scholarly journals Beneficial Effect of Oral Tigecycline Treatment on Clostridium difficile Infection in Gnotobiotic Piglets

2014 ◽  
Vol 58 (12) ◽  
pp. 7560-7564 ◽  
Author(s):  
Hyeun Bum Kim ◽  
Quanshun Zhang ◽  
Xingmin Sun ◽  
Gillian Beamer ◽  
Yuankai Wang ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Beneficial Effect ◽  
Oral Treatment ◽  
Clinical Signs ◽  
Gut Microflora ◽  
Human Gut ◽  
Content Type ◽  
Gnotobiotic Pig ◽  
Gnotobiotic Piglets ◽  
Lesion Severity

ABSTRACTThe efficacy of oral tigecycline treatment (2 mg/kg of body weight for 7 days) ofClostridium difficileinfection (CDI) was evaluated in the gnotobiotic pig model, and its effect on human gut microflora transplanted into the gnotobiotic pig was determined. Tigecycline oral treatment improved survival, clinical signs, and lesion severity and markedly decreased concentrations ofFirmicutesbut did not promote CDI. Our data showed that oral tigecycline treatment has a potential beneficial effect on the treatment of CDI.

scholarly journals MBX-500 Is Effective for Treatment of Clostridium difficile Infection in Gnotobiotic Piglets

2013 ◽  
Vol 57 (8) ◽  
pp. 4039-4041 ◽  
Author(s):  
Jennifer Steele ◽  
Quanshun Zhang ◽  
Gillian Beamer ◽  
Michelle Butler ◽  
Terry Bowlin ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Systemic Disease ◽  
Clinical Signs ◽  
The Novel ◽  
Content Type ◽  
High Doses ◽  
Gnotobiotic Pig ◽  
Severe Systemic Disease ◽  
Gnotobiotic Piglets ◽  
Lesion Severity

ABSTRACTThe novel antibiotic MBX-500, dosed at 100, 200, or 400 mg/kg twice daily for 7 days, was evaluated for the treatment ofClostridium difficileinfection (CDI) in the gnotobiotic pig model. MBX-500 increased survival at all doses and at high doses improved clinical signs and reduced lesion severity, similar to vancomycin. Our results show that MBX-500 is an effective antibiotic for the treatment of diarrhea associated with CDI and prevents severe systemic disease.

scholarly journals A Tetraspecific VHH-Based Neutralizing Antibody Modifies Disease Outcome in Three Animal Models of Clostridium difficile Infection

2016 ◽  
Vol 23 (9) ◽  
pp. 774-784 ◽  
Author(s):  
Diane J. Schmidt ◽  
Gillian Beamer ◽  
Jacqueline M. Tremblay ◽  
Jennifer A. Steele ◽  
Hyeun Bum Kim ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Neutralizing Antibody ◽  
Antibiotic Resistant ◽  
Content Type ◽  
New Therapeutic Approaches ◽  
Cell Assays ◽  
Life Threatening ◽  
Hospital Stays ◽  
Serious Disease ◽  
Gnotobiotic Piglets

ABSTRACTClostridium difficileinfection (CDI), a leading cause of nosocomial infection, is a serious disease in North America, Europe, and Asia. CDI varies greatly from asymptomatic carriage to life-threatening diarrhea, toxic megacolon, and toxemia. The incidence of community-acquired infection has increased due to the emergence of hypervirulent antibiotic-resistant strains. These new strains contribute to the frequent occurrence of disease relapse, complicating treatment, increasing hospital stays, and increasing morbidity and mortality among patients. Therefore, it is critical to develop new therapeutic approaches that bypass the development of antimicrobial resistance and avoid disruption of gut microflora. Here, we describe the construction of a single heteromultimeric VHH-based neutralizing agent (VNA) that targets the two primary virulence factors ofClostridium difficile, toxins A (TcdA) and B (TcdB). Designated VNA2-Tcd, this agent has subnanomolar toxin neutralization potencies for bothC. difficiletoxins in cell assays. When given systemically by parenteral administration, VNA2-Tcd protected against CDI in gnotobiotic piglets and mice and to a lesser extent in hamsters. Protection from CDI was also observed in gnotobiotic piglets treated by gene therapy with an adenovirus that promoted the expression of VNA2-Tcd.

