Anidulafungin for the treatment of invasive candidiasis

Authors


Corresponding author: C. Lass-Flörl, Director, Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Fritz Pregl Str. 3/III, 6020 Innsbruck, Austria
E-mail: cornelia.lass-floerl@i-med.ac.at

Abstract

Clin Microbiol Infect 2011; 17 (Suppl. 1): 1–12

Abstract

Candidaemia/invasive candidiasis (C/IC) is the most frequently occurring invasive fungal infection worldwide, with a particularly strong impact and high incidence in the intensive-care unit, where there is a need for new treatment options and strategies. The echinocandin anidulafungin has broad in vitro activity against a wide range of Candida species, along with favourable pharmacokinetics that allow administration in hepatic and renal impairment and with any comedication without the need for dose adjustments. The efficacy and safety of anidulafungin for the treatment of C/IC were demonstrated in a number of clinical studies and by some limited data from clinical practice. In a randomized comparative trial for the treatment of C/IC in adults, 76% of patients receiving anidulafungin and 60% of those given fluconazole were treated successfully (95% CI for difference: 4–27; p 0.01). Post hoc analyses suggest that anidulafungin is significantly more effective than standard-dose fluconazole for the treatment of candidaemia in critically ill patients. Anidulafungin is generally well tolerated, with commonly reported side effects including headache, hypokalaemia, gastrointestinal symptoms, abnormal liver function test results, and rash. In pharmaco-economic analyses, anidulafungin compared favourably with fluconazole (in terms of overall costs and hospital resource use) as well as with other echinocandins. Echinocandins, including anidulafungin, are now generally recommended as first-line therapy in moderately to severely ill patients, those with prior azole exposure, and patients with C/IC caused by Candida glabrata or Candida krusei.

Introduction

Candidaemia/invasive candidiasis (C/IC) is the most frequently occurring invasive fungal infection worldwide and, in terms of incidence and outcomes, has a particularly heavy impact on intensive-care unit (ICU) patients [1–5]. The incidence of invasive Candida infections has risen along with the increased use of intravenous catheters, broad-spectrum antibiotics, parenteral nutrition, immunosuppressive therapy, and invasive procedures, all of which are important relevant risk factors [6–8] (Table 1). In the USA, candidaemia is the third and fourth most common nosocomial bloodstream infection in ICUs and non-ICU wards, respectively [10], and in Europe the rate of candidaemia ranges from 0.17 to 20 per 1000 hospital admissions, depending on country and patient population [8,11,12]. Incidence rates of invasive Candida infections appear to have stabilized in the USA during the period 1996–2003, but may be increasing in some European nations [2,8,9,13–18]. Incidence rates vary significantly according to specific patient populations. In solid organ transplant patients, for example, both the prevalence of invasive fungal infections and the associated mortality depend on the specific type of organ transplant, with invasive candidiasis (IC) being most common in liver transplant patients [19]. The incidence of candidaemia in the ICU is five to 10 times higher than among other hospitalized patients, and over 100 times greater than in the general population [1]. Approximately 10% of ICU patients are affected by IC, with up to 15% of nosocomial infections in this population being attributable to Candida species [20]. Furthermore, in critically ill patients, C/IC generally results in higher mortality rates. Crude mortality rates remain substantial, ranging from 38% to 62% in Europe [5,12,20–22]; fatality rates of up to 75% have been reported in the USA [13]. A recent study in patients at a single UK hospital estimated the mortality attributable to candidaemia as 35% [23], and a similar study in North American patients reported a rate of 49% [24]. Candidaemia is also associated with considerable increases in overall treatment cost and length of stay in the ICU [2,23,25–28].

Table 1.   Common risk factors for invasive Candida infections [6,8,9]
Candida speciesRisk factors
Candida species overallInvasive surgical procedures, especially gastrointestinal surgery
Intravenous catheters
Total parenteral nutrition
Neutropenia
Immunosuppressive therapy
Use of broad-spectrum antibiotics
Cancer chemotherapy
Use of H2 blockers
Premature birth
Prolonged intensive-care unit stay
Renal failure/haemodialysis
Mucosal Candida colonization
Candida kruseiNeutropenia
Corticosteroid therapy
Prior use of azole antifungals
Haematological malignancy
Stem cell transplantation
Candida glabrataOlder age
Solid organ transplantation
Candida parapsilosisRecent surgery
Peripherally inserted central venous catheters

Outcomes of C/IC appear to vary significantly according to patient age as well as the causative Candida species; the highest mortality rates are observed with Candida krusei, followed by Candida tropicalis and Candida glabrata [6,12]. Species distribution and antifungal susceptibility both show considerable geographical variation, underscoring the importance of understanding local epidemiology to the effective management of IC [1,8,29–31]. Although Candida albicans remains the predominant cause of C/IC, the frequency of infections caused by non-albicans species is rapidly increasing across the globe [1,6,8,9,32,33]. In fact, some studies report that less than half of all cases in the USA and Europe are now caused by C. albicans [6,33]; the incidence rate may fall below 20% at some individual institutions [31]. This is a worrying trend, as some of the emerging species are associated with intrinsic or acquired resistance to fluconazole [9,13,30–32], which is the mainstay of candidaemia treatment, as well as with higher mortality rates [6]. Along with geographical differences, certain underlying risk factors may also contribute to variations in epidemiology [6,8,9]. For instance, C. glabrata candidaemia seems more common in older patients and solid organ transplant recipients, whereas risk factors for C. krusei include the prior use of antifungal agents, haematological malignancy, and neutropenia (Table 1) [6].

