scholarly journals A Novel Agent Effective against Clostridium difficile Infection

2011 ◽  
Vol 56 (3) ◽  
pp. 1624-1626 ◽  
Author(s):  
Sofya Dvoskin ◽  
Wei-Chu Xu ◽  
Neal C. Brown ◽  
Ivan B. Yanachkov ◽  
Milka Yanachkova ◽  
...  

ABSTRACTN2-(3,4-Dichlorobenzyl)-7-(2-[1-morpholinyl]ethyl)guanine (MorE-DCBG, 362E) is a synthetic purine that selectively inhibits the replication-specific DNA polymerase ofClostridium difficile. MorE-DCBG and its analogs strongly inhibited the growth of a wide variety ofC. difficilestrains. When administered orally in a hamster model ofC. difficile-specific colitis, 362E was as effective as oral vancomycin, the current agent of choice for treating severe forms of the human disease.

2012 ◽  
Vol 56 (9) ◽  
pp. 4786-4792 ◽  
Author(s):  
Michelle M. Butler ◽  
Dean L. Shinabarger ◽  
Diane M. Citron ◽  
Ciarán P. Kelly ◽  
Sofya Dvoskin ◽  
...  

ABSTRACTClostridium difficileinfection (CDI) causes moderate to severe disease, resulting in diarrhea and pseudomembranous colitis. CDI is difficult to treat due to production of inflammation-inducing toxins, resistance development, and high probability of recurrence. Only two antibiotics are approved for the treatment of CDI, and the pipeline for therapeutic agents contains few new drugs. MBX-500 is a hybrid antibacterial, composed of an anilinouracil DNA polymerase inhibitor linked to a fluoroquinolone DNA gyrase/topoisomerase inhibitor, with potential as a new therapeutic for CDI treatment. Since MBX-500 inhibits three bacterial targets, it has been previously shown to be minimally susceptible to resistance development. In the present study, thein vitroandin vivoefficacies of MBX-500 were explored against the Gram-positive anaerobe,C. difficile. MBX-500 displayed potency across nearly 50 isolates, including those of the fluoroquinolone-resistant, toxin-overproducing NAP1/027 ribotype, performing as well as comparator antibiotics vancomycin and metronidazole. Furthermore, MBX-500 was a narrow-spectrum agent, displaying poor activity against many other gut anaerobes. MBX-500 was active in acute and recurrent infections in a toxigenic hamster model of CDI, exhibiting full protection against acute infections and prevention of recurrence in 70% of the animals. Hamsters treated with MBX-500 displayed significantly greater weight gain than did those treated with vancomycin. Finally, MBX-500 was efficacious in a murine model of CDI, again demonstrating a fully protective effect and permitting near-normal weight gain in the treated animals. These selective anti-CDI features support the further development of MBX 500 for the treatment of CDI.


2012 ◽  
Vol 56 (11) ◽  
pp. 5986-5989 ◽  
Author(s):  
Manoj Kumar ◽  
Tarun Mathur ◽  
Tarani K. Barman ◽  
G. Ramkumar ◽  
Ashish Bhati ◽  
...  

ABSTRACTThe MIC90of RBx 14255, a novel ketolide, againstClostridium difficilewas 4 μg/ml (MIC range, 0.125 to 8 μg/ml), and this drug was found to be more potent than comparator drugs. Anin vitrotime-kill kinetics study of RBx 14255 showed time-dependent bacterial killing forC. difficile. Furthermore, in the hamster model ofC. difficileinfection, RBx 14255 demonstrated greater efficacy than metronidazole and vancomycin, making it a promising candidate forC. difficiletreatment.


2013 ◽  
Vol 57 (11) ◽  
pp. 5266-5270 ◽  
Author(s):  
Kristin J. Nagaro ◽  
S. Tyler Phillips ◽  
Adam K. Cheknis ◽  
Susan P. Sambol ◽  
Walter E. Zukowski ◽  
...  

ABSTRACTNontoxigenicClostridium difficile(NTCD) has been shown to prevent fatalC. difficileinfection in the hamster model when hamsters are challenged with standard toxigenicC. difficilestrains. The purpose of this study was to determine if NTCD can preventC. difficileinfection in the hamster model when hamsters are challenged with restriction endonuclease analysis group BIC. difficilestrains. Groups of 10 hamsters were given oral clindamycin, followed on day 2 by 106CFU of spores of NTCD strain M3 or T7, and were challenged on day 5 with 100 CFU of spores of BI1 or BI6. To conserve animals, results for control hamsters challenged with BI1 or BI6 from the present study and controls from previous identical experiments were combined for statistical comparisons. NTCD strains M3 and T7 achieved 100% colonization and were 100% protective against challenge with BI1 (P≤ 0.001). M3 colonized 9/10 hamsters and protected against BI6 challenge in the colonized hamsters (P= 0.0003). T7 colonized 10/10 hamsters, but following BI6 challenge, cocolonization occurred in 5 hamsters, 4 of which died, for protection of 6/10 animals (P= 0.02). NTCD colonization provides protection against challenge with toxigenic BI group strains. M3 is more effective than T7 in preventingC. difficileinfection caused by the BI6 epidemic strain. Prevention ofC. difficileinfection caused by the epidemic BI6 strain may be more challenging than that of infections caused by historic BI1 and non-BIC. difficilestrains.