scholarly journals Suppression of Clostridium difficile in the Gastrointestinal Tracts of Germfree Mice Inoculated with a Murine Isolate from the Family Lachnospiraceae

2012 ◽  
Vol 80 (11) ◽  
pp. 3786-3794 ◽  
Author(s):  
Angela E. Reeves ◽  
Mark J. Koenigsknecht ◽  
Ingrid L. Bergin ◽  
Vincent B. Young
Keyword(s):  
Microbial Community ◽  
Clostridium Difficile ◽  
Clinical Signs ◽  
Colonization Resistance ◽  
Content Type ◽  
E Coli ◽  
Mild Disease ◽  
Treatment And Prevention ◽  
The Family ◽  
Indigenous Microbial Community

ABSTRACTThe indigenous microbial community of the gastrointestinal (GI) tract determines susceptibility toClostridium difficilecolonization and disease. Previous studies have demonstrated that antibiotic-treated mice challenged withC. difficileeither developed rapidly lethalC. difficileinfection or were stably colonized with mild disease. The GI microbial community of animals with mild disease was dominated by members of the bacterial familyLachnospiraceae, while the gut community in moribund animals had a predominance ofEscherichia coli. We investigated the roles of murineLachnospiraceaeandE. colistrains in colonization resistance againstC. difficilein germfree mice. MurineLachnospiraceaeandE. coliisolates were cultured from wild-type mice. The ability of each of these isolates to interfere withC. difficilecolonization was tested by precolonizing germfree mice with these bacteria 4 days prior to experimentalC. difficilechallenge. Mice precolonized with a murineLachnospiraceaeisolate, but not those colonized withE. coli, had significantly decreasedC. difficilecolonization, lower intestinal cytotoxin levels and exhibited less severe clinical signs and colonic histopathology. Infection of germfree mice or mice precolonized withE. coliwithC. difficilestrain VPI 10463 was uniformly fatal by 48 h, but only 20% mortality was seen at 2 days in mice precolonized with theLachnospiraceaeisolate prior to challenge with VPI 10463. These findings confirm that a single component of the GI microbiota, a murineLachnospiraceaeisolate, could partially restore colonization resistance againstC. difficile. Further study of the members within theLachnospiraceaefamily could lead to a better understanding of mechanisms of colonization resistance againstC. difficileand novel therapeutic approaches for the treatment and prevention ofC. difficileinfection.

scholarly journals Fecal Microbiota Transplantation Eliminates Clostridium difficile in a Murine Model of Relapsing Disease

2015 ◽  
Vol 83 (10) ◽  
pp. 3838-3846 ◽  
Author(s):  
Anna M. Seekatz ◽  
Casey M. Theriot ◽  
Caitlyn T. Molloy ◽  
Katherine L. Wozniak ◽  
Ingrid L. Bergin ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Gut Microbiota ◽  
Murine Model ◽  
Fecal Microbiota Transplantation ◽  
Clinical Signs ◽  
Fecal Microbiota ◽  
Content Type ◽  
Health Care Associated Infections ◽  
Specific Community

RecurrentClostridium difficileinfection (CDI) is of particular concern among health care-associated infections. The role of the microbiota in disease recovery is apparent given the success of fecal microbiota transplantation (FMT) for recurrent CDI. Here, we present a murine model of CDI relapse to further define the microbiota recovery following FMT. Cefoperazone-treated mice were infected withC. difficile630 spores and treated with vancomycin after development of clinical disease. Vancomycin treatment suppressed bothC. difficilecolonization and cytotoxin titers. However,C. difficilecounts increased within 7 days of completing treatment, accompanied by relapse of clinical signs. The administration of FMT immediately after vancomycin clearedC. difficileand decreased cytotoxicity within 1 week. The effects of FMT on the gut microbiota community were detectable in recipients 1-day posttransplant. Conversely, mice not treated with FMT remained persistently colonized with high levels ofC. difficile, and the gut microbiota in these mice persisted at low diversity. These results suggest that full recovery of colonization resistance againstC. difficilerequires the restoration of a specific community structure.

scholarly journals Effects of Tigecycline and Vancomycin Administration on Established Clostridium difficile Infection

