both incidence of and fluconazole resistance to C. glabrata. Also of interest is the predilection for fluconazole-resistant C. glabrata to display cross-resistance to other azole antifungals (23). As such, many experts now recommend that patients with invasive infection due to C. glabrata be empirically treated with agents other than the azoles. The utility of susceptibility testing would be to allow for appropriate deescalation in therapy once results are known (13, 21). The financial impact of deescalating echinocandin therapy is not without precedence. Other studies have investigated the cost savings by using peptide nucleic acid fluorescence in situ hybridization to rapidly identify C. albicans in order to decrease echinocandin use (1, 8).
|
View this table: [in a new window] |
TABLE 1. C. glabrata fungemias in the United States
|
|
|
|---|
The decision tree was created using decision analysis software (DATA; TreeAge, Inc.). Data collected from literature reports, reference material, and expert opinion were used to populate the model (Table 2). Medication acquisition cost was added to labor cost and the price of testing to determine overall treatment cost. Univariate and multivariate sensitivity analysis (Monte Carlo simulation) enhanced the robustness of the model through variation of all probabilities and costs that populated the model.
|
View this table: [in a new window] |
TABLE 2. Decision analytic model variables
|
8 mg/liter as tested by broth microdilution according to CLSI standards were considered susceptible to standard doses of fluconazole (7). A mean susceptibility rate of 60% was obtained from literature reports and was used in the base case. Susceptibility rates were varied between 90% and 25% (3, 15, 16, 23). Realizing that not all institutions begin echinocandin therapy after identification of yeast isolates, a second model was developed under the assumption that patients would receive 2 days of fluconazole after identification of yeast by Gram staining. Patients were then changed to an echinocandin on day 3 after identification of C. glabrata. Depending on susceptibility of the isolate, patients received either 14 days (fluconazole to echinocandin and then back to fluconazole) or 16 days (fluconazole to echinocandin) of total therapy.
Institution and send-out turnaround times for completion of susceptibility testing after identifying yeast on Gram stain was estimated at 5 and 7 days, respectively. In order to investigate the financial effects of early discharges and longer treatment courses of other disease states, we varied the total treatment duration between 4 and 28 days in the sensitivity analysis.
The base case utilized the average wholesale price (AWP) or Federal Supply Schedule (FSS) price of fluconazole and micafungin (2, 27). Recent trials have demonstrated that all three echinocandins (anidulafungin, caspofungin, and micafungin) are effective in the treatment of candidemia (5, 24, 25). Micafungin was used in this review because it had the lowest listed echinocandin price (2). A daily dose of 400 mg intravenous (i.v.) fluconazole was chosen based on guideline recommendations (21). The impact of dosing fluconazole at 800 mg i.v. daily was considered in the sensitivity analyses. For micafungin, a daily dose of 100 mg was based on a recent, double-blind, noninferiority trial (25). Medication cost was varied between $0 and AWP in the sensitivity analyses.
The cost of in-house susceptibility testing was determined by adding the cost of commercially prepared broth microdilution plates (YeastOne; Trek Diagnostics, Cleveland, OH), inoculation broth, and demineralized water. A cost per test of $71 was used in the base case and varied by ±50% in the sensitivity analysis. The cost of labor for in-house susceptibility testing was determined by summing the times to set up, read, and enter results of testing into the computer system. Total testing time was estimated at 99 min. Laboratory technologist hourly wage was obtained from the 2005 U.S. Bureau of Labor Statistics and valued at $18.90 per hour for a total cost of $34 for in-house testing (26).
The cost of commercially available send-out testing used in the base case was $59 and was obtained from the Fungus Testing Laboratory at the University of Texas Health Science Center at San Antonio (http://strl.uthscsa.edu/fungus/; accessed 7 January 2007). Labor time was estimated at 15 min to subculture and complete paperwork, totaling $5 in labor cost. The cost of labor ranged between $0 and twice the estimated cost in the sensitivity analysis.
|
|
|---|
|
View this table: [in a new window] |
TABLE 3. Summary of model results
|
![]() View larger version (17K): [in a new window] |
FIG. 1. Sensitivity analysis of the daily cost of echinocandin therapy. Send-out testing becomes the preferred option with a daily echinocandin cost (cEchinocandin) of $70. Any form of susceptibility testing loses the financial advantage with an echinocandin cost of $51 per day. EV, expected treatment cost.
|
A two-way sensitivity analysis was performed on the cost of echinocandin therapy and rates of susceptibility to fluconazole (Fig. 2). Susceptibility testing, whether in-house or sent out, maintained an advantage over no testing in a majority of situations. The difference in institutional testing versus send-out testing was variable depending on the cost of echinocandin and the rates of susceptible agents.
