Studies show spread of MCR-1 gene in China

MCR-1 culture
MCR-1 culture

Culture of E coli with MCR-1 gene., Walter Reed Army Institute of Research

Two studies today in The Lancet Infectious Diseases indicate that a gene that can confer resistance to the last-resort antibiotic colistin has spread widely in clinical settings in China.

The gene, known as MCR-1, was first identified in China in November 2015 in Escherichia coli samples from pigs, pork products, and a handful of human cases. It has since been detected in more than 30 countries, including the United States. The emergence of the resistance gene was believed to be connected to widespread use of colistin in Chinese agriculture. China banned use of the drug in animal feed in 2016, based in part on the findings of that study.

Though there have been few cases so far of human infections involving the gene—which has mostly been found in animals—MCR-1 has become a significant public health concern because colistin is one of the few antibiotics left that can be used to treat multidrug-resistant infections. And because the gene is carried on mobile pieces of DNA called plasmids, it can be passed not only to different strains within a single family of bacteria—such as E coli—but also to different types of bacteria.

Among the most worrisome scenarios is the emergence of bacteria that harbors the MCR-1 gene along with other antibiotic-resistance genes. If the superbug carbapenem-resistant Enterobacteriaceae (CRE) were to acquire the gene, for example, it could present clinicians with infections that are nearly impossible to treat with current antibiotics.

Studies analyze thousands of isolates

In the first study, led by members of the team that initially identified the MCR-1 gene, investigators from the United Kingdom and China tested more than 21,000 Enterobacteriaceae isolates collected at two hospitals in China's Zhejiang and Guangdong provinces from 2007 to 2015.

Of the more than 17,000 isolates that were associated with infection, MCR-1 was detected in 76 of 5,332 E coli isolates (1.4%), 13 of 3,480 Klebsiella pneumoniae isolates (0.4%), 1 of 890 Enterobacter cloacae isolates (0.1%), and 1 of 162 Enterobacter aerogenes isolates (0.6%). The researchers noted an increase in the prevalence of MCR-1–positive E coli in both hospitals over the sampling period.

The team then did a retrospective case-control study to determine the risk factors for infection with MCR-1–positive E coli, comparing 76 MCR-1–positive E coli isolates with 508 MCR-1–negative isolates. Their findings indicated that colistin-resistant infections tended to occur more among men who were immunosuppressed and had used antibiotics, particularly carbapenems and fluoroquinolones, in the previous 3 months.

The researchers were also interested in risk factors for colonization with MCR-1–positive E coli. When they screened a mix of infected patients and healthy volunteers, they discovered that while antibiotic use was a major risk factor, living near a farm was not. This was something of a surprise, given that the initial MCR-1 study had linked the emergence of the gene to animal husbandry and use of colistin in livestock. This suggests, the authors note, that the gene could be spreading through environmental exposure.

In the second study, a team of Chinese scientists screened more than 2,000 E coli and K pneumoniae isolates collected from patients with bloodstream infections at 28 hospitals in China from 2013 through 2014. They detected MCR-1 in 20 of the 1,495 E coli isolates (1.3%), and only 1 of the 571 K pneumoniae isolates (0.2%).

The fact that both studies detected MCR-1 in several different pathogenic E coli strains, from hospitals in several provinces, is a sign that the gene has spread widely in community and healthcare settings throughout the country. One of the strains, ST131, "has long been recognized as the virulent global epidemic strain associated with human disease," the authors of the first study write. The strain, which has exhibited multidrug resistance, has become a major source of urinary tract infections throughout the world.

'Doomsday scenario' not yet seen

The good news from both studies was that the overall prevalence of colistin-resistant isolates from infections was low, and neither team found many instances in which MCR-1–positive bacteria was also carbapenem resistant. In the first study, only five MCR-1 positive E coli isolates were resistant to carbapenems, although resistance to other antibiotics was common.

The second study found only one isolate that was also carrying the NDM-5 enzyme, which enables bacteria to neutralize carbapenems and other beta-lactam antibiotics. In addition, the MCR-1–positive isolates were found to be susceptible to several other antibiotics. None of the patients with colistin-resistant bloodstream infections died.

"Therefore, 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," infectious disease experts David Paterson, MBBS, PhD, and David van Duin, MD, PhD, write in an accompanying commentary.

But what's concerning is that colistin will soon be introduced into clinical settings in China. And if the MCR-1 gene has been spreading in China because of selection pressure caused by the use of colistin in agriculture, it could potentially take off when hospitals start using the drug, especially if use of other antibiotics is a risk factor.

"The withdrawal of the drug 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," Timothy Walsh, DSc, lead author of the first study and a professor at Cardiff University in Wales, said in a journal press release. "The spread of colistin resistant bacteria will likely worsen when the drug is introduced in humans."

To date, MCR-1 has been detected in five human isolates in the United States. The US Centers for Disease Control and Prevention says it has increased surveillance for the gene in healthcare settings.

See also:

Jan 27 Lancet Infect Dis MCR-1 study #1

Jan 27 Lancet Infect Dis MCR-1 study #2

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