In this retrospective cost-of-illness study of candidemia, the cost of hospitalization, antifungal drugs, and other medical treatments each comprised about 25% of the total costs for the treatment of candidemia, which is in contrast to data from the United States, where costs for hospitalization account for up to 90% of the total costs. Regarding the cost-increasing factors, ICU-onset candidemia and an antifungal switch to second-line agents or more for any reason were associated with increases in the total costs. With regard to the mean daily cost, ICU onset candidemia, hematologic malignancy, the presence of a central venous line, non-albicans species, and the failure of first-line antifungal drugs were associated with increases in daily costs. The success of first-line antifungal therapy was found to be the only modifiable cost factor in the present study.
The reason why hospitalization costs in Korea formed a relatively small portion of the total costs being compared to those from the United States can be explained by differences in the healthcare finance systems of the two countries. Korean medical insurance system is public, patients usually pay only a small portion (5 to 20%) of the total costs and the rest is paid by the government. Government organizations are responsible for setting the price of medical resources as well. The cost of hospital stay per day in superior general hospitals in Korea was $28.2 for non-ICU ward and $83.7 for ICU, while the cost per day in U.S. hospitals was calculated as $1,383 for the non-ICU ward and $2,726 for the ICU in one study (14
). Although hospitalization cost is not a major cost driver here, we consider that increased costs due to a switch to second-line agents might be due to an increased hospital stay (), and this finding is consistent with data from the United States in that an increase in hospital stay was associated with major costs (5
The importance of first-line therapy for candidemia has been described in previous studies. Inappropriate initial therapy for candidemia was associated with prolonged LOS and increased costs (1
). Significant additional costs and resources use were observed when second-line treatment was required in patients treated with fluconazole (4
). The results of the present study support the finding that an antifungal switch to second-line agents or more is a significant cost-increasing factor in Korea, where hospitalization costs are relatively low. Improvements in the appropriate selection of initial antifungal agents by empirical use of echinocandins was even more cost-effective than the use of fluconazole (22
) or amphotericin B deoxycholate (19
) in model simulation studies, despite the higher costs of echinocandins compared to fluconazole or amphotericin B deoxycholate.
Conflicting data have been published about the relationship between first-line therapy and survival. A prospective case-control study showed that inadequate initial therapy and high APACHE score were independent variables associated with mortality (2
), and a retrospective study showed that patients who switched to second-line antifungal had a higher mortality rate (34.5%) than patients without antifungal switch (25.1%) (P
< 0.001) (4
). Another study found that a longer time from culture positivity to antifungal initiation was associated with mortality in cancer patients with candidemia (17
). However, two studies found that inappropriate initial therapy was not associated with mortality (1
), and one study demonstrated a tendency of lower mortality with appropriate initial therapy (21
). In the present study, the failure of first-line antifungal therapy was an independent risk factor for mortality. Although we did not evaluate the appropriateness of initial therapy, our data emphasize the importance of choosing initial antifungal agents with lower probability of failure in order to decrease mortality.
