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 www.eurofins.com/pharmadiscovery
Disclosures Lynn Miesel is a Eurofins Pharma Discovery Services employee. This research was performed under contract between Eurofins Panlabs Taiwan and Cidara Therapeutics.
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
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 6-7 0 Dog N/A 5 Cyno Monkey N/A 8 0 Chimpanzee 5-8 0 8 a. R. Hajdu, et al. Antimicrob. Agents Chemother. (997) :9 b. K. James, et al. ICAAC (0) A-69 and A-69
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) 0.0 0.0 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
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
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
Azole-resistant C. albicans R57 disseminated infection model Model development vary the inoculum density Log 0 CFU/g kidney 9 8 7 6 5 0 hr 7 hr hr 7 hr hr 7 hr hr 7 hr LOD 0 6 0 5 0 0 Inoculum count (CFU); Infection duration (hr) 8
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
Azole-resistant C. albicans R57 disseminated infection model Log 0 CFU/g kidney 9 8 7 6 5 0 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 9 8 7 6 5 0 7 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
Azole-resistant C. albicans R57 disseminated infection model Change in counts (Log 0 ) 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 ) 0 - - - 7 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
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