Anidulafungin for the treatment of candidaemia caused by Candida parapsilosis: Analysis of pooled data from six prospective clinical studies

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1 Received: 1 February 2017 Revised: 11 May 2017 Accepted: 11 May 2017 DOI: /myc ORIGINAL ARTICLE Anidulafungin for the treatment of candidaemia caused by Candida parapsilosis: Analysis of pooled data from six prospective clinical studies Dimitrios P. Kontoyiannis 1 Matteo Bassetti 2 Marcio Nucci 3 Maria Rita Capparella 4 Jean L. Yan 5 Jalal Aram 5 Patricia A. Hogan 5 1 The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Department of Medicine, University of Udine, Udine, Italy 3 Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil 4 Pfizer PFE, Paris, France 5 Pfizer Inc, New York, NY, USA Correspondence Dr Dimitrios P. Kontoyiannis, Texas 4000 Distinguished Endowed Professor for Cancer Research, Deputy Head, Division of Internal Medicine, Department of Infectious Diseases, Infection Control and Employee Health, Unit 1460, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. dkontoyi@mdanderson.org Funding information This study was sponsored by Pfizer. Summary Concerns with echinocandin use for infections caused by Candida parapsilosis complex species have driven the need for data to support echinocandin clinical efficacy in such patients. Data from six prospective studies were pooled to assess efficacy and safety of anidulafungin in patients with candidaemia caused by C. parapsilosis. Patient- level data were pooled from patients with microbiologically confirmed candidaemia due to C. parapsilosis treated with anidulafungin. Patients received a 200 mg intravenous (IV) loading dose of anidulafungin (day 1) and 100 mg daily thereafter. IV treatment could be switched to oral azole therapy after 5 or 10 days. Primary endpoint was global response at end of IV therapy (EOIVT). Seventy patients had candidaemia caused by C. parapsilosis. Global response was 77.1% (95% CI: 67.3, 87.0) at EOIVT and 70.0% (95% CI: 59.3, 80.7) at end of treatment. Three of 55 isolates (with MICs available) were resistant to anidulafungin (MIC 8 mg/l). All- cause mortality was 5.7% (n=4/70) by day 14 and 14.3% (n=10/70) by day 28. IV anidulafungin was effective for the treatment of C. parapsilosis candidaemia in this population, consistent with efficacy previously demonstrated for other Candida species. (ClinicalTrials.gov identifiers: NCT , NCT , NCT , NCT , NCT , NCT ). KEYWORDS anidulafungin, Candida parapsilosis, invasive candidiasis, patient-level data, pooled analysis 1 INTRODUCTION Candida species are among the leading causes of invasive fungal disease worldwide and are one of the most common hospital- acquired bloodstream infections. 1 Such infections are associated with substantial morbidity and mortality as well as increased healthcare costs. 2 In some countries, Candida parapsilosis is the second most commonly isolated Candida species from blood cultures after C. albicans. 3 The Infectious Diseases Society of America update of the treatment guideline for candidiasis recommends the empiric use of an echinocandin. 4 A recent study supports the recommendations: in 307 patients with C. parapsilosis candidaemia there was no difference in 30- day mortality between patients receiving an echinocandin or fluconazole. 5 In patients with a history of prior treatment with an echinocandin, and those with C. parapsilosis infection, testing for echinocandin susceptibility is suggested, as breakthrough C. parapsilosis infections during echinocandin treatment have been observed. 6 Anidulafungin is an agent of the echinocandin class that has been approved in Europe and the United States for the treatment of candidaemia and other forms of invasive candidiasis. When compared with other Candida species, C. parapsilosis exhibits higher in vitro minimum Mycoses. 2017;60: wileyonlinelibrary.com/journal/myc 2017 Blackwell Verlag GmbH 663