![]() View larger version (66K): [in a new window] |
FIG. 2. Two-way sensitivity analysis on the cost of echinocandin therapy and varying susceptibility rates to fluconazole.
|
The difference in treatment cost between institutional testing and no testing was greatest when fluconazole was initiated after identification of yeast by Gram staining and prior to identification of C. glabrata ($1,292). The total costs of therapy were $1,916, $2,214, and $3,208 for the groups using in-house, send-out, and no testing, respectively. The use of FSS pricing and fluconazole initially resulted in the lowest treatment cost in all models for institutional testing ($1,035).
|
|
|---|
One limitation was the use of AWP in the base case. The daily cost of both fluconazole and echinocandin is likely lower than AWP at most institutions. The cost of echinocandin therapy declined in 2006 after the introduction of competing class alternatives. Despite this, the acquisition price of echinocandins remains high. The choice of agent and contract price may vary depending on the institution. We feel the sensitivity analyses enhance the generalizability of this study. Results displayed in Fig. 2 and the results of the analysis using FSS pricing make it possible for individual institutions to predict the best alternative based on echinocandin pricing structure and their own susceptibility patterns. At the same time, some clinicians may feel more comfortable using higher dosing of fluconazole. When we used an 800-mg daily dose of i.v. fluconazole, results still favored testing.
As with the cost of medication therapy, the cost of competing testing methods, susceptibility turnaround time, time and ability to deescalate therapy once testing results are known, and cost of labor may be highly variable depending on the institutional laboratory or send-out facility. Changes in the cost of testing and labor did not impact the results of our model, and the turnaround time of send-out laboratories must be very near to that of an internal laboratory to display a cost advantage. Institution susceptibility testing was preferred in most scenarios. Of interest, the availability of fluconazole disks for susceptibility testing by disk diffusion will result in additional cost reductions for susceptibility testing and will enhance the benefit of performing this testing in-house as applied in this model.
We solely utilized the treatment of candidemia caused by C. glabrata in the base case of our analysis. This was chosen because of the standard treatment duration of 14 days after a positive blood culture (21). However, we believe our results may translate to other infections requiring longer durations of therapy. Our findings support the idea that deescalation of therapy from an echinocandin to fluconazole would provide an even more pronounced economic benefit when treatment continues for weeks or months. When total treatment time was increased to 28 days, the difference between testing and no testing was $2,489 per patient.
Although our study focused on the financial incentives of antifungal susceptibility testing, it is even more important to review the clinical implications. A crucial question is whether in vitro susceptibility testing affects clinical outcomes. If it does not, then most clinicians would find it to be of little utility in practice. Logically, one would think that clinical outcomes would correlate well with the results of in vitro susceptibilities. Surprisingly, the literature does not always support this logic as it relates to antifungal susceptibility testing. Indeed, several studies have found that the acute physiology and chronic health evaluation score at the time of fungemia, not in vitro susceptibility test results, was the most important factor in predicting mortality (16). The reason for this discrepancy more likely reflects the severely ill condition of most patients with fungemia rather than refuting the validity of susceptibility testing (16). Regarding the echinocandins, one study showed that patients with Candida isolates having higher caspofungin MICs (>2 µg/ml) had superior clinical outcomes compared to those with isolates displaying caspofungin MICs of <1 µg/ml (14). However, since only three patients treated with caspofungin were infected with isolates with MICs of >2 µg/ml, this study does not supply enough data to make any conclusions regarding the effect of elevated echinocandin MICs on outcome. Conversely, a recent review by Pfaller and colleagues provides ample evidence that fluconazole MIC does correlate clinically. Analysis of MIC correlation to clinical outcome in studies of patients with mucosal and invasive candidiasis showed that higher doses (meaning a dose/MIC ratio of >25:1) are more often associated with successful outcomes than are lower doses (22). In addition, a recent study found that the fluconazole dose/MIC ratio was significantly higher in survivors of candidemia (13.3 ± 10.5) than in nonsurvivors (7.0 ± 8.0) (20). As such, fluconazole susceptibility testing provides crucial information that can be utilized to optimize both clinical and financial outcomes.
Another potential clinical advantage of susceptibility testing (especially when done in-house) is in facilitating quicker interventions. In the base case model of our study, echinocandin treatment was initiated when yeast was detected on Gram stain. The decision to initiate fluconazole or an echinocandin empirically is a source of controversy and depends largely on local susceptibility patterns. Recent literature showing a correlation between time to initiation of appropriate antifungal therapy and in-hospital mortality due to candidemia has exemplified the importance of this decision (9, 18). More rapid susceptibility results would shorten the time to make appropriate therapy adjustments in the case of inappropriate empirical therapy.
This study supports the assumption that antifungal susceptibility testing is a necessity in today's world of resistant organisms and expensive agents. As such, institutions are left with two options: in-house testing and send-out testing. Both methods increase laboratory costs while decreasing pharmacy costs to a greater extent. Instituting this practice into hospital microbiology laboratories, which are often already financially constrained, is a practical barrier that must be addressed.
Conclusion. The decision model indicates that susceptibility testing of C. glabrata isolates should result in lower overall treatment costs for patients with documented C. glabrata fungemias.
Published ahead of print on 4 April 2007. ![]()
Present address: Department of Pharmacy at New York-Presbyterian Hospital, New York, NY 10032. ![]()
|
|
|---|
This article has been cited by other articles:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Copyright © 2009 by the American Society for Microbiology. For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»