Category Archives: C. diff. Research Community

C. diff. Research and Development - August 2015

Microbiota and Subsequent Effects on Colonization Resistance against Clostridium difficile

Alyxandria M. Schubert, Hamide Sinani, Patrick D. Schloss

To read this paper in its entirety :

http://mbio.asm.org/content/6/4/e00974-15.short?rss=1&ssource=mfr

The gastrointestinal tract harbors a complex community of bacteria, known as the microbiota, which plays an integral role preventing its colonization by gut pathogens. This resistance has been shown to be crucial for protection against Clostridium difficile infections (CDI), which are the leading source of hospital-acquired infections in the United States. Antibiotics are a major risk factor for acquiring CDI due to their effect on the normal structure of the indigenous gut microbiota. We found that diverse antibiotic perturbations gave rise to altered communities that varied in their susceptibility to C. difficile colonization. We found that multiple coexisting populations, not one specific population of bacteria, conferred resistance. By understanding the relationships between C. difficile and members of the microbiota, it will be possible to better manage this important infection.

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The spore-associated protein BclA1 affects the susceptibility of animals to colonization and infection by Clostridium difficile

To read this paper in its entirety :

http://onlinelibrary.wiley.com/doi/10.1111/mmi.12611/abstract

The paper shows that so-called “hypervirulent” strains of C. difficile, such as the 027 ribotype strains, are actually less infectious than the existing strains of C. difficile carried in humans and animals. We were able to show this by characterizing one gene of C. difficile that encodes the BclA1 protein. BclA1 is involved in the early stages of colonization and its presence enables spores of C. difficile to colonise the host. When this protein is removed or truncated the ability of spores to colonise is much reduced. This then raises the question of how hypervirulent strains are more efficient at infecting a host, in other words, how they can be more virulent. The answer is probably the hypervirulent strains are able to produce more toxins. This work raised the concept that C. difficile is similar to influenza. For example, with influenza the most infectious influenza strains do not normally cause fatality (ie, the seasonal flu strains). On the other hand, the pandemic strains (avian influenza) are not very infectious (that is, they spread poorly) yet when they do infect they cause a dangerous infection more likely to lead to fatality. C. difficile we reason behaves in a similar way, the hypervirulent strains are poorly infectious yet cause a more potent infection while highly infectious strains cause a less potent infection. We plan to use this knowledge to type new isolates of C. difficile and assess their risk to humans.

Professor Simon M. Cutting
School of Biological Sciences,
Bourne Laboratories, 4-26,
Royal Holloway, University of London
Egham,
Surrey TW20 OEX
UK

In The News - Synthetic Biologics’ SYN-004 Microbiome-Protecting Preclinical Data Highlighted in Late-Breaking Poster at DDW 2015

syntheticbiologics

Synthetic Biologics, Inc. a clinical-stage company focused on developing therapeutics to protect the microbiome while targeting pathogen-specific diseases, presented preclinical results in a late-breaking poster at Digestive Disease Week® (DDW) 2015 in Washington, DC today. The research supports the development of SYN-004, the Company’s candidate therapy designed to degrade certain intravenous (IV) beta-lactam antibiotics within the gastrointestinal (GI) tract and maintain the natural balance of the gut microbiome for the prevention of C. difficile infection and antibiotic-associated diarrhea (AAD). Beta-lactam antibiotics are a mainstay in hospital infection management, and include commonly used penicillin and cephalosporin antibiotics, such as ceftriaxone.

The “SYN-004, a Clinical Stage Oral Beta-Lactamase Therapy, Protects the Intestinal Microflora from Antibiotic-Mediated Damage in Humanized Pigs” poster summarized preclinical efficacy data that support the ability of SYN-004 to degrade certain beta-lactam antibiotics in the GI tract, with the following conclusions:

  • In fistulated dogs, oral delivery of SYN-004 resulted in efficient degradation of ceftriaxone in the GI tract, and
  • In humanized pigs, SYN-004 protected the intestinal microflora from ceftriaxone and maintained the natural balance of the microbiome.