Treatment outcomes are also heavily dependent on the appropriate use of available therapy options. As compared with other bloodstream infections, fungaemias appear to be associated with a particularly high rate of inappropriate first-line treatment, mainly in the form of delay or even complete omission of antifungal therapy [13]. This situation is a serious cause for concern, as a number of studies have demonstrated that early, adequate treatment of C/IC significantly improves patient survival [34–37]. The early treatment of IC is mainly impeded by a lack of rapid and sensitive diagnostics. Much ongoing work is therefore aiming to develop risk factor assessments for the identification of those patients who would profit most from antifungal prophylaxis or early treatment [13,38–40].

Antifungal prophylaxis may reduce candidaemia incidence rates as well as mortality in selected populations [13,39,41,42], and thus seems a very attractive management approach, albeit one that is still under discussion for non-neutropenic ICU patients [39,42]. Routine fluconazole prophylaxis in the ICU may be associated with a significant increase in non-albicans, azole-resistant fungaemia, and should therefore be considered carefully; antifungal prophylaxis may also result in avoidable drug-related toxicity [3,42]. Some authors recommend that triazole prophylaxis for the prevention of invasive Candida infections should be reserved only for particularly high-risk ICU populations, such as patients undergoing repeated abdominal surgery for tertiary peritonitis and/or acute pancreatitis [43]. Pre-emptive therapy, i.e. early initiation of treatment before C/IC has been diagnosed with certainty, may thus be a more appropriate alternative to chemoprophylaxis, especially when combined with infection control measures [13,42,43]. Pre-emptive therapy is based on a combination of risk factor evaluations and assessment of diagnostic markers (e.g. Candida colonization, β-d-glucan, procalcitonin, fungal DNA, mannan/anti-mannan antibodies, and Candida germ-tube antibodies) [44–46], and as such, encompasses a variety of different strategies aimed at selecting patients suitable for early treatment [41–43,47]. For example, a ‘Candida score’ integrating the presence of risk factors and the extent of Candida colonization has been shown to be a good predictor of IC [45]. A somewhat simpler validated risk-score model was also recently published, and may constitute a useful tool for the rapid identification of patients at increased likelihood of developing candidaemia [38]. Another early therapy approach is termed empirical treatment, and denotes the administration of antifungals to patients symptomatic for an infection but without microbiological confirmation [42]. However, empirical treatment for C/IC remains questionable. For example, in a recent large, placebo-controlled, randomized trial in ICU patients, unresolved fever refractory to broad-spectrum antibiotics was used as an indication to initiate fluconazole therapy. The trial demonstrated that this particular approach to empirical antifungal treatment did not improve a composite outcome measure when compared with placebo [48]. The various approaches proposed for early therapy have considerable potential, but need to be refined and validated in additional clinical studies [41,47]. Regardless of the specific treatment strategy, the relatively high incidence of C/IC, the substantial associated mortality rates and the increasing prevalence of fluconazole resistance suggest the need for more effective antifungals to manage this condition. In this respect, the echinocandins (anidulafungin, caspofungin, and micafungin) appear to hold particular promise.

Overview of anidulafungin

Anidulafungin is a novel broad-spectrum antifungal that is indicated for the treatment of candidaemia and other forms of IC in adult non-neutropenic patients [49] (see Table 2 for a comprehensive overview of C/IC treatment options available in Europe). Like other members of the echinocandin class, it is a potent and selective inhibitor of the fungal enzyme β-(1,3)-d-glucan synthase, thus ultimately disrupting the integrity of fungal cell walls. Anidulafungin exhibits potent in vitro fungicidal activity against a wide range of Candida species, including strains resistant to fluconazole [29,58–61]. Like all the echinocandins, anidulafungin is less active against Candida parapsilosis isolates [7,62–64], although in vitro it may be more potent against this species than both caspofungin and micafungin [65]. However, the clinical significance of these findings is unknown; in clinical trials for instance, C. parapsilosis infection was not significantly less responsive to echinocandin treatment than invasive mycoses caused by other Candida species [7,62,66–69]. For example, a pooled analysis of two phase III clinical trials demonstrated that the causative Candida species had no impact on 42-day survival and clinical success for C/IC patients, whether treated with caspofungin, micafungin, or liposomal amphotericin B (L-AmB). Lack of catheter removal, APACHE II scores >20, age ≥70 years, neutropenia, and corticosteroid treatment, on the other hand, did negatively impact on both of these outcome variables [70].

