Safety, tolerability, systemic exposure, and metabolism of CRS3123, a methionyl-tRNA synthetase inhibitor developed for treatment of Clostridium difficile, in a Phase 1 Study

Antimicrobial Agents and Chemotherapy

Volumn 61, Issue 8, 2017, Pages

  Nayak, Seema U ^a   Griffiss, J McLeod ^b   Blumer, Jeffrey ^c   O’Riordan, Mary Ann ^d   Gray, Wesley ^c   McKenzie, Robin ^a   Jurao, Robert A ^a   An, Amanda T ^a,f   Le, Melissa ^a   Bell, Stacie J ^e   Ochsner, Urs A ^e   Jarvis, Thale C ^e   Janjic, Nebojsa ^e   Zenilman, Jonathan M ^a  

^a JOHNS HOPKINS UNIVERSITY   (United States)

^b Clinical RM Inc   (United States)

^c UNIVERSITY OF TOLEDO   (United States)

^d CASE WESTERN RESERVE UNIVERSITY   (United States)

^e Crestone Inc   (United States)

^f ROSS UNIVERSITY SCHOOL OF MEDICINE   (Dominica)

Author keywords

Antimicrobial agents; Clostridium difficile; CRS3123; Glucuronidation; Gram positive bacteria; Pharmacokinetics

Indexed keywords

ANTIBIOTIC AGENT; CALCIUM; CRS 3123; ESTERASE; HEMOGLOBIN; LEUKOCYTE ESTERASE; LIGASE INHIBITOR; METHIONINE TRANSFER RNA LIGASE; NITRITE; PLACEBO; UNCLASSIFIED DRUG; ANTIINFECTIVE AGENT; BENZOPYRAN DERIVATIVE; REP 3123; THIOPHENE DERIVATIVE;

ABNORMAL URINE COMPOSITION; ADULT; ALLERGIC REACTION; ARTICLE; CALCIUM BLOOD LEVEL; CONTROLLED STUDY; DIZZINESS; DOSE RESPONSE; DOUBLE BLIND PROCEDURE; DRUG ABSORPTION; DRUG DOSE COMPARISON; DRUG DOSE ESCALATION; DRUG EXPOSURE; DRUG GLUCURONIDATION; DRUG METABOLISM; DRUG SAFETY; DRUG TOLERABILITY; EOSINOPHIL COUNT; ERYTHROCYTE URINE LEVEL; FEMALE; FIRST IN HUMAN STUDY; HEADACHE; HEMOGLOBIN BLOOD LEVEL; HUMAN; HUMAN EXPERIMENT; LEUKOCYTE COUNT; LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY; MALE; MUSCULOSKELETAL PAIN; NEUTROPHIL COUNT; NORMAL HUMAN; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; SIDE EFFECT; SINGLE DRUG DOSE; UNSPECIFIED SIDE EFFECT; ANTAGONISTS AND INHIBITORS; CLINICAL TRIAL; CLOSTRIDIUM INFECTION; CROSS INFECTION; DRUG EFFECTS; PEPTOCLOSTRIDIUM DIFFICILE; YOUNG ADULT;

ADULT; ANTI-BACTERIAL AGENTS; BENZOPYRANS; CLOSTRIDIUM DIFFICILE; CLOSTRIDIUM INFECTIONS; CROSS INFECTION; DOSE-RESPONSE RELATIONSHIP, DRUG; DOUBLE-BLIND METHOD; FEMALE; HUMANS; MALE; METHIONINE-TRNA LIGASE; PLACEBOS; THIOPHENES; YOUNG ADULT;

EID: 85026417389     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.02760-16     Document Type: Article

References (21)