“The data suggest that SYN-004 has the potential to protect the human microbiome and to become the first prophylactic therapy designed to prevent antibiotic-mediated microbiome damage, including C. difficile infection, in patients receiving beta-lactam antibiotics,” stated Michael Kaleko, M.D., Ph.D., Senior Vice President, Research & Development of Synthetic Biologics.

“These findings support our ongoing Phase 2a clinical trial that is evaluating the ability of two different dose strengths of SYN-004 to degrade residual IV ceftriaxone in the GI tract of up to 20 healthy participants with functioning ileostomies, without affecting the concentrations of IV ceftriaxone in the bloodstream,” noted Jeffrey Riley, Chief Executive Officer of Synthetic Biologics.

“We are on schedule to report topline data from the Phase 2a clinical trial of SYN-004 this quarter, with a Phase 2b clinical trial anticipated to initiate during the second half of this year.”

The U.S. Centers for Disease Control and Prevention (CDC) has categorized C. difficile as an “urgent public health threat,” and has stated the need for research to better understand the role of normal gut bacteria. SYN-004 is intended to block the unintended harmful effects of certain IV antibiotics within the GI tract and maintain the natural balance of the gut microbiome, potentially preventing the 1.1 million C. difficile infections[i] and 30,000 C. difficile-related deaths[ii] in the United States each year. Approximately 118 million doses of IV beta-lactam antibiotics[iii] that could be inactivated in the GI tract by SYN-004, were administered to approximately 14 million hospitalized U.S. patients during 2012.

About Synthetic Biologics, Inc.

Synthetic Biologics, Inc. (NYSE MKT: SYN) is a clinical-stage company focused on developing therapeutics to protect the microbiome while targeting pathogen-specific diseases. The Company is developing an oral biologic to protect the gut microbiome from intravenous (IV) antibiotics for the prevention of C. difficile infection and an oral statin treatment to reduce the impact of methane producing organisms on irritable bowel syndrome with constipation (IBS-C). In addition, the Company is developing a monoclonal antibody combination for the treatment of Pertussis in collaboration with Intrexon Corporation (NYSE: XON), and a Phase 2 oral estriol drug for the treatment of relapsing-remitting multiple sclerosis (MS) and cognitive dysfunction in MS. For more information, please visit Synthetic Biologics’ website at www.syntheticbiologics.com.

This release includes forward-looking statements on Synthetic Biologics’ current expectations and projections about future events. In some cases forward-looking statements can be identified by terminology such as “may,” “should,” “potential,” “continue,” “expects,” “anticipates,” “intends,” “plans,” “believes,” “estimates,” and similar expressions. These statements are based upon current beliefs, expectations and assumptions and are subject to a number of risks and uncertainties, many of which are difficult to predict and include statements regarding the potential for SYN-004 to protect the human microbiome and to become the first prophylactic therapy designed to prevent antibiotic-mediated microbiome damage, anticipated timing of the topline data from the Phase 2a and the initiation of the Phase 2b clinical trial and the size of the market. The forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those set forth or implied by any forward-looking statements. Important factors that could cause actual results to differ materially from those reflected in Synthetic Biologics’ forward-looking statements include, among others, the ability of SYN-004 to perform as expected, the results of the clinical trials and other factors described in Synthetic Biologics’ report on Form 10-K for the year ended December 31, 2014 and any other filings with the SEC. The information in this release is provided only as of the date of this release, and Synthetic Biologics undertakes no obligation to update any forward-looking statements contained in this release on account of new information, future events, or otherwise, except as required by law.

[i] This information is an estimate derived from the use of information under license from the following IMS Health Incorporated information service: CDM Hospital database for full year 2012. IMS expressly reserves all rights, including rights of copying, distribution and republication.