Controversy remains as to which first-line drug is the most cost-effective. Although echinocandins appear to be more cost-effective than fluconazole or amphotericin B in the United States (19
), they have not been approved as first-line drugs by the Korea Food and Drug Administration due to the fact that the drug unit cost for amphotericin B deoxycholate is the lowest. Given that clinical decisions regarding drug choice are complicated by factors such as host immunity, Candida
species, drug efficacy, and cost, data for direct cost comparisons between fluconazole and amphotericin B are scarce (7
). Our data show that amphotericin B was no more cost-effective than fluconazole. Fluconazole and amphotericin B did not differ in total cost and cost per day. Even though the cost of amphotericin B was less than that of fluconazole, other medication costs and lab test costs were higher in the amphotericin B group, leading to a net zero balance between fluconazole and amphotericin B. Although 30-day mortality was not different, the treatment success rates were significantly lower when amphotericin B was used as first-line therapy (15/56 [26.8%] with amphotericin B versus 60/129 [46.5%] with fluconazole, P
With regard to the choice between fluconazole and amphotericin B deoxycholate, we could not determine the exact reason why clinicians prescribed one agent versus another as initial therapy. However, we can presume that amphotericin B deoxycholate was preferred in patients with more serious illness (). Patients who were started on amphotericin B deoxycholate had underlying cancer, CVC, or mechanical ventilation more frequently that those who were started on fluconazole, suggesting that amphotericin B is given in more critical patients. This finding is also consistent with current practice of clinicians in Korea. Although echinocandins and liposomal amphotericin B are not admitted as first-line agents against invasive candidiasis or candidemia in Korea, we usually prescribe fluconazole for the treatment of candidemia. Amphotericin B deoxycholate is chosen when it is considered necessary for broader spectrum of coverage or for immunocompromised hosts. Some may presume that the loss of cost-effectiveness of amphotericin B compared to fluconazole in this study could be partially explained by the increase in other medical treatment costs because disease severity in amphotericin B deoxycholate group might have been worse. However, significantly higher rate of treatment failure and rate of switch to second-line antifungal agents with the use amphotericin B was seen, and these have led to increased costs.
Comparison of clinical characteristics of patients treated with fluconazole and amphotericin B deoxycholate prescribed as a first-line agent
Among the limitations of the present study is its retrospective nature. First, since 30 patients were lost to follow-up prior to day 30, 30-day mortality data were available only for 169 subjects, limiting the results of the mortality analysis. Important clinical variables that would have been associated with mortality were not collected. For example, the APACHE II score, which is the only independent predictor of mortality of candidemia in one study (11
), could not be calculated. Other clinical indices, such as the SOFA or SAPS II score, also were not available. Instead, we used indirect measures for disease severity, such as underlying malignancies, ICU acquisition of candidemia, central venous catheterization, and the need for mechanical ventilation (). Second, the appropriateness of antifungal therapy also was not assessable since antifungal susceptibility tests were not available at most institutions. However, we believe that most therapies might have been appropriate because the fluconazole resistance rate among Candida
species in Korea is low (~0.8%); for example, the resistance rate of C. glabrata
was 2.8% (8
). Third, calculation of an exact estimate of costs attributable only to candidemia was complicated by other comorbidities that might have overlapped candidemia in resource utilization. Fourth, the sample size was relatively small, which might compromise the ability to generalize our results. However, we collected data at four different institutions from three provinces in Korea to overcome the small sample size and construct a representative sample. Fifth, the four university-affiliated medical centers in the present study are rated as superior general hospitals in Korea, which means that an additional 30% of fees are charged for every medical resource provided. Total costs for treatment of candidemia may be cheaper in smaller hospitals or private clinics. However, given that candidemia occurs mostly in nosocomial settings or critically ill patients, we believe our data could reflect the real practice. Finally, since patients who were not treated with antifungal agents or who died too early to receive antifungal agents were excluded from the study, the clinical outcomes of our study are not representative of all cases of candidemia.
Despite these limitations, this is the first study to estimate the attributable costs for treating candidemia in Korea, encompassing epidemiology, treatment strategies, and outcome altogether. Comparing direct costs between treatment with fluconazole and amphotericin B deoxycholate and demonstrating the importance of first-line antifungal agents in association with cost and mortality may contribute to establishing cost-effective treatment strategies for candidemia in resource-poor countries. Further studies are warranted to prospectively compare the direct costs of amphotericin B deoxycholate to those of fluconazole and to compare the costs of these older drugs to those of new echinocandins in the treatment of candidemia.
In summary, an antifungal switch to second-line agents for any reason was the only modifiable factor that increased attributable costs for treating candidemia and hospital LOS in the present study. In addition, treatment failure of first-line antifungal agents was an independent risk factor for mortality. Treatment with fluconazole and amphotericin B did not differ in terms of mortality and total costs. Our data show that the selection of appropriate first-line antifungal agents is important for the reduction of medical costs and to improve outcomes.