Antimicrobial Drug Development for Clostridium difficile: Overwhelmingly large number of Antimicrobial resistance (AMR) cases reported from all over the world compelled United Nations to hold high-level meeting 2016 to address this issue of AMR as “one of the biggest threats to global health”. The biggest dilemma is that, antibiotic stewardship to address the issue of resistance and required high costs of long drawn out drug development process discourages bringing any new antibiotic to clinic. Due to lack of any life-saving antibiotics left available that could be effective against infections of multidrug resistant bacteria labelled as “nightmare bacteria” by Center for Disease Control and Prevention (CDC) has resulted in 23,000 annual deaths recorded from such cases in US. Clostridium difficile infections (CDI) and associated disease (CDAD) classified by (CDC) as an "Urgent Public Health Threat" is one of these antibiotic resistant organisms that claimed more than 50% of all deaths from infections with the multidrug resistant bacteria.
CDAD appears most frequently within hospitals and eldercare settings and is clearly abetted by the frequent use of broad spectrum antibiotics that inevitably also destroy the normal intestinal flora. Moreover, the emergence of new hyper-virulent C. difficile strains (e.g., NAP1/B1/027) has increased the seriousness of CDAD and the number of deaths resulting from it. Based on data from a 2015 study, the CDC revised estimates are that approximately half a million infections, 29,000 deaths, and $4 billion in excess medical costs in the U.S. alone are to be expected per year with limited effective interventions. Even with some differences in the reported numbers of deaths from these resistant microbes, it is clear that these problems are global and significant and cannot be ignored.
Treatment of CD infection with antibiotics is a challenge as it should be active against CD but should do minimal damage to normal gut flora. At present, metronidazole (MET), Vancomycin (VAN), and Fidaxomicin (FDX, a new antibiotic) are used to treat CD infection, but these drugs suffer from high recurrence rates: 15-30 % after the first episode and 40-60% after the second episode. There is, thus, an urgent need for discovery and development of new therapies for CDI.
KamTek has discovered a number of promising compounds for treatment of CDAD and has received patents for this discovery. Out of which, generic antibiotic ‘Clofazimine’ (CFM) has been studied in more detail. It has been found to have as narrow a spectrum of activity against normal gut bacteria as FDX and in some cases even better. KamTek has been issued a patent for this discovery.
At the same time, it is encouraging to note that Clofazimine (CFM) has dismal record of inducing resistance in the target microbes even after 50 plus years of use against Leprosy and multidrug resistant tuberculosis (MDRTB). Our additional IP discovery of synergistic effect on susceptibility of virulent strains to combination of this antibacterial agent in even smaller doses with significantly smaller doses of currently used antibiotics Metronidazole and Vancomycin promises to be a great therapeutic alternative. Such a strategy of using combination therapy with significantly reduced amounts of each agent makes it a great candidate to combat CDI epidemic as well as antibiotic resistance. In addition, repurposing antibiotics already used in clinics for decades greatly de-risks the drug development process.
Initial investigations funded by private angel investment and KamTek internal resources received a great boost by SBIR Phase I grant from NIAID/NIH followed by NIH sponsored I-Corp program award geared to train scientists about the ecosystem of very expensive and long drawn out drug development process. With this support from NIH, KamTek has certainly moved the needle a bit forward to show CFM in-vivo efficacy with further affirmations to develop it as a second line of treatment for CDI(CDAD) patients. Currently, KTI is engaged in establishing its clinical significance by operating on two fronts: 1) Extensive in-vitro evaluation of susceptibility of large number clinical isolates to this drug and 2) development and evaluation of tablet formulation of this agent for large scale in-vivo pharmacokinetic and pharmacodynamic studies. For these investigations, we are using capabilities already established at KamTek as well as collaborating with well-established scientists in this area of translational research and working with validated companies by taking advantage of areas and resources that are not part of KamTek portfolio of operations. Business partners and Associates…
In a ground breaking discovery, researchers at KamTek observed that Clofazimine had excellent narrow spectrum of activity against C. difficile, especially against its resistant strains as compared to the rest of gut bacteria. Further, it had a synergistic effect in combination with metronidazole and demonstrates ability to differentially kill C. difficile, while barely affecting many other ‘friendly’ gut microbes. KamTek has been granted US patents (US 20170143707 A1, and US 2018 10,064,860 B2 ) by the US Patent and Trademark Office for this discovery.
Based on data generated toward the development of an antibiotic to treat CDAD, researchers at KamTek presented posters at two American Society of Microbiology (ASM) meetings.