[ii] U.S. Department of Health & Human Services. Agency for Healthcare Research and Quality. January 25, 2012. http://www.ahrq.gov/news/nn/nn012512.htm Accessed: September 30, 2013.

[iii] This information is an estimate derived from the use of information under license from the following IMS Health Incorporated information service: CDM Hospital database for full year 2012. IMS expressly reserves all rights, including rights of copying, distribution and republication.

Service Evaluation Study Data Shows DIFICLIR [TM] fidaxomicin by Astellas Pharma EMEA Reduces Recurrence and All-Cause Mortality When Used First-Line in All Patients Diagnosed With Clostridium Difficile (CDI) Infection

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Presented May 20th, 2015 at the 5th International Clostridium Difficile Symposium (ICDS) in Bled, Slovenia, the CDI Service Evaluation Study is the first and only real-world multicenter study assessing the effectiveness of current CDI treatment in NHS Secondary Care Trusts in England.[6]

“This study builds on the growing evidence that adopting fidaxomicin as first-line treatment for all patients with CDI, rather than reserving it for more severe cases, provides the best outcomes in terms of recurrence, all-cause mortality and cost effectiveness compared to older treatments - vancomycin and metronidazole”, comments Dr Simon Goldenberg, Consultant Microbiologist and Infection Control Doctor, Guy’s and St Thomas’ NHS Foundation Trust. “A previous study also showed that first-line use of fidaxomicin reduces environmental contamination compared to those treated with vancomycin or metronidazole, further demonstrating the role fidaxomicin may play in reducing the spread and incidence of CDI alongside stringent hospital hygiene protocols.”

In Europe the incidence and severity of CDI is increasing,[1],[2],[3],[4] with nearly 125,000 cases a year,[5] posing a major threat to healthcare systems and patientsData presented today from the CDI Service Evaluation study shows that the adoption pattern of treatment impacts CDI outcomes. Compared to traditional broad-spectrum antibiotics, first-line use of fidaxomicin - a targeted treatment - in all CDI patients provides the best outcomes in terms of recurrence rate, all-cause mortality and cost effectiveness, compared to use in selected patients only.[6] CDI is associated with high-mortality[7] and cost burden,[8] therefore reducing the incidence and recurrence of CDI is a priority for clinicians, payers and health authorities alike.
Over 1,450 patients were included in the analysis conducted in seven UK hospitals that introduced fidaxomicin, a narrow-spectrum antibiotic for the treatment of CDI, between July 2012 and July 2013.[6] Data collected from 177 patients treated first-line with fidaxomicin during the 12-month evaluation period were compared with those from a retrospective cohort treated with broad-spectrum antibiotics - vancomycin and metronidazole - during the previous 12-month period.[6]

In the two centres (A and B) where fidaxomicin was adopted as a first-line treatment for all patients diagnosed with CDI, a significant reduction in 28-day all-cause mortality was observed, from 18.2% to 3.1% (P<0.001) and 17.3% to 6.3% (P<0.05) respectively.[6],[9] The real-world analysis also supports clinical trial data in highlighting dramatically reduced recurrence rates: from 12.1% and 23.5% with vancomycin and metronidazole, to 3.1% in both centres with first-line fidaxomicin. For every 50 patients treated, this would result in 5 and 10 recurrences avoided in the two centres respectively.[6]

A separate study recently looked at the impact of CDI treatment on environmental contamination. The analyses showed those treated with fidaxomicin are more than 20% less likely to contaminate their environment with CDI (36.8%) compared to patients treated with metronidazole and/or vancomycin (57.6%). This significant decrease in environmental contamination may further contribute to a reduction in secondary cases of CDI.[10]

“The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) identified recurrence as the next big challenge to be met in the treatment of CDI, since it occurs in up to 25% of patients treated with current broad-spectrum therapies,” comments Professor Mark Wilcox, Professor of Medical Microbiology, Leeds Teaching Hospitals & University of Leeds. “Fidaxomicin has limited activity against the ‘good bacteria’ in the gut and so can be considered to be a targeted treatment option. Preservation of the gut microflora likely contributes to the lower rates of recurrence seen after fidaxomicin treatment of CDI compared with those associated with broader-spectrum antibiotics like vancomycin.”

