Investigational drug therapies currently in early-stage clinical development for the treatment of clostridioides (clostridium) difficile infection

References

• Zimlichman E, Henderson D, Tamir O, et al. Health care–associated infections: A meta-analysis of costs and financial impact on the us health care system. JAMA Intern Med. 2013;173(22):2039–2046.
   PubMed Web of Science ®Google Scholar
• Centers for Medicare & Medicaid Services (CMS). Medicare program; hospital inpatient value-based purchasing program. Final rule. Fed Regist. 2011 May6;76(88):26490-26547. PubMed Central PMCID: PMC21548401
   Google Scholar
• Centers for Medicare and Medicaid Services: Medicare Learning Network. Hospital Value-Based Purchasing; 2017. Available from: https://www.cms.gov/Outreach-and-Education/Medicare-Learning-Network-MLN/MLNProducts/downloads/Hospital_VBPurchasing_Fact_Sheet_ICN907664.pdf [Cited 2018 Dec 1].
   Google Scholar
• Stone PW, Glied SA, McNair PD, et al. CMS changes in reimbursement for HAIs: setting a research agenda. Med Care. 2010 May;48(5):433–439. PubMed PMID: 20351584; PubMed Central PMCID: PMCPMC2881841.
   PubMed Web of Science ®Google Scholar
• Peery AF, Dellon ES, Lund J, et al. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology. 2012 Nov;143(5):1179–1187 e3. PubMed PMID: 22885331; PubMed Central PMCID: PMCPMC3480553.
   PubMed Web of Science ®Google Scholar
• Wilcox MH, Gerding DN, Poxton IR, et al. Bezlotoxumab for prevention of recurrent clostridium difficile infection. N Engl J Med. 2017 Jan 26;376(4):305–317. PubMed PMID: 28121498.
   PubMed Web of Science ®Google Scholar
• McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018 Mar 19;66(7):e1–e48. PubMed PMID: 29462280; PubMed Central PMCID: PMCPMC6018983. eng.
   PubMed Web of Science ®Google Scholar
• Olsen MA, Yan Y, Reske KA, et al. Impact of Clostridium difficile recurrence on hospital readmissions. Am J Infect Control. 2015 Apr 1;43(4):318–322. PubMed PMID: 25690876; eng.
   PubMed Web of Science ®Google Scholar
• Olsen MA, Yan Y, Reske KA, et al. Recurrent Clostridium difficile infection is associated with increased mortality. Clin Microbiol Infect. 2015 Feb;21(2):164–170. PubMed PMID: 25658560.
   PubMed Web of Science ®Google Scholar
• Johnson S, Louie TJ, Gerding DN, et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014 Aug 1;59(3):345–354. PubMed PMID: 24799326; eng.
   PubMed Web of Science ®Google Scholar
• Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011 Feb 3;364(5):422–431. PubMed PMID: 21288078; eng.
   PubMed Web of Science ®Google Scholar
• Cornely OA, Crook DW, Esposito R, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis. 2012 Apr;12(4):281–289. PubMed PMID: 22321770; eng.
   PubMed Web of Science ®Google Scholar
• Polage CR, Gyorke CE, Kennedy MA, et al. Overdiagnosis of Clostridium difficile Infection in the Molecular Test Era. JAMA Intern Med. 2015 Nov;175(11):1792–1801. PubMed PMID: 26348734; PubMed Central PMCID: PMCPMC4948649. eng.
   PubMed Web of Science ®Google Scholar
• Trzasko A, Leeds JA, Praestgaard J, et al. Efficacy of LFF571 in a hamster model of Clostridium difficile infection. Antimicrob Agents Chemother. 2012 Aug;56(8):4459–4462. PubMed PMID: 22644020; PubMed Central PMCID: PMCPMC3421564.
   PubMed Web of Science ®Google Scholar
• Dalhoff A, Rashid MU, Kapsner T, et al. Analysis of effects of MCB3681, the antibacterially active substance of prodrug MCB3837, on human resident microflora as proof of principle. Clin Microbiol Infect. 2015 Aug;21(8):767 e1–4. PubMed PMID: 26047854.
   Web of Science ®Google Scholar
• Fulco P, Wenzel RP. Ramoplanin: a topical lipoglycodepsipeptide antibacterial agent. Expert Rev Anti Infect Ther. 2006 Dec;4(6):939–945. PubMed PMID: 17181409.
