DAV132 - Preventing occurence and recurrence of Clostridium difficile infection

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DAV132 is a product designed as a prophylactic treatment intended to prevent the development of Clostridium difficile infection, by binding with and neutralizing common antibiotics in the gut. DAV132 more generally preserves the integrity of the intestinal microbiota during antibiotic cures.

It has two clinical objectives:

  • Prevent the occurrence and recurrence of C. difficile infections in high risk patients receiving antibiotics such as oral and parenteral fluoroquinolones and cephalosporins;
  • Decrease significantly the disruption of the intestinal microbiota for patients under antibiotic treatment.

Explicative video

Discover the DAV132 mechanism of action in the following video:

The majority of orally administered antibiotics are only partially absorbed and for some of them, a significant part of the administered drug (depending on the antibiotic) remains intact in the intestinal tract. The outcome is similar for intramuscular or intravascular administered antibiotics that are recycled via the hepatobiliary route from the blood into the small intestine.

After antibiotic intake, active residues progress to the colon, at doses that are orders of magnitude higher than the MIC (minimum inhibitory concentration) for most commensal bacteria. These residues provoke serious collateral damage amongst the intestinal microbiota of patients. The microbiota balance is disturbed: several bacterial populations are erased whereas some strains proliferate - the patient's microbiota will take months to recover. In the meantime, Clostridium difficile proliferates and causes Clostridium difficile infections.

DAV132, by protecting the microbiota from the alteration by antibiotics, is designed to prevent the emergence and recurrence of Clostridium difficile infections.

DAV132 is a non specific adsorbent which can irreversibly capture antibiotics in the late ileum, caecum and colon before they could alter significantly the microbiota. It is encapsulated in a specific drug delivery system (specific coating) patented by Da Volterra that allows a precise delivery to the lower gastro-intestinal tract in order to avoid all interactions with drug absorption that occurs in the small intestine.

Four clinical trials of DAV132 were already performed successfully (see here and here). The next trial in patients at risk of C.difficile is being prepared. DAV132 is not yet commercialized.

CDI and most of all, recurrence of CDI in high risk patients, is a known growing medical problem worldwide: C.difficile Acute Diarrhea (CDAD) is observed in hospitals (acquired hospital infection) but also in the community, particularly in nursing homes. The number and the severity (including mortality) of the recurrences of C.difficile infections are increasing. CDI is the most severe case of antibiotic-associated diarrhea. All antibiotics can lead to CDAD, but clindamycine, cephalosporins and fluoroquinolones are considered as the major risk factors. These antibiotics are very often used in patients, particularly in elderly patients, for treating urinary tract or respiratory tract infections.

In 2013, the Center for Disease Control (CDC) qualified C.difficile infections (CDI) as an urgent threat. In the United States, the latest estimations available reported 453,000 infections per year, requiring hospitalization or affecting already hospitalized patients, and resulting in approximately 29,000 deaths1. For every 1000 patients spending one day in the hospital, there were roughly four cases of CDI. The CDC also highlighted that deaths attributable to C. difficile infection rose by 400% between 2000 and 2007, in part because of emerging new hyper-virulent strains.

The significant impact of CDI on the US healthcare system is also concerning as each case is estimated to generate extra costs of about $11,000 for hospitalized patients2, while these estimates do not reflect the additional loss of economic revenues resulting from longer hospital stays and the inability to return to work. A recent meta-analysis of 45 study concluded CDI costs ranged from $8,911 to $30,049 for hospitalized patients while Quimbo et al. have estimated this extra cost to be $31 800 for immunocompromised patients and up to 115,600 for patients with renal impairments3. Furthermore, a 2012 study indicates that CDI may have resulted in $4.8 billion in excess costs in US acute-care facilities after analyzing data from 20084.

CDI economic burden is equally heavy in Europe. In 2006, a study of the European Centre for Disease Prevention and Control (ECDC) estimate the potential cost of CDI to be €3 billion per annum in the European Union (EU), and expected it to almost double over the next four decade5.

Moreover, the even greater cost of recurrent cases of CDI also has to be taken into account: hospitalization costs resulting from a CDI recurrence has been estimated to add an additional £20,249 on top of an estimated £13,1466.

With overuse and misuse of antibiotics fuelling the rise of CDI and the emergence of resistant strains, CDI will undoubtedly become a top public health threat, not only in the US and Europe but worldwide.

References

(1)Fernanda C. Lessa et al., “Burden of Clostridium Difficile Infection in the United States,” New England Journal of Medicine 372, no. 9 (February 25, 2015): 825–34, doi:10.1056/NEJMoa1408913
(2)Natasha Nanwa et al., “The Economic Impact of Clostridium Difficile Infection: A Systematic Review,” The American Journal of Gastroenterology 110, no. 4 (April 2015): 511–19, doi:10.1038/ajg.2015.48
(3)R. A. Quimbo et al., “PIN13 The Incremental Economic Burden of Clostridium-Difficile Associated Diarrhea Among Hospitalized Patients at High Risk of Recurrent Infection,” Value in Health 15, no. 4 (June 1, 2012): A239, doi:10.1016/j.jval.2012.03.1289.
(4)Erik R. Dubberke and Margaret A. Olsen, “Burden of Clostridium Difficile on the Healthcare System,” Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America 55 Suppl 2 (August 2012): S88–92, doi:10.1093/cid/cis335.
(5)E. J. Kuijper et al., “Emergence of Clostridium Difficile-Associated Disease in North America and Europe,” Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases 12 Suppl 6 (October 2006): 2–18, doi:10.1111/j.1469-0691.2006.01580.x
(6)St George's: Cost-effectiveness of fidaxomicin as first-line treatment for Clostridium difficile infection. Presentation, 2014. Astellas Pharma Ltd Data on File DIF14036UK

 

* DAV132 n'est pas commercialisé pour le moment.