Drug development critical to combating antibiotic resistance

Since they were first discovered in 1928, antibiotics have saved countless lives from deadly infections. Continued antibiotic misuse, however, has contributed to antimicrobial resistance, a significant threat to human health that sickens more than 2 million people and kills at least 23,000 annually in the United States, according to the CDC.

The global view is just as bleak. WHO has documented resistance worldwide to carbapenem antibiotics — the therapy of last resort in the treatment of Klebsiella pneumoniae — and widespread resistance to fluoroquinolones. In some countries, fluoroquinolones are ineffective in more than half of treated patients.

“The problem of antibiotic resistance continues to grow, and our inability to meet the challenge, in particular with antibiotics, is even greater than it was 5 years ago,” Helen W. Boucher, MD, director of the Infectious Diseases Fellowship Program at Tufts Medical Center and associate professor at Tufts University School of Medicine, told Infectious Disease News.

Return to a pre-antibiotic era

What is more, there are few prospects in the antibiotic research and development pipeline, which could mean a return to the pre-antibiotic era, when simple infections were a death sentence.

“We’re coming dangerously close to a time when we have to tell our patients that we can’t offer therapies that we really think they deserve, such as organ transplants, chemotherapy for cancer or neonatal intensive care,” said Boucher, who also is a member of the Infectious Diseases Society of America’s (IDSA) Antimicrobial Resistance Committee. “This is incredibly scary. We don’t want to get to another pre-antibiotic era.” 

Combating antibiotic resistance is possible, however, with a multipronged approach that includes infection prevention, antibiotic stewardship and new drug development. To encourage development of antibacterial agents, in 2010 the IDSA established its 10 x ’20 initiative, a global call to develop 10 new antibiotics by 2020. This initiative is primarily focused on developing systemically administered antibiotics that target the ESKAPE pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter species.

“The 10 x ’20 initiative is really just a rallying point to identify problems to get stakeholders thinking about what the issue is,” Stephen B. Calderwood, MD, chief of the division of infectious diseases at Massachusetts General Hospital and president of the IDSA, said in an interview.

At the midpoint of the initiative, Infectious Disease News spoke with experts about the success of the initiative so far, the federal response to antibiotic resistance and the challenges that remain in creating a more robust antibiotic pipeline.

Six new antibiotics since 2010

Since the initiative was launched, the FDA has approved six new antibiotics.

“We are gratified with the progress that we’ve seen, but we have a long way to go,” Boucher said.

Teflaro (ceftaroline fosamil, Forest Laboratories) was approved in 2010 as a treatment for community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections (ABSSSIs). In 2014, there was an explosion of FDA approvals, with four agents securing a nod: Dalvance (dalbavancin, Durata Therapeutics), Sivextro (tedizolid phosphate, Cubist Pharmaceuticals) and Orbactiv (oritavancin, The Medicines Co.) — all for ABSSSIs — and Zerbaxa (ceftolozane/tazobactam, Cubist Pharmaceuticals), which was approved for complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs).

Avycaz (ceftazidime/avibactam, Actavis) also won FDA approval early this year for the treatment of cIAIs in combination with metronidazole and cUTIs, including pyelonephritis.

Physicians are glad to have additional antibacterial options; however, these drugs fail to address the bulk of the unmet needs, such as treatments for the most urgent threats: Clostridium difficile, carbapenem-resistant Enterobacteriaceae (CRE) and drug-resistant Neisseria gonorrhea.

Many unmet needs remain

“Although these drugs are welcomed, it was not in the area of greatest need,” Henry F. “Chip” Chambers, MD, a professor of medicine and director of clinical research services at the University of California, San Francisco’s Clinical & Translational Science Institute, told Infectious Disease News. “But it kind of shows that the initiative works and that it gets companies on board.”

Discovering treatments for gram-negative infections is paramount. Because of their intrinsic resistance to many antibiotics, “developing an antibiotic against a gram-negative organism is the next order of magnitude in degree of difficulty,” Chambers said. “When your drug of choice is the drug of last resort, there is no choice.”

The good news is that two of the most recent antibiotics on the market, ceftolozane/tazobactam and ceftazidime/avibactam, were approved for the treatment of gram-negative infections. “They are exactly what we’ve been waiting for,” Boucher said.

Additional research may demonstrate a wider clinical utility for some of the gram-positive agents approved in 2014. “Our hope is that several of these antibiotics — dalbavancin, oritavancin and tedizolid — will be studied in more serious infections like bloodstream infections and bone infections, where the unmet need is the greatest,” Boucher said.

Encouraging drug development

Despite the spate of approvals since 2014, there is still a critical lack of effective agents and new drug classes. Consequently, developing new agents and finding new drug classes is considered by many a top priority. The first step in encouraging drug development involves an investment in basic research, according to Calderwood.

“NIH and NIAID particularly, and also [Biomedical Advanced Research and Development Authority (BARDA)], have been really trying to put money into the fundamental discoveries that would identify new targets and new approaches to targets,” he said.