2014 ◽  
Vol 59 (3) ◽  
pp. 1596-1604 ◽  
Author(s):  
Casey M. Theriot ◽  
Cassie A. Schumacher ◽  
Christine M. Bassis ◽  
Anna M. Seekatz ◽  
Vincent B. Young
Keyword(s):  
Clostridium Difficile ◽  
Untreated Control ◽  
Clinical Signs ◽  
Disease Development ◽  
Soft Tissue Infections ◽  
Gram Negative ◽  
Content Type ◽  
Complicated Skin ◽  
Abdominal Infections

ABSTRACTThe glycylcycline antibiotic tigecycline was approved in 2005 for the treatment of complicated skin and soft tissue infections and complicated intra-abdominal infections. Tigecycline is broadly active against both Gram-negative and Gram-positive microorganisms, includingClostridium difficile. Tigecycline has a low MIC againstC. difficilein vitroand thus may represent an alternate treatment forC. difficileinfection (CDI). To assess the use of tigecycline for treatment of established CDI, 5- to 8-week-old C57BL/6 mice were colonized withC. difficilestrain 630. AfterC. difficilecolonization was established, mice (n= 10 per group) were treated with either a 5-day course of tigecycline (6.25 mg/kg every 12 h subcutaneously) or a 5-day course of vancomycin (0.4 mg/ml in drinking water) and compared to infected, untreated control mice. Mice were evaluated for clinical signs of CDI throughout treatment and at 1 week posttreatment to assess potential for disease development. Immediately following a treatment course,C. difficilewas not detectable in the feces of vancomycin-treated mice but remained detectable in feces from tigecycline-treated and untreated control mice. Toxin activity and histopathological inflammation and edema were observed in the ceca and colons of untreated mice; tigecycline- and vancomycin-treated mice did not show such changes directly after treatment. One week after the conclusion of either antibiotic treatment,C. difficileload, toxin activity, and histopathology scores increased in the cecum and colon, indicating thatC. difficile-associated disease occurred.In vitrogrowth studies confirmed that subinhibitory concentrations of tigecycline were able to suppress toxin activity and spore formation ofC. difficile, whereas vancomycin did not. Taken together, these data show how tigecycline is able to alterC. difficilepathogenesis in a mouse model of CDI.

scholarly journals Interspecies Interactions between Clostridium difficile and Candida albicans

mSphere ◽  
2016 ◽  
Vol 1 (6) ◽  
Author(s):  
Pim T. van Leeuwen ◽  
Jasper M. van der Peet ◽  
Floris J. Bikker ◽  
Michel A. Hoogenkamp ◽  
Ana M. Oliveira Paiva ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Clostridium Difficile ◽  
Biofilm Formation ◽  
Bacterial Disease ◽  
Opportunistic Pathogens ◽  
Human Gut ◽  
Aerobic Conditions ◽  
Content Type ◽  
Hypha Formation ◽  
Wide Range

ABSTRACT Candida albicans and Clostridium difficile are two opportunistic pathogens that reside in the human gut. A few studies have focused on the prevalence of C. albicans in C. difficile-infected patients, but none have shown the interaction(s) that these two organisms may or may not have with each other. In this study, we used a wide range of different techniques to better understand this interaction at a macroscopic and microscopic level. We found that in the presence of C. albicans, C. difficile can survive under ambient aerobic conditions, which would otherwise be toxic. We also found that C. difficile affects the hypha formation of C. albicans, most likely through the excretion of p-cresol. This ultimately leads to an inability of C. albicans to form a biofilm. Our study provides new insights into interactions between C. albicans and C. difficile and bears relevance to both fungal and bacterial disease. The facultative anaerobic polymorphic fungus Candida albicans and the strictly anaerobic Gram-positive bacterium Clostridium difficile are two opportunistic pathogens residing in the human gut. While a few studies have focused on the prevalence of C. albicans in C. difficile-infected patients, the nature of the interactions between these two microbes has not been studied thus far. In the current study, both chemical and physical interactions between C. albicans and C. difficile were investigated. In the presence of C. albicans, C. difficile was able to grow under aerobic, normally toxic, conditions. This phenomenon was neither linked to adherence of bacteria to hyphae nor to biofilm formation by C. albicans. Conditioned medium of C. difficile inhibited hyphal growth of C. albicans, which is an important virulence factor of the fungus. In addition, it induced hypha-to-yeast conversion. p-Cresol, a fermentation product of tyrosine produced by C. difficile, also induced morphological effects and was identified as an active component of the conditioned medium. This study shows that in the presence of C. albicans, C. difficile can persist and grow under aerobic conditions. Furthermore, p-cresol, produced by C. difficile, is involved in inhibiting hypha formation of C. albicans, directly affecting the biofilm formation and virulence of C. albicans. This study is the first detailed characterization of the interactions between these two gut pathogens. IMPORTANCE Candida albicans and Clostridium difficile are two opportunistic pathogens that reside in the human gut. A few studies have focused on the prevalence of C. albicans in C. difficile-infected patients, but none have shown the interaction(s) that these two organisms may or may not have with each other. In this study, we used a wide range of different techniques to better understand this interaction at a macroscopic and microscopic level. We found that in the presence of C. albicans, C. difficile can survive under ambient aerobic conditions, which would otherwise be toxic. We also found that C. difficile affects the hypha formation of C. albicans, most likely through the excretion of p-cresol. This ultimately leads to an inability of C. albicans to form a biofilm. Our study provides new insights into interactions between C. albicans and C. difficile and bears relevance to both fungal and bacterial disease.

