China has banned colistin as an additive in animal feed but will soon begin allowing the so-called antibiotic of last resort to be used in a clinical setting for the first time, raising concerns among some researchers about the spread of colistin resistance.
In two studies published in The Lancet Infectious Diseases, researchers reported locating the plasmid-mediated colistin resistance gene mcr-1 in a variety of strains of bacteria in China and showed that it was more likely to be found in patients who had been on antibiotics before being hospitalized.
As mcr-1 emerged over the past 15 months as a “threatening development” to global health, China’s government moved to stop the use of colistin as a growth stimulator in agriculture. According to Timothy R. Walsh, DSc, professor in the department of medical microbiology and infectious disease at Cardiff University in Wales, the ban was put in writing on Nov. 1, 2016, but will not take effect until April 1 of this year — the same day China is expected to begin using colistin to treat patients for the first time.
Walsh was part of the research team that first documented mcr-1 during a routine antimicrobial resistance surveillance project in China. Despite concerns over the spread of mcr-1, he told Infectious Disease News that introducing colistin for clinical use in China is important because of the threat that multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of carbapenem-resistant Enterobacteriaceae (CRE) pose to hospitals there. He said such strains are already a “huge problem” in the environment and community.
In China, colistin will be used to treat infections caused by MDR gram-negative pathogens like CRE, an otherwise virtually untreatable infection that the CDC has called a “nightmare bacteria.”
“Colistin is one of the few drugs left,” Walsh told Infectious Disease News.
Emergence and spread
Walsh and colleagues first discovered mcr-1 in an Escherichia coli strain from a pig farm in China and later detected it in hospital patients. Their November 2015 report about the finding declared, “The emergence of mcr-1 heralds the breach of the last group of antibiotics.”
The gene was later found in three E. coli isolates from the 1980s, when China first started using colistin in food-producing animals. The researchers who made the discovery described it as “surprising” and said they did not observe mcr-1 again until it showed up sporadically in 2004 and 2006.
China has banned the use of colistin in animal feed but will soon begin allowing its use in a clinical setting, raising concerns about the spread of the colistin resistance gene mcr-1. The gene has been found in farm animals and humans, and may also be harbored in companion animals such as dogs, according to researchers.
Research has suggested that companion animals such as dogs and cats may harbor mcr-1, and that the gene can be transmitted between the animals and humans.
The gene had been found in food, food animals and humans, and was detected in a patient in the United States for the first time last year, although research shows it has been here since at least 2014. It has been found in a number of humans and farm animals in the U.S., including a patient in New Jersey whose E. coli infection was the first time resistance to both colistin and carbapenems was detected in the U.S.
According to Walsh and colleagues, infections that show resistance to both colistin and carbapenems “is of great concern, because the occurrence of the mcr-1 gene in CRE would seriously compromise treatment options not only in China but also globally.”
No ‘doomsday scenario’ yet
Walsh and colleagues studied bacteria carrying mcr-1 from two hospitals in Zhejiang and Guangdong, China. Among 17,498 isolates associated with infection, they detected mcr-1 in approximately 1.4% of E. coli isolates (76 of 5,332), 0.4% of Klebsiella pneumoniae isolates (13 of 3,480), 0.1% of Enterobacter cloacae isolates (1 of 890), and 0.6% of Enterobacter aerogenes isolates (1 of 162).
Walsh and colleagues studied the E. coli isolates carrying the mcr-1 gene and found that risk factors included being male and using antibiotics before hospitalization, particularly carbapenems and fluoroquinolones.
“The withdrawal of [colistin] from agricultural use, and its introduction in the clinic might reduce colistin resistance rates in the community, and increase resistance in hospitals where they may be harder to treat or spread more easily,” Walsh said in a news release. “Our study finds that there are significant risk factors for the spread of mcr-1 infections, beyond just rural living and diet. The spread of colistin resistant bacteria will likely worsen when the drug is introduced in humans.”
In the second study, Yunsong Yu, MD, professor at the Zhejiang University School of Medicine, and colleagues screened 2,066 clinical isolates of E. coli and K. pneumoniae from patients with bloodstream infections at 28 hospitals in China and detected mcr-1 in approximately 1.3% of the E. coli isolates (20 of 1495) and just 0.2% of the K. pneumoniae isolates (1 of 571).
"The most troubling problem for clinicians would be the transfer of colistin resistance to a bacterium which is already carbapenem resistant, making it multidrug resistant,” Yu said in the news release. “This does not appear to have happened to any great extent in clinical isolates, but the situation should be monitored carefully as the country prepares to introduce colistin for use in humans."
In a related editorial, David van Duin, MD, PhD, associate professor of medicine at the University of North Carolina, and David L. Paterson, PhD, professor in the center for clinical research at the University of Queensland in Australia, wrote that “at this stage we can conclude that the doomsday scenario of convergence of carbapenem resistance and colistin resistance (via mcr-1) has not yet occurred to any great extent in China.”
Van Duin and Paterson said there is a risk that low-cost generic copies of new antibiotics that are introduced for medical use in China will be used in agriculture.
“We must be vigilant to this possibility and urge Chinese authorities to proactively prohibit use of these crucial antibiotics outside of appropriate use in human beings,” they wrote. “Without such interventions, there will doubtless be more serious problems than mcr-1 in China in the near future.” – by Gerard Gallagher
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Disclosures: The researchers report no relevant financial disclosures. Paterson reports receiving personal fees and grants from Merck and non-financial support from Allergen, Shionogi, and Achaogen. Van Duin reports serving on advisory boards for Astellas, Achaogen, Allergan, Tetraphase, Shionogi, and Sanofi-Pasteur.