Although it came as no surprise to epidemiologists, the report of a Pennsylvania patient carrying a “superbug” strain of colistin-resistant Escherichia coli in her urine sent media outlets into a frenzy earlier this year. After the discovery, CDC director Thomas Frieden, MD, notably cautioned that it appears “the end of the road isn't very far away for antibiotics.”
In November 2015, the resistance gene, mcr-1, was first recognized in E. coli recovered from hospitalized patients and raw pork in China. Since then, the gene has appeared in animals and humans in 30 countries. Most recently, a patient in New York became the second in the U.S. to provide a positive E. coli isolate, according to a study published in July by Antimicrobial Agents and Chemotherapy.
In that study, as part of the worldwide SENTRY Antimicrobial Surveillance Program, researchers tested 390 colistin-resistant E. coli and Klebsiella pneumoniae isolates collected from hospitals in 2014 and 2015 and found that 19 (4.9%) carried mcr-1.
The isolates were implicated in urinary tract, bloodstream, skin, respiratory tract, and intra-abdominal infections, according to the study. Most were susceptible to cephalosporins, and all were susceptible to carbapenems, amikacin, tigecyline, ceftazidime-avibactam, and other antibiotics.
Still, there are 2 noteworthy reasons for the public health uproar, according to experts. First, the gene occurs on a plasmid, a mobile element that can easily and broadly spread, said Henry Chambers, MD, FACP, a professor of medicine at the University of California, San Francisco, and spokesman for the Infectious Diseases Society of America.
“The reason why that's kind of scary is that an organism can then donate [the gene] to other organisms,” he said. “So it doesn't spread just by transmitting it to its progeny, but in principle, it can spread it to other gram-negatives, as well.”
More obviously, the gene confers resistance to a drug of last resort. Although both U.S. patients were part of surveillance studies and did not need to receive colistin, the fear is that mcr-1 will wind up in an organism where colistin would be the only alternative, said Daniel Diekema, MD, FACP, director of the division of infectious diseases and clinical professor of infectious diseases and pathology at the University of Iowa Carver College of Medicine in Iowa City.
“The concern is that if it's widespread, as more resistance to traditional antibiotics increases, then it takes that last-resort antibiotic off the table,” he said.
The hospitalist's role
The CDC currently recommends that if hospitals perform susceptibility testing for colistin and find resistant bacteria, they should send the isolate to a lab that can test for the gene. “These tests are now being developed and published, so there may be wider screening sometime soon,” Dr. Diekema said. “But right now, it's unlikely that a hospitalist would have any idea whether their patient were harboring this particular resistance determinant.”
However, hospitalists can still do their part to stop the spread. “The best approach right now for hospitalists is the old message to practice good infection prevention, good hand hygiene, and good standard precautions, and then combining that with antimicrobial stewardship,” he said. Physicians could also make sure their laboratorian or infection prevention program coordinator is aware of the most up-to-date CDC guidance, Dr. Diekema said, since the hospital microbiology laboratory would conduct resistance testing if necessary.
Dr. Chambers highlighted the gross overuse of antibiotics in patients who don't have bacterial infections, and estimates show that 20% to 50% of all antibiotics prescribed in U.S. acute care hospitals are either unnecessary or inappropriate. “There is a whole lot of empirical antibiotic use...that is based on a presumption that antibiotics are harmless, more or less. They're not very toxic, so the threshold for starting treatment is quite low,” he said.
In addition, multidrug-resistant organisms tend to affect sicker patients who have received multiple antibiotics, Dr. Chambers noted. “The organism isn't any worse and often is not as bad as a full-blown pathogenic organism, but their impact is that they're harder to treat because you're not using the most potent antibiotics, as those might not work,” he said.
Colistin resistance is only the latest antimicrobial-resistance problem, so stewardship is crucial, Dr. Chambers said, noting that hospitalists are well positioned to reduce use of antibiotics. “If you reduce antibiotic exposure, there will be less resistance,” he said. “It's really that simple.”
