Summary:
Microbes are evolving resistance faster than the pharmaceutical industry can bring new products to market. Microbes have been persistently clever in evolving resistance to antibiotics soon after introduction. Emergence of "Bad Bugs, No Drugs" situation; high economic burden and will gradually worsen. Call to action from the infectious disease community (IDSA). A new type of product specialization is required (relying on rapid molecular diagnostic tests), but this runs counter to the blockbuster model of large pharmaceutical companies. Opportunity for smaller companies. US government under pressure to create incentives for the large pharmaceutical companies to remain in antibiotic discovery. Some incentives in the FDAAA act, but disincentives remain. (Published: 08/05/08)
Notes:
- early 1940s: streptomycin and penicillin
- treatment of staphylococcus, streptococcus and Mybacterium tuberculosis infections
- today: more thatn 130 antibiotic products available
- problem: despite/because of number of antibiotic products, microbes are getting upper hand
- evolving resistance faster than the pharmaceutical industry can bring new products to market
- number of patients infected with resistant microbes small
- but economic burden high
- number of resistant bugs expected to increase
- Infectious Disease Society of America (IDSA)
- documented the microbial infections that are especially troublesome in a "Bad Bugs, No Drugs" policy statement
- provided a call to action from the infectious disease community
- MRSA among the "Bad Bugs" that has received appropriate notoriety
- S. aureus
- normal skin flora
- becomes a problem when the skin is broken
- from abrasions, traumas, surgeries and placements of in-dwelling devices
- staphylococcal infections can quickly become deadly
- those infected rely on antibiotics to eliminate the infection
- MRSA infection has been health problem in hospitals for more than a decade
- more than 60% of US hospital-acquired S. aureus infections are now MRSA
- new MRSA strain has become prevalent in community-acquired infections
- total number of infections due to MRSA increased 119% between '99 and '05
- large economic cost
- estimated in the billions in the US
- due to longer hospital stays and increased expenses of treatment
- until very recently, antibiotic treatment for hospital-acquired MRSA limited to vancomycin
- first developed in US in 1958
- new antibiotic therapies approved for treatment of hospital-acquired MRSA include Zyvox (Pfizer), Cubicin (Cubist) and Synercid (King Pharamceuticals)
- resistance to these products already posing challenges
- microbes have been persistently clever in evolving resistance to antibiotics soon after introduction
- even vancomycin proved vulnerable
- initially purported to be "resistance-proof" because its target is a necessary component of th ebacterial cell wall, not an evolvable protein
- wide range of molecular mechanisms of resistance have emerged
- e.g. broad spectrum efflux pumps
- eliminate most antibiotics from the bacterial cell possessing these pumps
- e.g. expanded spectrum beta-lactamases (EBSLs)
- inactivate the newest generation of beta-lactam products
- these resistance mechanisms make the discovery of effective new antibiotics even more difficult
- create market opportunities for new products
- emergence of "specific spectrum" agents
- aimed at specific species and resistance targets
- e.g. Affinium Pharmaceuticals antibiotic in Phase 1: targets Stahpylococcus, including MRSA, but is relatively inactive against other bacterial species
- utiliy will rely on the recent emergence of new FDA approved molecular diagnostics for MRSA
- can assess the infectious agents in hours, rather than days
- e.g. BD GeneOhm StaphSR Assay
- this type of product specialization runs counter to the blockbuster model of large pharmaceutical companies
- maturation of the antibiotics market over the past decade has resulted in a large number of marketed antibiotics products
- each with relatively low annual sales revenues
- 2001: six antibiotics products had blockbuster status
- today: only Augmentin and the Levaquin/Floxin franchise have billion-dollar annual revenues
- recent introductions have failed to reach blockbuster status
- patents expirations, generic competition, and the withdrawal due to safety challenges or limited use have fragmented the market
- loss of profitability of antibiotics has caused the departure of many pharmaceutical companies from investing in the discovery of new antibiotic products
- smaller companies have seen opportunity and some generic companies have expanded into proprietary products
- Forest Laboratories invested significantly in new antibiotic products
- several large pharmaceutical companies spun out their antibiotic and development efforts into new companies, or licensed their later-stage products to biotechnology companies
- new entrants into antibiotic development face cash constraints that often limit the size and complexity of clinical trials
- US government
- has been under pressure to create incentives for the large pharmaceutical companies to remain in antibiotic discovery
- has largely been resisted
- however: Food and Drug Administration Amendment Act (FDAAA) of 2007
- includes creative incentives for the development of new treatments for tropical diseases, including tuberculosis, malaria and other specifically named diseases
- as well as "any other infectious disease for which there is no significant market in developed nations, and that disproportionally affects poor and marginalized populations, designated by the Secretary."
- priority review vouchers are awarded for the succesful approval of new products to treat these "tropical diseases"
- can be transferred or sold to the sponsor of any new drug application
- falls short of pharmaceutical industry's desire for patent extension
- but may have sufficient value to influence the discovery and development of new agents for treatment of these diseases
- additionally, FDAAA provides a mechanism in which new drugs for the treatment of antibiotic-resistant infections may qualify for Orphan Drug status
- incentives associated with Orphan Drugs, e.g. access to government funding of clinical trials
- disincentives remain
- IDSA: documented the uncertainty of antibiotic clinical trial designs and the lack of guidance documents for antibiotic development