2 664 KONTOYIANNIS et al. inhibitory concentrations (MICs) to echinocandins. 7 Data for the efficacy of anidulafungin in patients with candidaemia caused by C. parapsilosis are currently limited. In this analysis, data from six studies were pooled to assess the efficacy and safety of anidulafungin in this group of patients. 2 PATIENTS AND METHODS 2.1 Study design and treatment Patient- level data were pooled from six studies of patients treated with anidulafungin who had microbiologically confirmed candidaemia due to C. parapsilosis. The studies included two double- blind studies evaluating anidulafungin and caspofungin (Pfizer data on file), and four open- label studies These prospective clinical trials were comparable with regard to anidulafungin treatment regimen, inclusion/ exclusion criteria and outcome measures. All studies were registered with ClinicalTrials.gov and were conducted in compliance with the Declaration of Helsinki and Good Clinical Practice Guidelines established by the International Conference on Harmonisation. All study documentation was reviewed and approved by the Institutional Review Boards and the Independent Ethics Committees of the investigating centres. All studies were sponsored by Pfizer Inc. All patients provided written, informed consent. Eligible patients were aged 18 years with blood culture positive for Candida species isolated within 96 hours of entry to the study. Patients were enrolled in these studies based on microbiological evidence suggestive of Candida infection (eg, positive blood culture for yeast); however, confirmation of Candida species was required within 96 hours to remain in the study. Patients were excluded from studies if they had received >48 hours of prior antifungal therapy, had prosthetic devices at infection sites that were not able to be removed within 24 hours of study entry, or had previously failed treatment for the current episode of Candida infection. Patients with mixed infections were withdrawn from the study and treated as appropriate by the investigator. positive culture for Candida species isolated within 96 hours of entry to the study). In this pooled dataset, global response comprised the clinical and microbiological responses. Clinical success was defined as the resolution of signs and symptoms of candidaemia and no need for additional systemic antifungal therapy for the treatment of confirmed Candida infection. Microbiological success was defined as the eradication of Candida species present at baseline, as determined by followup blood culture. The secondary endpoint included global response at end of treatment (EOT) and all- cause mortality recorded at days 14 and 28 after initiation of IV therapy in the modified ITT population. A catheter- associated C. parapsilosis infection occurred if patients catheters were believed to be a source of Candida infection. Anidulafungin MICs were determined using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method according to the M27- A3 document, and results were interpreted according to the CLSI M27- S3 document. 12, Safety and tolerability endpoints The ITT population (all patients who received 1 dose of anidulafungin) was used for the safety analysis (secondary endpoint). Serious adverse events and the incidence and severity of treatment- emergent adverse events of all causalities were summarised by Medical Dictionary for Regulatory Activities (MedDRA) preferred term. 2.5 Statistical analyses This was an analysis in estimation and no hypotheses for efficacy endpoints were tested. Evaluation consisted of descriptive statistics. Success rates for global response were estimated with exact 95% confidence intervals (CI) for binomial proportion (Clopper- Pearson method). In efficacy analyses, indeterminate or missing data were considered failures. 3 RESULTS 2.2 Treatments Patients received a 200 mg loading dose of intravenous (IV) anidulafungin on day 1 followed by 100 mg daily thereafter. In all studies except study A (NCT ), investigators had the option to switch to an oral azole (fluconazole or voriconazole) after 5 or 10 days of treatment with anidulafungin based on prespecified criteria. 2.3 Efficacy endpoints The purpose of the current analysis was to determine the efficacy of anidulafungin for the treatment of candidaemia caused by C. parapsilosis and the primary endpoint was global response at end of IV therapy (EOIVT) in the modified intent- to- treat (ITT) population (all patients who received 1 dose of anidulafungin and who had a Seventy patients with culture- confirmed candidaemia caused by C. parapsilosis at baseline were identified in the database (modified ITT population). Ten of these patients were co- infected with other Candida baseline pathogens including five C. glabrata, three C. albicans, one C. norvegensis and one C. tropicalis. Baseline patient characteristics for this group are shown in Table 1. The majority of patients were male and white. The mean age was 54.9 years. Acute Physiology and Chronic Health Evaluation II (APACHE II) score was collected in 69 patients who had a mean baseline score of Twenty- seven patients had a score 15. Haematological malignancies were present in 10% of patients (7/70) and 18.6% of patients had solid tumours (13/70). The most common risk factors (occurring in 50% of patients) for candidaemia were use of broad spectrum antibiotics and central venous catheters (Table 2); 35.7% (25/70) of patients had catheterassociated C. parapsilosis infection as judged by the investigators, and

