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Colistin: breaking the last line of antibiotic defense

Written by LVS on in the category Insights with the tags .


A first case of colistin resistance has been described in the US. This is troubling news, since colistin is used as a last-resort drug in combating infections with highly antibiotic-resistant bacteria. The intensive use of colistin in the pork industry, mainly in China, is suspected to have caused the development of this resistance. Now, the trait is spreading rapidly; does this herald the beginning of a post-antibiotics era?

Recently, a US woman’s urinary tract infection shook the scientific world. The E. coli strain causing the infection was found to be colistin-resistant.

Right now, you’re probably asking yourself two things: “coli-what now?” and “why is this important?” Let me clear this up for you. Colistin is a half-century-old antibiotic drug that never found mainstream success in the bacteria-killing business due to its relative patient-unfriendliness. In high doses, the drug causes damage to the kidneys and nerves, although extended low dose usage is generally well tolerated. Because of these properties, colistin is used as a last-resort drug for patients infected with highly antibiotic-resistant bacteria. Since colistin was rarely used in the past, no resistance to the drug had spread. That is, until now.

Which brings us to the question of why this newfound colistin resistance is important. Well, Thomas Frieden, director of the Center of Disease Control and Prevention (CDC), puts it like this:

It basically shows us that the end of the road isn’t very far away for antibiotics.
 

Wow. When top US public health officials dish out these kinds of words, you know they mean serious business. And, to be honest, we all knew this was coming. Antibiotic resistance has long been recognized as the most pressing problem in healthcare today. Now, even our last line of antibiotic treatments is starting to fail.

Livestock on drugs

Although this is the first case of colistin resistance in the US, the trait is not quite as new as some news items suggest. The first reports of resistance came from China, where colistin is used massively as an additive for pig feed. In November 2015, a colistin-resistant E. coli strain was found during a routine antibiotic resistance surveillance project. Even more worrisome was the fact that mcr-1, the gene that makes bacteria resistant to colistin, was located on a plasmid. These very mobile DNA elements can easily jump to other bacterial species, resulting in a rapid spread of resistance. Looking back at older samples, researchers found the mcr-1-containing plasmid in samples dating as far back as 2011, also in Europe. These facts warn us that colistin resistance has been developing silently over the past few years and is now going global fast.

The fact that colistin resistance was first observed in pigs is not trivial. The use of antibiotics in livestock is the bedrock of the global antibiotics resistance problem. Because certain antibiotics can increase an animal’s feed conversion into muscle, milk or other products, antibiotics are used in obscene amounts to boost output. A baffling 80 to 90% of all antibiotics sold in the US are used on food-producing animals. Think about that. Only a small fraction of antibiotic drugs are actually used for their expected purpose: curing infections. Regrettably, their widespread use on livestock is preventing them from doing just that.

Back to the dark ages of infectious disease treatment

Mcr-1 has now set foot in the US. Luckily, the identified strain was still susceptible to other antibiotics. The real danger is that colistin resistance can now spread to bacteria that are already resistant to many other antibiotics. Once one of these strains hits resistance bingo, no antibiotics will be left to treat the resultant superbug infections. In terms of healthcare, this would set us back to 1900 and before, when simple urinary tract infections or bouts of pneumonia could be fatal. Today, 700,000 people die annually from infections with antibiotic-resistant bacteria. By 2050, the global annual death toll is estimated to reach 10 million.

Not only would basic infections become deadly once again, but also other medical interventions would be jeopardized. Routine surgeries depend heavily on antibiotics to ensure safe procedures. Cancer patients undergoing chemotherapy have weakened immune systems and are particularly susceptible to infections; antibiotics are their much-needed protection.

So what about new antibiotics? Why not simply develop antibiotics to which bacteria aren’t resistant? While that might sound like a straightforward strategy, it would only be a temporary solution: We’re already pretty sure that we won’t win a molecular arms race against the bacteria, as they develop resistances a lot faster than we can develop new antibiotics. Furthermore, drug developers aren’t too keen on creating new antibiotics. The costs can mount to $1 billion for one new molecule. Traditionally, antibiotics are pretty cheap and only used for a short while, until the infection clears. This makes it challenging to get a sizable return on investment.

All in all, the future for traditional antibiotics is looking pretty bleak. The antibiotics crisis now calls for a drastically different approach to infection management, and some alternatives are starting to be revealed. The designer enzyme Artilysine® was developed at KU Leuven to combat superbugs. Also, bacteriophages, predatory bacteria and the gene-editing tool CRISPR-Cas9 are being reviewed for use as antimicrobials. But will these exotic alternatives be ready in time to prevent disaster?

References

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 16.2 (2016): 161-168.

McGann, Patrick, et al. "Escherichia coli Harboring mcr-1 and blaCTX-M on a Novel IncF Plasmid: First report of mcr-1 in the USA." Antimicrobial agents and chemotherapy (2016).


Global antibiotics ‘revolution’ needed, BBC news

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