(* Antibiotic Resistance Apocalypse)

Over the last several weeks, I’ve been discussing the greater concern over the increasing resistance of our current medicines and our lack of emerging antibiotics in the pharmaceutical industry. As I close out this month of blogs, I’d like to visit one more time with a couple of recent articles which discuss where we are as well as where we really need to be regarding new antibiotics.

The Infectious Disease Society of America (IDSA) is very concerned with the development and increasing resistance to antibiotics. In 2010, the IDSA issued a challenge to the US government and big pharma: develop and get regulatory approval for 10 new, safe and effective antibiotics by 2020, i.e. the “10 x ’20” initiative. The ultimate goal was to “support the development of 10 new systemic antibacterial drugs through the discovery of new drug classes as well as exploring possible new drugs from existing classes of antibiotics.” To help the push, many other organizations also endorsed the collaborative effort, including: the American Academy of Pediatrics, American Gastroenterological Association, Trust for America’s Health, Society for Healthcare Epidemiology of America, Pediatric Infectious Disease Society, Michigan Antibiotic Resistance Reduction Coalition, National Foundation for Infectious Diseases and the European Society of Clinical Microbiology and Infectious Diseases.

Earlier this year, two groups posted their reviews of our current situation. Writing on behalf of the IDSA, Helen Boucher et al. summarized the progress of the development of new drugs which are active against Gram-Negative Bacilli (GNB) since 2010 and later, in the Annals of Clinical Microbiology and Antimicrobials, Matteo Bassetti et al. wrote a comprehensive summary of the antibiotics we are developing or have developed over the last 10 years.

Boucher identified just 7 parenteral drugs that are in clinical development for treatment of infections caused by MDR (Multi-drug resistant) GNB and one other drug whose phase 2 trial has been halted. Of those 7 antibiotics, 4 are β-lactam plus β-lactamase inhibitor combination drugs. While that may be a great way to enhance the therapeutic options of this class of drugs, not one of these drugs demonstrated activity against the entire spectrum of clinical GNB. Even worse, only 5 of the top 11 major pharmaceutical companies had drugs in clinical trials and there were only 4 drugs in phase 2/3 trials that showed promise against either GNB or GPB (Gram-Positive Bacilli). Of course, the current trend of pharmaceutical companies seems to be to leaving the initial discovery and early testing to smaller biotechnology companies, so there is some hope that hidden discoveries are still underway. There is also some hope as various government leaders have begun to focus on the continuing crisis. But we need to get products moving now in order to fulfill the 10 x ’20 goal in just 7 short years.

Bassetti catalogued nearly 30 antibiotics that have been developed recently as tie-in to Boucher’s paper. There is more that is hopeful in this summarization, including 11 drugs which are in Phase 3 trials (9 of which are primarily against GPB). But only one of these, the combination of Ceftazidime/Avibactam is primarily targeted against MDR. Perhaps more importantly however, there are another 11 drugs which are currently in Phase 2 trials, and 3 in Phase 1 trials that are specifically targeting GNB or MDR. Only time will tell if these will prove to have the efficacy that we need as well as benignancy in regard to inadvertent side effects.

Ultimately, I believe there is hope for us, although the significant hurdles of regulatory approvals remain. The IDSA is helping to push for clearer regulatory guidance in the study of antibiotics, working with the FDA for more urgent approval of pathogen-specific clinical trials and the creation of a new FDA approval pathway for limited-population antibacterial drugs. But if overly-complicated approval pathways and the potential failure of profitability continue to haunt the pharmaceutical companies which are necessary to bring these drugs to us, our ARA doomsday clock may strike Midnight far sooner than we think.

Boucher, H. W., Talbot, G. H., Benjamin, D. K., Bradley, J., Guidos, R. J., Jones, R. N., & Gilbert, D. (2013). 10×’20 progress—Development of new drugs active against gram-negative bacilli: An update from the infectious diseases society of america. Clinical Infectious Diseases, 56(12), 1685-1694.

Bassetti, M., Merelli, M., Temperoni, C., & Astilean, A. (2013). New antibiotics for bad bugs: where are we?. Annals of clinical microbiology and antimicrobials, 12(1), 1-15.

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