Table 2.   Currently available management options for invasive Candida infections
AgentRelevant licensed indications in Europe [49–57]
  1. Some of these agents are also licensed for the treatment of other invasive fungal diseases or for non-invasive Candida infections.

  2. aThe decision to use micafungin should take into account a potential risk for the development of liver tumours. Micafungin should therefore only be used if other antifungals are not appropriate.

Echinocandins
 AnidulafunginTreatment of invasive candidiasis in adult non-neutropenic patients
 Caspofungin1. Treatment of invasive candidiasis in adult or paediatric patients
2. Empirical therapy for presumed Candida infections in febrile, neutropenic adult or paediatric patients
 Micafungina1. Treatment of invasive candidiasis in adult or paediatric patients (including neonates)
2. Prophylaxis of Candida infection in adult or paediatric patients undergoing allogeneic haematopoietic stem cell transplantation or who are expected to have neutropenia
Polyenes
 Conventional amphotericin BTreatment of disseminated candidiasis
 Amphotericin B lipid complexTreatment of severe invasive candidiasis
 Liposomal amphotericin B1. Treatment of severe systemic and/or deep mycoses (including disseminated candidiasis) where toxicity (particularly nephrotoxicity) precludes the use of conventional systemic amphotericin B in effective dosages
2. Empirical treatment of presumed fungal infections (including disseminated candidiasis) in febrile neutropenic patients where the fever has failed to respond to broad-spectrum antibiotics and appropriate investigations have failed to define a bacterial or viral cause
Triazoles
 Fluconazole1. Treatment of systemic candidiasis, including candidaemia, disseminated candidiasis, and other forms of invasive candidal infection
2. Prophylaxis of fungal infections in immunocompromised patients considered to be at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, including bone marrow transplant patients
 Posaconazole1. Prophylaxis of invasive fungal infections in high-risk patients receiving remission-induction chemotherapy for acute myelogenous leukaemia or myelodysplastic syndromes expected to result in prolonged neutropenia and who are at high risk of developing invasive fungal infections
2. Prophylaxis of invasive fungal infections in high-risk haematopoietic stem cell transplant recipients who are undergoing high-dose immunosuppressive therapy for graft-versus-host disease
 Voriconazole1. Treatment of candidaemia in non-neutropenic patients
2. Treatment of fluconazole-resistant serious invasive Candida infections (including Candida krusei)

Anidulafungin was also shown to be active against C. albicans and C. parapsilosis biofilms in vitro and in animal studies, a possible class effect of the echinocandins [71,72] (Long et al., 20th ECCMID, 2010, Poster 1919). If this activity can be confirmed in clinical trials, echinocandins may emerge as an effective management strategy for catheter-related candidaemia [72]. Echinocandins also exhibit a so-called post-antifungal effect (PAFE), i.e. suppression of fungal growth after limited exposure to an antifungal. An in vitro study comparing the PAFE of anidulafungin against C. albicans with that of fluconazole, caspofungin and amphotericin B found that anidulafungin generally produced prolonged PAFEs even at concentrations below the MIC for this agent. In contrast, fluconazole did not result in a PAFE at any concentration, and caspofungin produced only a very short (0–2 h) PAFE at concentrations below its MIC; the PAFE of amphotericin B also tended to have shorter durations at levels below the MIC [73]. Caspofungin, anidulafungin and amphotericin B all displayed a prolonged PAFE of >12 h when tested at concentrations above their MICs [73]. In contrast, some Candida isolates may exhibit continued growth at echinocandin concentrations well above the MICs for these agents; this so-called Eagle effect (or paradoxical growth) differs according to the Candida species and the specific echinocandin agent. Although in vitro paradoxical growth appears to be more frequent with caspofungin and micafungin than with anidulafungin, the clinical significance of this phenomenon remains unknown [74,75].

The pharmacokinetics of anidulafungin, characterized in healthy subjects, special populations and patients, allow for once-daily, fixed-dose intravenous (IV) administration in adult patients. It is given at a loading dose of 200 mg on the first day, followed by 100 mg daily thereafter [49,76]; the requirement for only once-daily administration is shared by all currently available echinocandins [49–51]. However, anidulafungin has certain distinctive pharmacokinetic properties that set it apart from other echinocandins (Table 3). Clearance of anidulafungin occurs through slow chemical degradation, and the resulting non-active primary metabolite appears to be further degraded by plasma peptidases. There is no evidence of hepatic metabolism mediated by cytochrome P450, nor does anidulafungin appear to be an inhibitor or inducer of the cytochrome P450 isozymes that are commonly involved in drug metabolism [78]. There is also only negligible renal involvement in the metabolism of anidulafungin, which is almost exclusively eliminated through the faeces (up to 90% as degradation products), presumably via biliary excretion [78]. Finally, the parent drug is not a substrate for organic anion-transporting protein or P-glycoprotein, both of which are key transporters involved in the biliary elimination of drugs; excretion of anidulafungin into the bile therefore probably occurs via passive diffusion (Inskeep et al., 18th ECCMID, 2008, Poster 1049). The lack of hepatic and renal involvement in anidulafungin metabolism was further confirmed by results of pharmacokinetic studies in renally or hepatically impaired populations [79]. Unlike the other echinocandins, anidulafungin can therefore be administered without dose adjustments to patients with any degree of renal/hepatic insufficiency, and also does not require dose adjustments with any concomitant drugs [49,78,79]. These properties make anidulafungin particularly suited to the treatment of C/IC in ICU patients [80–82], who tend to present with organ dysfunction and/or multiple comedications. In this context, it should be noted that therapy with the echinocandin micafungin requires close monitoring of liver function (because of the potential risk of liver tumour development) and should be conducted following a careful risk–benefit evaluation, particularly in patients with severe liver function impairment or certain chronic liver diseases, or those receiving concomitant hepatotoxic agents [50].

