Health System Struggles Against New Bugs

Since World War II, most of the developed world has lived through a golden period where infectious diseases were a concern of generations past.

Vaccines and antibiotics like penicillin kept the most virulent diseases at bay, and children grew up in a world where scarlet fever, cholera and tuberculosis were virtually unheard of.

Our victory over these illnesses seemed so complete that in 1967, Surgeon General William H. Stewart announced it was "time to close the book on infectious diseases, declare the war against pestilence won, and shift national resources to such chronic problems as cancer and heart disease."

Now that halcyon period may be ending. "The golden era of medicine has come to term," said Kate Robins, a spokeswoman for drug maker Pfizer.

As new and deadly strains of bacteria and viruses emerge, government officials and the pharmaceutical industry have devoted few resources to address this immediate threat.

Health Doesn't Pay

Most drug companies, in fact, have severely cut back or eliminated all research and development in antibiotics.

"Antibiotics ... are a victim of their own success," said Dr. Mark Goldberger, director of the office of drug evaluation in the Center for Drugs at the Food and Drug Administration.

"One sees drugs that can be used for five to 10 days and are likely to be very effective," he said. These antibiotics yield relatively little profit for manufacturers, compared to drugs to treat chronic conditions such as hypertension, HIV and hepatitis.

Pharmaceutical industry critics decry what they see as an industry trend away from lifesaving antibiotics and antivirals, and an increased investment in "lifestyle" drugs to deal with conditions such as baldness, erectile dysfunction and obesity. Though these drugs have little or no medical benefit, they virtually guarantee huge profits for pharmaceutical companies.

But Dr. John E. Edwards, professor of medicine at the David Geffen School of Medicine at UCLA and chief of infectious diseases at Harbor-UCLA Medical Center, finds no reason to blame the pharmaceutical industry for the shortage of new antibiotics.

"There are very significant financial disincentives for pharmaceutical companies to pursue these anti-infectives," Edwards said. "It's not their fault -- it's a societal conundrum."

R&D Costs Soar

A significant part of the problem is the lengthy and expensive process of developing, testing and bringing a new drug to market.

According to a 2001 study by the Tufts Center for the Study of Drug Development at Tufts University in Boston, the average cost to develop a new drug is more than $800 million. Part of the cost includes years -- even decades -- of research and clinical evaluation before a drug can gain FDA approval.

When the stakes are as high as that, it's no wonder large drug companies shy away from expensive, time-consuming antibiotic research that may produce little profit and could expose the company to expensive lawsuits.

"That's why it's going to boil down to legislative reform before we address this issue, which is a major public health problem," said Edwards.

But even as major pharmaceutical companies are scaling back or eliminating antibiotic research and development, a handful of other companies is stepping in to gamble on new antibiotics.

"Biotech companies like us can fill the void that's been created by the exit of the big pharmaceutical companies," said Dr. Francis Tally, chief scientific officer at Cubist Pharmaceuticals in Lexington, Mass. "$300 [million] to $400 million in sales won't cut it with big pharmaceutical companies."

'A Constant Fight'

Cubist has developed Cubicin, one of the only antimicrobials (drugs specifically targeting microorganisms) to come to market in many years. Initial research on the drug was started in the 1980s by pharmaceutical giant Eli Lilly, which abandoned research efforts on the drug in 1991 but now has a licensing agreement with Cubist.

"The only two new [antimicrobial] drugs in 25 years are Cubicin and Zyvox," Tally said. "And both of these new ones were discovered about 25 years ago."

Pfizer, maker of Zyvox, is one of the only large drug manufacturers that has increased its research efforts in antimicrobials.

"We had around 40 people working in this area -- now we have over 160," said Martin Mackay, senior vice president of worldwide research and technology for Pfizer. "We've mounted a substantial campaign in this area. Our size gives us this benefit."

But Mackay acknowledges the challenges of antibiotic research are significant. One of the most frustrating problems is the ability of bacteria to mutate and develop drug-resistant strains, confounding the best efforts of medical researchers.

"We're in a constant fight with bacteria," Mackay said. "Just when you think you're ahead of the game, lo and behold, 10 years later you're back in the fight again."

"Infectious diseases mutate, so if you work on [a drug] for 20 years, by the time you get it out the door, it's a different disease," added Robins.

Nothing in the Pipeline

The Infectious Diseases Society of America has issued a report entitled "Bad Bugs, No Drugs" that highlights the alarm among some medical professionals and government officials.

The report, issued in July, cites a study from the May issue of the journal Clinical Infectious Diseases that found 506 new drugs in development, but only five were antibiotics, due in large part to the number of companies withdrawing from antibiotic research.

And many of the antibiotics in development are "broad-spectrum" antibiotics, intended to combat a wide range of disease-causing organisms. The use of broad-spectrum antibiotics has been cited as a leading cause of the emergence of antibiotic-resistant bacteria.

In 2003, partly as a result of efforts by the IDSA and others, Sens. Orrin Hatch, R-Utah, and Joseph Lieberman, D-Conn., introduced legislation designed to spur investment by major drug companies in antibiotic research and development.

The legislation, often referred to as BioShield II, seeks to implement a number of incentives to drug companies including tax incentives, liability protection, patent extensions and small business grants.

"The first issue to be addressed is what anti-infectives will be included in Bioshield II, and what kind of disincentives can be removed," said Edwards, one of the authors of the 2004 IDSA report.

Safety vs. Speed

The FDA is also looking at ways to facilitate the introduction of new antibiotics.

"We can control the costs of development in one basic way -- that is to try to shorten the development time," said Goldberger. The FDA was, for example, able to fast-track the approval of Cubicin, recognizing the importance of the drug in combating methicillin-resistant Staphylococcus aureus, one of the new drug-resistant "superbugs."

There are cases, Goldberger says, where the medical community and the public are willing to accept the introduction of a disease-fighting drug even if there are some concerns about the drug's safety.

"For serious infections, you will tolerate a little more of a safety issue," he said. "For the drugs that are really important -- those for cancer and HIV -- the trend has been to move those drugs through more quickly."

The public influences this debate by insisting on inexpensive and highly effective drugs that are also extremely safe for large populations of users -- a difficult endeavor for any drug maker or regulatory agency.

But in choosing between safety and availability, "there's always going to be tension between those two areas," Goldberger said.

10 Years Behind Schedule

Even the best efforts of those working in the drug industry, academics and the government may not be enough to stem the rising tide of antibiotic-resistant infectious organisms.

Dr. John G. Bartlett, professor of medicine and chief of infectious diseases at Johns Hopkins University School of Medicine, notes that if research began immediately on antibiotics to combat new strains of bacteria, it would be many years before any of these drugs were available.

"We're trying to deal with the bugs of 2008 and 2010," he said. "There are constant surprises, and ... we're at a period where there aren't any drugs in development."

As the IDSA report notes, "Time is running out. Even if all the incentives outlined in this paper were implemented today, it likely would take 10 or more years for companies to move safe and effective new drugs to market."

This article is the second of a three-part series.