A CDI recurrence has been previously estimated to add an additional £20,249 on top of an estimated £13,146 spent to treat the initial infection due to prolonged hospital stay, ICU stay, high cost drugs and the surgery necessary to tackle it.[11] An in-depth costing analysis at the two centres that adopted fidaxomicin as a first-line treatment revealed that in centre A the 5 recurrences that could be avoided for every 50 patients treated with the narrow-spectrum antibiotic would result in a cost saving of £19,490, and in centre B, for the 10 recurrences avoided, a cost saving of £121,144.[6] With nearly 125,000 cases of CDI occurring in Europe each year,[5] the potential cost saving for the treatment of this potentially fatal condition is likely to be far greater.

The cost-effectiveness of fidaxomicin has been reinforced in a recent study in France, with fidaxomicin proving to be both clinically and cost-effective compared to vancomycin.[12] The main driver of cost-effectiveness was a significant reduction in the rate of recurrence, resulting in a reduced cost of hospitalisation.[12] In the base case, fidaxomicin was cost-effective compared to vancomycin for all patients at a cost per QALY of €24,242.[12] The cost per recurrence avoided was €1,877 and cost per faecal transplant avoided was €8,967.[12]

In Europe the incidence and severity of CDI is increasing, posing a major threat to healthcare systems and patients.[1],[2],[3],[4] Information suggests that CDI results in death for 9% (2% primary cause, 7% contributory) of all diagnosed patients.[7] This suggests that CDI contributes to the death of around 27,000 people each year across Europe,[7] around five times that of MRSA associated deaths.[13]

ESCMID guidelines currently recommend DIFICLIR as a first line therapy option in CDI patients at risk of recurrence and in patients with severe and non-severe CDI.[14]

NOTES TO EDITORS

About the CDI Service Evaluation study[6]

The CDI Service Evaluation Project is the first and only real-world multicenter study assessing the effectiveness of current CDI treatment for UK patients in NHS Secondary Care Trusts in England. This evaluation looked specifically at the cost-effectiveness of fidaxomicin in clinical practice versus standard of care treatments (vancomycin and metronidazole) in seven trial centres from across the UK:

• Leeds Teaching Hospitals NHS Trust

• Guy’s and St Thomas’ NHS Foundation Trust

• County Durham & Darlington NHS Foundation Trust

• University Hospitals of Morecambe Bay - NHS Foundation Trust

• St George’s Healthcare NHS Trust

• University Hospitals of Leicester NHS Trust

• Derby Hospitals NHS Foundation Trust

 

The study was sponsored by Astellas Pharma Ltd.

About Clostridium difficile Infection

CDI is a recurring and preventable illness resulting from infection of the internal lining of the colon by C. difficile bacteria.[15] The bacteria produce toxins that cause inflammation of the colon, diarrhoea and, in some cases, death.[16] Patients typically develop CDI after the use of broad-spectrum antibiotics that disrupt normal bowel flora, allowing C. difficile bacteria to flourish.[17] CDI is highly infectious[18] and has surpassed MRSA as a leading cause of healthcare-acquired infection.[19] It is most common in those taking broad-spectrum antibiotics that result in the disruption of normal bowel flora,[20] and threatens those most vulnerable, including the elderly, patients who are immunocompromised or with renal impairment and those who have prolonged periods of hospitalisation.[21],[22] People in hospital with CDI are up to three times more likely to die in hospital (or within a month of infection) than those without CDI.[23],[24] Information suggests nearly 125,000 cases of CDI occur in Europe each year,[5] and that CDI results in death for 9% (2% primary cause, 7% contributory) of all diagnosed patients.[7] Recurrence of CDI occurs in up to 25% of patients within 30 days of initial treatment with current therapies.[25],[26],[27] The ESCMID has identified recurrence as being the most important problem in the treatment of CDI.[28]

