scholarly journals SMT19969 for Clostridium difficile infection (CDI): in vivo efficacy compared with fidaxomicin and vancomycin in the hamster model of CDI

2015 ◽  
Author(s):  
A. Sattar ◽  
P. Thommes ◽  
L. Payne ◽  
P. Warn ◽  
R. J. Vickers
Keyword(s):  
Clostridium Difficile ◽  
Clostridium Difficile Infection ◽  
Hamster Model ◽  
In Vivo Efficacy

scholarly journals MBX-500, a Hybrid Antibiotic withIn VitroandIn VivoEfficacy against Toxigenic Clostridium difficile

2012 ◽  
Vol 56 (9) ◽  
pp. 4786-4792 ◽  
Author(s):  
Michelle M. Butler ◽  
Dean L. Shinabarger ◽  
Diane M. Citron ◽  
Ciarán P. Kelly ◽  
Sofya Dvoskin ◽  
...  
Keyword(s):  
Weight Gain ◽  
Clostridium Difficile ◽  
Severe Disease ◽  
Normal Weight ◽  
New Drugs ◽  
Hamster Model ◽  
Resistance Development ◽  
Content Type

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.

Protective effect of a mixture of kefir-isolated lactic acid bacteria and yeasts in a hamster model of Clostridium difficile infection

Anaerobe ◽  
2013 ◽  
Vol 21 ◽  
pp. 28-33 ◽  
Author(s):  
Patricia A. Bolla ◽  
Paula Carasi ◽  
María de los Angeles Bolla ◽  
Graciela L. De Antoni ◽  
María de los Angeles Serradell
Keyword(s):  
Lactic Acid ◽  
Clostridium Difficile ◽  
Lactic Acid Bacteria ◽  
Protective Effect ◽  
Clostridium Difficile Infection ◽  
Hamster Model

scholarly journals Efficacy of Macrolides and Telithromycin against Leptospirosis in a Hamster Model

2006 ◽  
Vol 50 (6) ◽  
pp. 1989-1992 ◽  
Author(s):  
James E. Moon ◽  
Michael C. Ellis ◽  
Matthew E. Griffith ◽  
Joshua S. Hawley ◽  
Robert G. Rivard ◽  
...  
Keyword(s):  
Body Weight ◽  
Untreated Control ◽  
Antimicrobial Agents ◽  
Leptospira Interrogans ◽  
In Vitro Activity ◽  
Hamster Model ◽  
In Vivo Efficacy ◽  
Daily Dose

ABSTRACT Human studies support the use of β-lactams and tetracyclines in the treatment of leptospirosis. Additional agents from these and other classes of antimicrobials also have in vitro activity against Leptospira species, though corroborating in vivo data are limited or lacking. We evaluated the therapeutic efficacy of azithromycin, clarithromycin, and telithromycin in a lethal hamster model of leptospirosis using Leptospira interrogans serogroup Canicola serovar Portlandvere. A range of dosages for each antimicrobial was given to the infected animals on days 2 through 7 (5 days) of the 21-day survival model. All untreated control animals survived less than 10 days from infection. Ninety to 100% of doxycycline controls, treated for 5 days with 5 mg/kg of body weight of drug, survived to 21 days. Treatment with azithromycin (daily dose: 6.25, 12.5, 25, 50, 100, or 200 mg/kg) resulted in 100% survival at all evaluated doses. Animals receiving 20 mg/kg or more of clarithromycin (daily dose: 1, 5, 10, 15, 20, 40, 60, or 100 mg/kg) had improved survival. Ninety-eight percent of animals treated with telithromycin (daily dose: 1, 5, 10, 15, 20, or 40 mg/kg) survived. We conclude that all agents tested have demonstrated in vivo efficacy in treating acute leptospirosis. These results provide support for further evaluation of macrolide and ketolide antimicrobial agents in human trials.

scholarly journals The HtrA-Like Protease CD3284 Modulates Virulence of Clostridium difficile

2014 ◽  
Vol 82 (10) ◽  
pp. 4222-4232 ◽  
Author(s):  
Dennis Bakker ◽  
Anthony M. Buckley ◽  
Anne de Jong ◽  
Vincent J. C. van Winden ◽  
Joost P. A. Verhoeks ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Virulence Factors ◽  
Pathogenic Bacteria ◽  
Microarray Data Analysis ◽  
Toxin A ◽  
Hamster Model ◽  
Golden Syrian Hamster ◽  
Content Type