Table 3.   Comparison of pharmacokinetic parameters and properties between the currently available echinocandins [49–51,77]
 AnidulafunginCaspofunginMicafungin
  1. Vss, volume of distribution at steady state; T1/2, half-life; CL, total clearance.

  2. aTerminal elimination half-life.

  3. bβ-Phase half-life (plasma concentrations decline in a polyphasic manner).

Key pharmacokinetic parameters/propertiesIntravenous administration onlyIntravenous administration onlyIntravenous administration only
Linear pharmacokineticsModerate non-linear pharmacokineticsLinear pharmacokinetics
>99% plasma protein binding92.4–96.5% plasma protein binding>99% plasma protein binding
Vss 30–50 LVss unknownVss 18–19 L
T1/2 40–50 haT1/2 9–11 hbT1/2 10–17 ha
CL 1 L/hCL 10–12 mL/minCL 0.15–0.3 mL/min/kg
Biotransformation: occurs via slow chemical degradation and subsequent metabolism by plasma peptidases; no hepatic involvementBiotransformation: occurs via spontaneous degradation and subsequent peptide hydrolysis and N-acetylationBiotransformation: some involvement of hepatic cytochrome P450 enzymes
Elimination: mainly via biliary excretion; negligible renal clearance (<1%)Elimination: about 40% of total dose eliminated via urineElimination: primarily non-renal
Use in renal/hepatic impairmentNo dose adjustments for any degree of hepatic impairment


No dose adjustments for any degree of renal impairment
No dose adjustments for mild hepatic impairment; dose adjustments for moderate hepatic impairment; no recommendation for severe hepatic impairment
No dose adjustments for any degree of renal impairment
No dose adjustments for mild to moderate hepatic impairment; no recommendation for severe hepatic impairment

No dose adjustments for any degree of renal impairment
Drug–drug interactionsNone knownClosely monitor liver enzymes with concomitant cyclosporin A
Adjustment of concomitant tacrolimus dosage mandatory based on tacrolimus plasma levels
Increase caspofungin dosage with concomitant efavirenz, nevirapine, rifampicin, dexamethasone, phenytoin or carbamazepine
Sirolimus, nifedipine and itraconazole dosage should be decreased in case of observed toxicity

Clinical efficacy and safety

Initial clinical studies indicating the efficacy and safety of anidulafungin in the treatment of C/IC included a phase II, dose-ranging trial in this setting, which showed microbiological eradication rates (but not treatment-related adverse events) to be dose-dependent [83]. On the basis of the results of that study, phase III trials of anidulafungin for C/IC, including that caused by C. parapsilosis, were suggested, using a 100-mg maintenance dose [69,83]. Such a trial was subsequently conducted in the form of a randomized, controlled, double-blind comparison of anidulafungin with fluconazole for the first-line therapy of documented C/IC [62]. Participants were ≥16 years of age and had at least one blood or tissue culture positive for Candida within 96 h prior to enrolment. Another inclusion criterion was the presence of one or more of the following: fever, hypothermia, hypotension, local signs and symptoms of IC, and/or radiological findings of IC. Key exclusion criteria comprised prior azole prophylaxis, C. krusei infection, refractory C/IC, and a diagnosis of Candida osteomyelitis, endocarditis, or meningitis. Eligible patients were randomized to either IV anidulafungin (200 mg on day 1, and 100 mg daily thereafter) or IV fluconazole (at the generally recommended dose of 800 mg on day 1, and 400 mg daily thereafter) in a 1 : 1 ratio. After 10 days of IV therapy, patients were allowed to switch to oral fluconazole (400 mg daily) if they had been afebrile for at least 24 h, blood culture was negative for Candida, and they had shown clinical improvement. Antifungal treatment continued for at least 14 days after the first negative blood culture and clinical improvement of C/IC, for a maximum of 42 days. The primary efficacy endpoint of the study was global response at the end of IV therapy (EOIT) in the modified intention-to-treat (MITT) population, i.e. those patients who received at least one dose of study drug and had confirmed invasive Candida infection at baseline. Death, lack of significant clinical improvement, persistent or recurrent C/IC or any indeterminate response were considered as treatment failure. An overview of this trial and of other key studies evaluating echinocandins for the therapy of C/IC is presented in Table 4.