About DIFICLIR (fidaxomicin)

DIFICLIR (fidaxomicin) is a first-in-class macrocyclic antibiotic targeted to kill the C. difficile bacteria[29] while sparing the ‘good’ gut bacteria,[30],[31],[32] and represents the newest development in CDI for over 20 years.[33],[34] In the largest Phase III trials in this area fidaxomicin was shown to be non-inferior in initial cure and clearly superior to current standard of care treatment - vancomycin - in achieving sustained clinical cure and addressing recurrence.[27],[35] ESCMID guidelines recommend DIFICLIR as a first line therapy option in CDI patients at risk of recurrence and in patients with severe and non-severe CDI.[14] The safety profile of DIFICLIR is based on data from 564 patients with CDI treated with fidaxomicin in Phase III studies.[33]

About Astellas Pharma EMEA

Astellas Pharma EMEA operates in 40 countries across Europe, the Middle East and Africa, and is the EMEA regional business of Tokyo-based Astellas Pharma Inc. Astellas is a pharmaceutical company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceuticals. The organisation’s focus is to deliver outstanding R&D and marketing to continue growing in the world pharmaceutical market. Astellas presence in Europe also includes an R&D site and three manufacturing plants. The company employs over 4,500 people across the EMEA region. In 2013 Astellas was awarded SCRIP Pharmaceutical Company of the Year in recognition of its commercial success and pipeline development.

FOR FULL ARTICLE:

http://www.liberoquotidiano.it/news/comunicati/11791316/DIFICLIR-TM—Fidaxomicin-.html

C. diff. cases higher in the Spring according to a study conducted by researchers at the University of Texas at Austin

People may be more likely to get infected with the sometimes deadly gut infection called “C. diff” during the spring, according to a new study.

Researchers analyzed information from people who were discharged from U.S. hospitals between 2001 and 2010. During this time period, about 2.3 million people were released from a hospital following an infection with Clostridium difficile, which can cause severe diarrhea, and frequently comes back after treatment.

In the spring, there were about 62 cases of C. difficile for every 10,000 people discharged from the hospital, the study found.

In winter and summer, there were 59 C. difficile cases per 10,000 people discharged from the hospital, and the lowest rate was seen in the fall, when there were 56 C. difficile cases per 10,000 hospital discharges.

Most cases of C. difficile occur after people take antibiotics, which disturb the normal balance of gut bacteria, giving harmful bacteria the chance to overgrow. It’s possible that the rates of C. difficile infection are the highest in the spring because people use more antibiotics during the winter months to treat respiratory infections, the researchers said. There can be a one- to two-month lag between the time a person takes antibiotics, or antimicrobials, and when he or she develops a C. difficile infection.

The new finding “emphasizes the importance of antimicrobials’ use as a risk factor” for C. difficile infections, the researchers said. The results also underscore the need to better control infections and use antibiotics only when they are needed,” particularly during high-risk seasons and in high-risk areas, the researchers wrote.

The study also found that, over the 10-year study period, the rates of C. difficile infection were the highest in the Northeast, where the overall rate was 80 cases per 10,000 hospital discharges, followed by the Midwest (64 cases per 10,000 hospital discharges), the South (50 cases per 10,000 hospital discharges) and the West (48 cases per 10,000 hospital discharges).

These regional differences in C. difficile could be partly due to differences in the number of older adults in each area, with the Northeast possibly having a higher proportion of older adults, the researchers said. Older adults are at increased risk for C. difficile infection. In fact, the overall rate of C. difficile infections during the study was 160 cases per 10,000 hospital discharges among adults age 65 and older, compared with 35 cases per 10,000 discharges in adults under 65 and 12 cases per 10,000 discharges in children.

“Our findings indicate the need for additional resources when and where health care burdens are highest,” the researchers said.

The study, conducted by researchers at the University of Texas at Austin, is published in the May issue of the American Journal of Infection Control.