scholarly journals Characterizations of Clinical Isolates of Clostridium difficile by Toxin Genotypes and by Susceptibility to 12 Antimicrobial Agents, Including Fidaxomicin (OPT-80) and Rifaximin: a Multicenter Study in Taiwan

2012 ◽  
Vol 56 (7) ◽  
pp. 3943-3949 ◽  
Author(s):  
Chun-Hsing Liao ◽  
Wen-Chien Ko ◽  
Jang-Jih Lu ◽  
Po-Ren Hsueh
Keyword(s):  
Clostridium Difficile ◽  
Care Setting ◽  
Antimicrobial Agents ◽  
Teaching Hospitals ◽  
Binary Toxin ◽  
Content Type ◽  
Vancomycin Mics ◽  
Major Teaching ◽  
Southern Taiwan

ABSTRACTA total of 403 nonduplicate isolates ofClostridium difficilewere collected at three major teaching hospitals representing northern, central, and southern Taiwan from January 2005 to December 2010. Of these 403 isolates, 170 (42.2%) were presumed to be nontoxigenic due to the absence of genes for toxins A or B or binary toxin. The remaining 233 (57.8%) isolates carried toxin A and B genes, and 39 (16.7%) of these also had binary toxin genes. The MIC90of all isolates for fidaxomicin and rifaximin was 0.5 μg/ml (range, ≤0.015 to 0.5 μg/ml) and >128 μg/ml (range, ≤0.015 to >128 μg/ml), respectively. All isolates were susceptible to metronidazole (MIC90of 0.5 μg/ml; range, ≤0.03 to 4 μg/ml). Two isolates had reduced susceptibility to vancomycin (MICs, 4 μg/ml). Only 13.6% of isolates were susceptible to clindamycin (MIC of ≤2 μg/ml). Nonsusceptibility to moxifloxacin (n= 81, 20.1%) was accompanied by single or multiple mutations ingyrAandgyrBgenes in all but eight moxifloxacin-nonsusceptible isolates. Two previously unreportedgyrBmutations might independently confer resistance (MIC, 16 μg/ml), Ser416 to Ala and Glu466 to Lys. Moxifloxacin-resistant isolates were cross-resistant to ciprofloxacin and levofloxacin, but some moxifloxacin-nonsusceptible isolates remained susceptible to gemifloxacin or nemonoxacin at 0.5 μg/ml. This study found the diversity of toxigenic and nontoxigenic strains ofC. difficilein the health care setting in Taiwan. All isolates tested were susceptible to metronidazole and vancomycin. Fidaxomicin exhibited potentin vitroactivity against all isolates tested, while the more than 10% of Taiwanese isolates with rifaximin MICs of ≥128 μg/ml raises concerns.

scholarly journals Pharmacokinetics and Pharmacodynamics of the Nitroimidazole DNDI-0690 in Mouse Models of Cutaneous Leishmaniasis

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Gert-Jan Wijnant ◽  
Simon L. Croft ◽  
Raul de la Flor ◽  
Mo Alavijeh ◽  
Vanessa Yardley ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Mouse Models ◽  
Drug Exposure ◽  
Oral Treatment ◽  
Drug Application ◽  
Skin Tissue ◽  
Drug Candidate ◽  
Topical Formulation ◽  
Content Type