   PubMedGoogle Scholar
• Locher HH, Seiler P, Chen X, et al. In vitro and in vivo antibacterial evaluation of cadazolid, a new antibiotic for treatment of Clostridium difficile infections. Antimicrob Agents Chemother. 2014;58(2):892–900. PubMed PMID: 24277020; PubMed Central PMCID: PMCPMC3910819.
   PubMed Web of Science ®Google Scholar
• Knight-Connoni V, Mascio C, Chesnel L, et al. Discovery and development of surotomycin for the treatment of Clostridium difficile. J Ind Microbiol Biotechnol. 2016 Mar;43(2–3):195–204.. PubMed PMID: 26670919.
   PubMed Web of Science ®Google Scholar
• Hammond RA, Barnes MH, Mack SL, et al. Bacillus subtilis DNA polymerase III: complete sequence, overexpression, and characterization of the polC gene. Gene. 1991 Feb 1;98(1):29–36. PubMed PMID: 1901559; eng.
   PubMed Web of Science ®Google Scholar
• Pacitti DF, Barnes MH, Li DH, et al. Characterization and overexpression of the gene encoding Staphylococcus aureus DNA polymerase III. Gene. 1995 Nov 7;165(1):51–56. PubMed PMID: 7489915; eng.
   PubMed Web of Science ®Google Scholar
• Foster KA, Barnes MH, Stephenson RO, et al. DNA polymerase III of Enterococcus faecalis: expression and characterization of recombinant enzymes encoded by the polC and dnaE genes. Protein Expr Purif. 2003 Jan;27(1):90–97. PubMed PMID: 12509989; eng.
   PubMed Web of Science ®Google Scholar
• Torti A, Lossani A, Savi L, et al. Clostridium difficile DNA polymerase IIIC: basis for activity of antibacterial compounds. Curr Enzyme Inhib. 2011 Oct;7(3):147–153. PubMed PMID: 22844265; PubMed Central PMCID: PMCPMC3404731. eng.
   PubMedGoogle Scholar
• Xu WC, Wright GE, Brown NC, et al. 7-Alkyl-N(2)-substituted-3-deazaguanines. Synthesis, DNA polymerase III inhibition and antibacterial activity. Bioorg Med Chem Lett. 2011 Jul 15;21(14):4197–4202. PubMed PMID: 21684746; PubMed Central PMCID: PMCPMC3128661. eng.
   PubMed Web of Science ®Google Scholar
• Dvoskin S, Xu WC, Brown NC, et al. A novel agent effective against Clostridium difficile infection. Antimicrob Agents Chemother. 2012 Mar;56(3):1624–1626. PubMed PMID: 22203600; PubMed Central PMCID: PMCPMC3294905.
   PubMed Web of Science ®Google Scholar
• van Eijk E, Boekhoud IM, Kuijper EJ, et al. Genome location dictates the transcriptional response to sub-inhibitory concentrations of PolC-inhibitors in Clostridium difficile. bioRxiv. 2018. DOI:10.1101/362137.
   Google Scholar
• Acurx Pharmaceuticals. ACX-362E; Available from: http://www.prnewswire.com/news-releases/acurx-pharmaceuticals-to-enter-clinical-trials-with-first-in-class-antibiotics-to-treat-selected-gram-positive-bacterial-infections-300724541.html?tc=eml_cleartime [ Cited 2018 Nov 18].
   Google Scholar
• Kumar M, Mathur T, Joshi V, et al. Effect of DS-2969b, a novel GyrB inhibitor, on rat and monkey intestinal microbiota. Anaerobe. 2018 Jun;51:120–123. PubMed PMID: 29758524.
   PubMed Web of Science ®Google Scholar
• Mathur T, Barman TK, Kumar M, et al. In Vitro and In Vivo Activities of DS-2969b, a Novel GyrB Inhibitor, against Clostridium difficile. Antimicrob Agents Chemother. 2018 Apr;62(4). PubMed PMID: 29439962; PubMed Central PMCID: PMCPMC5913969. DOI:10.1128/AAC.02157-17.
   Web of Science ®Google Scholar
• Tyrrell KL, Citron DM, Merriam CV, et al. In vitro activity of DS-2969b and comparator antimicrobial agents against Clostridioides (Clostridium) difficile, methicillin-resistant Staphylococcus aureus, and other anaerobic bacteria. Anaerobe. 2018. DOI:10.1016/j.anaerobe.2018.04.010.
