Just how hard is antimicrobial resistance?

Situation critical

This week, the World Health Organization released a revised list of antimicrobial resistance priorities [1]. Their list summarises the top threats to global health from microbes that are difficult or impossible to treat with antibiotics. At the very top is a small group of multidrug resistant bacteria with diminishing treatment options and no foreseeable replacements. This critical group contains carbapenem resistant enteric bacteria like Klebsiella, carbapenem resistant Acinetobacter baumannii and multiresistant Pseudomonas aeruginosa. The threat from these and other multidrug resistant bacteria is though to cause tens of thousands of deaths per year in Europe, a loss of global domestic product and already impacts on the health of millions of people around the world.

Bad language

This gloomy message doesn’t seem to be taken very seriously outside the UK where the general public voted AMR as a more serious threat than international terrorism. You could be forgiven for thinking that an abstract concept known by a technical acronym is a good way to bury an issue of general importance. There are additional problems with the language of AMR; the very idea is an abstract concept to all but the biomedical scientists who detect, measure and analyse resistance to antibiotics in medically significant bacteria. AMR is an acronym for a clumsy adjectival clause, applied to the microbes that in their turn cause disease. So the issue here is really about a growing collection of previously treatable diseases that are now difficult to treat. Clearly things are getting out of hand when doctors are running out of options. Another problem with the language of untreatable infection is that AMR is only the tip of an acronym iceberg [see acronym sampler below]. Thus we see CRE, ESBL, MRSA, MDRTB and VRE, to name but five. Once you enter into the seriously arcane realm of AMR research, you will encounter numbered variants such as CTX-M-15, which denote specific mechanisms of resistance.

HARD or HARM?

If we home in on what really matters to the patient and their physician, it is a combination of the damage done by highly antibiotic resistant microbes (HARM) whose unrestrained proliferation cause highly antibiotic resistant diseases (HARD) in some patients. The difference may seem subtle, but for those involved in diagnosis, treatment and infection control, it is the difference between a microbiologist’s and a physician’s perspective. Clinical microbiology has shaped its antimicrobial susceptibility test repertoire around a handful of notorious AMR mechanisms, while physicians are far more interested in what antibiotics they can use now. True, these are different sides of the AMR coin, and it can land either way when you toss it. But we have to give the patient with an infectious disease priority. Learn how to deal with HARD and we limit the potential for HARM.

Why is it so hard?

There are three broad categories of AMR; resistance to antibiotics that have never been effective against that particular microbial species (intrinsic), resistance gained by adding genes for new resistance mechanisms that aid survival in a hostile environment (acquired), and resistance that develops during prolonged antibiotic exposure that reverts when the antibiotics stop (adaptive) [2]. The headline grabbing forms of AMR are all acquired; the nasty surprised that render new antimicrobial drugs ineffective shortly after their introduction. But if you consider all forms of AMR as a general ability to resist the drugs we use to treat infectious diseases, they all work by hardening medically important bacteria to hold out in the face of overwhelming chemical odds. Acquired resistance is therefore akin to those bacteria putting on serious armour and bunkering down. Multidrug resistance, the escalating global health threat, can be considered as a series of alliances to share equipment, fortifications and manufacturing. This would be easier to cope with if multidrug resistant bacteria were innocuous environmental microbes that chose to retire from raids on human health. Sadly, there is growing evidence that the trade-off between AMR and virulence doesn’t always hold good for medically important microbes. In fact, the ability to cause disease can in some cases link to antibiotic resistance. Many of these bacteria have molecular pumps that clear out toxic substances that enter bacterial cells [3]. These efflux pumps are more than bilge pumps that keep a ship afloat. They add a wicked efficiency to specific AMR mechanisms that can’t always be predicted by standard lab tests. The more we make life difficult for microbes with antibiotics and other microbially hostile environments, the faster they learn by sharing the latest and greatest type of resistance. This puts us all between a rock and a HARD place, at increased risk of HARM.

Time for action

In a previous dispatch I wrote about the need for specific action [4]. Don’t just observe; reserve antibiotics for proven indications, preserve our dwindling stocks of effective therapies and conserve our remaining antimicrobial capability. The UN General Assembly debated the growing global threat from AMR and committed member states to a two-year action plan. These important steps have yet to filter down to effective actions at a doctor-patient level. The strategy needs to be converted into a coordinated series of tactics at an operational level [5]. Once again, we need to return to the O’Neill Report [6} for a check list of the key priorities and to the CDC for specific recommendations on countermeasures [7}

AMR acronym sampler

More on the topic

1. WHO list of antimicrobial resistance priorities

2. Fernandez L, Hancock REW. Adaptive and mutational resistance: role of porins and efflux pumps in drug resistance. Clinical Microbiology Reviews 2012; 661–681.

3. Amaral L, Martins A, Spengler G, Molnar J. Efflux pumps of Gram-negative bacteria: what they do, how they do it, with what and how to deal with them. Frontiers in Pharmacology 2014; 4: 168

4. AMR: tragedy or trivia? TJ Inglis, Medium.

5. Inglis TJ and Urosevic T. Towards a convergence of sepsis and antimicrobial countermeasures. Frontiers in Public Health, 2017.

6. The O’Neill Report on antimicrobial resistance, HM Government, UK.

7. AMR at the Centers for Disease Control