Table 4.   Summary of major comparative phase III trials evaluating the echinocandins in candidaemia/invasive candidiasis (C/IC)
 Anidulafungin (Reboli et al. 2007) [62]Caspofungin (Mora-Duarte et al. 2002) [84]Micafungin (Kuse et al. 2007) [85]
  1. AmB, amphotericin B; IV, intravenous; L-AmB, liposomal amphotericin B; MITT, modified intention-to-treat; PP, per-protocol.

  2. aIn the primary efficacy population of each trial.

  3. bAfter adjustment for neutropenic status and APACHE II score.

  4. cAfter adjustment for neutropenic status.

  5. dCalculated on the basis of numbers in the intention-to-treat population, including the 12-week follow-up period.

Study designDouble-blind, randomized, multinational, non-inferiority/superiority studyDouble-blind, randomized, multinational, non-inferiority/superiority studyDouble-blind, randomized, multinational, non-inferiority study
Patient populationAdults (>16 years) with confirmed C/IC within 96 h prior to enrolmentAdults (>18 years) with confirmed C/IC within 96 h prior to enrolmentAdults (>16 years) with confirmed C/IC within 96 h prior to enrolment
DoseAnidulafungin IV 100 mg/day (loading dose 200 mg on day 1)
After ≥10 days, patients could be switched to oral fluconazole 400 mg/day, under certain conditions
Caspofungin IV 50 mg/day (loading dose 70 mg on day 1)
After ≥10 days, patients could be switched to oral fluconazole 400 mg/day, under certain conditions
Micafungin IV 100 mg/day (2 mg/kg for patients weighing <40 kg). Could be increased up to 200 mg/day if needed
Comparator agentFluconazole IV 400 mg/day (loading dose 800 mg on day 1)

After ≥10 days, patients could be switched to oral fluconazole 400 mg/day, under certain conditions
Conventional AmB IV
 Non-neutropenic patients: 0.6–0.7 mg/kg/day
 Neutropenic patients: 0.7–1.0 mg/kg/day
After ≥10 days, patients could be switched to oral fluconazole 400 mg/day, under certain conditions
L-AmB 3 mg/kg/day. Could be increased up to 5 mg/kg/day if needed
Treatment duration14–42 days, for ≥14 days after a negative blood culture and improvement in signs/symptomsNot specified, but 14 days after last positive blood culture14–28 days (up to 56 days in cases of chronic disseminated candidiasis, Candida osteomyelitis or Candida endocarditis)
Primary efficacy endpointGlobal response (defined as both clinical and microbiological success) at the end of IV treatment in the MITT populationGlobal response (defined as both clinical and microbiological success) at the end of IV treatment in the MITT populationGlobal response (defined as both clinical and microbiological success) at the end of treatment in the PP population
Patient numbersaAnidulafungin: 127
Fluconazole: 118
Caspofungin: 109
AmB: 115
Micafungin: 202
L-AmB: 190
Primary efficacy resultsAnidulafungin: 75.6%
Fluconazole: 60.2%
(95% CI for difference: 3.9–27.0)
Caspofungin: 73.4%
AmB: 61.7%
(95.6% CI for difference: −0.7 to 26.0)b
Micafungin: 89.6%
L-AmB: 89.5%
(95.6% CI for difference: −5.3 to 6.7)c
All-cause mortalityAnidulafungin: 23%
Fluconazole: 31%
(p 0.13)
Caspofungin: 34%
AmB: 30%
(p 0.53)
Micafungin: 40%d
L-AmB: 40%d

Of 261 enrolled patients, 245 were included in the MITT population; of these, 127 received anidulafungin and 118 fluconazole. Treatment arms did not differ in patient demographics, baseline Candida species, treatment duration, or frequency and exposure to oral fluconazole. The most common causative pathogen was C. albicans (62%), followed by C. glabrata, which was isolated in 16% and 25% (p 0.08) of those in the anidulafungin and fluconazole groups, respectively. Ninety-six per cent of all isolates were fluconazole-susceptible. At EOIT, there was a significantly greater global response rate with anidulafungin (76%) than with fluconazole (60%; p 0.01); the difference was 15 percentage points (95% CI 4–27). A number of statistical analyses all failed to demonstrate the potential influence of a centre effect on the primary outcome [62]. Anidulafungin also showed better efficacy at EOIT and at 2 weeks after EOIT, and was non-inferior at 6 weeks post-EOIT. There was no statistically significant difference in mortality rates between fluconazole and anidulafungin (31% vs. 23%; p 0.13). It is of note that approximately 20% of patients in each arm had APACHE II scores >20, and in this subpopulation the response rates with anidulafungin and fluconazole were similar [62]. A number of reports suggest that high baseline APACHE II scores may negatively impact on mortality and the success of antifungal therapy in patients with C/IC [86–88], which could explain these findings.