   Web of Science ®Google Scholar
• Dennie J, Vandell AG, Inoue S, et al. A Phase I, Single-Ascending-Dose Study in Healthy Subjects to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DS-2969b, a Novel GyrB Inhibitor. J Clin Pharmacol. 2018 May 10 PubMed PMID: 29746725. DOI:10.1002/jcph.1151.
   PubMedGoogle Scholar
• Vandell AG, Inoue S, Dennie J, et al. Phase 1 Study To Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Oral Doses of DS-2969b, a Novel GyrB Inhibitor, in Healthy Subjects. Antimicrob Agents Chemother. 2018 May;62(5). PubMed PMID: 29439973; PubMed Central PMCID: PMCPMC5923173. eng. DOI:10.1128/aac.02537-17.
   PubMed Web of Science ®Google Scholar
• Leeds JA, Sachdeva M, Mullin S, et al. Mechanism of action of and mechanism of reduced susceptibility to the novel anti-Clostridium difficile compound LFF571. Antimicrob Agents Chemother. 2012 Aug;56(8):4463–4465. PubMed PMID: 22644023; PubMed Central PMCID: PMCPMC3421628. eng.
   PubMed Web of Science ®Google Scholar
• Citron DM, Tyrrell KL, Merriam CV, et al. Comparative in vitro activities of LFF571 against Clostridium difficile and 630 other intestinal strains of aerobic and anaerobic bacteria. Antimicrob Agents Chemother. 2012 May;56(5):2493–2503. PubMed PMID: 22290948; PubMed Central PMCID: PMCPMC3346664. eng.
   PubMed Web of Science ®Google Scholar
• Leeds JA. Antibacterials Developed to Target a Single Organism: mechanisms and Frequencies of Reduced Susceptibility to the Novel Anti-Clostridium difficile Compounds Fidaxomicin and LFF571. Cold Spring Harb Perspect Med. 2016 Feb 1;6(2):a025445.. PubMed PMID: 26834162; PubMed Central PMCID: PMCPMC4743069. eng.
   PubMed Web of Science ®Google Scholar
• Ting LS, Praestgaard J, Grunenberg N, et al. A first-in-human, randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study to assess the safety and tolerability of LFF571 in healthy volunteers. Antimicrob Agents Chemother. 2012 Nov;56(11):5946–5951. PubMed PMID: 22964250; PubMed Central PMCID: PMCPMC3486596. eng.
   PubMed Web of Science ®Google Scholar
• Mullane K, Lee C, Bressler A, et al. Multicenter, randomized clinical trial to compare the safety and efficacy of LFF571 and vancomycin for Clostridium difficile infections. Antimicrob Agents Chemother. 2015 Mar;59(3):1435–1440. PubMed PMID: 25534727; PubMed Central PMCID: PMCPMC4325808. eng.
   PubMed Web of Science ®Google Scholar
• Bhansali SG, Mullane K, Ting LS, et al. Pharmacokinetics of LFF571 and vancomycin in patients with moderate Clostridium difficile infections. Antimicrob Agents Chemother. 2015 Mar;59(3):1441–1445. PubMed PMID: 25534724; PubMed Central PMCID: PMCPMC4325791. eng.
   PubMed Web of Science ®Google Scholar
• Harmoinen J, Mentula S, Heikkila M, et al. Orally administered targeted recombinant Beta-lactamase prevents ampicillin-induced selective pressure on the gut microbiota: a novel approach to reducing antimicrobial resistance. Antimicrob Agents Chemother. 2004 Jan;48(1):75–79. PubMed PMID: 14693521; PubMed Central PMCID: PMCPMC310163. eng.
   PubMed Web of Science ®Google Scholar
• Harmoinen J, Vaali K, Koski P, et al. Enzymic degradation of a beta-lactam antibiotic, ampicillin, in the gut: a novel treatment modality. J Antimicrob Chemother. 2003 Feb;51(2):361–365. PubMed PMID: 12562703; eng.
   PubMed Web of Science ®Google Scholar
• Pitout JD. IPSAT P1A, a class A beta-lactamase therapy for the prevention of penicillin-induced disruption to the intestinal microflora. Curr Opin Invest Drugs. 2009 Aug;10(8):838–844. PubMed PMID: 19649928; eng.
   PubMedGoogle Scholar
• Tarkkanen AM, Heinonen T, Jogi R, et al. P1A recombinant beta-lactamase prevents emergence of antimicrobial resistance in gut microflora of healthy subjects during intravenous administration of ampicillin. Antimicrob Agents Chemother. 2009 Jun;53(6):2455–2462. PubMed PMID: 19307374; PubMed Central PMCID: PMCPMC2687246. eng.