 

To read article in its entirety click on the following link:

http://news.yahoo.com/deadly-gut-bacteria-infections-peak-spring-145430313.html;_ylt=A0LEVxPSvkNV1ooA0MFXNyoA;_ylu=X3oDMTEza2t0ajNjBGNvbG8DYmYxBHBvcwMxBHZ0aWQDVklQNTY0XzEEc2VjA3Nj

Synthetic Biologics Discuss Preventing C. diff. Infection with SYN-004 on “C diff Spores and More,” C. diff. Radio

cdiffRadioLogoMarch2015

 

Join us on Tuesday, March 31st at 11:00 a.m. Pacific, 1 p.m. Central, 2 p.m. Eastern Time for the live broadcast - Synthetic Biologics: Preventing C. diff. Infection with SYN-004

 

 

 

Synthetic Biologic, Inc.’s Lewis Barrett, BS, MBA, Senior Vice President, Commercial Strategy and Dr. Joseph A. Sliman, MD, MPH, Senior Vice President, Clinical & Regulatory Affairs will discuss the novel point-of-care preventive approach, the clinical development pathway and the potential of the Company’s lead pathogen-specific product candidate, SYN-004.

 

For direct access to the “C. diff. Spores and More Program” please click on the link below:

http://www.voiceamerica.com/episode/84381/synthetic-biologics-preventing-c-diff-infection-with-syn-004

 

The majority of C. difficile cases are caused by the unintended consequences of antibiotic therapy to the gut microbiome. Intravenous (IV) antibiotics excreted to the gut often wipe out the natural balance of microflora, which can lead to recurring diarrhea and perforation of the intestinal wall, with potentially fatal outcomes. Co-administered with IV
antibiotics, Synthetic Biologics’ product candidate, SYN-004, is designed to be a preventive therapy intended to protect the gut microbiome by degrading IV antibiotics, thereby preventing the onset of a C. difficile infection.
Synthetic Biologics, Inc. (NYSE MKT:SYN)

http://www.syntheticbiologics.com

 

Study Advances Development of Preventative Approach for C. difficile Infection - Synthetic Biologics Initiates Phase 2a Clinical Trial of SYN-004 to Protect the Microbiome and Prevent C. difficile

Study Advances Development of Preventive Approach for C. difficile Infection
Synthetic Biologics, Inc.. a developer of pathogen-specific therapies for serious infections and diseases, with a focus on protecting the microbiome, announced on March 30, 2015, the initiation of a Phase 2a clinical trial to evaluate the gastrointestinal (GI) antibiotic-degrading effects and the safety of SYN-004, the Company’s investigational oral beta-lactamase enzyme designed to protect the microbiome and prevent C. difficile infection (CDI). C. difficile is the leading type of hospital acquired infection and is frequently associated with intravenous (IV) antibiotic treatment. Beta-lactam antibiotics are a mainstay in hospital infection management, and include commonly used penicillin and cephalosporin antibiotics, such as ceftriaxone.
“We are excited to start our Phase 2a trial of SYN-004 on schedule. Synthetic Biologics believes SYN-004 holds the potential to protect the microbiome from the damaging effects of antibiotics and dramatically reduce C. difficile infections through prevention vs. treatment,” said Jeffrey Riley, Chief Executive Officer of Synthetic Biologics. “We anticipate reporting topline results from this Phase 2a clinical trial during the second quarter of 2015, and initiating the Phase 2b clinical trial in the second half of this year.”
The U.S. Centers for Disease Control and Prevention (CDC) has categorized C. difficile as an “urgent public health threat,” and has stated the need for research to better understand the role of normal gut bacteria. SYN-004 is intended to block the unintended harmful effects of antibiotics within the GI tract and maintain the natural balance of the gut microbiome, potentially preventing the 1.1 million C. difficile infections and 30,000 C. difficile-related deaths in the United States each year. During 2012, approximately 14 million U.S. patients received approximately 118 million doses of IV beta-lactam antibiotics that could be inactivated in the GI tract by SYN-004.

