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 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.

Increase in Use of Vancomycin for Clostridium difficile Infection in US Hospitals

2010 ◽  
Vol 31 (8) ◽  
pp. 867-868 ◽  
Author(s):  
Amy L. Pakyz ◽  
Norman V. Carroll ◽  
Spencer E. Harpe ◽  
Michael Oinonen ◽  
Ronald E. Polk
Keyword(s):  
Clostridium Difficile ◽  
Primary Treatment ◽  
Epidemic Strain ◽  
First Line ◽  
Oral Vancomycin ◽  
Treatment Practices ◽  
First Line Therapy ◽  
Life Threatening ◽  
Vancomycin Resistant ◽  
Serious Disease

Clostridium difficile infection (CDI) is a potentially serious disease for which the epidemiology has recently changed, because of an emerging drug-resistant strain of the pathogen. Metronidazole and oral vancomycin are the primary treatment agents.2 Metronidazole has been historically favored as the first-line agent, partly to reduce the selection pressure for vancomycin-resistant enterococci (VRE), although metronidazole can also select for VRE. Vancomycin was traditionally reserved for metronidazole treatment failure or life-threatening disease. In a study conducted before emergence of the epidemic strain, vancomycin was reported to be superior for the initial treatment of severe CDI and for treatment of CDI that does not respond to metronidazole. Expert opinion calling for the use of vancomycin as first-line therapy, especially for severe CDI emergence of the epidemic strain, and reports of decreased metronidazole efficacy may have impacted CDI treatment practices. The purpose of this study was to characterize trends in CDI treatment in US hospitals.

scholarly journals Memory B Cells Encode Neutralizing Antibody Specific for Toxin B from the Clostridium difficile Strains VPI 10463 and NAP1/BI/027 but with Superior Neutralization of VPI 10463 Toxin B

2015 ◽  
Vol 84 (1) ◽  
pp. 194-204 ◽  
Author(s):  
T. Scott Devera ◽  
Gillian A. Lang ◽  
Jordi M. Lanis ◽  
Pragya Rampuria ◽  
Casey L. Gilmore ◽  
...  
Keyword(s):  
B Cells ◽  
Clostridium Difficile ◽  
Mononuclear Cells ◽  
Neutralizing Antibody ◽  
Memory B Cells ◽  
Lethal Challenge ◽  
Toxin B ◽  
Content Type ◽  
Antibody Titers

Secreted toxin B (TcdB) substantially contributes to the pathology observed duringClostridium difficileinfection. To be successfully incorporated into a vaccine, TcdB-based immunogens must stimulate the production of neutralizing antibody (Ab)-encoding memory B cells (Bmem cells). Despite numerous investigations, a clear analysis of Bmem cellular responses following vaccination against TcdB is lacking. B6 mice were therefore used to test the ability of a nontoxigenic C-terminal domain (CTD) fragment of TcdB to induce Bmem cells that encode TcdB-neutralizing antibody. CTD was produced from the historical VPI 10463 strain (CTD1) and from the hypervirulent strain NAP1/BI/027 (CTD2). It was then demonstrated that CTD1 induced strong recall IgG antibody titers, and this led to the development of functional Bmem cells that could be adoptively transferred to naive recipients. Bmem cell-driven neutralizing Ab responses conferred protection against lethal challenge with TcdB1. Further experiments revealed that an experimental adjuvant (Imject) and a clinical adjuvant (Alhydrogel) were compatible with Bmem cell induction. Reactivity of human Bmem cells to CTD1 was also evident in human peripheral blood mononuclear cells (PBMCs), suggesting that CTD1 could be a good vaccine immunogen. However, CTD2 induced strong Bmem cell-driven antibody titers, and the CTD2 antibody was neutralizingin vitro, but its protection against lethal challenge with TcdB2 was limited to delaying time to death. Therefore, CTD from differentC. difficilestrains may be a good immunogen for stimulating B cell memory that encodesin vitroneutralizing Ab but may be limited by variable protection against intoxicationin vivo.

scholarly journals Potent Killing of Pseudomonas aeruginosa by an Antibody-Antibiotic Conjugate

mBio ◽  
2021 ◽  
Author(s):  
Kimberly K. Kajihara ◽  
Homer Pantua ◽  
Hilda Hernandez-Barry ◽  
Meredith Hazen ◽  
Kiran Deshmukh ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Treatment ◽  
Clinical Success ◽  
Therapeutic Approaches ◽  
Preclinical Stage ◽  
Content Type ◽  
New Therapeutic Approaches ◽  
Life Threatening

Antibiotic treatment of life-threatening P. aeruginosa infections is associated with low clinical success, despite the availability of antibiotics that are active in standard microbiological in vitro assays, affirming the need for new therapeutic approaches. Antibiotics often fail in the preclinical stage due to insufficient efficacy against P. aeruginosa .

scholarly journals Simultaneous Host-Pathogen Transcriptome Analysis during Granulibacter bethesdensis Infection of Neutrophils from Healthy Subjects and Patients with Chronic Granulomatous Disease

