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Wednesday 20 June 2018

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FEATURE: ANTIBIOTIC RESISTANCE - Antisocial behaviour

Written by Trevor Morton
June 2016

Alarm bells are at last ringing to the potential consequences of unchecked evolution of the bacteria and viruses we now call superbugs since the UK’s Chief Medical Officer made the clarion call that brought antibiotic resistance to the fore. Trevor Morton writes

On February 12th 1941, a minor injury while pruning roses resulted in a 43-year old policeman from Oxford becoming one of the first human ‘guinea-pig’ trials for antibiotics. Facing imminent death from an abscess caused by a scratch to the face from the rose bush, Constable Albert Alexander was administered an early formulation of penicillin. Within 24 hours he was in remission. The recovery, nothing short of miraculous at the time, marked a watershed in mankind’s battle to control the countless bacterial infections that can and do kill by the thousands. Despite his remission, the limited supply of penicillin, first isolated by Alexander Fleming thirteen years earlier, proved insufficient. The event was a defining moment that heralded the coming of a golden age of antibiotics based on the work of Fleming and others at Oxford University. But with Britain consumed at the time by the events of World War Two, research quickly moved to the US. There, advances in its efficacy coupled and the introduction of mass production facilities soon unleashed a bountiful supply of the wonder-drug by firms that would go on to become global pharmaceutical brands to today. Supplies soon reached the battlefields of Europe in time to save countless lives of injured soldiers who, like Albert Alexander, were exposed to potentially fatal pathogens.

Such was the unprecedented success of antibiotics that by the late 1960s, the US Surgeon General is reputed to have said it was time to “close the book on infectious diseases, and declare the war against pestilence won”. But, in the seventy or so years since near miracle cure of Albert Alexander, the words of the US Surgeon General have turned out be apocryphal.

The natural process of evolution has enabled bacteria not only to develop immunity but also fend off antibacterial agents by plundering the genetic make-up of otherwise benign micro-organisms. As if to look a gift horse in the mouth, mankind has – and continues to exacerbate the demise of the twenty-two existing classes of man-made antibiotics. Excessive consumption in humans coupled with rampant abuse by agriculture is leading to the demise of available antibiotics that are the backbone of modern medicine. According to Professor Colin Garner, chief executive at Antibiotic Research UK, “Alarm bells are at last ringing to the potentially apocalyptic consequences AMR (antimicrobial resistant) organisms we now class as Superbugs. Such is their virility, the discovery of new strains of antibiotic resistant (ABR) bacteria has become routine.”

The March 2014 outbreak of Ebola, a viral epidemic which resulted in 15,000 confirmed infections and 11,000 deaths across three countries, became a catalyst for the launch of the Global Health Security Agenda (GHSA) initiative. In his September 2015 message from the White House, Obama highlighted the mobility and with it, increased risk of transmission from epidemics in a connected world.

The increasing rate of AMR (antimicrobial resistance) should come as no surprise. Bacteria, thought to have existed for some three billion years, constitute a greater part of the biomass of planet Earth than all animal and plant life forms. They evolve at a pace that outstrips nearly all other life forms with generation times of twenty minutes for E.coli, and thirty for the equally pernicious Staphylococcus aureus (MRSA). Medical research into the rise into the immunity of bacteria has confirmed their ability to mutate and evolve from generation to generation in a manner more akin to science fiction. Conceding to their complexity and voracity, among the first steps to cope with resistance of bacteria was appeasement. This started with passive campaigns aimed at reducing the volley of antibiotics through public awareness. Many doubt their effectiveness – including the very GPs who prescribe antibiotics every day. Frequently harassed by patients who see them as a panacea and an automatic entitlement, their overuse has been confirmed as driver of antimicrobial resistance that results in the risk of severe infections, extended hospital stays and increased mortality. Further contributions to the growing gene pool of antibiotic resistance bacteria include failing to complete a course, sharing tablets, or worse still, taking tablets intermittently. Look to the developing world where unregulated pharmaceutical markets are the norm. Here, antibiotics of all types are sold over the counter, often without either a GP prescription or qualified pharmacist’s advice. The practice of selling of pills individually in poorer countries further exacerbates antibiotic resistance in populations already at high risk.