In terms of causative pathogens, global responses with anidulafungin at EOIT were highest for C. tropicalis (93%) and lowest for C. glabrata (56%); C. parapsilosis, which exhibited the highest MICs of anidulafungin, had an EOIT response rate of 64%. It is of note that the global response rates against C. albicans infections were remarkably different between the two study treatments (81% for anidulafungin vs. 62% for fluconazole; p 0.02) [62]. Microbiological failure in patients with C. albicans infection was significantly lower with anidulafungin than with fluconazole, whereas no significant differences were evident in other baseline Candida infections [89]. Similar advantages in microbiological clearance were not observed in clinical trials with other echinocandins [89]. These observations are important, considering that C. albicans remains the most common pathogenic Candida species overall [6,8,13].

Critically ill patients comprise another important patient subgroup, and a post hoc analysis was therefore conducted to compare the responses to anidulafungin and fluconazole in this population [90]. For the purposes of that analysis, three groups of critically ill patients were identified from the original trial [62]: those in the ICU at study entry (= 89); patients with APACHE II scores ≥15 (= 113); and patients with severe sepsis and organ dysfunction (= 118) [90]. Global responses at EOIT were better with anidulafungin in each of these subgroups, but the difference only reached statistical significance in the second group. Among those in the ICU at study entry, global response rates were 63% and 45% for anidulafungin and fluconazole, respectively (95% CI for difference: −2% to 40%). Similarly, response rates in the second group were 68% and 46% (95% CI for difference: 4–40%), respectively, and they were 68% and 52% (95% CI for difference: −2% to 34%) in the third group. Among patients with multiple organ dysfunction (= 45), global response rates were 76% for anidulafungin and 30% for fluconazole (95% CI for difference: 21–73%). Across groups, no significant survival advantages at either day 14 or day 28 were observed. The investigators concluded that anidulafungin was significantly more effective than fluconazole for the treatment of candidaemia in critically ill patients (defined as either those with sepsis and multiple organ dysfunction or those with APACHE II scores ≥15) [90]. This observation lends support to current guidelines [4,7,42] recommending echinocandins as first-line C/IC treatment in this population [90].

In conjunction with the main trial [62], an open-label, non-comparative study was also conducted [77]. This additional study was similar in design, but evaluated anidulafungin in patients who were excluded from the main study because of previous azole prophylaxis, known azole hypersensitivity, treatment with medications contra-indicated with fluconazole, and/or C. krusei infection. The resultant global response rate at EOIT was 68% in the overall MITT population, with global, clinical and microbiological success being sustained from 2 to 6 weeks after treatment initiation [77]. Anidulafungin thus appears to be effective in a wider patient population, including those with C/IC after azole prophylaxis and patients who are intolerant of azole therapy.

Anidulafungin presented with a very favourable safety and tolerability profile in all clinical studies [62,83]. Commonly reported side effects with this agent are headache, hypokalaemia, diarrhoea/vomiting/nausea, abnormal liver or kidney function test results, rash/pruritis, flushing, disorders of the blood clotting system, and convulsions. Uncommon side effects include cholestasis, injection site pain, hives, hyperglycaemia, hypertension, hot flushes, and stomach pain [49]. In the randomized trial comparing anidulafungin and fluconazole for C/IC, both agents resulted in similar numbers of treatment-related adverse events (24% and 26% of patients, respectively), including those of a serious nature. The majority of all-causality adverse events were mild to moderate in intensity [62]. Elevated liver function test findings related to study treatment were observed in more patients on fluconazole (7%) than anidulafungin (2%; p = 0.03). In addition, significantly more patients treated with fluconazole than with anidulafungin discontinued the study drug because of adverse events (p 0.02); however, many of these side effects associated with fluconazole may actually have been caused by worsening clinical status rather than being true treatment-related adverse events [62]. The safety of anidulafungin was also assessed in hospitalized, neutropenic children aged 2–17 years who were given anidulafungin empirically as part of an open-label study [91]. Study participants (= 24) received either 0.75 mg/kg or 1.5 mg/kg IV anidulafungin daily. All patients experienced at least one all-causality adverse event, most of which were mild to moderate in severity; five patients in each dosage group experienced serious adverse events. No patients in the higher-dosage group experienced adverse events that led to treatment discontinuation or that were considered to be related to anidulafungin. In the lower-dose group, four patients experienced anidulafungin-related side effects, but none was serious or led to discontinuation of the study drug. The authors concluded that, at the doses studied, anidulafungin was well tolerated in neutropenic paediatric patients at high risk for invasive fungal infections [91]. It is of note that anidulafungin is currently not indicated for use in children [49].

A recent meta-analysis of randomized clinical trials in C/IC showed that echinocandins overall were non-inferior to other pertinent antifungals, but exhibited a better safety profile [89]. This analysis suggested superior efficacy of anidulafungin over fluconazole in terms of treatment and microbiological success, despite the lack of significant differences in survival rates. Comparative studies with other echinocandins (but conducted against polyenes, not fluconazole) did not demonstrate any significant differences in overall treatment and microbiological failure. The authors pointed out that fluconazole should be avoided for empirical monotherapy in severely ill patients, in whom rapid microbiological clearance of Candida is essential [89].

