by Sabin Russell
Dr. Ian Friedland was sitting at his Mountain View office on a rainy October afternoon when the telephone rang with some long-awaited news: The Food and Drug Administration had just approved doripenem, the powerful antibiotic he had labored over since 2004.
"Shortly after the drug was approved," the 50-year-old Johnson & Johnson researcher said, "we began to hear stories about it being used successfully in patients." It was the kind of outcome that pharmaceutical scientists spend their lives trying to attain.
It is also the kind of story that has become frighteningly rare.
Since the early 1990s, drug companies that had built their businesses on early antibiotic research have been leaving the field. As a consequence, there has been a steady decline in the number of new antibiotics approved by the FDA - even as the existing ones are losing ground to a surge of drug-resistant bacterial strains such as Staphylococcus aureus.
In the five-year period from 1983 through 1987, the FDA approved 16 new antibiotics. During a similar five-year span that ended last year, only five made the cut.
At the same time, the overall level of antibiotic drug research has dropped. In 2006, a survey by the Infectious Diseases Society of America counted only 13 potential new antibiotics in mid- to large-scale clinical trials - a stage of drug development that requires years to complete and offers no guarantee of success.
Medical researchers describe the supply of new drugs under development as "the pipeline." The pipeline for new antibiotics is running dry.
Intravenous doripenem, approved on Oct. 12, is the only important antibiotic licensed since 2005. Distantly related to penicillin, it will be used at first to treat severe and life-threatening abdominal infections in hospitalized patients.
The reasons for the decline in antibiotic research and development are complex, but drug company economics are at the core of it. Drugs that treat chronic conditions such as heart disease, arthritis and diabetes must be taken for a lifetime. A good antibiotic can clear an infection in a week to 10 days.
With the cost of developing new drugs ranging between $110 million and $800 million, cautious investors are putting their money into research that promises the biggest payout.
But scientists also acknowledge that the bugs themselves are proving more difficult to fight. Most antibiotics are derived from toxins created by bacteria to use as weapons against competing bugs. Much of drug development in the second half of the 20th century relied on finding molds that produced these natural toxins, and then tinkering with them to make them easier to manufacture.
More recent efforts focus on the deliberate design of new drugs. Scientists probe disease-causing organisms for weaknesses, and create molecules to attack those weak points. The approach has worked for AIDS drugs, but has yet to hit gold in the effort to find new antibiotics.
Dr. Jack Edwards, chief of infectious diseases at Harbor-UCLA Medical Center, said it was "quite easy" in the 1970s to make new antibiotics such as cephalosporins - a penicillin-like family of drugs that includes well-known products such as Keflex. "It's clear now that it is not so easy to make a new antibiotic," he said.
The struggle to find new antibiotics to replace the old has been going on since the start of the antibiotic revolution.
Scottish researcher Alexander Fleming discovered penicillin in 1928 when a spot of mold contaminated a petri dish of Staphylococcus aureus and produced a distinctive ring where the bacteria would not grow.
It took another 15 years before British and American scientists came up with a practical way to make penicillin on a commercial scale. Yet almost as soon as penicillin went into common use in the 1940s, a new variety of staph appeared that the antibiotic could not treat.
Hospitals eventually set up special wards to isolate the growing number of patients with penicillin-resistant staph. A new antibiotic, methicillin, came out in 1960, but within a year some staph germs had developed a defense against that drug, too.
Alarmed by the need to keep ahead of rapidly mutating bacterial strains, researchers since then have developed four successive generations of cephalosporins - the first came out in 1964.
These drugs repeatedly raised hopes that the resistance problem could be tamed, but even as scientists developed new generations of cephalosporins, bacteria methodically evolved ways to sidestep each one.
When bacteria began to resist the fourth - and final - generation of cephalosporins, researchers came up with carbapenems, yet another promising family distantly related to penicillin. Carbapenems are, like thoroughbreds, powerful, expensive and potentially dangerous.
Doripenem, the new Johnson & Johnson antibiotic, is the latest carbapenem.
While germs such as methicillin-resistant Staphylococcus aureus, or MRSA, have been grabbing headlines of late, there are other bugs such as Acinetobacter, Klebsiella and Pseudomonas that are evolving resistance to most existing antibiotics at an alarming pace. Those three, classified as Gram-negative, carry microscopic pumps that drive antibiotics out of their system. They have proved particularly adept at dodging new drugs, and researchers have been largely stumped in their efforts to come up with substitutes.
Lawmakers in Washington have repeatedly offered bills containing packages of incentives to encourage drug companies to develop new antibiotics more rapidly, but specialists such as UCLA's Edwards acknowledge that is a hard sell in Congress.
"There is a general dissatisfaction with the pharmaceuticals industry, based in part on the concept that their profit margins are too large," he said. "But we need to keep industry interested in making new antibiotics."
The latest effort to spur on the drug companies occurred last year, but by the time a large FDA reauthorization bill reached President Bush's desk for signature on Sept. 27, key incentives - such as allowing antibiotic makers to stave off generic competition when they find new uses for their drugs - had been stripped out.
"There are no provisions in the bill that will directly lead to stimulation of antibiotic development," said UCLA infectious disease specialist Dr. Brad Spellberg.
With few incentives to keep big drug companies from bowing out, entrepreneurs such as John and Mike Flavin are trying to fill the gap.
John is president and Mike chief executive of Advanced Life Sciences, a Chicago-area startup that is carrying out late-stage clinical trials of cethromycin. The antibiotic was initially developed, and later dropped, by nearby Abbott Laboratories. The Flavin brothers acquired rights and continued to test it because it shows promise as a pneumonia drug and a treatment for inhaled anthrax.
