Impact of First-line Antifungal Agents on the Outcomes and Costs of Candidemia

31 Pages·2012·0.53 MB·English

AAC Accepts, published online ahead of print on 23 April 2012
Antimicrob. Agents Chemother. doi:10.1128/AAC.06258-11
Copyright © 2012, American Society for Microbiology. All Rights Reserved.
Impact of First-line Antifungal Agents on the Outcomes and Costs
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of Candidemia
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4 Young Eun Ha1, Kyong Ran Peck1, Eun-Jeong Joo1, Shin Woo Kim2, Sook-In Jung3,
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5 Hyun Ha Chang2, Kyong Hwa Park3, Sang Hoon Han4 ow
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7 1 Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of e
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8 Medicine, Seoul, Republic of Korea ro
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9 2Division of Infectious Diseases, Kyungpook National University Hospital, Daegu, Republic of Korea h
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10 3Division of Infectious Diseases, Chonnam National University Medical School, Gwangju, Republic :
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11 of Korea a
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12 4Division of Infectious Diseases, Severance hospital, Yonsei University College of Medicine, Seoul, s
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13 Republic of Korea .o
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17 Key words: Candidemia, Cost of illness, Fluconazole, Amphotericin B, Mortality 7
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18 Running title: Attributable costs and outcome of candidemia 0
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20 Correspondence: Kyong Ran Peck, MD, PhD u
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21 Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School t
22 of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Republic of Korea
23 Office Telephone: [phone]; Office Fax: [phone]
24 Email: [email protected]
25 Abstract
26 Candida species are the leading causes of invasive fungal infection among hospitalized
27 patients and are responsible for major economic burdens. The aims of this study were to
28 estimate costs directly associated with the treatment of candidemia and factors associated D
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29 with increased costs, as well as the impact of first-line antifungal agents on the outcomes and lo
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30 costs. A retrospective study was conducted in a sample of 199 patients from 4 university- d

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31 affiliated tertiary care hospitals in Korea over 1 year. Only costs attributable to the treatment m

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32 of candidemia were estimated by reviewing resource utilization during treatment. Risk factors p
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33 for increased costs, treatment outcome and hospital length of stay (LOS) were analyzed. c
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34 Around 65% of patients were treated with fluconazole and 28% were treated with m
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35 conventional amphotericin B. The overall treatment success rate was 52.8% and the 30-day /

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36 mortality rate was 47.9%. Hematologic malignancy, need for mechanical ventilation and M
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37 treatment failure of first-line antifungal agents were independent risk factors for mortality.
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38 The mean total cost for the treatment of candidemia was USD 4,743 (SD; USD 7,049) per 2
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39 patient. Intensive care unit (ICU) stay at candidemia onset and antifungal switch to second- b
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40 line agents were independent risk factors for increased costs. LOS was also significantly u
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41 longer in patients who switched antifungal agents to second-line drugs. Antifungal switch to
42 second-line agents for any reasons was the only modifiable risk factor of increased costs and
43 LOS. Choosing an appropriate first-line antifungal agent is crucial for better outcomes and
44 reduced hospital costs of candidemia.
45 Introduction
46 Invasive fungal infections by Candida species have become increasingly important
47 worldwide. They are the fourth most common cause of nosocomial bloodstream infections in
48 the United States and the fifth to tenth most common causative pathogen in European studies D
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49 (1-3, 13). Candidemia is responsible for substantial medical and economic burdens(5). About lo
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50 33-55% of all episodes occur in intensive care units (ICUs) and are associated with high ICU d

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51 mortality rates and resource use (9, 13, 18). Mortality rates range from 28 to 42% (16, 20), m

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52 and attributable costs of candidemia range from $35,000 to $68,000 per adult case in the p
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53 United States (5, 15, 20). Hospitalization charges due to increased length of stay (LOS) are c
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54 the major driving force behind excess costs. Increased LOS attributable to candidemia is m
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55 estimated at 10-20 days per episode in US (5). Antifungal therapy is the next largest cost item, /