http://cdifffoundation.org/2015/02/25/c-diff-new-cdc-study-national-burden-of-clostridium-difficile-c-diff-infections/
The Phase 2a randomized, multi-center, open-label study is expected to evaluate the ability of two different dose strengths of SYN-004 to degrade residual IV ceftriaxone in the GI tract of up to 20 healthy participants with functioning ileostomies, without affecting the concentrations of IV ceftriaxone in the bloodstream. The study consists of two treatment phases for all participants: 1) the administration of IV ceftriaxone alone, and 2) the administration of one of two doses of oral SYN-004 and IV ceftriaxone. Chyme samples will be collected from the participants to measure the ability of SYN-004 to degrade the residual antibiotic. Participants will be enrolled at up to four trial sites located in the United States and Canada.

For more information visit Synthetic Biologics website:

www.syntheticbiologics.com

C. diff. Research and Development Community March 2015, Infection and Immunity. Dynamics and Establishment of Clostridium difficile Infection

Microscope - 5

Shared by Dr. David Cook, MS, PhD

C. diff. Research and Development Community:

March 2015

Review of: Konigsknecht MJ, CM Theriot, IL Bergin, CA Schumacher, PD Schloss and VB Young. 2015. Infection and Immunity. Dynamics and establishment of Clostridium difficile infection in the murine gastrointestinal tract. Vol 83 (3): pages 934-41.

 
In this paper from Vince Young’s lab at the University of Michigan Medical School, Konigsknecht et al measure the early events associated with C. difficile infection in a mouse model. Investigators followed the germination, growth, toxin production and histopathology following infection with C. difficile strain VPI 10463 subsequent to a 5 day antibiotic treatment of cefoperazone in the drinking water. Strengths of the work include the sampling every 6 hours of the mouse GI tract-including stomach, small intestine, cecum and colon-over the first 36 hours post-infection. In this brief time span, the investigators observe evidence of bacterial germination and growth, initially in the cecum and large intestine but later spreading to all regions of the small intestine and stomach, with concomitant pathologic effects and mortality. Both spores and toxin are detectable by 24 hours post-infection, consistent with the observation that the transcriptional program associated with sporulation is also likely involved in toxin production. This observation suggests that disease caused by toxin requires a minimal titer in the GI tract, and is consistent with the observation in humans that some individuals are colonized by low levels of C. difficile without evidence of clinical symptoms.
By 30-36 hours post-infection, the levels of vegetative organisms and spores are comparable in stomach and cecum-colon, with lower amounts in the small intestine.Despite the (unexpectedly) high levels of C. difficile observed in stomach and small intestine, tissue damage in the mouse is confined to the cecum and colon, consistent with the site of C. difficile pathology in humans. The authors demonstrate that bile acid profiles are shifted away from detectable secondary bile acids. In addition, microbiota diversity is dramatically decreased in the colon, primarily as a result of the antibiotic regimen, to favor an abundance of Lactobacillus. Both of these observations are consistent with previously published results from the Young lab (Theriot et al, 2014. Nature Communications).

These results further refine our understanding of infection in the mouse model and will enable other researchers to make more precise use of the model in developing new therapies. It should be noted, however, that there are important differences between C. difficile infection and disease in mice and in humans. In the mouse, C. difficile infection leads to rapid mortality. In humans, disease is slower, more chronic due to relapse, and is fatal only in a minority of cases. The microbiome changes are also different. Depending on the antibiotic used, mice can become dominated by a single microbe unlike humans. In the present case, mice were completely dominated by Lactobacillus, a normal commensal in the mouse but one that is mostly absent in humans. The observation in the Konigsknecht study that C. difficile grows in the stomach of mice is also at odds with our understanding of C. difficile infection in humans. Despite these caveats, this is an important work that furthers the science behind understanding C. difficile infection.