Antibiotic resistance – a clear and present danger

Widely recognised as one of the biggest threats to humankind, antimicrobial resistant infections presented further cause for concern recently. Antimicrobial resistant infections are infections that are no longer treatable with one or more drugs. Commonly thought of as ‘antibiotic resistance’, the problem is much broader and extends across all kinds of microbes such as bacteria, fungi, parasites and viruses (hence antimicrobial is a more suitable term). Recently, the journal, Lancet Infectious Diseases, published a paper that reported the emergence of a new kind of antimicrobial resistance mechanism to one of our last lines of defence against Gram-negative bacteria. Bacteria can be classified on the composition of their cell wall, either as Gram-positive or Gram-negative, following the work of a Danish physician Hans Christian Gram, who showed bacterial cells take up stains differently depending on the presence of a second membrane that helps protect their cell wall. It is the cell wall that has traditionally offered our best target for producing drugs to kill bacteria and is the target of some of our most important antimicrobial drugs such as penicillins, cephalosporins and carbapenems. By blocking the growth of the bacterial cell wall, we can stop the growth of the bacteria and so kill them.

In recent years, the media has largely focused on Gram-positive bacteria such as methicillin-resistance Staphylococcus aureus (MRSA) and Clostridium difficile (often referred to as Cdiff) as the major antimicrobial resistant infections threatening humans – the so-called superbugs. However, clinicians are increasingly worried about antimicrobial resistant Gram-negative bacteria such as Escherichia coli (E. coli) and Klebsiella pneumonia (K. pneumonia), where new drugs are difficult to develop because of the second membrane that protects the cell wall.

Due to this lack of new drugs for Gram-negative bacteria, when antimicrobial resistant infections arise clinicians have had to resort to old drugs such as Polymyxins, one of which, colistin, has been viewed as the last line of defence against drug resistant E. coli and K. pneumonia. One major positive from this is that as colistin is an old drug it is cheap. It is this low cost that has led us down a dangerous path, however, because meanwhile in China, India and in some EU countries, colistin has found application as a growth promoter in animal feed, enabling animals to put on muscle mass quicker and reduce veterinary bills in the competitive intensive farming industry.

Up until now, colistin resistance in bacteria infecting humans has arisen as mutations on the bacterial chromosome (small DNA changes that enable resistance to occur, but are restricted to that particular population of bacteria). The recent report in Lancet Infectious Diseases, however has shown that a new kind of colistin resistance has arisen and one that potentially is much more dangerous. This new colistin resistance, encoded by a gene called MCR-1, is found on a plasmid, which means it is mobile and can be passed between individual bacteria, even those from different species, making it much more dangerous to humans. This MCR-1 plasmid was first found in bacteria isolated from pigs, suggesting that the use of colistin in agriculture has resulted in the emergence of this kind of resistance. The discovery is the first transmissible colistin resistance mechanism, and is important as it has breached one of our last lines of defence against Gram-negative bacteria. The authors also stated that the MCR-1 plasmid is currently confined to China, but that it may only be a matter of time before bacteria carrying this plasmid are circulating in humans across the world.

However, nobody could have predicted that it would take less than a week for this MCR-1 resistance gene to be discovered in Europe; indeed, it was also shown that it’s been here for sometime already! It was identified through the interrogation of whole bacterial genome sequences for the presence of the MCR-1 gene that had been collected over the last few years in Denmark. This discovery emphasises the need for a concerted effort to fight antimicrobial resistance globally, through good drug stewardship (by clinicians, by patients and by pharmacists) and awareness of antimicrobial use, in addition to the urgent need to discover new antimicrobial drugs. More information on this can be found at British Society for Antimicrobial Chemotherapy, The Learned Society Partnership of Antimicrobial Resistance, Antibiotic action and on Twitter @theurgentneed.

Liu, Y. et al. (2015). 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. DOI: 10.1016/S1473-3099(15)00424-7