   PubMed Web of Science ®Google Scholar
• Stiefel U, Nerandzic MM, Koski P, et al. Orally administered beta-lactamase enzymes represent a novel strategy to prevent colonization by Clostridium difficile. J Antimicrob Chemother. 2008 Nov;62(5):1105–1108. PubMed PMID: 18693236; eng.
   PubMed Web of Science ®Google Scholar
• Kaleko M, Bristol JA, Hubert S, et al. Development of SYN-004, an oral beta-lactamase treatment to protect the gut microbiome from antibiotic-mediated damage and prevent Clostridium difficile infection. Anaerobe. 2016 Oct;41:58–67. PubMed PMID: 27262694; eng.
   PubMed Web of Science ®Google Scholar
• Bristol A, Hubert S, Hofmann F, et al. Formulation development of SYN-004 (ribaxamase) oral solid dosage form, a beta-lactamase to prevent intravenous antibiotic-associated dysbiosis of the colon. Int J Pharm. 2017 Dec 20;534(1–2):25–34. PubMed PMID: 28986322; eng.
   PubMedGoogle Scholar
• Kokai-Kun JF, Bristol JA, Setser J, et al. Nonclinical safety assessment of SYN-004: an oral beta-lactamase for the protection of the gut microbiome from disruption by biliary-excreted, intravenously administered antibiotics. Int J Toxicol. 2016 May;35(3):309–316. PubMed PMID: 26700136; eng.
   PubMed Web of Science ®Google Scholar
• Roberts T, Kokai-Kun JF, Coughlin O, et al. Tolerability and pharmacokinetics of SYN-004, an orally administered beta-lactamase for the prevention of Clostridium difficile-associated disease and antibiotic-associated diarrhea, in two phase 1 studies. Clin Drug Investig. 2016 Sep;36(9):725–734. 10.1007/s40261-016-0420-0. PubMed PMID: 27283946; eng.
   PubMed Web of Science ®Google Scholar
• Connelly S, Bristol JA, Hubert S, et al. SYN-004 (ribaxamase), an oral beta-lactamase, mitigates antibiotic-mediated dysbiosis in a porcine gut microbiome model. J Appl Microbiol. 2017 Feb 28 PubMed PMID: 28245091. DOI:10.1111/jam.13432.
   PubMed Web of Science ®Google Scholar
• Kokai-Kun JF, Roberts T, Coughlin O, et al. The Oral beta-Lactamase SYN-004 (Ribaxamase) Degrades Ceftriaxone Excreted into the Intestine in Phase 2a Clinical Studies. Antimicrob Agents Chemother. 2017 Mar;61(3). PubMed PMID: 28052855; PubMed Central PMCID: PMCPMC5328510. eng. DOI:10.1128/aac.02197-16.
   PubMed Web of Science ®Google Scholar
• Kokai-Kun J, Roberts T, Coughlin O, et al. SYN-004 (ribaxamase) prevents New Onset Clostridium difficile Infection by Protecting the Integrity Gut Microbiome in a Phase 2b Study. Open Forum Infect Dis. 2017 FallOct04; 4(Suppl 1):S12–S12.. PubMed PMID: PMC5631845
   Google Scholar
• Kokai-Kun NJF, Le C, Trout K, et al. SYN-004 (ribaxamase) reduces the Emergence of Antimicrobial Resistance in the Gut Microbiome of Patients Treated with Ceftriaxone. San Francisco, CA: ID Week; 2018.
   Google Scholar
• Synthetic Biologics Announces Positive Outcome of End-of-Phase 2 Meeting with FDA on SYN-004 (ribaxamase) Development: Synthetic Biologics; 2018 updated 2018;Nov 25, 2018 Nov 21, 2018;Nov 21, 2018;Nov 25. Available from: https://www.syntheticbiologics.com/news-media/press-releases/detail/266/synthetic-biologics-announces-positive-outcome-of
   Google Scholar
• Kaleko M, Furlan-Freguia C, Subramanian P, et al. Orally delivered beta-lactamase prevents gut microbiome dysbiosis caused by IV and oral antibiotics and mitigates propagation of antibiotic resistance in porcine and canine models. Poster Sa1839. Digestive Disease Week 2018 2018.