Second, it is essential to make drug development more financially appealing. Developing new antibiotics requires a huge investment in time, money and research. According to a Forbes analysis, a pharmaceutical company will spend $350 million bringing a single agent to the market. The return on investment is quite small by comparison.

“Antibiotics, surprisingly, don’t represent a good economic investment, although they used to in the past,” Calderwood said. This is because they are administered for short periods of time, and their prices are quite a bit lower than other novel therapies like cancer drugs, he said.

As a result of these financial disincentives, nearly all of the large pharmaceutical companies have abandoned their antibiotic research and development programs. This has caused the drug pipeline to dry up and delay potential new agents needed to treat life-threatening infections.

“We need a continuous pipeline of antibiotic development so that we will continue to have new drugs to meet the challenge of resistance for our children and their children,” Boucher said.

As of December 2014, there are only 37 new antibiotics in the development pipeline, according to the Pew Charitable Trusts, which tracks antibiotic progress as part of its Antibiotic Resistance Project. Given the low success rate for drug development — approximately 60% of agents that reach phase 3 trials will win FDA approval, according to one recent study by Hay and colleagues — the existing pipeline is not robust enough to meet current health care needs.

The Generating Antibiotic Incentives Now (GAIN) Act, which President Barack Obama signed into law in 2012, has helped address the economic issue. The GAIN Act offers a 5-year extension on patent life for new antibacterial agents that are designated as qualified infectious disease products (QIDPs), increasing their value. The act also accelerates the approval process and requires the FDA to provide updated clinical trial guidance.

Of the antibiotics currently under development, about 24 have been designated as QIDPs, according to the Pew Charitable Trusts. All of the antibiotics approved since 2014 have had the QIDP designation.

“We’re starting to see some antimicrobials in the pipeline, even if they won’t all be ready by 2020. We are at least seeing more action with drug development,” Keith S. Kaye, MD, MPH, professor of medicine and corporate medical director, Infection Prevention, Epidemiology and Antibiotic Stewardship at Detroit Medical Center and Wayne State University in Detroit, and an Infectious Disease News Editorial Board member, said in an interview.

One promising agent in the pipeline is Carbavance (meropenem/RPX7009, The Medicines Co.), which is currently in phase 3 trials. “There’s excitement about this drug being active against carbapenem-resistant Enterobacteriaceae,” Kaye said.

Eravacycline (Tetraphase Pharmaceuticals), also in phase 3 development, is demonstrating potential against CRE and Acinetobacter, according to Kaye.

Of the remaining drugs in the pipeline, 10 are in phase 1 trials, and 18 are in phase 2 trials. In addition to Carbavance and eravacycline, six other antibiotics are in phase 3 trials, according to the Pew Charitable Trusts.

Regulatory hurdles

The regulatory process required to bring a new drug to market represents a huge obstacle to drug development, according to Calderwood.

For instance, conducting the traditional clinical trials that are required to secure FDA approval for new antibiotic agents is challenging, he said. First, the gold standard for these trials is an active control, which often does not exist with resistant bacteria. In addition, the FDA typically would like to see trials that involve large numbers of patients. Once again, this is often not possible with antimicrobial agents because some of these infections occur in such small numbers of patients.

Legislation introduced in the U.S. House of Representatives in 2013 may make clearing these hurdles a bit easier. The Antibiotic Development to Advance Patient Treatment (ADAPT) Act of 2013 aims to accelerate the FDA approval process for antibacterial and antifungal therapies for the treatment of patients with serious or life-threatening infections who have limited treatment options. It will establish a new accelerated approval process, the Limited Population Antibacterial Drug approval mechanism, which clears the regulatory path for agents that address an urgent unmet need in a limited patient population. Of course, pharmaceutical companies must still demonstrate the safety and efficacy of the drugs being considered for approval.

“An antibiotic could be developed for much more narrow indications … just for people with the most-resistant infections, who are the sickest, perhaps,” Boucher said. “It could be studied in fewer patients and maybe in a more expeditious way, but then the label would reflect that it had just been studied in that narrow population.”

Strong federal support

In addition to the GAIN and ADAPT acts, the federal government has responded strongly to the antimicrobial resistance problem. In March, the White House unveiled its National Action Plan for Combating Antibiotic-Resistant Bacteria, based on Executive Order 13676. Developed by the Interagency Task Force for Combating Antibiotic-Resistant Bacteria, the plan outlines goals for the next 5 years to improve prevention, detection and control of antibiotic resistance:

Furthermore, Obama’s 2016 budget provides a sizable investment — $1.2 billion in federal funding — to achieve these goals. More than $615 million goes to the NIH and BARDA for the development of new drugs and rapid diagnostics. The CDC will net more than $280 million for stewardship programs and outbreak surveillance. The FDA will receive $47 million to assess new antimicrobials and antibiotic stewardship in animal agriculture.

The attention and support at the federal level for this issue has been tremendous, according to Elizabeth S. Dodds Ashley, PharmD, MHS, of the University of Rochester in Rochester, New York, and an Infectious Disease News Editorial Board member.

“To have antibiotic resistance mentioned in the State of the Union address for 2014 and to have the White House issue guidance about antimicrobial resistance has greatly elevated the attention focused on this important issue,” Dodds Ashley said.

