New Antibiotics in the Pipeline But Situation Still Dire

Daniel M. Keller, PhD

October 22, 2011

October 22, 2011 (Boston, Massachusetts) — Although there has been progress in the clinical development of new antimicrobial agents against resistant Gram-negative bacteria, there are still none active against panresistant Gram-negative bacteria.

In its 10 ₓ '20 campaign, the Infectious Diseases Society of America (IDSA) has set a goal of developing 10 effective and safe systemic antimicrobial agents by 2020.

Helen Boucher, MD, associate professor of medicine in the division of geographic medicine and infectious diseases and director of the infectious diseases fellowship program at Tufts University School of Medicine in Boston, Massachusetts, described the campaign here at the IDSA 49th Annual Meeting.

In a 2009 survey, no development-stage antimicrobial with a purely Gram-negative spectrum of activity had reached phase 2 clinical testing.

Infections that are resistant to all current antibiotics are occurring more often. The situation is now dire because several large pharmaceutical companies have ended the research and development of any new antimicrobials. Since the 2009 report, only telavancin and ceftaroline fosamil have reached the market.

After a recent literature review, the use of the clinical trials registry, and interviews with pharmaceutical leaders, Dr. Boucher and colleagues have found that there are 9 intravenous compounds active against Gram-negative bacteria in development: 1 β-lactamase inhibitor combination in a phase 3 study of complicated urinary tract infections (cUTI), and 8 compounds (3 β-lactamase inhibitor combinations) in phase 2 studies to treat acute bacterial skin and skin structure infections, cUTI, and/or complicated intraabdominal infections. There are other compounds in phase 1 or preclinical development.

Only a few of the 9 compounds are active against the worst pathogens, such as Acinetobacter baumannii and Pseudomonas aeruginosa. Two of the compounds in phase 2 testing have novel mechanisms of action. One is a transfer RNA synthetase inhibitor and the other is a peptide mimetic. However, novel mechanisms of action raise safety concerns.

The investigators found no ongoing studies of antimicrobials to treat community-acquired bacterial pneumonia, hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia, or bloodstream infections — all among the most dangerous infections that physicians treat and with the most severely limited therapeutic options.

"We all know that with antibiotics, attrition happens, even in the later stages of development, so we can't count on getting all or even the majority of these 9 compounds to market. Further, and very importantly, none of these drugs is available today, and our patients need new drugs now," Dr. Boucher said in a news conference. "In a nutshell, our survey demonstrates tangible progress in the clinical development of new antibiotics that target infections caused by resistant Gram-negative bacilli."

If some of these compounds are approved by the US Food and Drug Administration (FDA), it is reasonable to think that the first ones could enter the market in about 4 years, she noted.

Progress and clarification of FDA regulatory clinical trial guidances, which pharmaceutical companies currently identify as a major disincentive for antibiotic development, will be needed to encourage a richer drug development environment. There will also have to be fair and appropriate economic incentives for small and large pharmaceutical companies.

James Hughes, MD, professor of medicine and public health and director of the program in global infectious diseases at the Emory University School of Medicine in Atlanta, Georgia, and president of the IDSA, said that antimicrobial resistance "is a problem at the national level and at the local level. It's a problem for patients, it's a problem for clinicians,...and it's a problem for other health officials."

The problems are in the drug development pipeline and in terms of shortages of drugs that are currently approved for use. "We face the threat of returning to the preantibiotic era," Dr. Hughes warned. "We're facing a market failure and an innovation gap."

He also said that, hand-in-hand with the development of antimicrobials, there is a need for rapid point-of-care diagnostics to facilitate physicians' decisions about the selection of appropriate antibiotics to treat patients.

There was no commercial funding for the study. Dr. Boucher reports being on the adjudication committee and receiving a consulting fee from Merck; being a Data Safety and Monitoring Board member; and receiving consulting fees from Wyeth/Pfizer, Durata, and PolyMedix. Dr. Hughes is president of IDSA, the sponsor of the 10 ₓ '20 campaign, but has disclosed no relevant financial relationships.

Infectious Diseases Society of America (IDSA) 49th Annual Meeting: Abstract LB-27. Presented October 22, 2001.


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