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56 representing up to 10% of total costs in treating candidemia (15). In addition, recent data M
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57 showed that initial inappropriate antifungal therapy was a major cause of increased LOS and
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58 costs as well as poor outcomes, which suggests the importance of appropriate first-line 2
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59 antifungal therapy in the treatment of invasive candidiasis (21). b
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60 However, most data in previous studies were from the United States, where the s
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61 health insurance system as well as treatment strategies for invasive Candida infection differ
62 from those of other countries worldwide. Although the 2009 guidelines for candidemia
63 treatment by the Infectious Disease Society of America (IDSA) recommend echinocandins as
64 the first-line antifungal agents in the setting of neutropenia or moderate to severe illness (12),
65 these drugs are not widely used worldwide as first-line agents due to their relatively high
66 costs, especially in resource-limited countries(6, 10). Fluconazole is still the most widely
67 used drug and amphotericin B deoxycolate is also frequently used for broader coverage of
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68 candidemia. With scarce data comparing the efficacy and cost-effectiveness of these
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69 antifungal agents, additional comparative analyses would add valuable knowledge to this d
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70 issue. The assessment of the economic burden attributable to the treatment of candidemia and ro
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71 major contributing factors that lead to increased costs are important because better treatment t
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72 strategies may be justified based on such data. a
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73 The primary aims of this study were to estimate costs directly associated with m
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74 treatment of candidemia and to identify modifiable factors that lead to increased costs. The /

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75 secondary aim was to assess the clinical impact of first-line antifungal agents on the treatment M
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76 outcomes of candidemia in terms of mortality, costs and hospital LOS.
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82 Methods
83 Study design and patient sample
84 We designed a retrospective, cost-of-illness study that examined the costs attributable to
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85 candidemia in 200 patients treated at 4 university-affiliated tertiary hospitals in South Korea: w
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86 Samsung Medical Center and Yonsei University Medical Center in Seoul, Kyungpook a
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87 National University Hospital in Daegu, and Chonnam National University Hospital in
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88 Gwangju. From each hospital, 50 consecutive patients who had candidemia and received
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89 antifungal treatment from July 2008 to June 2009 were included in the study. Using the :/
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90 electronic medical record system of each hospital, patients aged 18 years or older with .a
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91 positive blood cultures for Candida species were identified. Exclusion criteria were patients .o
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92 who were not treated with antifungal agents or who died too early to receive antifungal o
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93 agents. One patient was excluded from final data analyses due to coinfection with invasive a
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94 aspergillosis and recurrent episodes of bacterial sepsis. The study protocol was approved by 2
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95 the local Institutional Review Board of each institution. 1
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96 Data collection g
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97 For all patients, demographic characteristics, baseline clinical characteristics of candidemia
98 episodes, resource utilization during candidemia treatment, length of stay, treatment outcome
99 and survival data were collected retrospectively. Treatment outcome was assessed as either
100 treatment success or failure. Treatment success was defined as improvement in symptoms and
101 signs of infection or negative conversion of candidemia. Failure was defined as persistence or
102 progression of symptoms and signs of infection, persistent candidemia, a change of antifungal
103 agent due to poor clinical response, or death during antifungal therapy. Survival outcome was
104 measured as 30-day all-cause mortality rate.
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105 lo
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106 Resource utilization
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107 Resource use was measured for all patients and divided into six categories: hospitalization, t
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108 medication and antifungal drugs, imaging tests, laboratory tests, procedures or surgery, and a
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109 other medical treatment (dialysis, use of infusion pump, electrocardiogram monitoring, s
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110 oxygen supply, mechanical ventilation, and consultation). The number of units consumed by rg
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111 each patient was multiplied by the cost per unit of each resource to estimate the direct costs
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112 for each patient. Since the four hospitals in this study are rated as superior general hospitals c
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113 in Korea, additional 30% of costs are charged for every resource provided (Total costs = ,

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114 Number of units consumed x unit cost x 1.3). The unit cost of each resource was obtained 9

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115 from the health insurance fee schedule of Korea (Korea Health Insurance Review and g
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116 Assessment Service, 2010), and the medication cost was estimated from the weighted average t
117 cost (2009). The cost of treating adverse reactions to antifungal therapy was estimated from
118 resource utilization data supplied by the investigators of each institution. All costs were
119 calculated in 2009 Korean currency (KRW) and then converted into 2009 US dollars (USD).
120 The 2009 exchange rate for 1 USD was KRW 1,156.
121 Although caspofungin and voriconazole were approved by Korean Food and Drug
122 Administration in 2001, and micafungin in 2006(10) , use of these drugs as first line agents in
123 the treatment of invasive candidiasis or candidemia was limited due to their higher cost. D
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124 Fluconazole or amphotericin B deoxycolate is admitted as first line agents against Candida lo
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125 infection in Korea, and echinocandins admitted in the setting of treatment failure or toxicities d

