By Shankar Vedantam

Fifteen months ago, spurred by fears that bioterrorists armed with lethal strains of bacteria could launch an attack on the United States and kill millions of people, the federal government took the unusual step of pressuring Bayer Corp. to rush a medicine called Cipro through the approval process for the treatment of anthrax.

The older antibiotics penicillin and doxycycline were known to be effective against the disease, but there were fears that Russian scientists had engineered a strain of anthrax resistant to those drugs. Due to the rarity of the disease, Cipro had never been tested against anthrax in people.

But based on its effectiveness against other bacteria and an animal study from 1993, regulators at the Food and Drug Administration designated Cipro the only medicine officially approved for inhalation anthrax.

What regulators could not have known then -- and what has come true in the last three weeks -- is that the bioterrorist scare would unfold so differently from the worst-case scenario they had envisioned. The attack involved a strain of anthrax that was not bioengineered to be impervious to the other drugs, which are safer and cheaper. And the number of people exposed and sickened was far fewer than planners had feared.

But when the public discovered that Cipro was the only approved medicine for inhalational anthrax, demand soared. Little attention was paid to the fact that the current strain of anthrax had not been bioengineered. And the 60-day course was accepted as proven even though no studies had demonstrated that was necessary for the kind of attack that actually occurred.

The disparity between the imagined attack and the real one underscores the difficulty of formulating public health measures against little-known bioweapons, and the very real danger that some cures can cause more harm than the bioweapons themselves. For while the anthrax attack that has unfolded over the last three weeks has so far been much milder than the worst-case scenario, the consequences of over-aggressive treatment may not be mild at all.

The full impact of large numbers of people being put on Cipro by doctors -- and even larger numbers taking the medicine on their own -- will not be known for weeks or months.

But already, patients with other illnesses who desperately need Cipro have been deprived of the medicine, and patients around the country taking the drug have begun reporting such side effects as dizziness, headaches, nausea and achy joints.

Concerns are mounting that overusing Cipro will spawn the growth of resistant microbes, rendering ineffective a drug considered to be a last resort when no other antibiotics work.

"We have never faced the mass use of an antibiotic for 60 days; there's no precedent for that in medicine," said William Hall, president of the American College of Physicians and the American Society of Internal Medicine.

"We are conducting the world's largest uncontrolled experiment, including all these people and TV personalities," said Stephen Porter, a Tennessee pharmacologist who runs Virtual Drug Development Inc., a company that is trying to make an alternative medicine to Cipro.

The studies that originally established the safety of Cipro involved regimens of seven to 10 days, according to Philip Hanna, an anthrax expert at the University of Michigan at Ann Arbor. "When you start giving it for two months, that's a whole level of usage that hasn't been proven to be safe," he said.

Leigh Thompson, a South Carolina physician, took Cipro for 21 days when he came down with an infection in Cambodia that he couldn't diagnose with certainty. He took 500-mg tablets, occasionally twice a day, for 21 days.

His Achilles tendon became painfully inflamed -- damage to weight-bearing joints and tendons is a known side effect of Cipro's class of drugs. In clinical trials, the medicine has caused young dogs to become lame.

"I personally wouldn't take it prophylactically unless I knew I had big-time exposure, not if I had walked through a building where someone saw a white powder," said Thompson. About putting people prophylactically on 500-mg tablets of Cipro, twice a day for 60 days, he said, "God, that would be insane."

The 60-day recommendation, which was made at the FDA meeting in July last year, was among the measures designed for a worst-case scenario, where public health officials feared they would confront the specter of tens of thousands of deaths.

Since no one had a good idea how long anthrax spores could incubate within the body before turning lethal -- the last known outbreak occurred in a remote part of Russia in 1979, where people continued to fall sick weeks after billions of anthrax spores leaked from a Soviet bioweapons facility -- regulators suggested the 60-day regimen.

"The question was, if you've inhaled spores, how long will it be before you can be safely off antibiotics?" asked Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research. "People could develop cases weeks away from their exposure. We felt it was important to put out a definite recommendation. . . . That's where the 60-day course came from. It was a conservative recommendation -- it was intended for the worst-case scenario."

People found to have inhaled a lethal amount of spores should be aggressively treated, said Woodcock: "The problem with the public is they think that if they were nearby, they were exposed."

This week, the agency formally approved the use of penicillin and doxycycline against inhalation anthrax.

Much of the worst-case scenario was laid out in a paper that was published in the Journal of the American Medical Association in 1999, authored by a working group of 21 leading government, military and university scientists.

The authors wrote that "between 130,000 and 3 million deaths would follow the aerosolized release of 100 kg of anthrax spores upwind of the Washington, D.C. area -- lethality matching or exceeding that of a hydrogen bomb."

The scientists recommended starting victims on Cipro because of the reports that Russian scientists had engineered a strain of the anthrax bacterium "to resist the tetracycline (doxycycline) and penicillin classes of antibiotics."

At least one scientist questioned the group's recommendation: In 1992, the man who had been the Soviet Union's top bioweapons scientist defected to the United States and brought with him news that the Russians had strains of anthrax resistant to penicillin, doxycycline -- and Cipro.

Even if U.S. doctors feared that America would be attacked by a virulent Russian strain, Cipro might not have worked any better than penicillin or doxycycline.

If proof was needed that making Cipro-resistant anthrax was possible, scientists said that last year an American lab developed such a strain to find a cure.

"It was considered a pretty big deal to develop antibiotic-resistant strains of anthrax," said Ken Alibek, a former Soviet bioweapons scientist who now runs Hadron Inc., an Alexandria company trying to find cures for anthrax. "We developed resistant strains to penicillin, streptomycin, doxycycline and ciprofloxacin [Cipro] by the late '80s or early '90s."

Washington Post November 3, 2001; Page A15