Use of anidulafungin in clinical practice

The body of data reporting on actual clinical experience with anidulafungin remains limited, as this agent has only recently become available. One relevant publication describes a retrospective cohort study evaluating anidulafungin in clinical practice at a large tertiary medical centre [92]. The study included a total of 35 patients, 49% of whom received anidulafungin for empirical antifungal treatment. Anidulafungin was used to treat candidaemia or IC in 29% and 20% of patients, respectively. Of 13 evaluable patients, 77% experienced a favourable clinical outcome. However, one patient developed breakthrough candidaemia caused by C. parapsilosis while on anidulafungin. One patient reported an infusion-related reaction; otherwise anidulafungin exhibited good tolerability, including in patients receiving concomitant metronidazole. The authors suggest that, on the basis of their clinical experience, anidulafungin may be particularly useful in patients with hepatic dysfunction and those receiving concomitant medications that can interact with other echinocandins [92].

These properties may give anidulafungin somewhat of a practical advantage over caspofungin and micafungin in patient populations commonly affected by organ dysfunction and/or receiving multiple concomitant drugs, such as ICU patients. It should be noted, however, that the current evidence does not indicate any significant efficacy and tolerability differences among the echinocandins [89].

Cost considerations also play an increasingly important role in determining the practical usefulness of medications. A number of studies have shown that the overall expenses associated with the treatment of C/IC are significant and are largely driven by hospitalization costs [25–28]. Although generic fluconazole is relatively inexpensive, more effective first-line agents may thus not only improve clinical outcomes but also offset some of the higher acquisition costs. This was shown to be the case in a pharmaco-economic model comparing the cost-effectiveness of anidulafungin and fluconazole for the treatment of C/IC in Spain (Grau et al., 19th ECCMID, 2009, Poster 1745). The model was based on data from the pivotal clinical trial [62], and indicated that overall treatment costs with anidulafungin were slightly lower (€37 240 vs. €37 327), despite its acquisition costs being more than twice as high (€5780 vs. €2082). Furthermore, anidulafungin treatment resulted in improved clinical success (74% vs. 57%) and was associated with an incremental cost-effectiveness ratio of −€505 per successfully treated patient (Grau et al., 19th ECCMID, 2009, Poster 1745). Cost and outcome data from the phase III trial in C/IC [62] were also assessed from a US perspective [87] (Reboli et al., 19th ECCMID, 2009, Poster 1746). The results of both analyses suggest that anidulafungin significantly improves clinical outcomes among hospital inpatients in general and ICU patients in particular, when compared with fluconazole. In hospitalized patients overall, this was achieved while keeping total treatment costs similar to those with fluconazole (Reboli et al., 19th ECCMID, 2009, Poster 1746). For patients in the ICU at treatment initiation, anidulafungin exhibited a definite but non-significant trend towards lower costs, which was driven by reductions in ICU and hospital lengths of stay. After adjustment for baseline covariates, those ICU patients who received anidulafungin as first-line therapy for C/IC gained a significant advantage in the number of hospital-free days (18.2 vs. 4.3 days; p 0.04) [87].

Another pharmaco-economic study compared the three currently available echinocandins for the treatment of IC in a Spanish hospital setting. Anidulafungin therapy was found to have a lower drug acquisition cost per episode (€6000) than other echinocandins, for which costs are influenced by the potential requirement for dose adjustments. Treatment costs with caspofungin were reported to range from €4281 to €7991, depending on the specific dose requirements based on patient weight and hepatic function. Drug acquisition costs with micafungin were estimated at either €6000 (using a dose of 100 mg/day) or €10 741 (in cases where inadequate response requires a dose increase to 200 mg/day). The authors concluded that treating IC in adult, non-neutropenic patients with anidulafungin was a cost-saving option, and also allowed for better budget control (Garcia et al., 12th Annual European Congress of the International Society for Pharmacoeconomics and Outcomes Research, 2009, PIN12).

Treatment guidelines and recommendations

Current guidelines recommend either fluconazole or an echinocandin as the first-line agent for targeted or empirical therapy of C/IC in most adult non-neutropenic patients. The guidelines also stress the importance of early initiation of effective antifungal treatment to improve the odds of patient survival [4,7,42]. The specific drug should be selected on the basis of the antifungal susceptibility of the causative isolate, the clinical status of the patient (including organ function), prior antifungal treatment, and drug toxicity/tolerability [4]. These points are all addressed in the recent update of the clinical guidelines of the Infectious Diseases Society of America for the management of invasive candidiasis, which take into account novel options for antifungal therapy, particularly the echinocandins [7]. The updated guidelines state that, in non-neutropenic populations, the echinocandins (either anidulafungin, caspofungin, or micafungin) should be preferred in: (i) patients who are moderately to severely ill; (ii) patients who have had recent azole exposure; and/or (iii) potential or confirmed infections caused by C. glabrata or C. krusei. In cases of intolerance or unavailability of other antifungals, conventional amphotericin B or lipid formulations of amphotericin B are suggested as alternatives for first-line therapy [7]. Species identification and susceptibility testing constitute an important element of appropriate management, and should form the basis for potential changes in the first-line drug or for switching from a parenteral agent to an oral azole [4,7]. In particular, once the patient has become stable and the causative Candida strain has been confirmed as susceptible, step-down therapy from IV therapy to oral fluconazole or voriconazole should be initiated. First-line fluconazole is mainly recommended in non-neutropenic patients without prior azole exposure who are less critically ill, and in cases of C. parapsilosis infection. In neutropenic patients, either an echinocandin or amphotericin B lipid formulations are recommended for targeted therapy of documented candidaemia. Alternatively, fluconazole may be used in less critically ill neutropenic patients without prior azole exposure. The removal of IV catheters is strongly recommended for documented candidaemia in neutropenic patients, especially in infections caused by C. parapsilosis, and should be considered in non-neutropenic patients [4,7]. Therapy should be continued for 2 weeks after resolution of candidaemia symptoms and clearance of Candida from the bloodstream [7].