As far back 2001, research bodies such as the Department of Infectious Diseases’, UCLA, were predicting ‘an epidemic of antibiotic-resistant infections’. Despite intensive lobbying, and the work of an Interagency Task Force on Antimicrobial Resistance, the US Congress of 2006 chose to shelve planned legislation. Some ten years on, MRSA, an AMR-bacteria, kills more Americans that emphysema, HIV/AIDS, Parkinson’s and homicide combined. In the EU, multi-drug resistant bacteria accounted for 400,000 infections, 25,000 deaths, and healthcare and productivity losses of €1.5 million in 2009. As the reality of antibiotic resistance bites, there is recognition that action based on a multi-faceted approach that goes far beyond that of simply reducing consumption and misuse.

While humans are one part of the maelstrom; antimicrobial use in farming accounts for a greater proportion of total antibiotics than those used in human medicine. Whilst an EU-wide ban on the use of antibiotics as growth promoters has been in force since January 2006, banning them as feed additives to fatten up livestock, there is concern that elsewhere in the world, their use continues with the risk of passing antibiotic resistance across the food chain to humans.

It was not until early 2013 that the UK’s Chief Medical Officer, Professor Dame Sally Davies, made the clarion call that brought AMR to fore as a global threat it is. Ahead of the G8 Summit in County Fermanagh, Northern Ireland, Dame Sally described antibiotic resistance as a “ticking time bomb” with a stark warning that “routine operations could become deadly in just 20 years if we lose the ability to fight infection”. Her positioning antibiotic resistance as the risk to the nation on a par with terrorism resonated far and wide. Within 14 months, the then Prime Minister David Cameron led a call for global action to tackle the growing threat of antimicrobial resistance by commissioning an independent review. Internationally renowned economist Jim O’Neill was appointed to chair the review with Wellcome Trust co-funding and hosting, its goal to explore the economic issues surrounding antimicrobial resistance.

In his May 2016 report, ‘Tackling Drug-Resistance Infections Globally’, O’Neill’s opening gambit left no room for doubt. Aided by two leading consultancies to undertake detailed analyses, his conclusion was that the current 700,000 deaths per annum from AMR would, by 2050 reach a disturbing 10 million, far outpacing cancer, “if we do not slow down the rise of drug resistance now.”

In addition to the tragedy of the human from AMR, O’Neill estimated the cost in terms of lost production between now and 2050 at US$100 trillion “if we do not take action now”. Among other recommendations in the report was the need for a massive global public awareness campaign, improved hygiene and reductions in the spread of infection, global surveillance of drug resistance and antimicrobial consumption by humans and animals, all of which to be effective require international governmental cooperation.

Whilst 2050 may a human generation away, the timing of O’Neill’s recommendation could not be more as acute. Reports of antibiotic resistance cases in the UK are on the increase in line with international travel.

Four weeks after its publication, news broke of a 49 year-old woman from Pennsylvania with a urinary-tract infection. It became significant after its failure to respond to the antibiotics routinely used to treat what is a common condition. When colistin, an antibiotic of last resort also failed, a tangible shockwave followed. “It basically shows us that the end of the road isn’t very far away for antibiotics, that we may be in a situation where we have patients in our intensive care for which we do not have antibiotics.” Colistin resistance in China was reported in the February edition of The Lancet.

O’Neill’s final recommendation concludes that no one country or region, can alone tackle AMR. This has potential ramifications for the pharmaceutical sector where the development of new antibiotics has “put on the back burner” as firms pursue new treatments such as diabetes, rheumatism that come with lower risk, and significantly higher returns over the long term. “Global action is essential to make progress over the long term. It calls on the G20 and UN to now focus the supply and demand for antimicrobials and to spark a step change in the fight against AMR.”

Such is the hiatus in R&D, without the collaborative approach of leading academics, clinicians and pharmaceutical industry scientists, such as that espoused by Antibiotic Research UK, modern medicine as we know it may cease. Deaths from Sepsis, a blood infection currently standing at 44,000 per year, would skyrocket with the onset of untreatable, antibiotic resistant infections. Routine surgery will no longer be routine but a high-risk intervention. There are lights on the horizon in the form of new compounds such as Teixobactin or AR-12 as well new technologies such as the ‘iChip, a device able to capture the environmental organisms that produce antimicrobial compounds. The timing of the arrival of a new class of antibiotics will determine the risk of a return to the implications and risk pre-Penicillin world.



This article was published in the July 2016 issue of CIR Magazine.

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