Other ways to combat resistance

Until the research and development pipeline is consistently producing new antibiotics, there are other ways to combat resistance, according to experts.

Researchers are finding ways to extend the clinical utility of existing agents or those that have fallen out of favor. Many groups are working on optimizing the pharmacodynamics of older anti-infectives.

“Dosing regimens often were designed in the days when the organisms we were trying to fight did not have resistance,” Dodds Ashley said. Now, “we might be able to have novel dosing strategies that allow us to get more squeeze out of these antibiotics.”

Polymyxin B is a good example of this, she said. Largely abandoned because of its toxicity, polymyxin B is demonstrating effectiveness against some resistant pathogens.

Kaye and colleagues also are working with polymyxin B and colistin.

“We’re trying to figure out how we can best use some of our remaining active drugs to optimize clinical outcomes and also to prevent the emergence of resistance,” he said.

Another group found that an old tetracycline drug, IV minocycline, is effective against Acinetobacter and other resistant bacteria, according to Boucher.

Combining antibacterial drugs often can sidestep resistance, as well. Because of the dearth of highly active single agents, Acinetobacter commonly is treated with combination therapy, Calderwood said. The synergy produced by combination approaches “often produce more rapid killing and therefore, [reduce the] likelihood of development of resistance,” he said.

Although it is not a standard bacterial infection, tuberculosis is a perfect example. “Using combination therapy to prevent resistance is a well-established approach in certain infections like tuberculosis,” Calderwood said. “The question is how to adapt that for certain bacterial infections.”

Some research suggests it may be possible to re-sensitize bacteria to existing antibiotics. James J. Collins, MD, of the Wyss Institute at Harvard University, and colleagues have been studying this area, according to Calderwood. “He’s been looking at ways to change the physiology or metabolism of the bacterium and therefore, make it more susceptible to antibiotics than it would otherwise have been,” he said.

Rapid diagnostics also are important, according to Boucher.

“If we know what we’re treating … focusing our therapy is a really huge boost,” she said. “There are many studies that [suggest] if you treat appropriately upfront, the patient has a better chance of surviving. Rapid diagnostics are vitally important.”

With the approval this year of the BioFire FilmArray (BioFire Diagnostics) and other rapid respiratory panels, physicians have significantly improved their ability to identify respiratory infections, Boucher said.

Meeting the 10 x ’20 goal

Drug development, although critical, is just one piece of the puzzle. Reducing the spread of infection is just as important. Antibiotic stewardship — using the right antibiotic in the right patient at the right dose — is key.

However, the question remains whether the initiative will reach its goal within the next 5 years. According to Calderwood, it is reasonable to think so.

“The challenge will be [developing] antibiotics directed at the most important unmet medical needs, which are these resistant gram-negatives, including Acinetobacter,” he said.

It is essential that antibiotic development continues beyond the 2020 goal set by the IDSA initiative. “You always need new antibiotics for the problems coming down the line,” Chambers said. “We’re not going to eliminate the need for antibiotic development because resistance is inevitable. I think that we should spend more time, though, forestalling problems … and develop ways to try and preserve them.”

Boucher agreed, saying that 2020 is not the end.

“We look at it as the beginning,” she said. “We want to see an infrastructure in the United States that supports ongoing discovery and development of antibiotics.

“I hope [by 2020 that] the doomsday scenario of telling people they can’t get their heart transplant is further off in the future.” – by Colleen Owens

References:

CDC. Antibiotic Resistance Threats in the United States, 2013. www.cdc.gov/drugresistance/threat-report-2013/. Accessed May 13, 2015.
Hay M, et al. Nat Biotechnol. 2014;doi:10.1038/nbt.2786.
Herper M. Forbes. 2013. The Cost of Creating a New Drug Now $5 Billion, Pushing Big Pharma to Change. www.forbes.com/sites/matthewherper/2013/08/11/how-the-staggering-cost-of-inventing-new-drugs-is-shaping-the-future-of-medicine/. Accessed May 13, 2015.
Huque MF, et al. Stat Med. 2014;doi:10.1002/sim.6233.
Lee RE, et al. Nat Med. 2013;doi:10.1038/nm.3458.
Pew Charitable Trusts 2014. Tracking the Pipeline of Antibiotics in Development. www.pewtrusts.org/en/research-and-analysis/issue-briefs/2014/03/12/tracking-the-pipeline-of-antibiotics-in-development. Accessed May 13, 2015.
WHO. Antimicrobial resistance: global report on surveillance 2014. www.who.int/drugresistance/documents/surveillancereport/en/. Accessed May 13, 2015.

For more information:

Elizabeth S. Dodds Ashley, PharmD, MHS, can be reached at elizabeth_doddsashley@urmc.rochester.edu.
Helen W. Boucher, MD, can be reached at hboucher@tuftsmedicalcenter.org.
Stephen B. Calderwood, MD, can be reached at scalderwood@partners.org.
Henry F. “Chip” Chambers, MD, can be reached at henry.chambers@ucsf.edu.
Keith S. Kaye, MD, MPH, can be reached at kkaye@dmc.org.