Wednesday, March 01, 2006

Antibiotic work afflicted by the bottom line blues

March 1, 2006

The Dallas Morning News

DALLAS - Sylvia LaRue had been a nurse long enough to know that the golf-ball size lump shooting pain into her scalp was a staph infection. The test results still stunned her.

"I've been a nurse since 1977, and I've never seen a lab report like that," LaRue said of her 2004 encounter with Staphylococcus aureus. The bacteria were resistant or just marginally vulnerable to 10 of the 11 medicines on the list. The single option left to her was trimethoprim/sulfa - not a creation of high-tech science, but a combination developed decades ago.

In the modern antibiotic era, the old drugs are often the only drugs. Many of the world's pharmaceutical giants are losing interest in the pursuit of new antibiotics and slashing their antimicrobial research divisions. At the same time, the germs continue to strengthen their ability to defy the drugs already on the market.

Already, some patients are left with only one or two useful medications. As resistance climbs and research interest falls, infectious disease experts worry about a day when some infections may reach the point of being virtually unstoppable.

"I don't think it's a crisis right now," said Dr. George McCracken, head of infectious disease at Children's Medical Center Dallas. But it might be, he says, "in the next three to five years."
He and other experts are most concerned about the microbes that breed in hospitals, such as staph, pseudomonas and vancomycin-resistant enterococci. These germs seize on weakened patients connected to tubes that offer bacteria inviting portals to the body's innermost reaches. About 2 million people each year will contract an infection they didn't have upon admission.
"In most American hospitals, we are going to have at any point in time somewhere between one and two patients where we have to scramble to find adequate treatment," said Dr. John Bartlett, head of infectious diseases at Johns Hopkins University School of Medicine.

Once, new antibiotics flowed readily. Between 1935 and 1968, 11 new classes of antibiotics - a "class" targets bacteria in a unique way - came on the market. After that, none appeared for more than 30 years. One was approved in 2000, with two more in 2003 and 2005. But those newest antibiotic classes were the outcome of research that began more than a decade ago. Today, doctors lament the paucity of new drugs in the wings and say much of what are in the pipeline are simply updated versions of old medications.

Since 2000, some of the household names in the drug business - including Wyeth, Aventis, Eli Lilly, Bristol-Myers Squibb, Abbott Laboratories - have cut or eliminated antibiotics research. The reasons are complicated, but the bottom line is still about money. Drug companies are amassing into ever-larger conglomerates, and Wall Street is demanding the highest possible profit margins. From a strictly business standpoint, the most attractive prescription is the one taken by a lot of patients for a long time.

A successful new antibiotic - generally designed to be taken for short periods - might reap a few hundred million dollars a year during its brand-protected life. Compare that with the cholesterol-lowering Lipitor, which a patient might take for a lifetime. It brought in more than $12 billion to Pfizer in 2005. Among the top 20 prescription sellers last year, none was an antibiotic.

"These are critically important drugs. They save lives, and they save them fast," said Steven Projan, vice president of biological technologies for the drug giant Wyeth, which abandoned antibiotics discovery in 2002. But the reality is, "the therapy is going to be for three days to two weeks. It's not like you're giving somebody Lipitor for the rest of their lives."

Other issues, however, both scientific and regulatory, also discourage antibiotics research, Projan said. Antibiotic development can be harder than other drug endeavors, he believes, "and it's harder for reasons we are just starting to understand."

Bacteria have occupied the planet longer than humans, evolving sophisticated mechanisms to outsmart chemical assaults. Most of the current antibiotics, often found by accident, are based on substances extracted from other living things that have spent eons refining the tactics of chemical warfare. Today, the vein of natural compounds largely has been mined, and more modern approaches - techniques that rely on disabling a microbe's inner genetic machinery - have been disappointing.

When drug maker Eli Lilly & Co. mulled its future direction in 2002, the feeling was that "this is one area of drug discovery where I think the low-hanging fruit had been picked," said vice president Gail Cassell.

Each company has its own reasons for leaving antibiotic research, said Cassell, who is a microbiologist. "We consciously made the choice to focus our efforts in the area of oncology, diabetes and neuroscience. We viewed those as equally unmet needs."

Companies who continue to pursue antibiotics say they aren't expecting breathtaking payoffs. "This is not something that is a major blockbuster type of product," said Dr. Lynn Marks of GlaxoSmithKline, which submitted a new topical antibiotic for FDA approval in February. "I think our stockholders understand there's more to being a great corporation that just turning pure profit."

But where many big pharma companies see anemic profits for enormous effort, small entrepreneurs see opportunity. "Where it's happening," McCracken said of antibiotics research, "is with the small companies."

Biotech companies don't depend on a Lipitor-scale return.

"If we made $100 million, that would be real money to us," said Simon Lynch, director of research for Dallas-based Cumbre Inc. And smaller companies tout themselves as being leaner and more passionate than their famous counterparts, knowing that their entire survival depends on having a product to show for their time.

Companies like Cumbre have maybe two dozen or so research scientists, while the larger firms might employ hundreds. Yet finding a drug isn't necessarily a matter of having the most Petri dishes.

For example, Cumbre is tightly focused on defeating biofilm infections - the slimy, often impenetrable communities of bacteria that can coat the insides of catheters and the surface of bones.

But can small pharma succeed where big pharma can't? Wyeth's Projan remains skeptical. "We have a huge amount of experience doing this, and they tend to make all the mistakes we do," he said. He says he believes in the need; the last approved new drug class was a Wyeth invention. A turnaround in antibiotic discovery, he said, will depend on better innovation, not just better economics.

"What we need are new chemistries. We've been stuck in the solar system, and we need to get out into the galaxy."

Lynch's company, for example, is looking at how a bacterium shields itself from a chemical that would otherwise kill it. Many potential drugs don't work because bacteria have molecular pumps that enable them to bail out foreign chemicals as quickly as they come in. Disabling those pumps would allow antibiotics to become trapped in cells.

Other companies are exploring how to jam the communications that allow bacteria to sense one another's presence and, in essence, transform from a disorganized militia into a precision-trained force. Working together, bacteria can become meaner and more resistant to drugs than they could ever be in lesser groups.

"The optimistic view is that some of these biotechs are going to hit paydirt," said David Shlaes of Connecticut-based Anti-Infectives Consulting. "They will challenge big pharma in the marketplace, and big pharma is going to wake up."

Doctors have also taken proposed solutions to Congress, including measures that would provide financial incentives for antibiotic research and streamline clinical trials. However, some experts point out that more favorable regulation, by itself, won't bring new chemicals into the research pipeline.

Doctors campaigning for more antibiotics research are not against making money, said Dr. Richard Wenzel of Virginia Commonwealth University. The pharmaceutical industry is "driven by the free enterprise system in a straightforward, American way.

"We need drug companies to be able to make a profit," he continued. "The real question is how much when the public's health is at risk."

It's a public health issue that Beverly Perry hadn't considered until November, when her mother, Jean Baccus, suffered a stroke. Five days after Baccus entered the hospital, bacteria invaded her IV line and set up an outpost in her spine.

More than three months later, Baccus' stroke rehabilitation can't begin because the drug-resistant staph infection hangs on.

"You think, `OK, let's give her antibiotics and get it over with,'" Perry said. The stubbornness of the infection astonished her. "We tell her, `It's just going to be a couple more weeks.'"
And a couple of weeks turn into a couple more weeks. Baccus now must be taken to the hospital each day for antibiotic infusions that are sluggish in working. "She's in so much pain," Perry said. "I think everybody needs to know how serious this is."


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