   Google Scholar
• Connelly S, Furlan-Freguia C, Subramanian P, et al. Gut Antibiotic Inactivation by Β-Lactamases Is Intended to Prevent Microbiome Damage and Attenuate Antibiotic Resistance in Large Animal Models. Open Forum Infect Dis. 2017;4(Suppl_1):S232–S233.
   Google Scholar
• Kaleko M, Furlan-Freguia C, Subramanian P, et al. SYN-006, a Novel Carbapenemase, Intended to Protect the Gut Microbiome from Antibiotic-Mediated Damage May Also Reduce Propagation of Carbapenem-Resistant Pathogens. Open Forum Infect Dis. 2017;4(Suppl_1):S231–S232.
   Google Scholar
• Vickers RJ, Tillotson G, Goldstein EJ, et al. Ridinilazole: a novel therapy for Clostridium difficile infection. Int J Antimicrob Agents. 2016 Aug;48(2):137–143. PubMed PMID: 27283730.
   PubMed Web of Science ®Google Scholar
• Basseres E, Endres BT, Khaleduzzaman M, et al. Impact on toxin production and cell morphology in Clostridium difficile by ridinilazole (SMT19969), a novel treatment for C. difficile infection. J Antimicrob Chemother. 2016 May;71(5):1245–1251. PubMed PMID: 26895772; PubMed Central PMCID: PMCPMC4830417.
   PubMed Web of Science ®Google Scholar
• Goldstein EJ, Citron DM, Tyrrell KL. Comparative in vitro activities of SMT19969, a new antimicrobial agent, against 162 strains from 35 less frequently recovered intestinal Clostridium species: implications for Clostridium difficile recurrence. PubMed PMID: 24247123; PubMed Central PMCID: PMCPMC3910813 Antimicrob Agents Chemother. 2014;582:1187–1191.
   PubMed Web of Science ®Google Scholar
• Sattar A, Thommes P, Payne L, et al. SMT19969 for Clostridium difficile infection (CDI): in vivo efficacy compared with fidaxomicin and vancomycin in the hamster model of CDI. J Antimicrob Chemother. 2015;70(6):1757–1762. PubMed PMID: 25652749; PubMed Central PMCID: PMCPMC4498292.
   PubMed Web of Science ®Google Scholar
• Weiss W, Pulse M, Vickers R. In vivo assessment of SMT19969 in a hamster model of clostridium difficile infection. Antimicrob Agents Chemother. 2014 Oct;58(10):5714–5718.. PubMed PMID: 25022586; PubMed Central PMCID: PMCPMC4187990.
   PubMed Web of Science ®Google Scholar
• Vickers RJ, Tillotson GS, Nathan R, et al. Efficacy and safety of ridinilazole compared with vancomycin for the treatment of Clostridium difficile infection: a phase 2, randomised, double-blind, active-controlled, non-inferiority study. Lancet Infect Dis. 2017 Jul;17(7):735–744. PubMed PMID: 28461207; PubMed Central PMCID: PMCPMC5483507.
   PubMed Web of Science ®Google Scholar
• Corbett D, Wise A, Birchall S, et al. In vitro susceptibility of Clostridium difficile to SMT19969 and comparators, as well as the killing kinetics and post-antibiotic effects of SMT19969 and comparators against C. difficile. J Antimicrob Chemother. 2015;70(6):1751–1756. PubMed PMID: 25652750; PubMed Central PMCID: PMCPMC4498293.
   PubMed Web of Science ®Google Scholar
• Baines SD, Crowther GS, Freeman J, et al. SMT19969 as a treatment for Clostridium difficile infection: an assessment of antimicrobial activity using conventional susceptibility testing and an in vitro gut model. J Antimicrob Chemother. 2015 Jan;70(1):182–189. PubMed PMID: 25190720; PubMed Central PMCID: PMCPMC4267497.
   PubMed Web of Science ®Google Scholar
• Goldstein EJ, Citron DM, Tyrrell KL, et al. Comparative in vitro activities of SMT19969, a new antimicrobial agent, against Clostridium difficile and 350 gram-positive and gram-negative aerobic and anaerobic intestinal flora isolates. Antimicrob Agents Chemother. 2013 Oct;57(10):4872–4876. PubMed PMID: 23877700; PubMed Central PMCID: PMCPMC3811411.
