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In the 75 years since their introduction, antibiotics have saved countless lives by killing bacteria that cause infections. But heavy use has enabled dangerous bacteria to evolve resistance to these drugs, shrinking medicine's arsenal of effective antimicrobial tools.
New research from Utah documents an alarming increase in the reliance on old-line heavy weaponry, "drugs of last resort" known as polymyxins, which can be almost as hard on human kidneys as they are on deadly microbes.
This proves that doctors are increasingly confronting infections that won't respond to less-toxic antibiotics, said Makoto Jones, an assistant professor of internal medicine at the University of Utah.
He led a team of U. epidemiologists who recently published an analysis of antibiotic prescribing data from Veterans Affairs medical centers between 2005 and 2010.
The findings illustrate what is shaping up to be a public-health crisis, according to Portland, Ore., physician David Gilbert, a past president of the Infectious Diseases Society of America.
"Drug-resistant organisms will spread across the country in ever increasing numbers, and we are not going to be bailed out by the pharmaceutical industry," said Gilbert, a physician at Providence Medical Center in Portland. "There is nothing in the pipeline. It takes up to 15 years to bring a new drug through the approval process."
Drugs that patients take only for short-term illnesses don't carry big financial rewards, so pharmaceutical companies have reduced their investment in infection-fighting agents. Only two new classes of antibiotics have appeared in the past 30 years, according to Sharon Ladin, director of the Pew Health Group's Antibiotics and Innovation Project, which funded the U. study.
Looming costs, risks • Ladin warned of a "post-antibiotic world" in recent congressional testimony supporting the Generating Antibiotics Incentives Now Act.
"In this world, bacterial infections are increasingly difficult and costly to treat, and common medical procedures are excessively risky," she said. "Children, seniors and military personnel are at disproportionate risk of infection compared to the general population, so they would be unduly harmed if we fail to develop new antibiotics."
Ladin cited a recent survey of 500 infectious disease specialists, which found serious concerns about drug-resistant infections. Sixty-three percent reported caring for a patient with an infection resistant to all available antibiotics; 56 percent felt the number of untreatable infections is increasing.
The U. study, published in May in PLoS ONE, the online journal of the Public Library of Science, highlights the consequences of that trend.
Polymyxins were first isolated in the 1950s from the microbe Bacillus polymyxa and have proved effective against so-called Gram-negative pathogens when given to patients intravenously.
Doctors stopped prescribing the drug by the 1960s when it became clear that it damaged kidney and neural tissue, according to Gilbert. But polymyxins have made a comeback as doctors reach farther back into the medicine chest for an effective drug.
The U. epidemiologist analyzed five years of prescription data involving 13.6 million patient days in 127 acute-care V.A. centers, focusing on polymyxin and a more recently developed drug called tigecycline. These patients had already experienced, on average, 12 days of antibiotic therapy before they got polymyxin.
While polymyxin use remained rare, less than one day of therapy per 1,000 patient days, it increased by 25 percent during the study period. Tigecycline use increased four-fold.
Just eight of the 127 V.A. centers, concentrated in the Northeast, accounted for three-fourths of the polymyxin use. A single hospital accounted for half. Jones suspects that finding reflects where the epidemic of drug-resistant infections began.
"The Intermountain West has been spared. It's not as bad as the coasts," he said.
The intractable infections these "last-resort" drugs target tend to arise in hospitals and long-term care facilities, which often harbor drug-resistant bugs.
"These aren't infections you pick up at a school," said Utah professor of pediatrics Andrew Pavia, who was not an author on the U. paper. "We know that people getting these infections have a good chance of not leaving the hospital alive."
The battle with bacteria • A 2006 study, however, suggests polymyxin-induced kidney damage may not be the problem it once was.
The drug's toxic side effects seem to be less severe than they were in the early years because health care providers administer lower doses and take other steps to lower the risk of unwanted side effects, according to research led by Matthew Falagas of Tufts University.
But these measures, such as regular monitoring of renal function, tax the health care system and reduce the drug's effectiveness, Pavia noted. And another insult to their health does not bode well for acute-care patients' outcomes.
"A little bit of kidney injury is better than dying from an untreated infection," said Pavia, an expert in infectious diseases. "But their systems are already failing and now you give them a drug that could compromise a vital organ."
While patients wait for new antibiotics, doctors need to use existing drugs in smarter ways that lessen microbes' ability to adapt to them and disrupt the spread of drug-resistant bugs, experts say.
"Bacteria have been in this game for millions of years. They came up with the mechanism to become resistant to antibiotics long before we started to use penicillin," Jones said.
This 1950s-era class of antibiotic fell from favor long ago because of its toxic effects on kidneys and nerves. New research from the University of Utah shows these drugs are making a comeback in the face of a rising tide of drug-resistant infections. Observers say the findings highlight the need to develop new antibiotics because existing ones are losing their effectiveness against many pathogens.