1. Bartlett JG, Chang TW, Gurwith M, Gorbach SL, Onderdonk AB. 1978. Antibiotic associated pseudomembranous colitis due to toxin producing clostridia. N Engl J Med 298:531–534. https://doi.org/10.1056/NEJM197803092981003.
2. Labbé AN, Poirier L, MacCannell D, Louie T, Savoie M, Béliveau C, Laverdière M, Pépin J. 2008. Clostridium difficile infections in a Canadian tertiary care hospital before and during a regional epidemic associated with the BI/NAP1/027 strain. Antimicrob Agents Chemother 52: 3180–3187. https://doi.org/10.1128/AAC.00146-08.
3. Reveles KR, Lee GC, Boyd NK, Frei CR. 2014. The rise in Clostridium difficile infection incidence among hospitalized adults in the United States: 2001-10. Am J Infect Control 42:1028 –1032. https://doi.org/10.1016/j.ajic.2014.06.011.
4. Zimlichman E, Henderson D, Tamir O, Franz C, Song P, Yamin CK, Keohane C, Denham CR, Bates DW. 2013. Healthcare associated infections. JAMA Intern Med 173:2039–2046. https://doi.org/10.1001/jamainternmed.2013.9763.
5. Cocanour CS. 2011. Best strategies in recurrent or persistent Clostridium difficile infection. Surg Infect (Larchmt) 12:235–239. https://doi.org/10.1089/sur.2010.080.
6. Peery AF, Dellon ES, Lund J, Crockett SD, McGowan CE, Bulsiewicz WJ, Gangarosa LM, Thiny MT, Stizenberg K, Morgan DR, Ringel Y, Kim HP, Dibonaventura MD, Carroll CF, Allen JK, Cook SF, Sandler RS, Kappelman MD, Shaheen NJ. 2012. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology 143:1179–1187. https://doi.org/10.1053/j.gastro.2012.08.002.
7. Barbut F, Richard A, Hamadi K, Chomette V, Burghoffer B, Petit JC. 2000. Epidemiology of recurrences or reinfections of Clostridium difficile associated diarrhea. J Clin Microbiol 38:2386–2388.
8. Wilcox M. 2003. Clostridium difficile infection and pseudomembranous colitis. Best Pract Res Clin Gastroenterol 17:475–493.
9. Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, Pépin J, Wilcox MH. 2010. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America. Infect Control Hosp Epidemiol 31:431– 455. https://doi.org/10.1086/651706.
10. Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. 2007. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile associated diarrhea, stratified by disease severity. Clin Infect Dis 45: 302–307. https://doi.org/10.1086/519265.
11. Vardakas KZ, Polyzos KA, Patouni K, Raffailidis PI, Samonis G, Falagas ME. 2012. Treatment failure and recurrence of Clostridium difficile infection following treatment with vancomycin or metronidazole. Int J Antimicrob Agents 40:1– 8. https://doi.org/10.1016/j.ijantimicag.2012.01.004.
12. Pépin J, Alary ME, Valiquette L, Raiche E, Ruel J, Fulop K, Godin D, Bourassa C. 2005. Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada. Clin Infect Dis 40:1591–1597. https://doi.org/10.1086/430315.
13. Tickler IA, Goering RV, Whitmore JD, Lynn AN, Persing DH, Tenover FC. 2014. Strain types and antimicrobial resistance patterns of Clostridium difficile isolates from the United States, 2011 to 2013. Antimicrob Agents Chemother 58:4214 – 4218. https://doi.org/10.1128/AAC.02775-13.
14. Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y, Gorbach S, Sears P, Shue Y-K, OPT-80-003 Clinical Study Group. 2011. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 364: 422–431. https://doi.org/10.1056/NEJMoa0910812.
15. Konijeti GG, Sauk J, Shrime MG, Gupta M, Ananthakrishnan AN. 2014. Cost effectiveness of competing strategies for management of recurrent Clostridium difficile infection: a decision analysis. Clin Infect Dis 58: 1507–1514. https://doi.org/10.1093/cid/ciu128.
16. Bartsch SM, Umscheid CA, Fishman N, Lee BY. 2013. Is fidaxomicin worth the cost? An economic analysis. Clin Infect Dis 57:555–561. https://doi.org/10.1093/cid/cit346.
17. Critchley IA, Green LS, Young CL, Bullard JM, Evans RJ, Price M, Jarvis TC, Guiles JW, Janjic N, Ochsner UA. 2009. Spectrum of activity and mode of action of REP3123, a new antibiotic to treat Clostridium difficile infections. J Antimicrob Chemother 63:954–963. https://doi.org/10.1093/jac/dkp041.
18. Ochsner UA, Bell SJ, O’Leary AL, Hoang T, Stone KC, Young CL, Critchley IA, Janjic N. 2009. Inhibitory effect of REP3123 on toxin and spore formation in Clostridium difficile, and in vivo efficacy in a hamster gastrointestinal infection model. J Antimicrob Chemother 63:964–971. https://doi.org/10.1093/jac/dkp042.
19. Citron DM, Warren YA, Tyrell KL, Merriam V, Goldstein EJC. 2009. Comparative in vitro activity of REP3123 against Clostridium difficile and other anaerobic intestinal bacteria. J Antimicrob Chemother 63:972–976. https://doi.org/10.1093/jac/dkp037.
20. National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases, Office of Clinical Research Affairs. 13 July 2016. Development of criteria for volunteer participation in DMID clinical research. NIAID, Rockville, MD. https://www.niaid.nih.gov/sites/default/files/volpolicymb.pdf.
21. Ochsner UA, Young CL, Stone KC, Dean FB, Janjic N, Critchley IA. 2005. Mode of action and biochemical characterization of REP8839, a novel inhibitor of methionyl-tRNA synthetase. Antimicrob Agents Chemother 49:4253–4262. https://doi.org/10.1128/AAC.49.10.4253-4262.2005.