   PubMed Web of Science ®Google Scholar
• Skraban J, Dzeroski S, Zenko B, et al. Gut microbiota patterns associated with colonization of different Clostridium difficile ribotypes. PLoS One. 2013;8(2):e58005. PubMed PMID: 23469128; PubMed Central PMCID: PMCPMC3585249.
   PubMed Web of Science ®Google Scholar
• Louie TJ, Emery J, Krulicki W, et al. OPT-80 eliminates Clostridium difficile and is sparing of bacteroides species during treatment of C. difficile infection. Antimicrob Agents Chemother. 2009 Jan;53(1):261–263. PubMed PMID: 18955523; PubMed Central PMCID: PMCPMC2612159.
   PubMed Web of Science ®Google Scholar
• Orenstein R, Dubberke E, Hardi R, et al. Safety and Durability of RBX2660 (Microbiota Suspension) for Recurrent Clostridium difficile Infection: results of the PUNCH CD Study. Clin Infect Dis. 2016 Mar 1;62(5):596–602. PubMed PMID: 26565008; eng.
   PubMed Web of Science ®Google Scholar
• Dubberke ER, Mullane KM, Gerding DN, et al. Clearance of Vancomycin-Resistant Enterococcus Concomitant With Administration of a Microbiota-Based Drug Targeted at Recurrent Clostridium difficile Infection. Open Forum Infect Dis. 2016 Sep;3(3):ofw133. PubMed PMID: 27703995; PubMed Central PMCID: PMCPMC5047394.
   PubMed Web of Science ®Google Scholar
• Dubberke ER, Lee CH, Orenstein R, et al. Results from a Randomized Placebo-Controlled Clinical Trial of a RBX2660-a Microbiota-based Drug for the Prevention of Recurrent Clostridium difficile Infection. Clin Infect Dis. 2018 Mar 29 PubMed PMID: 29617739. DOI:10.1093/cid/ciy259.
   Google Scholar
• Inc. MCaR. Treatment of Recurrent Clostridium Difficile Infection With RBX7455 (ClinicalTrials.gov Identifier: NCT02981316) updated 2018;Nov 25, 2018 Feb 22, 2018;Nov 22, 2018;Nov 25. Available from: https://clinicaltrials.gov/ct2/show/NCT02981316
   Google Scholar
• Iscla I, Wray R, Blount P, et al. A new antibiotic with potent activity targets MscL. J Antibiot (Tokyo). 2015 Jul;68(7):453–462. PubMed PMID: 25649856; PubMed Central PMCID: PMCPMC4430313.
   PubMed Web of Science ®Google Scholar
• Wolfe C, Pagano P, Pillar CM, et al. Comparison of the in vitro antibacterial activity of Ramizol, fidaxomicin, vancomycin and metronidazole against 100 clinical isolates of Clostridium difficile by broth microdilution. Diagn Microbiol Infect Dis. 2018. DOI:10.1016/j.diagmicrobio.2018.06.002.
   PubMed Web of Science ®Google Scholar
• Rao S, Prestidge CA, Miesel L, et al. Preclinical development of Ramizol, an antibiotic belonging to a new class, for the treatment of Clostridium difficile colitis. J Antibiot (Tokyo). 2016 Dec;69(12):879–884. PubMed PMID: 27189122; PubMed Central PMCID: PMCPMC5399159.
   PubMed Web of Science ®Google Scholar
• Wright L, Rao S, Thomas N, et al. Ramizol((R)) encapsulation into extended release PLGA micro- and nanoparticle systems for subcutaneous and intramuscular administration: in vitro and in vivo evaluation. Drug Dev Ind Pharm. 2018 Sep;44(9):1451–1457. PubMed PMID: 29619851.
   PubMed Web of Science ®Google Scholar
• Cavalleri B, Pagani H, Volpe G, et al. A-16686, a new antibiotic from Actinoplanes. I. Fermentation, isolation and preliminary physico-chemical characteristics. J Antibiot (Tokyo). 1984 Apr;37(4):309–317. PubMed PMID: 6547132.
   PubMed Web of Science ®Google Scholar
• McCafferty DG, Cudic P, Frankel BA, et al. Chemistry and biology of the ramoplanin family of peptide antibiotics. Biopolymers. 2002;66(4):261–284. PubMed PMID: 12491539.
   PubMed Web of Science ®Google Scholar
• Boger DL. Vancomycin, teicoplanin, and ramoplanin: synthetic and mechanistic studies. Med Res Rev. 200109/2011;21(5):356–381.. PubMed Central PMCID: PMC11579438.
