Doctors spurned colistin for decades because it damages kidneys. Now the drug is deemed “critically important” and in demand worldwide to thwart the most obstinate infections.
The 53-year-old medicine, also used as an additive in chicken feed, is back in favor as resistance to antibiotics escalates and doctors run out of weapons to fight conditions ranging from urinary tract infections to pneumonia.
“Drugs that we previously discarded because their toxicity was too high now don’t look so bad if the alternative is death,” said Lindsay Grayson, editor-in-chief of the sixth edition of the medical text Kucer’s The Use of Antibiotics.
The generation of antibiotics that led to colistin’s early demise is losing potency because of the global spread of multidrug-resistant bacteria, often called superbugs. A growing number of infections don’t respond to a class of last-resort medicines called carbapenems and the World Health Organization says there is a dearth of new treatments in development.
“If current trends continue unabated, the future is easy to predict,” Margaret Chan, the WHO’s director-general, told a meeting in Copenhagen in March. “This will be a post-antibiotic era. In terms of new replacement antibiotics, the pipeline is virtually dry.”
In the meantime, colistin is helping to fill the void for the small but growing minority of patients whose infections resist standard treatment. The drug will become one of the WHO’s critically important antimicrobials for the first time when the list is updated this year, said Peter Collignon, director of infectious diseases and microbiology at Canberra hospital in Australia and an adviser to the United Nations agency on antibiotic resistance.
The antibiotic, first sold in 1959, is so old there is a dearth of clinical data to help guide prescribing physicians. Roger Nation and Jian Li, professors of pharmacology at Melbourne’s Monash University, are working to change that and say colistin is safer than previously thought.
“We’re basically re-developing a 50-year-old antibiotic,” said Nation, who together with Li, has written or contributed to more than 60 papers on colistin and related medicines known as polymyxins. “We get a lot of e-mails and phone calls from physicians from around the world wanting advice on dosing their patients.”
There’s no data available on global sales of polymyxin drugs, which are mostly reserved for rare infections in people and sometimes used in livestock production in countries such as Brazil to fight infection and promote growth.
Cipla Ltd., the Mumbai drugmaker that’s become the world’s largest supplier of AIDS medicines, began selling colistin under the brand Xylistin in 2008, and sales doubled to 155 million rupees ($2.8 million) in the year ended March 31, according to data from the All India Organization of Chemists and Druggists.
Forest Laboratories Inc. of New York, Mumbai-based Glenmark Pharmaceuticals Ltd., Xellia Pharmaceuticals AS of Oslo and a Brazilian unit of Tokyo-based Meiji Holdings Co. also make and sell the medicine.
Most drugmakers abandoned antibiotic-discovery efforts during the past decade, swayed by more lucrative treatments for chronic conditions and tougher testing requirements, said Karen Bush, a microbiologist at Indiana University in Bloomington who led teams that developed five bacteria-fighting drugs beginning in the 1970s.
AstraZeneca Plc, based in London, has a compound in late-stage patient studies for complicated urinary tract and intra-abdominal infections, and Basilea Pharmaceutica AG of Basel, Switzerland has one in early-stage trials that may fight some bacteria that currently defeat antibiotics of last resort.
Flying Off Shelves
Bacteria evading penicillin-based carbapenems can lead to difficult-to-treat conditions like pneumonia and bloodstream infections, and have caused deadly outbreaks in dozens of countries. In India, a gene dubbed NDM-1 is behind the toughest germs, often leaving colistin injection vials as the only cure.
“It’s no surprise that they may be flying off the shelves in India because of their NDM multi-resistant” bacteria, said Grayson, director of infectious diseases and microbiology at Melbourne’s Austin Hospital.
Genes that confer resistance to carbapenem are carried on mobile loops of DNA that can infiltrate dozens of bacterial species, from intestine-dwelling E. coli, soil-borne Pseudomonas aeruginosa, to the microbial culprits of cholera and typhoid.
In the U.S., a pneumonia-causing variant of the bowel-dwelling microbe Klebsiella pneumoniae, dubbed KPC, has been reported in 37 states, and associated with mortality rates as high as 40 percent. The germ can be carried in people as part of their normal intestinal flora without causing disease, potentially spreading to others via unclean hands.
There is a “silent dissemination” of KPC, especially in residents of long-term care facilities, said Robert Bonomo, a professor of medicine and pharmacology at Case Western University in Cleveland. “As a result, there is a major increase in the use of colistin.”
Discovered in the 1940s, colistin fell out of favor with doctors after about 15 years of use amid concerns about kidney damage when alternatives became widely available.
Nation and Li of Monash University began studying colistin 13 years ago, when they noted increased interest in the injectable medicine as a treatment for infections in cystic fibrosis patients. Their research has helped characterize its action and formulate suggestions on dosage regimens.
Reversible deterioration in kidney function occurs in about 30 percent to 50 percent of patients taking the medication, Nation said, citing 2009 and 2011 studies from the U.S. and South Korea.
“There are some physicians who probably wouldn’t touch the polymyxins with a barge pole because they’re concerned about potential toxicity,” he said. “The important thing is that the kidney impairment is usually relatively mild and almost always reversible, and that colistin has the potential to cure an otherwise fatal infection.”
When carbapenems don’t work, doctors typically turn to a polymyxin such as colistin, or to Tygacil, a newer antibiotic made by New York-based Pfizer Inc. Tygacil, however, isn’t recommended for use in children or for fighting bloodstream infections, and carries an increased risk of death.
Colistin’s growing popularity has a downside: resistance is now emerging, spurred by increased use of the drug in humans as well as farm animals. Use of antibiotics in food animals spurs development of drug-resistant E. coli that can be transferred to people via contaminated food or water, according to Collignon.
“In a few years, bacteria will be resistant to colistin as well and that will be the worst,” said Abdul Ghafur, an infectious diseases doctor in the Chennai, south India’s biggest city. “Common infections could kill people, and we’ll have nothing to treat them with.”