3 KONTOYIANNIS et al. 665 TABLE 1 Patient baseline characteristics (modified ITT population; n=70) TABLE 2 Success rates of patients according to baseline characteristics and MIC category Characteristics Value Characteristic EOIVT EOT Sex, N (%) Male 43 (61.4) Race, N (%) White 48 (68.6) Black 8 (11.4) Asian 12 (17.1) Other 2 (2.9) Mean age, y (SD) 54.9 (16.7) Mean APACHE II score (SD) 13.1 (6.3) Risk factors for candidaemia at baseline a, N (%) Mechanical ventilation 22 (33.3) Use of broad- spectrum antibiotics 57 (86.4) Use of central venous catheter 51 (77.3) Total parenteral nutrition 32 (48.5) Renal insufficiency/failure/dialysis 18 (27.3) Surgery 26 (39.4) Abdominal surgery 17 (25.8) Solid organ transplant 5 (7.6) Chemotherapy 11 (16.7) Use of systemic steroids or other immunosuppressive therapies catheters were removed in 88% (22/25) within 24 hours. Further information on the six studies is shown in Table S Efficacy The global response was 77.1% (n=54/70; 95% CI: 67.3, 87.0) at EOIVT and 70% (n=49/70; 95% CI: 59.3, 80.7) at EOT. Global response success rates according to catheter use and APACHE II score are shown in Table 2. All- cause mortality was 5.7% (n=4/70) by day 14 and 14.3% (n=10/70) by day 28. MICs to anidulafungin were available for 55 C. parapsilosis isolates and values ranged from mg/l (MIC50/90=2/4 mg/l). The overall clinical response success rate among these patients was 87.3% (n=48/55) at EOIVT and 78.2% (n=43/55) at EOT. Response rates according to anidulafungin MIC are shown in Table 2. The overall microbiological response success rate was 89.1% (n=49/55) at EOIVT and 81.8% (n=45/55) at EOT. Three C. parapsilosis isolates were resistant (anidulafungin MIC 8 mg/l) according to CLSI breakpoints; clinical and microbiological successes were assessed in 2/3 patients. Susceptibility of C. parapsilosis to study drugs was available for 58 isolates and is shown in Table (30.3) Length of ICU stay 4 d 31 (47.0) Neutropenia 8 (12.1) APACHE II, Acute Physiology and Chronic Health Evaluation II; ICU, intensive care unit; ITT, intent- to- treat; SD, standard deviation. a Patients may be counted in more than one category of risk factor. Catheter, N (%) Patients without catheter 3.2 Safety and tolerability Out of a total of 70 evaluable patients, 24 experienced serious adverse events and 58 experienced treatment- emergent adverse events, with infections and infestations being the most commonly reported MedDRA adverse event category. Most adverse events were mild or moderate in severity. No new anidulafungin safety concerns were identified in this analysis. 4 DISCUSSION 30/38 (78.9) 27/38 (71.1) 95% CI (66.0, 91.9) (56.6, 85.5) Patients with catheter 24/32 (75.0) 22/32 (68.8) 95% CI (60.0, 90.0) (52.7, 84.8) Catheter removed 19/25 (76.0) 17/25 (68.0) 95% CI (59.3, 92.7) (49.7, 86.3) Catheter not removed 5/7 (71.4) 5/7 (71.4) 95% CI (38.0, 100.0) (38.0, 100.0) APACHE II score, N (%) Score 15 17/27 (63.0) 16/27 (59.3) 95% CI (44.7, 81.2) (40.7, 77.8) Score <15 36/42 (85.7) 33/42 (78.6) 95% CI (75.1, 96.3) (66.2, 91.0) MIC categories, N (%) /13 (92.3) 12/13 (92.3) 1 12/13 (92.3) 10/13 (76.9) 2 18/21 (85.7) 17/21 (81.0) 4 4/5 (80) 2/5 (40) 8 2/3 (66.7) 2/3 (66.7) APACHE II, Acute Physiology and Chronic Health Evaluation II; CI, confidence interval; EOIVT, end of intravenous therapy; EOT, end of treatment; MIC, minimum inhibitory concentration. TABLE 3 In vitro activity of study drugs for 58 Candida parapsilosis isolates (including specimens other than blood) MIC 50/90 (mcg/ml) MIC range (mcg/ml) Anidulafungin 1/ Fluconazole 0.5/ Voriconazole 0.03/ % Susceptible To the best of our knowledge, this pooled analysis of six prospective studies comprising 70 patients is the largest clinical experience of the use of anidulafungin in fungaemia caused by C. parapsilosis.