In most cases, hospitalists should only use colistin after an infectious disease consultation, Dr. Diekema said. “It's unlikely, in my view, that folks would be using colistin without some specialist input, at least for treatment of multiple-drug-resistant bacterial infections,” he said.
Of interest, geography may play a role in antimicrobial resistance in the U.S. “There is a much greater problem in terms of prevalence with multiple-drug-resistant gram-negatives on the East Coast compared to the West Coast,” Dr. Chambers noted. For example, K. pneumoniae carbapenemase-producing bacteria and carbapenem-resistant Enterobacteriaceae (CRE), while also identified on the West Coast, are endemic in many Northeast hospitals, he reported.
“My suspicion is that this [new gene] reflects the general trend that resistance begets resistance because what happens is, when you get these more resistant organisms, doctors start using colistin, and then that creates a selective pressure for these resistant organisms to be selected out,” Dr. Chambers said.
What's being done?
The CDC has several strategies for increasing detection of antimicrobial resistance, said Jean Patel, PhD, deputy director of the Office of Antimicrobial Resistance. One of the newest investments is in the Antibiotic Resistance Lab Network, which will comprise 7 public health laboratories spread across the U.S. Set to launch this fall, these regional labs will have reference lab testing capabilities, will be able to confirm unusual resistance, and will be able to characterize those isolates, she said.
“Until now, most of that testing was done just by the CDC laboratory,” Dr. Patel said. “With funding the 7 laboratories, we'll be able to really increase the number of bacteria that can be tested and our ability to detect new resistance.” In addition to providing local data, the new labs will also allow isolates to be tested sooner. “The purpose of the testing is not just to collect numbers on the burden of antimicrobial resistance, but it's to detect new resistance that requires immediate prevention actions in a specific location,” she said.
The CDC is also making sure that all 50 states have antimicrobial testing capabilities, particularly for detecting CRE. “That's 1 of the urgent threats, and we're most worried about mcr-1 popping up in CRE because CRE infections are the ones where clinicians rely on colistin as a therapeutic agent,” Dr. Patel said. While testing CRE isolates, these nationwide labs will also be able to test for colistin susceptibility and send any resistant isolates to their regional lab, which could confirm the presence of mcr-1, she said.
The government is also working on the challenge of new antibiotic development. “Antibiotics, specifically, are not attractive to pharmaceutical companies because the more you use an antibiotic, the more likely it is that resistance will occur,” Dr. Patel said. “So a company will spend a lot of money developing an antibiotic only to have that antibiotic not be used very much.”
While the National Institutes of Health funds researchers developing new drug candidates, the Department of Health and Human Services' Biomedical Advanced Research and Development Authority (BARDA) initiative is funding new drug development, with a particular focus on developing new antibiotics for gram-negative infections, Dr. Patel said. “Those are the kind of infections where we would expect mcr-1 to cause more resistance and, therefore, have a need for more antibiotics,” she said.
The FDA has approved several new antibiotics in the past year or so, and others are in development. “But this is not a problem that can be solved by more drugs. How did we get in this mess in the first place? Drugs,” Dr. Chambers said. “Unless you do something to reduce the use of antibiotics overall, which is what stewardship is about, and use them appropriately for the right patient, then you can only go so far.”
Dr. Diekema added that the likelihood of finding more isolates containing mcr-1 is high. “The harder we look for this, the more likely we are to find it, and then the more use of colistin that occurs, that will also favor its spread,” he said. “The reason that it's so widespread already is likely because colistin is used so routinely in agriculture around the world.”
Although colistin is not routinely used in U.S. agriculture, antibiotic sales for food animal production in 2013 accounted for more than 70% of the country's total medically important antibiotic sales by volume, according to the FDA. “I think it should be banned,” Dr. Chambers said. “I'm not talking about antibiotic use to treat sick animals; I'm talking about using them broadly in a preventive fashion or to promote growth.” Dr. Diekema added that use of antibiotics outside the hospital, in farm animals and agriculture, is being reassessed. “Colistin and its relatives have been widely used in Asia and in Europe, so that favors the emergence and spread of a resistance element like this,” he said. “It's just long overdue to stop using these agents as either growth promoters or therapeutics.”