ABSTRACT The nitroimidazole DNDI-0690 is a clinical drug candidate for visceral leishmaniasis (VL) that also shows potent in vitro and in vivo activity against cutaneous leishmaniasis (CL). To support further development of this compound into a patient-friendly oral or topical formulation for the treatment of CL, we investigated the free drug exposure at the dermal site of infection and subsequent elimination of the causative Leishmania pathogen. This study evaluates the pharmacokinetics (PK) and pharmacodynamics (PD) of DNDI-0690 in mouse models of CL. Skin microdialysis and Franz diffusion cell permeation studies revealed that DNDI-0690 permeated poorly (<1%) into the skin lesion upon topical drug application (0.063% [wt/vol], 30 μl). In contrast, a single oral dose of 50 mg/kg of body weight resulted in the rapid and nearly complete distribution of protein-unbound DNDI-0690 from the plasma into the infected dermis (ratio of the area under the curve [0 to 6 h] of the free DNDI-0690 concentration in skin tissue to blood [fAUC0-6 h, skin tissue/fAUC0-6 h, blood] is greater than 80%). Based on in vivo bioluminescence imaging, two doses of 50 mg/kg DNDI-0690 were sufficient to reduce the Leishmania mexicana parasite load by 100-fold, while 6 such doses were needed to achieve similar killing of L. major; this was confirmed by quantitative PCR. The combination of rapid accumulation and potent activity in the Leishmania-infected dermis indicates the potential of DNDI-0690 as a novel oral treatment for CL.

scholarly journals Impact of Variations in Test Method Parameters onIn VitroActivity of Surotomycin against Clostridium difficile and Surotomycin Quality Control Limits for Broth Microdilution and Agar Dilution Susceptibility Testing

2015 ◽  
Vol 54 (3) ◽  
pp. 749-753 ◽  
Author(s):  
Maria M. Traczewski ◽  
Jennifer Deane ◽  
Daniel Sahm ◽  
Steven D. Brown ◽  
Laurent Chesnel
Keyword(s):  
Quality Control ◽  
Clostridium Difficile ◽  
Calcium Concentration ◽  
Susceptibility Testing ◽  
Test Method ◽  
Test Parameter ◽  
Content Type ◽  
Parameter Variations ◽  
Agar Dilution ◽  
Control Limits

Test parameter variations were evaluated for their effects on surotomycin MICs. Calcium concentration was the only variable that influenced MICs; therefore, 50 μg/ml (standard for lipopeptide testing) is recommended. Quality control ranges forClostridium difficile(0.12 to 1 μg/ml) andEggerthella lenta(broth, 1 to 4 μg/ml; agar, 1 to 8 μg/ml) were approved by the Clinical and Laboratory Standards Institute based on these data.

Experimental delayed radiation necrosis of the brain

1979 ◽  
Vol 51 (5) ◽  
pp. 587-596 ◽  
Author(s):  
Albert N. Martins ◽  
Ralph E. Severance ◽  
James M. Henry ◽  
Thomas F. Doyle
Keyword(s):  
Rhesus Monkeys ◽  
Radiation Necrosis ◽  
Clinical Signs ◽  
Control Group ◽  
Content Type ◽  
Brain Irradiation ◽  
Primate Brain ◽  
High Doses ◽  
The Brain ◽  
Male Rhesus

✓ The authors have designed an experiment to detect a hitherto unrecognized interaction between high doses of the glucocorticoid, dexamethasone, and brain irradiation. Eighteen juvenile male rhesus monkeys received 1800 rads to the whole brain in 8.5 minutes. For 1½ days before and 10½ days after the irradiation, nine animals received approximately 2.9 mg/kg/day of dexamethasone intramuscularly in addition to irradiation, while the remaining nine animals served as the control group and received saline. All animals eventually developed a progressive neurological syndrome, and died of delayed radiation necrosis of the brain. The two groups were compared with regard to latency to onset of clinical signs, survival time, and number, distribution, and location of lesions of radionecrosis. Large doses of dexamethasone did not alter the susceptibility of the primate brain to delayed radiation necrosis. Detailed morphological study of the radionecrotic lesions supports the hypothesis that most, if not all, of the lesions develop as the consequence of injury to blood vessels.

Sign in / Sign up

Export Citation Format

Share Document