ABSTRACTIn the past decade,Clostridium difficilehas emerged as an important gut pathogen. Symptoms ofC. difficileinfection range from mild diarrhea to pseudomembranous colitis. Besides the two main virulence factors toxin A and toxin B, other virulence factors are likely to play a role in the pathogenesis of the disease. In other Gram-positive and Gram-negative pathogenic bacteria, conserved high-temperature requirement A (HtrA)-like proteases have been shown to have a role in protein homeostasis and quality control. This affects the functionality of virulence factors and the resistance of bacteria to (host-induced) environmental stresses. We found that theC. difficile630 genome encodes a single HtrA-like protease (CD3284; HtrA) and have analyzed its rolein vivoandin vitrothrough the creation of an isogenic ClosTron-basedhtrAmutant ofC. difficilestrain 630Δerm(wild type). In contrast to the attenuated phenotype seen withhtrAdeletion in other pathogens, this mutant showed enhanced virulence in the Golden Syrian hamster model of acuteC. difficileinfection. Microarray data analysis showed a pleiotropic effect ofhtrAon the transcriptome ofC. difficile, including upregulation of the toxin A gene. In addition,the htrAmutant showed reduced spore formation and adherence to colonic cells. Together, our data show thathtrAcan modulate virulence inC. difficile.

scholarly journals Human Monoclonal Antibodies Directed against Toxins A and B Prevent Clostridium difficile-Induced Mortality in Hamsters

2006 ◽  
Vol 74 (11) ◽  
pp. 6339-6347 ◽  
Author(s):  
Gregory J. Babcock ◽  
Teresa J. Broering ◽  
Hector J. Hernandez ◽  
Robert B. Mandell ◽  
Katherine Donahue ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Clostridium Difficile ◽  
Human Monoclonal Antibodies ◽  
Toxin A ◽  
Hamster Model ◽  
Cytotoxic Effects ◽  
Toxin B ◽  
Reduction Of Mortality

ABSTRACT Clostridium difficile is the leading cause of nosocomial antibiotic-associated diarrhea, and recent outbreaks of strains with increased virulence underscore the importance of identifying novel approaches to treat and prevent relapse of Clostridium difficile-associated diarrhea (CDAD). CDAD pathology is induced by two exotoxins, toxin A and toxin B, which have been shown to be cytotoxic and, in the case of toxin A, enterotoxic. In this report we describe fully human monoclonal antibodies (HuMAbs) that neutralize these toxins and prevent disease in hamsters. Transgenic mice carrying human immunoglobulin genes were used to isolate HuMAbs that neutralize the cytotoxic effects of either toxin A or toxin B in cell-based in vitro neutralization assays. Three anti-toxin A HuMAbs (3H2, CDA1, and 1B11) could all inhibit the enterotoxicity of toxin A in mouse intestinal loops and the in vivo toxicity in a systemic mouse model. Four anti-toxin B HuMAbs (MDX-1388, 103-174, 1G10, and 2A11) could neutralize cytotoxicity in vitro, although systemic toxicity in the mouse could not be neutralized. Anti-toxin A HuMAb CDA1 and anti-toxin B HuMAb MDX-1388 were tested in the well-established hamster model of C. difficile disease. CDA1 alone resulted in a statistically significant reduction of mortality in hamsters; however, the combination treatment offered enhanced protection. Compared to controls, combination therapy reduced mortality from 100% to 45% (P < 0.0001) in the primary disease hamster model and from 78% to 32% (P < 0.0001) in the less stringent relapse model.

scholarly journals The Clostridium difficile Dlt Pathway Is Controlled by the Extracytoplasmic Function Sigma Factor σVin Response to Lysozyme

2016 ◽  
Vol 84 (6) ◽  
pp. 1902-1916 ◽  
Author(s):  
Emily C. Woods ◽  
Kathryn L. Nawrocki ◽  
Jose M. Suárez ◽  
Shonna M. McBride
Keyword(s):  
Cell Wall ◽  
Clostridium Difficile ◽  
Sigma Factor ◽  
Intestinal Tract ◽  
Dependent Manner ◽  
Hamster Model ◽  
Content Type ◽  
Rapid Amplification ◽  
Extracytoplasmic Function Sigma Factor

