Efficacy of a Novel Echinocandin, CD101, in a Mouse Model of Azole-Resistant Disseminated Candidiasis

Transcription

1 Efficacy of a Novel Echinocandin, CD0, in a Mouse Model of Azole-Resistant Disseminated Candidiasis L. Miesel, K-Y Lin, J. C. Chien, M. L. Hsieh, V. Ong, and K. Bartizal Eurofins Panlabs, Taipei, Taiwan Cidara Therapeutics Inc., San Diego, CA LynnMiesel@eurofins.com

2 Disclosures Lynn Miesel is a Eurofins Pharma Discovery Services employee. This research was performed under contract between Eurofins Panlabs Taiwan and Cidara Therapeutics.

3 Rationale Candidiasis is becoming more prevalent among nosocomial infections, ranking fourth among BSIs in the USA () C. albicans is the predominant cause but non-albicans species are increasingly prevalent Resistance to azole antifungals is now more common due to widespread fluconazole use The IDSA and ESCMID now recommend echinocandins as firstline treatment (, ) This study aimed to test CD0 for potential use against azoleresistant candidiasis using a disseminated mouse infection model () M. Sanguinetti, B. Posteraro, and C. Lass-Flörl. 05 Mycoses. 58 p- () PG Pappas et al. 05 Clinical Infectious Disease () OA Cornely et al. 0 Clin Microbiol Infect. 8 Suppl 7 p9 7

4 CD0, a highly stable echinocandin Enhanced chemical stability Long-acting pharmacokinetics In development for once-weekly therapy Half-life (hr) Species Caspofungin a Anidulafungin b CD0 b SD Rat Dog N/A 5 Cyno Monkey N/A 8 0 Chimpanzee a. R. Hajdu, et al. Antimicrob. Agents Chemother. (997) :9 b. K. James, et al. ICAAC (0) A-69 and A-69

5 In vitro potency of CD0 against C. albicans Candida albicans 0 0 clinical isolates (n=00)* Azolesusceptible (n=90) Fluconazole-resistant (n=0) MIC 90 (µg/ml) CD0 has potent in vitro activity against azole-susceptible and -resistant clinical isolates *D Hall, R Bonifas, DL Shinabarger, and CM Pillar. Evaluation of the In Vitro Activity of CD0, a Novel Echinocandin, and Comparators Against Recent Clinical Isolates of Candidaspp. ICAAC/ICC (05) M-850 5

6 Azole-resistant C. albicans R57 C. albicans strain R57 is an azole-resistant human blood isolate Antifungal agent Endpoint (% inhibition) MIC (µg/ml) Susceptibility (CLSI) Fluconazole 50% >6 R Voriconazole 50% >6 R Posaconazole 50% >6 Amphotericin B 00% 0.5 S Caspofungin 50% 0.5 S CD0 50% 0.5 Azole resistance in R57 CaERG increased expression:.x CaERG changes: D6E, D5E, and E66D No significant changes in CDR or MDR expression 6

7 Azole-resistant C. albicans R57 disseminated infection model cpm Procedure Host: ICR Mouse IV infection cpm kidney counts - qd dose Neutropenia cyclophosphamide (cpm) days -, - Infection, Candida albicans R57, 0 5 CFU/mouse Test article administration: one (qd) dose hr after infection Vehicle, CD0 Intraperitoneal (IP) Amphotericin B (AM-B) Intravenous (IV) Fluconazole (FLU) oral (PO) Kidney counts (CFU /g) 8, 7 hr after infection 7

8 Azole-resistant C. albicans R57 disseminated infection model Model development vary the inoculum density Log 0 CFU/g kidney hr 7 hr hr 7 hr hr 7 hr hr 7 hr LOD Inoculum count (CFU); Infection duration (hr) 8

9 Azole-resistant C. albicans R57 disseminated infection model 8 Efficacy of antifungals 7 Log 0 CFU/g kidney \ 6 5 *, # 0 Initial hr counts Vehicle, IV, 7 hr FLU, 0 mg/kg, PO, 7 hr AM-B, mg/kg, IV, 7 hr AM-B, mg/kg, IV, 7 hr 9

10 Azole-resistant C. albicans R57 disseminated infection model Log 0 CFU/g kidney Efficacy of antifungals - fungal counts 8 hr 7 hr 8 hr after infection # # *,# *,# *,# Initial hr counts Vehicle, IP, 8 hr FLU, 0 mg/kg, PO AM-B, mg/kg, IV AM-B, mg/kg, IV CD0, mg/kg, IP CD0, 0 mg/kg, IP CD0, 0 mg/kg, IP Log 0 CFU/g kidney hr after infection # # *,# *,# *,# *,# Initial hr counts Vehicle, IP, 7 hr FLU, 0 mg/kg, PO AM-B, mg/kg, IV AM-B, mg/kg, IV CD0, mg/kg, IP CD0, 0 mg/kg, IP CD0, 0 mg/kg, IP # * 99% reduction p < 0.05 vs. vehicle 0

11 Azole-resistant C. albicans R57 disseminated infection model Change in counts (Log 0 ) Efficacy of antifungals - difference in counts 8 hr 7 hr 8 hr after infection Initial hr counts Vehicle, IP, 8 hr FLU, 0 mg/kg, PO AM-B, mg/kg, IV AM-B, mg/kg, IV CD0, mg/kg, IP CD0, 0 mg/kg, IP CD0, 0 mg/kg, IP Change in counts (Log 0 ) hr after infection Initial hr counts Vehicle, IP, 7 hr FLU, 0 mg/kg, PO AM-B, mg/kg, IV AM-B, mg/kg, IV CD0, mg/kg, IP CD0, 0 mg/kg, IP CD0, 0 mg/kg, IP

12 Conclusions CD0, a novel echinocandin, demonstrated efficacy in a disseminated infection model of azole-resistant candidiasis Efficacy persisted 7 hr consistent with long-acting pharmacokinetics CD0 treatment resulted in a fungicidal effect