Antibiotic Breach: The Fall of Another Powerful Antibiotic Drug

Experts have long cautioned against the “Antibiotic Apocalypse,” a world where drug-resistant bacteria are so prevalent that basic medical procedures are life-threatening, and a minor cut can kill. Agencies such as the World Health Organization (WHO) and the US Centers for Disease Control and Prevention (CDC) have repeatedly warned that, without intervention, this issue will result in a global health crisis. Antibiotic resistance is the development of drug resistance by bacteria and falls under the umbrella of antimicrobial resistance, which describes the resistance of all types of microbes. Antibiotic resistance is currently of greatest concern because antibiotics are frequently misused in both human and veterinary medicine. It is in the latter realm that researchers recently unveiled an alarming discovery. One study, published in The Lancet Infectious Diseases, describes the first known case of transmittable, plasmid-mediated bacterial resistance to any form of polymyxin, a class of antibiotics used as a last resort when others fail to be effective. Polymyxin’s two clinical forms, polymyxin B and polymyxin E (also known as colistin), have similar pharmacological effects.

Prior to this study, researchers had observed polymyxin resistance in bacteria only as a result of chromosomal mutations in core DNA. This chromosomally mediated resistance is not transmittable between two existing bacteria; rather, it is inherited from a “parent” bacterium when the resistant gene’s mutations are passed on through reproduction. However, this type of resistance is also “often unstable [and] imposes a fitness cost upon the bacterium,” and is therefore generally not sustainable in the long term. A more robust way to develop resistance is through plasmid-mediated mechanisms, in which bacteria incorporate small DNA molecules called plasmids into their cellular structure. Because bacteria can exchange plasmids directly without disrupting their own DNA, this type of resistance is not only transmittable but is also more efficient and resilient, making it much more dangerous to public health.

When the authors observed a sharp increase in E. coli resistance to colistin among livestock in China, they investigated the possibility of plasmid-mediated resistance. In particular, one strain of E. coli obtained from a pig farm in Shanghai was resistant to most classes of antibiotics. Researchers attempted to transfer the colistin-resistant plasmid to multiple strains of bacteria collected from hospital patients, slaughterhouse pigs, and retail meat samples in China. The successful transfer of the donor plasmid to these other bacteria would be the first evidence of plasmid-mediated, transmittable resistance to polymyxin. The authors identified and designated the colistin-resistant gene in the plasmid as mcr-1.

Results show high transfer rates of the plasmid from the original E. coli strain to multiple other recipient strains, leading to an eight to 16-fold increase of colistin required to inhibit visible bacterial growth. This means that colistin, an otherwise powerful antibiotic, becomes much less effective as the resistance spreads. These laboratory results were subsequently confirmed in rodent testing. The authors conclude that the mcr-1 gene increases colistin resistance to bacteria and can be spread through plasmid-mediated mechanisms.

An analysis of past E. coli samples taken from slaughterhouse pigs and retail meats in China reveals that the proportion of mcr-1-positive samples increased between 2011 and 2014. Additionally, the authors find that mcr-1-positive bacteria are currently present in human patients with infections, increasing the risk of resistance transmission to human pathogens. This is especially concerning because “with the advent of transmissible colistin resistance, progression…from extensive drug resistance to pan-drug resistance is inevitable and will ultimately become global.” The fear is that, without immediate action and intervention, the spread of colistin resistance will eventually confer resistance to bacteria against all antimicrobials, including “last resort” drugs like polymyxin.

This study highlights the urgent need to regulate antibiotic prescription and usage. China’s use of colistin in agriculture is one of the highest in the world and could have caused the acquisition of mcr-1 by E. coli. With continued agricultural overuse of colistin, mcr-1-positive bacteria will have a considerable survival advantage, leading to further spread of colistin resistance among livestock microbes, and inevitable transmission to human pathogens. The authors note that, by 2021, the global demand for colistin in agriculture will reach 16,500 tonnes, with an average annual growth rate of 4.75 percent.

To avoid a global health crisis, in which a proliferation of drug-resistant “superbugs” renders our arsenal of medications ever less effective, successful policies must minimize the use of antimicrobials in all affected sectors. The Food and Agriculture Organization of the United Nations (FAO) has issued a code of practice regarding antimicrobial resistance, and the WHO recently published its Global Action Plan on Antimicrobial Resistance. Both emphasize guidelines such as controlled antimicrobial distribution to humans and animals; continued surveillance and research; and increased awareness through training, communication, and education.

Policy guidelines from other prominent organizations include:

The White House’s National Action Plan for Combating Antibiotic-Resistant Bacteria (2015)

The USDA’s Antimicrobial Resistance Action Plan (2014)

The CDC’s A Public Health Action Plan to Combat Antimicrobial Resistance (2012)

 

Article Source: Liu, Yi-Yun, et al. “Emergence of Plasmid-Mediated Colistin Resistance Mechanism MCR-1 in Animals and Human Beings in China: A Microbiological and Molecular Biological Study,” The Lancet Infectious Diseases, 2015.

Featured Photo: cc/(CAHO – Council of Academic Hospitals of Ontario)