Echinocandins in the treatment of candidaemia and invasive candidiasis: clinical and economic perspectives

Abstract

Candidaemia and invasive candidiasis (IC) complicate modern medical therapy, contributing to high morbidity and mortality. Managing candidiasis is costly, with an additional healthcare expenditure of nearly US$300 million annually. Recent consensus guidelines have suggested the use of newer antifungal agents, such as echinocandins, for the treatment of candidaemia and IC owing to promising clinical outcomes compared with older-generation antifungal agents, but at higher drug acquisition and administration costs. Comprehensive cost-effectiveness data for echinocandins in treating candidaemia and IC remain relatively scant, underlining the need for more studies to incorporate robust economic analyses into clinical decisions. Assessment of the cost efficiencies of these expensive antifungal agents is essential for maximising health outcomes within the constraints of healthcare resources. This review will explore the epidemiology of candidaemia and IC in the context of clinical and economic aspects of the antifungal agents used to treat IC, especially the echinocandins. Standardising the outcome measure, methodology and reporting of results used in economic studies is central to ensure validity and comparability of the findings. Future studies comparing the economic advantages of all available antifungal treatment options and in the context of new diagnostic tools for fungal infections are anticipated.

Introduction

Candidaemia and invasive candidiasis (IC) are increasingly common, costly and life-threatening infections, particularly among the immunocompromised and critically ill [1], [2], [3]. Surveillance programmes in the USA report Candida spp. as the fourth leading isolate and the only fungal pathogen among the top 10 causative organisms for nosocomial bloodstream [4] and healthcare-associated infections [5]. Globally, Candida spp. ranked number three for causing infections in intensive care units (ICUs) [6]. More than 70% of invasive fungal infections in hospitalised patients were due to Candida spp., the majority presenting as candidaemia [7]. Population-based studies on the incidence of candidaemia (1991–2006) in Europe, Canada, the USA and Australia reported 1.7–24.0 cases per 100 000 head of population per year [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]. In the USA, the incidence of IC has increased to 29 cases per 100 000 head of population per year in 2003, translating to an annual national burden of about 63 000 infections [20]. Not only is the burden of candidaemia and IC substantial [21], [22], [23], [24], a shift in the proportion of cases occurring in specialised hospital wards and ICUs to the general hospital and community settings has also been noted for candidaemia [12], [25].

Crude and attributable mortalities of candidaemia and IC have been reported as 28–81% and 15–71%, respectively [19], [21], [23], [24], [26], [27], [28], [29], [30], [31]. These infections have resulted in prolonged hospital stays of 3–30 days [22], [23], [26], [27], [30], [32] and in additional costs of US$21, 590–68, 311 per patient [22], [23], [30], [32] or US$216–281 million per year [22]. Given the significant clinical and economic burden, identifying an optimal approach to treating candidaemia and IC is important. Accordingly, this review will provide a brief overview of the epidemiology and current treatment options for candidaemia and IC. It will focus primarily on clinical and pharmacoeconomic data as well as the considerations, challenges and gaps for future pharmacoeconomic research for the antifungal agents used in this setting, in particular the echinocandins.

There are at least 17 pathogenic Candida species and/or species complexes, but >90% of invasive infections are attributed to five species, namely Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis and Candida krusei [20], [33]. However,

species epidemiology of candidaemia varies in different parts of the world and the relative incidence of the various Candida spp. is changing over time [34]. Multicentre and laboratory-based surveillance programmes (1997–2006) reported that C. albicans was the predominant isolate (>60%) in North Europe and Switzerland and comprised 48–58% of the Candida spp. isolated in the remaining European countries and the USA; non-albicans spp. (58–60% of the Candida isolates) were more commonly found in Asia and South America [34]. Local hospital- or ICU-based epidemiological studies have also reported similar patterns, except in the USA (predominantly C. albicans) and southern Europe (non-albicans spp. predominated) [34]. In Australia, C. albicans accounts for 47.3–62.0% of invasive Candida isolates, followed by C. parapsilosis (7.8–19.9%), C. glabrata (13.0–17.9%), C. tropicalis (4.4–5.6%) and C. krusei (3.9–4.9%) [19], [35], [36]. Although C. albicans remains the most common species in candidaemia and IC isolates, lately there appears to be a shift towards non-albicans spp. [19], [36], as evidenced in recent surveillance studies worldwide [37], [38], [39], [40].

To optimise clinical outcomes for patients with candidaemia and IC, appropriate selection of antifungal agent and timing of antifungal treatment are critical [41]. Inappropriate selection or delays in antifungal therapy are linked to poorer prognosis, increased mortality and substantial costs [42], [43], [44], [45], [46], [47]. According to the clinical practice guidelines developed by the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) [48], the Infectious Diseases Society of America (IDSA) [2], the Australian consensus working group [1] and the German-speaking Mycological Society and the Paul-Ehrlich-Society for Chemotherapy [49], several classes of antifungal agents can be used for the treatment of IC. These include triazoles (i.e. fluconazole and voriconazole), echinocandins (i.e. caspofungin, micafungin and anidulafungin) and polyenes [i.e. liposomal amphotericin B (LAmB) and conventional amphotericin B (CAmB)]. The choice of antifungal agents is mainly influenced by the presence of co-morbid conditions (e.g. renal failure) and the clinical status of the patient, followed by a patient's previous exposure to antifungal agents and incidence of fluconazole-resistant non-albicans strains [50].