   PubMed Web of Science ®Google Scholar
• Farver DK, Hedge DD, Lee SC. Ramoplanin: a lipoglycodepsipeptide antibiotic. Ann Pharmacother. 2005 May;39(5):863–868.. PubMed PMID: 15784805.
   PubMed Web of Science ®Google Scholar
• Citron DM, Merriam CV, Tyrrell KL, et al. In Vitro Activities of Ramoplanin, Teicoplanin, Vancomycin, Linezolid, Bacitracin, and Four Other Antimicrobials against Intestinal Anaerobic Bacteria. Antimicrob Agents Chemother. 2003;47(7):2334–2338.
   PubMed Web of Science ®Google Scholar
• Freeman J, Baines SD, Jabes D, et al. Comparison of the efficacy of ramoplanin and vancomycin in both in vitro and in vivo models of clindamycin-induced Clostridium difficile infection. J Antimicrob Chemother. 2005 Oct;56(4):717–725. PubMed PMID: 16143709.
   PubMed Web of Science ®Google Scholar
• Kraus CN, Lyerly MW, Carman RJ. Ambush of Clostridium difficile spores by ramoplanin: activity in an in vitro model. Antimicrob Agents Chemother. 2015 May;59(5):2525–2530.. PubMed PMID: 25691641; PubMed Central PMCID: PMCPMC4394778.
   PubMed Web of Science ®Google Scholar
• Pelaez T, Alcala L, Alonso R, et al. In vitro activity of ramoplanin against Clostridium difficile, including strains with reduced susceptibility to vancomycin or with resistance to metronidazole. Antimicrob Agents Chemother. 2005 Mar;49(3):1157–1159. PubMed PMID: 15728918; PubMed Central PMCID: PMCPMC549223.
   PubMed Web of Science ®Google Scholar
• Pullman JPJ, Leach TS Ramoplanin versus vancomycin in the treatment of Clostridium difficile diarrhea: a phase 2 study. 44th Intersci. Conf. Antimicrob. Agents Chemother. Washington, DC 2004. p. abstr. K-985a.
   Google Scholar
• Critchley IA, Green LS, Young CL, et al. Spectrum of activity and mode of action of REP3123, a new antibiotic to treat Clostridium difficile infections. J Antimicrob Chemother. 2009 May;63(5):954–963. PubMed PMID: 19258353.
   PubMed Web of Science ®Google Scholar
• Citron DM, Warren YA, Tyrrell KL, et al. Comparative in vitro activity of REP3123 against Clostridium difficile and other anaerobic intestinal bacteria. J Antimicrob Chemother. 2009 May;63(5):972–976. PubMed PMID: 19240076.
   PubMed Web of Science ®Google Scholar
• Ochsner UA, Bell SJ, O’Leary AL, et al. 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. 2009 May;63(5):964–971. PubMed PMID: 19251726.
   PubMed Web of Science ®Google Scholar
• Nayak SU, Griffiss JM, Blumer J, et al. Safety, Tolerability, Systemic Exposure, and Metabolism of CRS3123, a Methionyl-tRNA Synthetase Inhibitor Developed for Treatment of Clostridium difficile, in a Phase 1 Study. Antimicrob Agents Chemother. 2017 Aug;61(8). PubMed PMID: 28584140; PubMed Central PMCID: PMCPMC5527627. DOI:10.1128/AAC.02760-16.
   PubMed Web of Science ®Google Scholar
• Rashid MU, Dalhoff A, Backstrom T, et al. Ecological impact of MCB3837 on the normal human microbiota. Int J Antimicrob Agents. 2014 Aug;44(2):125–130. PubMed PMID: 24931053.
   PubMed Web of Science ®Google Scholar
• Rashid MU, Dalhoff A, Weintraub A, et al. In vitro activity of MCB3681 against Clostridium difficile strains. Anaerobe. 2014 Aug;28:216–219. PubMed PMID: 25016084.
   PubMed Web of Science ®Google Scholar
• Endres BT, Basseres E, Alam MJ, et al. Cadazolid for the treatment of Clostridium difficile. Expert Opin Investig Drugs. 2017 Apr;26(4):509–514. PubMed PMID: 28286992.
   PubMed Web of Science ®Google Scholar
• Gehin M, Desnica B, Dingemanse J. Minimal systemic and high faecal exposure to cadazolid in patients with severe Clostridium difficile infection. Int J Antimicrob Agents. 2015 Nov;46(5):576–581.. PubMed PMID: 26419191.
