Antimicrobial resistance gene detected for first time in Brazil

Researchers detect mcr-1 in bacteria isolated from food animals and report the first case of human infection in Brazil by a colistin-resistant strain of E. coli also harboring the gene.

By Diego Freire  |  Agência FAPESP – Recently discovered in China and also found in Europe and Africa, as well as other Asian countries, the gene mcr-1, which causes resistance to a class of antibiotics used to treat infections by multidrug-resistant bacteria, has been detected for the first time in Brazil in strains of the bacterium Escherichia coli isolated from food-producing animals.

The researchers at the University of São Paulo’s Biomedical Science Institute (ICB-USP) who detected the gene also reported the first case of human infection in Brazil, in a tertiary care hospital in Natal, Rio Grande do Norte State, by a colistin-resistant strain of E. coli that also harbored the gene mcr-1. Colistin, also called polymyxin E, is one of the most potent antibiotics available and considered the drug of last resort for the treatment of infections caused by bacteria resistant to other drugs.

“This gene’s presence in Brazil could contribute to the appearance of totally antibiotic-resistant bacteria and the risk of a situation similar to the pre-antibiotic era, when people often died from commonplace ailments such as urinary tract infections or skin cuts,” said Nilton Lincopan, principal investigator for the FAPESP-funded research project.

The results were reported in the journals Eurosurveillance, published by the European Center for Disease Prevention & Control, and Antimicrobial Agents and Chemotherapy, published by the American Society for Microbiology.

Superbugs

Colistin was discovered in 1949 but fell out of favor in the 1970s owing to significant toxicity, although veterinary use was allowed. In the early twentieth century, however, with the appearance of bacteria that produce enzymes responsible for causing resistance to practically all beta-lactam antibiotics, such as penicillin, colistin was revived as a drug of last resort to treat severe multidrug-resistant Gram-negative bacterial infections, particularly when acquired by hospitalized patients.

According to Lincopan, for a long time, the international scientific community believed the development of bacterial resistance to colistin would be a difficult process. “But late last year, in an alarming paper in Lancet Infectious Diseases, Chinese researchers reported detection of a new gene, mcr-1, that confers resistance to polymyxin E and polymyxin B.”

Even more disconcerting, he added, was the discovery that mcr-1 is easily transferrable between species of bacteria via plasmids.

As extrachromosomal DNA fragments that can replicate independently, plasmids can be transferred between different bacterial species by conjugation, the direct transfer of genetic material between bacterial cells. DNA fragments transferred in this way recombine with genetic material in recipient cells, producing new genetic combinations that will be transmitted to daughter cells in the next cellular division.

Bacteria carrying mcr-1 have been found in both food-producing animals and human beings, raising suspicions that resistance to colistin may be conveyed via antibiotics in animal feed to humans who consume meat and dairy products, as well as to the environment.

Given the risk that many infections may become untreatable, a world alert was issued early this year by the Centers for Disease Control & Prevention (CDC), an agency of the US Department of Health & Human Services.

According to Lincopan, researchers in various countries have since published papers reporting the detection of mcr-1 in clinically important bacteria such as Salmonella spp. and Klebsiella pneumoniae, as well as E. coli.

“The most alarming thing about the gene is the ease with which it moves between species of bacteria. Moreover, some hospital bacteria have aligned this gene with others linked to antimicrobial drug resistance so that the recipient bacterium becomes resistant to practically all antibiotics,” Lincopan said. “Nothing can be done in many cases of severe infection by E. coli, for example.”

Epidemiological urgency

The main reason for mcr-1’s emergence and spread, according to Lincopan, is suspected to be excessive use of colistin by livestock breeders as a growth promoter. However, the gene has also been detected in samples taken from pets, food and aquatic environments, evidencing dissemination to different ecosystems.

“In Brazil, early this year, our research group detected mcr-1 for the first time in food animals in the Southeast – São Paulo State and Minas Gerais – and in the South – Paraná and Santa Catarina,” he said. “This should be deemed an urgent epidemiological threat. It also has serious implications for agribusiness, given Brazil’s importance as a major producer and exporter of animal products.”

Agricultural regulators should re-appraise the use of colistin and similar antibiotics, according to the researchers.

“The real impact of antimicrobial resistance in Brazil needs to be evaluated by the government and the scientific community,” said Miriam Fernandes, a PhD student at the University of São Paulo’s School of Pharmaceutical Sciences (FCF-USP) and first author of the published articles.

“In addition, priority must be given to education on the rational use of antibacterial drugs. In clinical terms, many studies and scientific conferences have warned that multidrug-resistant bacteria are becoming endemic in hospital settings, where they’re frequently associated with high rates of therapeutic failure and subsequent morbidity and mortality. These efforts could avoid an irreversible situation.”

For Lincopan, a global action plan is needed to address the risk of antibiotic collapse, including “rational use of antimicrobials in human and animal healthcare, stricter epidemiological surveillance, measures to foster research in the field, and education of human and veterinary health workers, farmers and the general public on the proper use of antibiotics. It’s also crucial to develop new compounds and diagnostic tools”.

The research findings are described in “First report of the globally disseminated IncX4 plasmid carrying the mcr-1 gene in a colistin-resistant Escherichia coli ST101 isolated from a human infection in Brazil”, available at aac.asm.org/content/early/2016/07/19/AAC.01325-16.abstract, and “Silent dissemination of colistin-resistant Escherichia coli in South America could contribute to the global spread of the mcr-1 gene”, available at eurosurveillance.org/ViewArticle.aspx?ArticleId=22458.