2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S333-S333
Author(s):  
Monique Bidell ◽  
Gregory Novak ◽  
Gurkirat Singh ◽  
Benjamin Bratek ◽  
Odirichukwu Duru ◽  
...  

Abstract Background Clostridium difficile infection (CDI) is a significant cause of morbidity and mortality. IDSA guidelines recommend oral vancomycin (VAN) for the treatment of CDI, although doses used in practice vary substantially. The purpose of this study was to determine differences in outcomes between patients treated with high dose (HD; ≥250 mg four times daily [QID]) vs. standard dose (SD; 125 mg QID) VAN for CDI. Methods This multicenter study evaluated patients at two hospitals in Albany, NY diagnosed with CDI and treated with oral VAN between January 2013 and August 2017. Hospitalized patients were included if: age ≥18 years, positive C. difficile toxin polymerase chain reaction (PCR), symptomatic infection (e.g., new onset or increased frequency of loose stools), and received ≥48 hours of VAN QID. Patients were excluded if: received ≥48 hours of metronidazole prior to VAN initiation, VAN per rectum, required surgical intervention ≤48 hours from PCR, had a history of fecal microbiota transplant, received ≥1 dose of fidaxomicin or tigecycline prior to or within 48 hours from PCR, or died ≤48 hours from PCR. The primary outcome was 90-day CDI recurrence; secondary outcomes included 30-day all-cause mortality and 90-day readmission. Variables with a P-value <0.2 in univariate analysis were evaluated in multivariate (MV) analyses. Results Four hundred fifty-eight patients were included (site 1: 270; site 2: 188). Two hundred twenty-four patients received SD VAN (48.9%); 234 received HD VAN [250 mg QID: 199 (43.5%); 500 mg QID: 35 (7.6%)]. Baseline demographics were similar between groups. Patients treated with HD were more likely to present with colitis (19.2 vs. 29.5%, P = 0.01) and have higher infection severity based on IDSA (P < 0.01), Zar (P < 0.01), and American College of Gastroenterology (P < 0.02) criteria. Modified APACHE II scores were similar between SD and HD groups (median: 12.2 vs. 12.9, P = 0.17). MV analysis identified no difference in 90-day recurrence with HD (OR 1.65, P = 0.13) after controlling for solid tumor cancers, immunosuppression, and IDSA severity. Similarly, no significant differences between SD and HD were observed for 30-day mortality and 90-day readmission. Conclusion No differences in recurrence, mortality, or readmission were identified between SD and HD oral VAN for the treatment of CDI, though HD VAN patients primarily received 250 mg QID. Disclosures All authors: No reported disclosures.


2015 ◽  
Vol 59 (11) ◽  
pp. 7007-7010 ◽  
Author(s):  
Jason C. Gallagher ◽  
Joseph P. Reilly ◽  
Bhagyashri Navalkele ◽  
Gemma Downham ◽  
Kevin Haynes ◽  
...  

ABSTRACTWe studied the clinical and economic impact of a protocol encouraging the use of fidaxomicin as a first-line drug for treatment ofClostridium difficileinfection (CDI) in patients hospitalized during a 2-year period. This study evaluated patients who received oral vancomycin or fidaxomicin for the treatment of CDI during a 2-year period. All included patients were eligible for administration of fidaxomicin via a protocol that encouraged its use for selected patients. The primary clinical endpoint was 90-day readmission with a diagnosis of CDI. Hospital charges and insurance reimbursements for readmissions were calculated along with the cost of CDI therapy to estimate the financial impact of the choice of therapy. Recurrences were seen in 10/49 (20.4%) fidaxomicin patients and 19/46 (41.3%) vancomycin patients (P= 0.027). In a multivariate analysis that included determinations of severity of CDI, serum creatinine increases, and concomitant antibiotic use, only fidaxomicin was significantly associated with decreased recurrence (adjusted odds ratio [aOR], 0.33; 95% confidence interval [CI], 0.12 to 0.93). The total lengths of stay of readmitted patients were 183 days for vancomycin and 87 days for fidaxomicin, with costs of $454,800 and $196,200, respectively. Readmissions for CDI were reimbursed on the basis of the severity of CDI, totaling $151,136 for vancomycin and $107,176 for fidaxomicin. Fidaxomicin drug costs totaled $62,112, and vancomycin drug costs were $6,646. We calculated that the hospital lost an average of $3,286 per fidaxomicin-treated patient and $6,333 per vancomycin-treated patient, thus saving $3,047 per patient with fidaxomicin. Fidaxomicin use for CDI treatment prevented readmission and decreased hospital costs compared to use of oral vancomycin.


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