   PubMed Web of Science ®Google Scholar
• Petrosillo N, Granata G, Cataldo MA. Novel Antimicrobials for the Treatment of Clostridium difficile Infection. Front Med (Lausanne). 2018;5:96. PubMed PMID: 29713630; PubMed Central PMCID: PMCPMC5911476.
   PubMed Web of Science ®Google Scholar
• Louie T, Nord CE, Talbot GH, et al. Multicenter, Double-Blind, Randomized, Phase 2 Study Evaluating the Novel Antibiotic Cadazolid in Patients with Clostridium difficile Infection. Antimicrob Agents Chemother. 2015 Oct;59(10):6266–6273. PubMed PMID: 26248357; PubMed Central PMCID: PMCPMC4576054. eng.
   PubMed Web of Science ®Google Scholar
• Gerding DN, Hecht DW, Louie T, et al. Susceptibility of Clostridium difficile isolates from a Phase 2 clinical trial of cadazolid and vancomycin in C. difficile infection. J Antimicrob Chemother. 2016 Jan;71(1):213–219. PubMed PMID: 26433782; PubMed Central PMCID: PMCPMC4681371. eng.
   PubMed Web of Science ®Google Scholar
• Taylor NP Johnson & Johnson scraps phase 3 antibiotic program acquired in $30B Actelion takeover: FierceBiotech; 2018 cited 2018 8/Nov/2018 Nov 8. Available from: https://www.fiercebiotech.com/biotech/j-j-scraps-phase-3-antibiotic-program-acquired-30b-actelion-takeover
   Google Scholar
• Alam MZ, Wu X, Mascio C, et al. Mode of Action and Bactericidal Properties of Surotomycin against Growing and Nongrowing Clostridium difficile. Antimicrob Agents Chemother. 2015;59(9):5165–5170.
   PubMed Web of Science ®Google Scholar
• Daley P, Louie T, Lutz JE, et al. Surotomycin versus vancomycin in adults with Clostridium difficile infection: primary clinical outcomes from the second pivotal, randomized, double-blind, Phase 3 trial. J Antimicrob Chemother. 2017 Dec 1;72(12):3462–3470. PubMed PMID: 28961905; eng.
   PubMed Web of Science ®Google Scholar
• Boix V, Fedorak RN, Mullane KM, et al. Primary Outcomes From a Phase 3, Randomized, Double-Blind, Active-Controlled Trial of Surotomycin in Subjects With Clostridium difficile Infection. Open Forum Infect Dis. 2017 Winter;4(1):ofw275. PubMed PMID: 28480267; PubMed Central PMCID: PMCPMC5414029. eng.
   PubMed Web of Science ®Google Scholar
• Magee G, Strauss ME, Thomas SM, et al. Impact of Clostridium difficile-associated diarrhea on acute care length of stay, hospital costs, and readmission: A multicenter retrospective study of inpatients, 2009–2011. Am J Infect Control. 2015 Nov;43(11):1148–1153. PubMed PMID: 26521932; eng.
   PubMed Web of Science ®Google Scholar
• Tabak YP, Zilberberg MD, Johannes RS, et al. Attributable burden of hospital-onset Clostridium difficile infection: a propensity score matching study. Infect Control Hosp Epidemiol. 2013 Jun;34(6):588–596. PubMed PMID: 23651889; eng.
   PubMed Web of Science ®Google Scholar
• Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile Infection in the United States. N Engl J Med. 2015;372(9):825–834. PubMed PMID: 25714160.
   PubMed Web of Science ®Google Scholar
• Bouza E. Consequences of Clostridium difficile infection: understanding the healthcare burden. Clin Microbiol Infect. 2012 Dec;18(Suppl 6):5–12.. PubMed PMID: 23121549; eng.
   PubMed Web of Science ®Google Scholar
• Chopra T, Goldstein EJ, Gorbach SL. Rethinking Strategies to Select Antibiotic Therapy in Clostridium difficile infection. Pharmacotherapy. 2016 Dec;36(12):1281–1289.. PubMed PMID: 27862113; eng.
   PubMed Web of Science ®Google Scholar
• Aguado JM, Anttila VJ, Galperine T, et al. Highlighting clinical needs in Clostridium difficile infection: the views of European healthcare professionals at the front line. J Hosp Infect. 2015 Jun;90(2):117–125. PubMed PMID: 25842241; eng.
   PubMed Web of Science ®Google Scholar