Similar treatment recommendations are made in a recent European publication covering the management of C/IC in adult, non-neutropenic ICU patients, which was based on a literature review and an expert panel discussion [42]. The authors suggest either echinocandins or polyenes whenever there is a high probability of azole-resistant invasive Candida infection (i.e. based on local epidemiology, colonization with fluconazole-resistant strains, or recent azole exposure). Echinocandins are recommended as the preferred first-line treatment in haemodynamically unstable patients, i.e. patients in septic shock or with sepsis complicated by organ dysfunction [4,42]. In haemodynamically stable patients without organ dysfunction, fluconazole is suggested as a reasonable choice for targeted therapy of IC; amphotericin B/lipid formulations of amphotericin B, anidulafungin, caspofungin and voriconazole are listed as alternatives in this setting [42] (Fig. 1). Guidelines have also been prepared by the European Conference for Infections in Leukaemia; these were last updated in 2009. These recommendations assign an AI level of evidence (i.e. good evidence from one or more randomized, controlled trials) to echinocandins, fluconazole, voriconazole and L-AmB as first-line treatment for candidaemia prior to species identification, but advise against the use of azoles to treat invasive Candida infections in patients with severe illness and/or prior azole exposure. After species identification, echinocandins (along with L-AmB and conventional amphotericin B) are given an AI grading against C. albicans and a BI grading against C. glabrata and C. krusei. In haematology patients, echinocandins, L-AmB and other lipid formulations of amphotericin B are assigned a BII (i.e. moderate evidence from one or more study) grading against all Candida species, both before and after species identification. The latest European Conference for Infections in Leukaemia guidelines therefore recommend echinocandins as one of the preferred treatment options for candidaemia in all clinical settings [93].

Figure 1.

 Clinical decision-making tree for treatment of candidaemia/invasive candidiasis, based on recent guidelines (adapted from Guery et al. 2009) [42]. AmB, conventional amphotericin B; LF-AmB, lipid formulations of amphotericin B. aDepending on recent azole exposure, local epidemiology or colonization with fluconazole-resistant Candida strains.

As the high mortality associated with C/IC [12,20,22–24] can be significantly reduced through early and adequate first-line treatment [34–37], new strategies to accurately identify patients with early infections are desperately needed. Some authors propose that such pre-emptive or empirical treatment should be reserved for those patients with a high risk (i.e. about 10–15%) of developing IC [40]. However, no single predictive algorithm is available to accurately identify such patients in the ICU. This currently leaves physicians with the option to base decisions about the need for early antifungal therapy on the frequent evaluation of clinical status and risk factors in each critically ill patient [40], until proposed prediction rules have been validated. Some authors have also called for further research on the potential need for antifungal dose adjustments in cases of haemodialysis, volume overload, and septic shock [4]; in this respect, it should be noted that the pharmacokinetics of anidulafungin do not seem to be altered by extended daily dialysis [94].

Conclusions

Anidulafungin is a useful option for the first-line treatment of C/IC, especially in critically ill patients, on the basis of its demonstrated clinical efficacy, good safety and tolerability, and favourable pharmaco-economics. In vitro studies suggest that anidulafungin may have better efficacy against C. parapsilosis than other currently available echinocandins, but the clinical significance of these findings is not known. Furthermore, anidulafungin has an excellent drug interaction profile, and is the only echinocandin that does not require dose adjustments with any concomitant drugs and any degree of renal or hepatic impairment. Echinocandins, including anidulafungin, are recommended as first-line therapy in moderately to severely ill patients, those with prior azole exposure, and those with invasive infections caused by C. glabrata or C. krusei.

Acknowledgements

Editorial support was provided by D. Wolf of PAREXEL, and was funded by Pfizer.

Transparency Declaration

Publication of this supplement and editorial support were funded by Pfizer, in collaboration with PAREXEL. M. Aigner declares no conflicts of interest. A. Mayr has received lecture fees from Pfizer. C. Lass-Flörl has received lecture fees from Gilead and Pfizer and unrestricted research grants from Basilea, Gilead, and Pfizer.