Doctors reconsider old antibiotics despite hazards
More than half a century ago, when antibiotics were transforming modern medicine, a now almost forgotten drug was hailed as something close to the miracle of miracles.
Doctors rushed to prescribe it for an array of medical problems — that is, until they discovered that the drug, chloramphenicol, sometimes had lethal side effects.
FOR THE RECORD:
Antibiotics: An article in Monday’s Section A about using old drugs to combat newly resistant strains of bacteria identified one such pathogen as acetinobacter. It is acinetobacter. —
Yet today, improbable as it may seem, an effort is underway to revive the use of chloramphenicol and other antibiotics that had largely been banished because of their potential danger.
How can this be?
Some scientists say the older antibiotics may be one way to fight sometimes deadly bacteria that have become resistant to modern drugs.
“People are going all the way back to the original antibiotics that were shelved because of toxicity. We are desperate,” said John S. Bradley, a pediatric infectious disease specialist at the UC San Diego School of Medicine.
The impulse to reexamine the older antibiotics is all the stronger because relatively few new antibiotics are in the development pipeline. And, because the old ones have not been heavily used in recent years, bacteria have not had much chance to develop resistance to them.
For example, one drug maker says in-house studies bolster evidence that chloramphenicol, a drug from the 1950s, is effective against methicillin-resistant Staphylococcus aureus, or MRSA, which killed an estimated 15,000 people in 2008.
Rifampin, a 1960s-era drug used to treat tuberculosis, is now sometimes employed in combination with other antibiotics to treat MRSA, Bradley said.
Colistin, a drug from the 1940s, is being used to treat resistant strains of acetinobacter and other pathogens collectively known as Gram-negative bacteria.
The challenge is figuring out ways to manage the possible side effects of the older medications and weigh the risks of administering them.
Philadelphia-based Lannett Co. says it will ask the Food and Drug Administration to approve chloramphenicol for use against MRSA.
“It works,” said Arthur Bedrosian, chief executive of Lannett. “We want to see if FDA will allow use of it as a drug of last resort.”
Chloramphenicol is still used overseas to treat meningitis and other ailments. It has been largely absent from the U.S. market for decades, although an injectable version of the drug is still available in this country, according to federal records.
The FDA declined to comment on Lannett’s plans to seek approval for a capsule version of chloramphenicol as a MRSA treatment.
But Dr. Edward Cox, head of the agency’s Office of Antimicrobial Products, said that “studying previously approved drugs for the treatment of patients with infections caused by resistant bacteria may provide useful data to assess their utility in treating these infections.”
When first introduced, chloramphenicol was a huge seller because, unlike other early antibiotics such as penicillin and streptomycin, it effectively attacked a range of pathogens and, in the early going at least, exhibited relatively few side effects.
But as it became more widely prescribed, doctors linked the drug to aplastic anemia, a potentially fatal illness in which the bone marrow produces insufficient quantities of new blood cells.
Estimates of the incidence of the illness range from 1 in 10,000 users of chloramphenicol to 1 in 80,000, according to Thomas Maeder, author of “Adverse Reactions,” a history of the drug’s development, marketing and eventual decline.
“That is not tremendously high, but that assumes you’re giving it to someone who needs it,” Maeder said.
In fact, Maeder said, chloramphenicol was overprescribed, given to patients who could have used an alternative because many physicians were smitten by the new drug’s powers.
Overuse continues to be a problem with antibiotics generally because of bacteria’s ability to mutate and develop resistance in response to continued exposure to a drug.
Bedrosian said he’d be willing to market chloramphenicol with a so-called black box warning about possible fatal side effects, a labeling drug makers normally resist strenuously.
“If you’re going to die anyway, you may as well try it,” Bedrosian said, referring to patients with severe MRSA infections. “This is a second or third line of defense if nothing else is working.”
In its mildest form, MRSA causes skin infections that sometimes clear up without drug treatment. Deadlier forms, typically acquired in hospitals, nursing homes or other healthcare facilities, can invade surgical sites or the bloodstream or cause pneumonia.
Some cases respond to treatment by antibiotics such as vancomycin or Zyvox, but others do not.
“If it’s for patients who either have failed or are intolerant of other courses of treatment, then [chloramphenicol] would be a reasonable option,” said Dr. Gary Noskin, an infectious-disease specialist and chief of staff at Northwestern Memorial Hospital in Chicago.
But Dr. Brad Spellberg, a member of the Infectious Diseases Society of America antimicrobial availability task force, said chloramphenicol is so dangerous and there are enough other options for treating MRSA that “it’s going to be a relatively rare case where I would be willing to use it.”
If the FDA approves the drug for use against MRSA, the agency also should require a risk management plan that would limit conditions under which it could be prescribed, Spellberg said.
Bedrosian, 64, an attorney by training and four-decade veteran of the generic drug industry, said he acquired the U.S. license for an oral formulation of chloramphenicol in the late 1980s.
Lannett has formulated chloramphenicol capsules with ingredients from a supplier in Spain, he said, and is testing them in preparation for an application to the FDA.
But chloramphenicol’s difficult history may complicate the process, Bedrosian acknowledged. “It’s a controversial issue,” he said. “We don’t know how FDA will look at it.”