By Cliff Mintz, Ph.D.
Antibiotics have been used for over 60 years and revolutionized the practice of medicine. However, during the past 20 years, the number of infections caused by multiple drug-resistant (MDR) bacteria has increased at an alarming rate. These observations have led several infectious diseases experts including Brad Spellberg, M.D., UCLA Medical School, and Barry Eisenstein, M.D., senior VP of scientific affairs at Cubist Pharmaceuticals, to publicly comment that the United States has reached a “crisis point” with growing antimicrobial resistance and a lack of new antibiotic treatments. During testimony before Congress last year, Eisenstein warned that the paucity of new antibiotics is “increasingly leaving infectious disease doctors with few, if any, effective therapies for certain bacterial infections.”
The Antibiotic Resistance Epidemic
There is general consensus among infectious diseases experts that the emergence of MDR bacteria resulted from the use of antibiotics as growth enhancers by the livestock industry and misuse of antibiotics by physicians over the past 50 years. According to UCLA’s Spellberg, the infectious diseases community has “not effectively dealt with the bacterial antibiotic resistance problem since the first penicillin-resistant mutants were isolated in the 1940s.”
In the late 1980s and early 1990s, antibiotic-resistant Gram-positive bacteria, including MRSA and vancomycin-resistant enterococci (VRE), were the first clinically relevant antibiotic-resistant bacteria to emerge. Although commercially available antibiotics like Cubist’s Cubicin (daptomycin) and Pfizer’s Tygacil (tigecycline) — approved by the FDA in 2003 and 2005 respectively — proved to be effective treatments against MRSA and VRE infections, the emergence of resistant strains and intravenous administration relegated these newer antibiotics to “second-line” treatment options. In other words, physicians are reluctant to use them unless all other conventional treatment options have been exhausted. This practice is commonly referred to as “antibiotic stewardship”: a strategy implemented over the past 10 years designed to preserve the antibacterial effectiveness of new antibiotics by using them sparingly only as a last resort for the most difficult-to-treat infections.
The identification of MRSA and VRE in the early 1990s caused many pharmaceutical and biotechnology companies to almost exclusively focus on developing new antibiotics to treat Gram-positive infections. Unfortunately, over the next 15 years or so, drugmakers paid little attention to the growing incidence of multiple drug-resistant Gram-negative bacteria.
The emerging “Gram-negative threat” was punctuated last year following the isolation of Gram-negative bacteria from both clinical and environmental sources that produce NDM-1 ß-lactamase, an enzyme that inactivates ß-lactam antibiotics (most notably cephalosporins and carbapenems) — commonly prescribed antibiotics used to treat Gram-negative infections. Further, strains that produce NDM-1 are frequently resistant to up to 14 other antibiotics. Also, NDM-1-producing bacteria are widely disseminated and recently were isolated from environmental sources including potable water and sewage effluent in India. Finally, more recent studies report that NDM-1-producing Gram-negative bacteria have been isolated in 20 countries on four continents.
Steve Projan, Ph.D., senior VP and head of infectious disease and vaccines at MedImmune, an AstraZeneca company, warns that NDM-1-producing Gram-negative bacteria are extremely dangerous and pose a significant public health threat. “While NDM-1-producing strains are not the end of the world, the location of the enzyme on a mobile genetic element and its continued rapid spread could possibly eliminate the use of ß-lactam antibiotics as the primary treatment for multiple-drug-resistant Gram-negatives. That would be truly disastrous,” he says. Cubist’s Eisenstein concurs. “Secondary antibiotics used to treat Gram-negative infection all have toxicity issues. That is why they are not frequently used, despite the fact that some of them were discovered almost 60 years ago,” he adds.
The Impact Of Business And Regulatory Concerns On R&D
Historically, large pharmaceutical companies were largely responsible for bringing new antibiotics to market. However, in the late 1990s and 2000s, many big pharma companies including Merck, Bristol-Myers Squibb, and Johnson & Johnson decided to jettison their antibiotic discovery programs. While a few big pharma companies including AstraZeneca, GlaxoSmithKline, Novartis, and sanofi-aventis remain in the antibacterial space, most new antibiotic drug discovery is now in the hands of smaller, less financially stable biotechnology companies.
The reasons frequently cited for “getting out” of the antibiotic discovery business included poor returns on investments (as compared with other drugs), downward pricing pressures, and generic encroachment. However, unlike many of his colleagues, MedImmune’s Projan does not believe big pharma’s exit from new antibacterial drug discovery for financial reasons was justified. “One of the great ironies about reasons given by many companies that get out of the field is that there isn’t any money to be made, and yet the worldwide anti-infective market is $90B, whereas the global oncology market is around $70B,” he says. “Therefore, the decision by some companies to abandon antibacterial R&D in favor of purportedly more lucrative indications like oncology is puzzling to me.”
Interestingly, Cubist’s Eisenstein contends that the practice of antibiotic stewardship, while medically prudent, paradoxically disincentivizes new antibiotic discovery. This is because lower sales and reduced profits do not allow companies to justify reinvestment into these programs. Additionally, Eisenstein believes the lack of efficacy standards and clearly defined clinical end points used to evaluate new antibiotics in human clinical trials have forced big pharma companies to reconsider their commitment to antibacterials. “The regulatory environment has been challenging for the past 10 years, and many companies decided to abandon antibiotic R&D because of escalating costs and low approval rates,” he says.