Clostridium difficile(also known asPeptoclostridium difficile) is a major nosocomial pathogen and a leading cause of antibiotic-associated diarrhea throughout the world. Colonization of the intestinal tract is necessary forC. difficileto cause disease. Host-produced antimicrobial proteins (AMPs), such as lysozyme, are present in the intestinal tract and can deter colonization by many bacterial pathogens, and yetC. difficileis able to survive in the colon in the presence of these AMPs. Our prior studies established that the Dlt pathway, which increases the surface charge of the bacterium by addition ofd-alanine to teichoic acids, is important forC. difficileresistance to a variety of AMPs. We sought to determine what genetic mechanisms regulate expression of the Dlt pathway. In this study, we show that adltnull mutant is severely attenuated for growth in lysozyme and that expression of thedltDABCoperon is induced in response to lysozyme. Moreover, we found that a mutant lacking the extracytoplasmic function (ECF) sigma factor σVdoes not inducedltexpression in response to lysozyme, indicating that σVis required for regulation of lysozyme-dependentd-alanylation of the cell wall. Using reporter gene fusions and 5′ RACE (rapid amplification of cDNA ends) analysis, we identified promoter elements necessary for lysozyme-dependent and lysozyme-independentdltexpression. In addition, we observed that both asigVmutant and adltmutant are more virulent in a hamster model of infection. These findings demonstrate that cell walld-alanylation inC. difficileis induced by lysozyme in a σV-dependent manner and that this pathway impacts virulencein vivo.

scholarly journals In Vitro and In Vivo Activities of Nitazoxanide against Clostridium difficile

2000 ◽  
Vol 44 (9) ◽  
pp. 2254-2258 ◽  
Author(s):  
Catherine S. McVay ◽  
Rial D. Rolfe
Keyword(s):  
Body Weight ◽  
Clostridium Difficile ◽  
Treatment Period ◽  
Intestinal Disease ◽  
Hamster Model ◽  
Complete Treatment ◽  
Toxigenic Strains ◽  
Adult Hamster

ABSTRACT We have used the hamster model of antibiotic-inducedClostridium difficile intestinal disease to evaluate nitazoxanide (NTZ), a nitrothiazole benzamide antimicrobial agent. The following in vitro and in vivo activities of NTZ in the adult hamster were examined and compared to those of metronidazole and vancomycin: (i) MICs and minimum bactericidal concentrations (MBCs) againstC. difficile, (ii) toxicity, (iii) ability to preventC. difficile-associated ileocecitis, and (iv) propensity to induce C. difficile-associated ileocecitis. The MICs and MBCs of NTZ against 15 toxigenic strains of C. difficilewere comparable to those of vancomycin or metronidazole. C. difficile-associated ileocecitis was induced with oral clindamycin and toxigenic C. difficile in a group of 60 hamsters. Subgroups of 10 hamsters were given six daily intragastric treatments of NTZ (15, 7.5, and 3.0 mg/100 g of body weight [gbw]), metronidazole (15 mg/100 gbw), vancomycin (5 mg/100 gbw), or saline (1 ml/100 gbw). Animals receiving saline died 3 days post-C. difficile challenge. During the treatment period, NTZ (≥7.5 mg/100 gbw), like metronidazole and vancomycin, prevented outward manifestations of clindamycin-induced C. difficileintestinal disease. Six of ten hamsters on a scheduled dose of 3.0 mg of NTZ/100 gbw survived for the complete treatment period. Of these surviving animals, all but three died of C. difficiledisease by between 3 and 12 days following discontinuation of antibiotic therapy. Another group of hamsters received six similar daily doses of the three antibiotics, followed by an inoculation with toxigenic C. difficile. All of the NTZ-treated animals survived the 15-day postinfection period. Upon necropsy, all hamsters appeared normal: there were no gross signs of toxicity or C. difficile intestinal disease, nor was C. difficiledetected in the cultures of the ceca of these animals. By contrast, vancomycin and metronidazole treatment induced fatal C. difficile intestinal disease in 20 and 70% of recipients, respectively.

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 ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Dna Polymerase ◽  
Clostridium Difficile Infection ◽  
Human Disease ◽  
Oral Vancomycin ◽  
Hamster Model ◽  
Content Type ◽  
Novel Agent

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.

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