Colistin Resistance Gene 'Pervasive' in China

Norra MacReady

February 09, 2017

Amid growing concerns about the global emergence of extensively drug-resistant "superbugs," two new studies provide a snapshot of the prevalence and risk factors for colistin-resistant Enterobacteriaceae among hospital patients in China.

The gene that confers colistin resistance is called mcr-1. It is considered particularly worrisome because it is located on a plasmid, rather than a chromosome, and thus can be readily transferred to other bacteria. Should mcr-1 be transferred to organisms that are already resistant to carbapenem, it would "seriously compromise treatment options not only in China but also globally," write Yang Wang, PhD, from the Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, and colleagues in one of two studies published online January 27 in the Lancet Infectious Diseases.

The researchers in both studies found that isolates with mcr-1 were pervasive and widespread, but were found only in a small proportion of patients. Significant risk factors for its dissemination were identified, including male sex, prior use of antibiotics, immunosuppression, and residing near a farm.

Many of the isolates also proved resistant to other drugs as well as colistin, although there was little evidence of extensive carbapenem coresistance.

The findings come as China changes its use of colistin. Formerly, the drug was added only to animal feed and medications. However, as of 2017, colistin will be banned from animal products and used exclusively as an antibiotic of last resort for humans.

This switch adds to concerns about resistance, Dr Yang and colleagues write, because risk factors for mcr-1 dissemination in humans "are likely to be exacerbated when colistin is used clinically."

Controlling the spread of mcr-1 has long been a concern in China. As reported earlier by Medscape Medical News, the percentage of mcr-1-positive isolates of Escherichia coli from pork and chicken multiplied from about 5% in 2011 to approximately 25% in 2014. The same investigators isolated the gene from 16 (1%) of 1322 infected hospital patients in 2014. Bacteria with similar genes also had been reported in isolates from Malaysia, a development the researchers called "deeply concerning."

There is also evidence that the gene may have established a foothold in the United States, where at least two cases of patients with colistin-resistant infections have occurred.

Organisms positive for mcr-1 have also been found in Denmark, Germany, Vietnam, and Spain.

Studies Show Evidence of Widespread Dissemination

In the first study, Dr Yang and colleagues studied the clinical and epidemiological characteristics of mcr-1-positive E coli (MCRPEC) infection, as well as risk factors for infection and carriage, among patients in two tertiary care hospitals in Zhejiang and Guangdong, China.

Their study had three parts: a retrospective, cross-sectional assessment of MCRPE prevalence from isolates of Gram-negative bacteria collected from hospital patients between 2007 and 2015; a retrospective case-control study of risk factors and mortality associated with all of the mrc-1-positive E coli isolates compared with a random sample of E coli isolates without mrc-1, collected between 2012 and 2015; and a prospective case-control study of risk factors for carriage of MCRPE. This consisted of comparing rectal swabs taken from hospital inpatients admitted for more than 2 days with samples taken from healthy volunteers.

Overall, the researchers obtained 21,621 unique isolates from 18,698 patients and 2923 healthy volunteers, including 146 isolates positive for mcr-1.

Of those, five of which were resistant to carbapenem as well as colistin: two from Guangdong and three from Zhejiang. mrc-1 positivity also was found in 13 isolates of Klebsiella pneumoniae, and 1 isolate each of Enterobacter cloacae and Enterobacter aerogenes.

In the cross-sectional analysis, the 76 MCRPEC isolates were significantly more resistant to several other drugs compared with isolates that were mcr-1 negative, including ciprofloxacin (P = .0005), cefotaxime (P = .0005), and cefepime (P = .001).

The finding of multiple-drug resistance in MCRPEC isolates suggests these organisms were able to recruit other resistance genes, "which could raise difficulties in the treatment of patients with clinical infection due to MCRPEC," the authors write.

In the second article, Jingjing Quan, MS, from the Department of Infectious Diseases at Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China, and colleagues conducted a multicenter, longitudinal study of the prevalence of mrc-1-positive E coli and K pneumoniae isolated from 2066 patients with bloodstream infections at 28 hospitals throughout China.

Of 1495 E coli isolates, 20 (1%) were positive for mrc-1. Only one of 571 K pneumoniae isolates (<1%) was positive for mrc-1. Most of these isolates were susceptible to one or more antibiotics tested, including amikacin (76% of isolates), piperacillin and tazobactam (95%), meropenem (95%), imipenem (95%), and tigecycline (100%). Susceptibility to cefepime, cefotaxime, and ciprofloxacin was seen in 14% of isolates for each drug.

All patients infected with mrc-1-positive organisms "had sufficient clinical responses to antimicrobial treatment and were cured and discharged within 30 days after the positive blood culture," the authors write. "Notably, no patients had a history of colistin use before specimen collection."

"Doomsday" Scenario Not Yet Common

Together, the two studies suggest 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," David L. Patterson, MD and David van Duin, MD, write in an accompanying comment.

However, Dr Patterson, from the Royal Brisbane and Women's Hospital Campus, Australia, and Dr van Duin, from the University of North Carolina, Chapel Hill, warn that the "more pertinent clinical questions in 2017 in China are what are the prevalence, risk factors, and effect on clinical outcome of carbapenem resistance in Gram-negative bacilli, especially causing infections with high risk of mortality such as bloodstream infection and pneumonia?"

Chinese authorities should establish tight restrictions upon the human and veterinary use of newer antibiotics that will inevitably come to market, they conclude. "Without such interventions, there will doubtless be more serious problems than mcr-1 in China in the future."

The study authors have disclosed no relevant financial relationships. Dr Paterson has received personal fees and grants from Merck and nonfinancial support from Allergen, Shionogi, and Achaogen. Dr van Duin has served on the advisory boards for Astellas, Achaogen, Allergan, Tetraphase, Shionogi, and Sanofi-Pasteur.

Lancet Infect Dis. Published online January 27, 2017. Wang abstract, Quan abstract, Comment extract

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