Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
How frequently do individuals taking antibiotics experience side effects? What are the main types of side effect people experience?
Like all drugs, antibiotics can have side-effects when administered to people. The most common (and often benign) side effect people experience when taking antibiotics is “associated diarrhea”. This illustrates the fact that antibiotics have an impact on the intestine!
This is due to the fact that each time patients take antibiotics, either orally or intravenously, part of the administered drug ends up in the intestine. There, it profoundly alters the normal healthy bacterial flora present in the gut: a human gut contain more than 1014 bacteria, forming a complex eco-system which can be completely disrupted by antibiotics. The antibiotic-associated diarrhea is the consequence of the flora disruption by residual antibiotic in the gut.
Antibiotic-associated diarrhea (AAD) is considered to be a frequent condition, i.e. occurring in 1 to 10% of the cases, for some antibiotics such as amoxicillin, cephalosporins, macrolides and fluoroquinolones. As an example, Amoxicillin-clavulanic acid is associated with AAD in about 10% of treated patients.
Could you please give a brief overview of Clostridium difficile infections? Why are people who have been treated with antibiotics commonly affected by C. difficile infections?
Clostridium difficile infection is a type of infectious diarrhea caused by the bacteria “Clostridium difficile”.
Clostridium difficile may be present harmlessly at very low level in a normal colonic flora. But when competing bacteria in the gut are eradicated by antibiotic treatments, then Clostridium difficile colonizes the gut and produce toxins which cause severe inflammations of the colon. This is painful and leads to severe diarrhea, which is referred to as Clostridium difficile-associated diarrhea (CDAD).
Worryingly, C. difficile infections may progress towards severe conditions: they are the most common cause of a pseudomembranous colitis, and in rare cases it can lead to toxic megacolon which can be life-threatening.
Even though the frequency of CDAD is evaluated as rare, it can reach several percents in patients the more at risk to develop the disease such as the eldery, immunodepressed or hospitalized patients. Moreover, in the last decade, the epidemics of Clostridium difficile became even harder to control.
Spreading in the environment from infected people whose intestinal flora was disrupted by antibiotic treatments, Clostridium difficile infections raise growing concerns and cause an increasing number of infections.
According to a study published in Oct 2013 by the U.S Centers for Disease Control and Prevention, Clostridium difficile infections cause 250,000 infections and 14,000 deaths per year in the United States for a medical cost superior to 1 billion dollars.
It is today clearly acknowledged that the antibiotic intake is a major risk factor for the occurrence of Clostridium difficile infection. This illustrates the need to protect our intestinal flora from alteration by antibiotics.
What are the main hurdles that need to be overcome in order to prevent the side effects of antibiotics and occurrence of C. difficile infections?
Da Volterra is developing DAV132, a novel product with a unique mechanism of action which can prevent the side effects of antibiotics on the flora, thus reducing the occurrence and recurrence of C.difficile infections. DAV132 is composed of an adsorbent encapsulated in a drug delivery system adapted to the human physiology for a targeted delivery to the lower gastro-intestinal tract.
DAV132 captures locally the residual antibiotics and inactivates them, without impacting their regular absorption into the blood. It thus (i) does not interfere with antibiotics’ efficient action to cure the bacterial infections but (ii) prevents them from altering the intestinal flora.
As a consequence the flora disruption adverse effect is avoided.
The main hurdles for Da Volterra were to identify the right “capturing compound” and fine-tune the innovative drug delivery system. These hurdles have now been overcome as DAV132 is currently evaluated in humans.
Could you please give a brief overview of the data Da Volterra presented at the recent European Conference of Microbiology and Infectious Diseases?
Da Volterra presented two series of results at the ECCMID conference earlier this month:
- The CL1001 study, a phase I clinical trial performed in the spring 2013 in Germany with 18 healthy volunteers, showed the expected targeted delivery of DAV132. The results demonstrate that DAV132 effectively exerts its adsorbing effect in the ileum and the colon, whereas DAV132 does not interfere upstream with antibiotics in the small intestine. Antibiotic treatments given together with DAV132 would thus be optimized, DAV132 reducing the alterations of the flora and their consequences such as Clostridium difficile infections or the emergence of resistant bacteria.
- A preclinical study performed in the reference hamster model of Clostridium difficile infections evidenced the preventive effect of DAV132. Animals treated with moxifloxacin only (an antibiotic) showed 100% mortality (no survivor after 7 days) in the experiment. Interestingly, animals treated with moxifloxacin and DAV132 during 5 days are protected from the lethal impacts of Clostridium difficile. The protective effect of DAV132 is dose-dependent and a total protection is reached at the highest doses. This study in a predictive model of the disease illustrates the protective effects of DAV132, co-administered with an antibiotic treatment, against Clostridium difficile infections.
What do you think the future holds with regards to preventing the side effects of antibiotics?
There is much heat today around the concepts of microbiome and intestinal flora alteration by antibiotics. For example, there is the book “Missing microbes” from Martin D. Blaser which tends to illustrate how the overuse of antibiotics may have fuelled some diseases widely encountered today. There is definitely some space to find novel and better ways to prescribe and use antibiotics.
Most of the products in development in the antibacterial field by our colleagues from the pharmaceutical and biotech industry target the treatment of infections with novel or improved antibiotics. Da Volterra is one of the only companies focused on preventing the antibiotic side effects and particularly CDI. This obviously brings an individual benefit for the patients, as well as a collective benefit: at the level of a hospital unit, protecting the patients’ intestinal flora during antibiotic treatments could prevent the dissemination of health-acquired infections in general which are known to be linked to the spread of faecal bacteria.
How does Da Volterra plan to add to this vision?
We believe Da Volterra is a pioneer in these open new fields of optimizing antibiotic use.
At Da Volterra we develop several products to protect the intestinal flora from the alterations by antibiotic treatments: for sure prescribers will always prefer preventing a disease such as Clostridium difficile, than treating it better.
DAV132, which is our most advanced product, will enable them to treat patients with antibiotics when necessary without fearing the impact on the flora, for the patient himself and the hospital unit.
In the long run, we can even imagine that DAV132 will be used along with any antibiotic treatment to guarantee a minimal adverse impact on the flora, just as an insurance, to mitigate the individual and collective adverse consequences of antibiotic use.
Where can readers find more information?
All our results and a description of the mechanism of action of DAV132 are available on our website: www.davolterra.com.
About Florence Séjourné
Florence Séjourné has been Chief Executive Officer of Da Volterra for the last 6 years.
Graduated from Mines ParisTech with a major in Biotechnology and from the University of Illinois at Chicago with a degree in Pharmaceutical Sciences, she previously led the biotech department of one of the first French bioincubators (Eurasanté). She then co-founded Genfit in 1999, a leading European biopharmaceutical company focused on cardiometabolic and liver disorders, holding positions including Chief Operating Officer, VP - Business Development and Alliance Management, and has been Member of the Board since Genfit’s inception.
Through her career, Florence SEJOURNE gained a wealth of entrepreneurial experience, focusing on companies’ business strategy, building and running efficient and professional organizations, managing R&D portfolios with a vision towards products market access, raising private, public money and grants, and structuring all types of partnering deals with international pharma and biopharma companies.