2015 ◽  
Vol 83 (11) ◽  
pp. 4277-4292 ◽  
Author(s):  
David E. Greenberg ◽  
Daniel E. Sturdevant ◽  
Kimberly R. Marshall-Batty ◽  
Jessica Chu ◽  
Anthony M. Pettinato ◽  
...  
Keyword(s):  
Chronic Granulomatous Disease ◽  
Pyruvate Dehydrogenase ◽  
Healthy Subjects ◽  
Bacterial Resistance ◽  
Metabolic Adaptation ◽  
Granulomatous Disease ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Protein Levels ◽  
Life Threatening

ABSTRACTPolymorphonuclear leukocytes (PMN) from patients with chronic granulomatous disease (CGD) fail to produce microbicidal concentrations of reactive oxygen species (ROS) due to mutations in NOX2. Patients with CGD suffer from severe, life-threatening infections and inflammatory complications.Granulibacter bethesdensisis an emerging Gram-negative pathogen in CGD that resists killing by PMN of CGD patients (CGD PMN) and inhibits PMN apoptosis through unknown mechanisms. Microarray analysis was used to study mRNA expression in PMN from healthy subjects (normal PMN) and CGD PMN during incubation withG. bethesdensisand, simultaneously, inG. bethesdensiswith normal and CGD PMN. We detected upregulation of antiapoptotic genes (e.g., XIAP and GADD45B) and downregulation of proapoptotic genes (e.g., CASP8 and APAF1) in infected PMN. Transcript and protein levels of inflammation- and immunity-related genes were also altered. Upon interaction with PMN,G. bethesdensisaltered the expression of ROS resistance genes in the presence of normal but not CGD PMN. Levels of bacterial stress response genes, including the ClpB gene, increased during phagocytosis by both normal and CGD PMN demonstrating responses to oxygen-independent PMN antimicrobial systems. Antisense knockdown demonstrated that ClpB is dispensable for extracellular growth but is essential for bacterial resistance to both normal and CGD PMN. Metabolic adaptation ofGranulibactergrowth in PMN included the upregulation of pyruvate dehydrogenase. Pharmacological inhibition of pyruvate dehydrogenase by triphenylbismuthdichloride was lethal toGranulibacter. This study expands knowledge of microbial pathogenesis ofGranulibacterin cells from permissive (CGD) and nonpermissive (normal) hosts and identifies potentially druggable microbial factors, such as pyruvate dehydrogenase and ClpB, to help combat this antibiotic-resistant pathogen.

scholarly journals A Single VHH-Based Toxin-Neutralizing Agent and an Effector Antibody Protect Mice against Challenge with Shiga Toxins 1 and 2

2013 ◽  
Vol 81 (12) ◽  
pp. 4592-4603 ◽  
Author(s):  
Jacqueline M. Tremblay ◽  
Jean Mukherjee ◽  
Clinton E. Leysath ◽  
Michelle Debatis ◽  
Kwasi Ofori ◽  
...  
Keyword(s):  
Cost Effective ◽  
Content Type ◽  
Shiga Toxins ◽  
Toxin Molecule ◽  
New Therapeutic Approaches ◽  
Food Borne ◽  
Uremic Syndrome ◽  
Neutralizing Agent ◽  
Serious Disease

ABSTRACTShiga toxin-producingEscherichia coli(STEC) is a major cause of severe food-borne disease worldwide, and two Shiga toxins, Stx1 and Stx2, are primarily responsible for the serious disease consequence, hemolytic-uremic syndrome (HUS). Here we report identification of a panel of heavy-chain-only antibody (Ab) VH(VHH) domains that neutralize Stx1 and/or Stx2 in cell-based assays. VHH heterodimer toxin-neutralizing agents containing two linked Stx1-neutralizing VHHs or two Stx2-neutralizing VHHs were generally much more potent at Stx neutralization than a pool of the two-component monomers tested in cell-based assays andin vivomouse models. We recently reported that clearance of toxins can be promoted by coadministering a VHH-based toxin-neutralizing agent with an antitag monoclonal antibody (MAb), called the “effector Ab,” that indirectly decorates each toxin molecule with four Ab molecules. Decoration occurs because the Ab binds to a common epitopic tag present at two sites on each of the two VHH heterodimer molecules that bind to each toxin molecule. Here we show that coadministration of effector Ab substantially improved the efficacy of Stx toxin-neutralizing agents to prevent death or kidney damage in mice following challenge with Stx1 or Stx2. A single toxin-neutralizing agent consisting of a double-tagged VHH heterotrimer—one Stx1-specific VHH, one Stx2-specific VHH, and one Stx1/Stx2 cross-specific VHH—was effective in preventing all symptoms of intoxication from Stx1 and Stx2 when coadministered with effector Ab. Overall, the availability of simple, defined, recombinant proteins that provide cost-effective protection against HUS opens up new therapeutic approaches to managing disease.

