Antibiotic development pipeline runs dry. New drugs to fight resistant organisms are not being developed, experts say.

New drugs to fight resistant organisms are not being developed, experts say

Infectious disease experts in the USA are calling on the US government to take the growing threat of drug-resistant bacteria just as seriously as it does the threat of bioterror. “There simply aren't enough new drugs in the pharmaceutical pipeline to keep pace with these 'super bugs'”, said Joseph R Dalovisio, president of the Infectious Disease Society of America (IDSA), last week (Nov 14) after Congress authorised US$890 million for fiscal year 2004 to fund “Project Bioshield”, a 10-year, $5·6 billion US initiative to encourage private-sector development of drugs, vaccines, and other bioterror counter-measures.

IDSA wants the government to launch another initiative—an initiative IDSA calls “Bioshield II”—to spur development of drugs to treat common infectious diseases. “More action is needed to protect the general public against naturally occurring infections”, Dalovisio said.

For some time, infectious-disease experts worldwide have warned that just as “super bugs” are becoming a greater threat, many pharmaceutical companies are curtailing their antibacterial research and development programmes, and, in some cases, pulling out of the market altogether.

The reason why drug companies are getting out of the business is not complex, says John Turnidge, director of microbiology and infectious disease at Women's and Children's Hospital, Adelaide, Australia. “In a nutshell, it costs the same to develop an antibiotic as it does other drugs”, Turnidge says. “But these drugs are given for 1–2 weeks compared to many drugs such as the lipid-lowering agents, which are lifelong. Hence the returns are lower.”

Penicillin-resistant Streptococcus pneumonlae makes up 70% of strains in some regions of Tanzania and Rwanda

Alan Goldhammer, associate vice president for domestic regulatory affairs at the Pharmaceutical Research and Manufacturers of America (PhRMA) in Washington, DC, agrees. “Each company only has a limited amount of resources”, he says. “And that weighs heavily in the decision of what products to develop and what goes on to the back burner. It's a difficult issue with antimicrobials because they fall at the lower end of the scale, in part because they're not used to treat chronic diseases.”

Another challenge is that to make an antibiotic profitable, it is often necessary to have it approved for several different indications. A single indication will not be very useful, says Goldhammer, and this means the manufacturer will have to do several different types of clinical trial. By comparison, an antihypertensive typically needs only a single indication to do well on the market.

Antibiotic research and discovery flourished from 1930 to 1970, and resistance, while not unknown, remained low. As new classes of potent drugs entered the marketplace, many formerly deadly infectious diseases almost disappeared—at least in industrialised nations—and a feeling of complacency set in. In 1969, US Surgeon General William H Stewart announced: “The time has come to close the book on infectious disease.”

Infectious diseases, however, have made a stunning comeback. Syphilis, gonorrhea, and tuberculosis are all re-emerging with vengeance, and the advent of AIDS, hepatitis C, and severe acute respiratory syndrome (SARS) has been a humbling experience.

However, the less publicised trend of bacterial resistance may pose an even greater threat. Statistics from WHO hint as to what the future may hold: Vibrio cholerae is 100% resistant to both tetracycline and chloramphenicol (1996 est) in Tanzania and Rwanda; in some regions, penicillin-resistant Streptococcus pneumoniae makes up 70% of strains; worldwide, multidrug-resistant Mycobacterium tuberculosis accounts for 1 to 22% of all new cases (1998 est). In the USA, meticillin-resistant Staphylococcus aureus now accounts for nearly 60% of hospital-acquired staphylococcal infections, and 20% of nosocomial infections in US hospitals are reported to be multidrug resistant.

The best way to combat antimicrobial resistance is by reducing or, preferably, eliminating the misuse of antibiotics in medicine and agriculture, says S Ragnar Norrby, professor and director-general of the Swedish Institute for Infectious Disease. “But we cannot stop looking for new antibiotics, and what is needed is a coordinated programme which involves both industry and academia.”

At present, the greatest concern is an almost complete lack of development of new antibiotics against multiresistant gram-negative bacteria, such as pseudomonas, stenotrophomonas, and acinetobacter, says Norrby. “This is the result of the pharmaceutical industry's tendency to be cyclic and concentrate on certain organisms. Over the past 15 years, the focus has been entirely on gram-positive organisms—in particular, staphylococci, pneumococci, and enterococci.” But even these investments have sometimes proven to be disappointing, says Steve Projan, director of antibacterial research at Wyeth Pharmaceuticals (Pearl River, NJ, USA), with some promising new drugs neither doing as well as expected clinically nor achieving the hoped-for commercial success.

A major problem is the soaring cost of drug development. It is estimated that it takes about $900 million to bring a drug to market, and pharmaceutical companies are finding it more difficult to recoup their costs, says John Bartlett, chair of the Antimicrobial Availability Task Force of the IDSA. The high cost of drug development “has had more of an effect on antibacterials, as compared to other anti-infective agents. There's been four new antiretroviral agents this year alone, but only two new antibiotics. Last year, there were none.” Right now, says Bartlett, there are about 400 drugs in the pipeline that are likely to be approved in the near future, but only five are antibacterial agents.

In addition to the high cost of developing new antibacterials, pressure to curtail usage to reduce emergence of resistant strains, widespread use of generics, and aggressive price controls on antibiotics in many countries all discourage investment, says Projan. The drug-approval process has also become far more difficult, he says, as regulatory authorities have come under increasing public and government scrutiny. It took just 2 years for tetracycline to come on the market; by contrast, the approval process for tigecycline—a novel glycylcycline that Wyeth is hoping to release in the near future—has already taken 10 years. Tigecycline, which has shown excellent in-vitro activity against a broad spectrum of pathogens, is currently being used to treat patients on a compassionate/emergency use basis. But the drug is not likely to make it to market until at least 2005.

Convincing pharmaceutical companies to return to the antimicrobial business will be a hard sell, and concrete solutions to these problems are still in the theoretical stage. “We're not blaming the drug companies; we don't expect them to be charitable organisations”, says Bob Guidos, IDSA's director of public policy. Guidos says it will be difficult to cut drug development costs, but the IDS A is working with the Food and Drug Administration (FDA) to see whether it would be possible to do clinical trials more cheaply without compromising patient safety.

Last year, PhRMA held a workshop with the FDA and IDSA to look at some of the regulatory impediments affecting antibiotic development. Since then, PhRMA and IDSA have made good progress and have addressed many of the key issues with the FDA, says Goldhammer. “I think the FDA shares our interest in facilitating the introduction of new classes of antibiotics”, says Goldhammer. The challenge, he says, is “if there are some regulatory impediments, can we identify them? And can we correct them?”

Guidos believes the government needs to take a leadership role, as they have during past public-health crises. “We have testified that, however commendable, Bioshield needs to address organisms that are affecting public health.” IDSA has had some success in raising awareness in the US Congress and Senate about the lack of antimicrobial research and development. Two senators have requested that the General Accounting Office, the investigative agency of the Congress, study the problem and issue a report. IDSA's task force is about to complete a white paper proposing a plan of action that it hopes will engage the FDA and US agencies, as well as the infectious diseases community and the pharmaceutical and biotechnology industries.

But Projan contends that this is a problem that no longer needs further study, another congressional hearing, or interagency task forces. We've already done that, he says, and what we need now is action. “I think the academic community knows this, but hasn't been aggressive enough in funding projects at the academic level for understanding bacteria physiology and resistance.”

“When antibiotics start failing, it's going to affect all other practices in the hospital”, Projan says. “It's all a little frustrating. Eventually people will get the message and demand to know why nothing is being done.”