4 666 KONTOYIANNIS et al. Intravenous anidulafungin was effective for the treatment of candidaemia in our study population, as shown by the global response success rate (77.1% at EOIVT). This was similar to global response success rate in the pivotal study (75.6%), 14 which included patients with candidaemia and other forms of invasive candidiasis. Other investigators have reported a caspofungin success rate of 74% (52/70) in patients with invasive candidiasis caused by C. parapsilosis. 15 Several investigators report decreased efficacy of echinocandins for the treatment of candidaemia due to C. parapsilosis. In a review by Andes et al., 16 the use of echinocandins and central venous catheter removal were factors positively influencing response in patients with candidaemia/invasive candidiasis; echinocandins were least successful for C. parapsilosis. Echinocandins may not be appropriate for all patients with C. parapsilosis infection. 17 In a Spanish investigation, patients with C. parapsilosis central venous catheter- related fungaemia had better outcomes when catheters were promptly removed; however, it could not be excluded that echinocandins were associated with a four- to five- times higher failure rate. 18 In another study, there have been high numbers of persistent C. parapsilosis candidaemias in caspofungin- treated patients. 19 Also, fluconazole has been shown to be more effective than anidulafungin in patients with C. parapsilosis in the registrational study. 14 One study limitation was that no information was available on sub- species of C. parapsilosis complex. Four studies were open- label and non- comparative, and all studies were carried out between different dates in different centres. This was a post hoc analysis with no predetermined plan in the study protocols to combine data at a later date. However, all studies had highly similar protocols and endpoints that allowed pooling of data. No propensity or multivariate analyses were performed due to the small number of patients. Also, eligible patients were not severely ill or profoundly immunosuppressed, suggesting that the study population may not be fully representative of real- world treatment of candidaemia. Finally, we were not able to determine the percentage of catheter- related fungaemia because catheter information was only captured for three of the six pooled studies. However, most patients with a catheter had the catheter removed promptly at the onset of fungaemia irrespective of whether the fungaemia was caused by the catheter. The small number of resistant C. parapsilosis isolates and high rate of clinical success in the current investigation precluded the correlation of anidulafungin MICs with outcome. Recent guidelines support testing for echinocandin susceptibility in patients with C. parapsilosis infection, although available evidence is of low quality. 4 Analysis of isolates from patients with oesophageal or invasive candidiasis in a caspofungin clinical trial database showed no correlation between in vitro MICs and outcomes. 20 Although breakthrough to anidulafungin C. parapsilosis fungaemia has been sporadically reported, 21 anidulafungin resistance in C. parapsilosis remains uncommon In the most recently published SENTRY surveillance study, no anidulafungin- resistant C. parapsilosis isolates were reported. 25 From another study of 2468 isolates collected from clinical laboratories in Europe, North America and Australia, for which MICs were determined by broth microdilution, only 13 isolates had MICs 8 μg/ml, 26 the resistant breakpoint for anidulafungin vs C. parapsilosis as defined by CLSI. 27 The results of this pooled analysis add to evidence that anidulafungin is an effective treatment option for patients with candidaemia due to C. parapsilosis and has a safety profile consistent with previous experience. ACKNOWLEDGEMENTS Medical writing support was provided by Neil Cockburn at Complete Medical Communications and was funded by Pfizer. Data from this analysis were presented at Trends in Medical Mycology, Lisbon, Portugal, 9-12 October DISCLOSURES D.P.K. has received research support from Merck, Pfizer, Astellas and T2 Biosystems, and has received honoraria from Merck, Astellas, Gilead, Cidara, Inc and Amplynx, Inc. M.B. has received honoraria from Pfizer, MSD, Astellas, Gilead and Basilea. M.N. serves on scientific advisory boards of, and has received speaker honoraria from, Pfizer, Merck, Astellas Pharma and Gilead Sciences. M.R.C is an employee of Pfizer PFE, Paris. J.L.Y., J.A. and P.A.H. are employees of Pfizer Inc. REFERENCES 1. Kullberg BJ, Arendrup MC. Invasive candidiasis. N Engl J Med. 2015;373: Zaoutis TE, Argon J, Chu J, Berlin JA, Walsh TJ, Feudtner C. 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