scholarly journals Immobilization of Antibacterial Dihydropyrrol-2-ones on Functional Polymer Supports To Prevent Bacterial InfectionsIn Vivo

2011 ◽  
Vol 56 (2) ◽  
pp. 1138-1141 ◽  
Author(s):  
Kitty Ka Kit Ho ◽  
Nerida Cole ◽  
Renxun Chen ◽  
Mark D. P. Willcox ◽  
Scott A. Rice ◽  
...  
Keyword(s):  
Staphylococcal Infection ◽  
Infection Model ◽  
Dependent Manner ◽  
Pathogenic Potential ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Polymer Supports ◽  
Wide Range ◽  
Life Threatening

ABSTRACTAntibiotic-resistantStaphylococcus aureusis of great concern, as it causes a wide range of life-threatening infections. The current study demonstrates that dihydropyrrolone (DHP)-coated polyacrylamide substrates are effective in reducing the number of culturable clinical isolates ofS. aureusin vitroin a dose-dependent manner and are able to reduce the pathogenic potential of staphylococcal infection in a subcutaneous infection model. Covalently bound DHPs therefore show great potential for use as an antimicrobial strategy in device-related applications.

scholarly journals Protection from Clostridium difficile Infection in CD4 T Cell- and Polymeric Immunoglobulin Receptor-Deficient Mice

2013 ◽  
Vol 82 (2) ◽  
pp. 522-531 ◽  
Author(s):  
Pehga F. Johnston ◽  
Dale N. Gerding ◽  
Katherine L. Knight
Keyword(s):  
Clostridium Difficile ◽  
Protective Immunity ◽  
Content Type ◽  
Immunoglobulin Receptor ◽  
Hospital Acquired Infection ◽  
Histocompatibility Complex ◽  
Serum Iga ◽  
Life Threatening ◽  
Primary Hospital ◽  
Hospital Acquired

ABSTRACTClostridium difficilerivals methicillin-resistantStaphylococcus aureusas the primary hospital-acquired infection.C. difficileinfection (CDI) caused by toxins A and/or B can manifest as mild diarrhea to life-threatening pseudomembranous colitis. Although most patients recover fully from CDI, ∼20% undergo recurrent disease. Several studies have demonstrated a correlation between anti-toxin antibody (Ab) and decreased recurrence; however, the contributions of the systemic and mucosal Ab responses remain unclear. Our goal was to use the CDI mouse model to characterize the protective immune response toC. difficile. C57BL/6 mice infected with epidemicC. difficilestrain BI17 developed protective immunity against CDI and did not develop CDI upon rechallenge; they generated systemic IgG and IgA as well as mucosal IgA Ab to toxin. To determine if protective immunity toC. difficilecould be generated in immunodeficient individuals, we infectedCD4−/−mice and found that they generated both mucosal and serum IgA anti-toxin Abs and were protected from CDI upon rechallenge, with protection dependent on major histocompatibility complex class II (MHCII) expression; no IgG anti-toxin Ab was found. We found that protection was likely due to neutralizing mucosal IgA Ab. In contrast,pIgR−/−mice, which lack the receptor to transcytose polymeric Ab across the epithelium, were also protected from CDI, suggesting that although mucosal anti-toxin Ab may contribute to protection, it is not required. We conclude that protection from CDI can occur by several mechanisms and that the mechanism of protection is determined by the state of immunocompetence of the host.

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 Coinfection and Emergence of Rifamycin Resistance during a Recurrent Clostridium difficile Infection

2016 ◽  
Vol 54 (11) ◽  
pp. 2689-2694 ◽  
Author(s):  
Emma C. Stevenson ◽  
Giles A. Major ◽  
Robin C. Spiller ◽  
Sarah A. Kuehne ◽  
Nigel P. Minton
Keyword(s):  
Clostridium Difficile ◽  
Recurrent Infection ◽  
Disease Symptoms ◽  
Content Type ◽  
Recurrent Clostridium Difficile Infection ◽  
High Incidence ◽  
Life Threatening ◽  
Pcr Ribotyping ◽  
Stool Samples ◽  
Health Care Associated Infection

Clostridium difficile ( Peptoclostridium difficile ) is a common health care-associated infection with a disproportionately high incidence in elderly patients. Disease symptoms range from mild diarrhea to life-threatening pseudomembranous colitis. Around 20% of patients may suffer recurrent disease, which often requires rehospitalization of patients. C. difficile was isolated from stool samples from a patient with two recurrent C. difficile infections. PCR ribotyping, whole-genome sequencing, and phenotypic assays were used to characterize these isolates. Genotypic and phenotypic screening of C. difficile isolates revealed multiple PCR ribotypes present and the emergence of rifamycin resistance during the infection cycle. Understanding both the clinical and bacterial factors that contribute to the course of recurrent infection could inform strategies to reduce recurrence. (This study has been registered at ClinicalTrials.gov under registration no. NCT01670149.)

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