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126 of which criteria are defined by HIRA. m

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127 :/
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128 Statistical analysis s
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129 Continuous variables such as costs, age, and length of hospital stay were expressed either as /
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130 means and standard deviations (for variables with normal distributions) or as medians and
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131 ranges (for variables with skewed distributions). Categorical variables were expressed as
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132 proportions and percentages. Student’s t tests or Mann-Whitney U-tests were used to compare 2
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133 continuous variables, and χ2 or Fisher’s exact tests were used to compare categorical b
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134 variables. To define risk factors for mortality, multivariate logistic regression analysis and e
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135 adjusted odds ratio (OR) with 95% Confidence interval (CI) were calculated. Variables that
136 were associated with mortality in univariate analyses with a P value <0.10 were entered into
137 multivariate analysis. Comparisons of costs for each clinical variable were done using
138 Student’s t tests or Mann-Whitney U-tests, then, multiple linear regression analyses were
139 used to define independent drivers for elevated costs. All reported P values were two-tailed,
140 and P<0.05 was considered statistically significant. Data analyses were performed using
141 PASW Statistics, version 18.0 (SPSS Inc., Chicago, IL, USA).
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154 Results
155 Patient Characteristics
156 A total of 199 patients were included in the analysis: 50 patients from each hospital, except
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157 for one hospital from which 49 patients were included. Of the 199 patients, 106 (53.3%) were w
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158 male and the median age was 68 (range, 34-88) years old. The majority of patients (103 a
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159 patients, 51.8%) had malignancies as underlying diseases. Sixty-eight (34.2%) underwent
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160 surgery during the admission before the onset of candidemia. The most frequent species was
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161 Candida albicans (90 patients, 45.2%), followed by C. tropicalis (51 patients, 25.6%), C. :/
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162 parapsilosis (29 patients, 14.6%), and C. glabrata (19 patients, 9.5%). .a
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164 Treatment outcomes
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165 Fluconazole was most commonly used as a first-line antifungal agent in 130 (65.3%) of the 7
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166 patients, followed by amphotericin B deoxycolate in 61 (30.7%), liposomal amphotericin B 1
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167 in 7 (3.5%), and itraconazole in 3 (1.5%). The median interval from candidemia onset to the y

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168 start of antifungal drug treatment was 2 (range 0-21) days. The median total duration of s
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169 antifungal agents was 15 days (range, 1-62 days). Fifty-nine (29.6%) patients switched to
170 second-line antifungal agents due to treatment failures (n=20), adverse events due to first-line
171 agents (n=23) or other reasons. Renal or hepatic adverse events occurred in 56 (28.1%)
172 patients. Eight (14.3%) patients changed antifungal agents due to renal toxicity and two
173 (3.6%) patients changed due to hepatic toxicity. The overall treatment success rate was 52.8%
174 (105 out of 199 patients), whereas 92 (46.2%) failed antifungal treatment and two were
175 undetermined. The most common reason for treatment failure was death during antifungal
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176 treatment (75 out of 92 patients, 81.5%).
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177 Of the 199 patients, 30 were lost to follow-up before 30th day with their clinical d

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178 outcome left to be unknown. Among the 169 patients who were followed up until 30 days m

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179 from the onset of candidemia, the overall 30-day mortality rate was 47.9% (81 out of 169 p
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180 patients died within 30 days of the onset of candidemia). In univariate analysis, hematologic c
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181 disease, presence of central venous catheter, ICU stay at the onset of candidemia, need for m
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182 mechanical ventilation and treatment failure of first line antifungal drugs were associated /

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183 with 30-day mortality (Table 2). Since the definition of first-line treatment failure also M
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184 included death during antifungal treatment, we excluded patients who died within 30 days of
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185 first-line treatment and repeated the analysis. Even after excluding such patients, first-line 2
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186 antifungal treatment failure was a significant risk factor for mortality in univariate analysis. b
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187 In multivariate analysis, hematologic diseases (OR, 5.18; 95% CI, 1.06-25.46; p=0.043), need u
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188 for mechanical ventilation (OR, 6.76; 95% CI, 2.11-21.66; p=0.001) and first-line treatment
189 failure (OR, 5.13; 95% CI 1.78-14.80; p=0.002) remained statistically significant risk factors
190 for mortality.