Eisenstein and other infectious disease experts contend that the regulatory framework for approval of new antibiotics needs to be modified to induce big pharmaceutical companies to return to the field. And, it seems that big pharma’s participation will be necessary to resuscitate antibiotic drug discovery. To wit, the number of approved antibiotics decreased from 52 from 1983 to 2007 to just 2 in the past three years.
A Way Forward
The dire need for new antibiotics resulted in legislation known as the Generating Antibiotic Incentives Now Act (GAIN) that was introduced in the U.S. Congress in late 2010. The goal of the bill is to provide incentives for U.S. drugmakers to induce them to develop new antibiotics to treat antibiotic-resistant bacteria. These incentives include a priority review of new antibiotics by the FDA and an obligation by the agency to act on applications for approval no later than six months after submission. The bill would also allow antibiotics to be eligible for the FDA fast-track approval program, and companies would be granted five additional years of market exclusivity for newly approved drugs. Unfortunately, Congress failed to act on the bill in 2010, and GAIN was reintroduced in the U.S. House of Representatives last June.
This past April, IDSA (Infectious Diseases Society of America) also published a policy statement (i.e. report) and issued recommendations to stimulate new antibiotic drug discovery and development. A major focus of the report was the formation of nonprofit, public-private partnerships (PPPs) between government agencies and private entities with the primary goal of quickly advancing promising new antibiotics to approved products.
PPP advocates contend that by removing the profit motive from the equation, novel new antibiotics can be developed regardless of market size and commercialization potential. PPPs would be funded by both public monies and private capital. UCLA’s Spellberg strongly believes that the creation of PPPs will stimulate antibiotic discovery, result in the identification of promising new leads, and ultimately induce big pharma companies to reenter the field to develop them into approved new drugs. Interestingly, MedImmune’s Projan is hesitant to commit to his company’s participation in the proposed PPPs. “It would really depend on the specific PPP, but historically we prefer to pursue individual academic partnerships. So far, I haven’t been impressed with anything that would specifically encourage me to work with a larger consortium as compared with an individual academic laboratory,” he says.
The IDSA also strongly advocates human clinical trial reforms that include fast-track approvals, organism-specific clinical trials, alternate or surrogate clinical endpoints, and more powerful statistical analysis of trial results. Most importantly, according to the IDSA, the FDA must balance “the public health risks of approving a less-effective drug with the risk of having no new, critically needed antibiotics available to treat patients infected with resistant pathogens.”
Finally, the IDSA’s report recommends greater coordination of relevant federal agency efforts, improved antibacterial resistance surveillance systems, better antibacterial resistance prevention and control programs, greater federal investments in antibacterial research, and elimination of nonjudicious antibiotic use in animals and humans.
Because of ongoing shortages of new, small-molecule antibiotics, several biotechnology companies have begun evaluating alternative protein-based strategies to treat infections caused by antibiotic-resistant bacteria. This represents a major shift in antibiotic drug discovery, because in the past, researchers shied away from protein-based drugs because of poor oral bioavailability and immunogenicity concerns. However, advances in protein science, immunology, and drug delivery increase the feasibility of protein-based drugs as antibiotics.
One promising approach employs the use of bacterial viruses called bacteriophages (phages) that infect and destroy certain types of bacteria. While the use of phages to treat infections is not a new concept, it is growing in popularity among infectious disease experts mainly because antibiotic-resistant bacteria retain their susceptiblity to phage infection. Alexander Sulakvelidze, Ph.D., CEO of Intralytix, a company founded in 1998 focused on the development of bacteriophage-based products to control bacterial pathogens, believes that phages can effectively be used to treat certain types of infections including difficult-to-treat wound infections and diabetic foot ulcers.
Sulakvelidze envisions that most phage-based products to treat infections will be phage “cocktails” containing eight or more phages that are customized for specific types of bacteria. While the FDA has been reluctant in the past to approve products with multiple active ingredients, Sulakvelidze believes that the agency is becoming more comfortable with the concept. “Phage therapy is safe, very targeted, and effective. Unfortunately, most people don’t know that they eat phage every day, and that they are ubiquitous. We need to better educate the public and regulators in order for phage therapy to ultimately be adopted,” he says.
Another promising approach being championed by new start-up companies like Vienna, Austria-based Arsanis is the use of monoclonal antibodies (mAbs) to treat antibiotic-resistant bacterial infections. “Advances in mAbs engineering and a much better understanding of bacterial virulence and antibiotic resistance mechanisms suggest that mAbs can be effective in treating a variety of bacterial diseases,” said Eszter Nagy, Ph.D., CEO of Arsanis. Not surprisingly, MedImmune’s Projan also believes mAbs represent a new frontier in antibacterial drug development. He boldly predicts that “mAbs and other biologics will definitely be in the mix as successful antibacterial products. The only question that remains is, can we succeed in a timely manner to stop and prevent the spread of multiple-drug-resistant bacterial infections?”
There is no longer any doubt that the incidence of antibiotic-resistant bacteria has reached epidemic proportions. Difficult-to-treat bacterial infections are a growing unmet medical need that many big pharmaceutical companies have chosen to overlook in favor of more lucrative therapeutic markets.
Government intervention and the formation of PPPs may help to begin to address this troubling unmet medical need. But, without the participation and cooperation of big pharmaceutical companies these efforts will likely be unsuccessful. If the current antibiotic shortage is not sufficiently addressed over the next few years, the number of deaths caused by antibiotic-resistant bacteria will likely approach those that routinely occurred during the pre-antibiotic era of the early 20th century.