They have raised $71 million through stock offerings to take the drug through final clinical trials.
"As entrepreneurs, the business case we saw was this lack of a pipeline," said John Flavin. "This product would address a growing need in the face of no real competition. That puts us in the right place, at the right time."
This month, as a result of provisions in the new FDA law signed by the president in September, federal regulators convened a meeting with infectious disease doctors and drugmakers to clarify just what kind of proof is required in clinical trials to win approval of drugs to treat pneumonia. A meeting will be held in April to turn those discussions into formal recommendations.
Looming over those talks is the unfortunate history of Ketek - and the question of how to balance speedy approval against the risk of serious side effects.
When Paris-based Sanofi-Aventis won FDA approval for Ketek as a treatment for respiratory illnesses in April 2004, there was talk of a blockbuster drug. More than 28 million prescriptions have been sold worldwide.
But in January 2006, an alert team of North Carolina physicians published online a startling discovery that has put a cloud over Ketek, Sanofi-Aventis and the FDA. Three patients treated at the same hospital had come down with serious liver problems within days of taking Ketek. A 51-year-old woman required a liver transplant, a 26-year-old man died, and a 46-year-old man became ill with jaundice until he stopped taking the pills.
"When you see three cases, same county, same hospital, you start to connect the dots," said Charlotte, N.C., liver specialist Dr. John Hanson, who co-authored an account of the three cases in the journal Annals of Internal Medicine.
By the end of that year, 53 cases of liver toxicity nationwide had been traced to Ketek, including 12 cases of acute liver failure, resulting in four deaths. A congressional investigation revealed that the drug was approved by the FDA despite the discovery that one doctor had fabricated data in a clinical trial. In February, under pressure from Congress, the FDA imposed a "black box" warning on the label of the drug, and dropped its approval for the two conditions for which it was most often prescribed: bronchitis and sinus infection.
Dr. Sidney Wolfe, director of Public Citizen's Health Research Group, acknowledged that antibiotic resistance is a serious problem, but warned that boosting financial incentives for drug companies to make new drugs could yield nothing more than other me-too products with problematic side effects. "I'm tired of all these lures to an industry making so much money today that they can't even see straight," he said.
Although doctors are frustrated by the slow pace of drug development, the biggest challenge may not be lawmakers or drugmakers, but the bugs themselves.
Among the most troubling forms of antibiotic resistance was one of the first encountered in the early days of penicillin. The penicillin molecule features a ring of carbon, called beta-lactam, which hobbles the ability of new bacteria to form cell membranes. But penicillin-resistant strains of bacteria quickly emerged equipped with enzymes called beta-lactamases, which can knock out those carbon rings.
UC Berkeley biochemistry Professor Hiroshi Nikaido, who has studied resistance mechanisms for 40 years, noted that some of the most difficult-to-treat classes of bacteria carry genes to make some form of beta-lactamase. "It must have been there for a long, long time, performing functions that nobody really understands," he said.
Bacteria have shown an extraordinary ability to develop new forms of the enzyme. At least 532 different types of beta-lactamases have been identified, according to Johns Hopkins University epidemiologist Dr. John Bartlett, who reported his findings last year in the journal Clinical Infectious Diseases.
Bacteria containing gangs of these enzymes - known as extended-spectrum beta-lactamases - are a growing threat, particularly in pneumonia-causing bugs such as Klebsiella and Pseudomonas. Bartlett said Pseudomonas aeruginosa seems to have a greater ability than most bacteria to develop resistance to "virtually any antibiotic." Some lab tests from hospitalized patients, he said, have already turned up resistance "to all available FDA-approved antibiotics."
It's a step toward what some researchers have labeled "the post-antibiotic era."
Martin Mackay, president for Global Research and Development at Pfizer Inc., the world's largest pharmaceutical firm, remembers as a young bacteriologist in the 1970s the optimism surrounding new antibiotics. "A lot of companies thought we'd cured infectious diseases," he said.
The years since have been a sobering reminder of the power of bacterial evolution. Mackay said neither he nor his company have given up, but instead have a new respect for the challenges ahead.
"I doubt there will ever be a time we really crack this resistance problem," he said. "I think this is going to be a constant war."
To learn more
Two bills designed to address antibiotic resistance are currently making their way through Congress. They are:
Preservation of Antibiotics for Medical Treatment Act: A bill introduced by Sens. Edward Kennedy, D-Mass., and Olympia Snow, R-Maine, would over a two-year period phase out of animal feeds antibiotics that are deemed important to human medicine.
-- To learn more: Go to links.sfgate.com/ZCGK.
The STAAR Act: A bill sponsored by Sens. Sherrod Brown, D-Ohio, and Orrin Hatch, R-Utah, was introduced last fall to address the problem of antibiotic-resistant bacteria through research and enhanced federal surveillance, prevention and control.
-- To learn more: Go to links.sfgate.com/ZCEF.
How to get involved
Want to tell your representatives in the U.S. Senate or the House of Representatives how you stand on the Preservation of Antibiotics for Medical Treatment Act or the STAAR Act?
-- Call Sen. Barbara Boxer at her Washington office at (202) 224-3553 or her San Francisco office at (415) 403-0100, or e-mail her by going to links.sfgate.com/ZCEK.
-- Call Sen. Dianne Feinstein at her Washington office at (202) 224-3841 or her San Francisco office at (415) 393-0707, or find her e-mail address at links.sfgate.com/ZCEL.
-- Contact information for your House representative can be found at links.sfgate.com/ZCEJ.
E-mail Sabin Russell at firstname.lastname@example.org.