Already, over 70% of all hospital-acquired infections exhibit resistance to at least one commonly used drug, while the rise of multiresistant strains of many kinds of infectious diseases threatens to provoke what the World Health Organisation (WHO) has described as a “return to the pre-biotic age”.

Add to this the growing evolution of novel resistance mechanisms by a number of gram-negative pathogenic bacteria, and the prospect of antimicrobial resistance (AMR) is a chilling one.

A growing health threat

With two million hospital patients contracting bacterial infections every year in the US alone, it is often the developed world’s ‘super-bugs’ such as methicillin-resistant staphylococcus aureus (MRSA) and clostridium difficile,that dominate the headlines, but the health threat posed by AMR is universal, and growing. According to the recent WHO publication, Global Strategy for Containment of Antimicrobial Resistance 2010, each year sees around 440,000 new cases of multidrug resistant tuberculosis (MDR-TB), resulting in more than 150,000 deaths. The newer and yet more recalcitrant form of extensively drug resistant TB (XDR-TB) is shaping up to do worse, while the supposedly ‘conquered’ scourge of gonorrhoea is resurgent around the world, with strains now exhibiting resistance to even last-line oral cephalosporins.

AMR is also causing similar problems for attempts to control non-bacterial pathogens. Treating malaria, for instance, has been complicated by the now widespread incidence of resistance to the conventional chloroquine and sulfadoxine-pyrimethamine treatments throughout most of the countries where the disease is endemic. In addition, artemisinin-resistant forms of plasmodium falciparum – the causative parasite of the most serious form of the disease – are appearing in South-East Asia, which are having a significant effect on post-treatment clear-up rates. For HIV too, resistance is emerging as a serious concern in the wake of the rapid increase in the use of anti-retroviral drugs around the world over recent years.

Inevitably, the consequences of all this are most directly felt by the ill, their families and local communities, but the ripples spread much further, increasing the cost of health care, jeopardising the advances already made in disease control and potentially damaging economic activities. From America where an estimated 80,000 people a year suffer bloodstream infections just as a result of catheter use, to Africa – the world’s most TB prone continent – while the specifics may vary, AMR is clearly a growing problem for us all.

“AMR is also causing similar problems for attempts to control non-bacterial pathogens.”

Causes and drivers

A disparate collection of medical, social, demographic and global factors lie behind the burgeoning rise of resistance. At its purest, it is what consultant biochemist, Dr Clare Miles, describes as ‘a Darwinian thing’ – organisms responding to the selective pressure that a drug represents. Those that are resistant survive exposure to the antimicrobial agent, and gradually possession of the gene that conveys that resistance becomes established as the norm within the local population of that particular pathogen. However, as she points out, it is seldom quite that simple.

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“There’s a whole range of other things going on alongside this. Sometimes antimicrobials get prescribed when they’re not really necessary, and that increases the risk of developing resistance; sometimes patients don’t finish the course they’re prescribed because they feel better, or they want to save the drugs in case they get ill again, or sometimes to give – or even sell – to somebody else. In some parts of the world the quality of drugs isn’t quite what would it should be, or the stockpile is old, so again the pathogens are exposed to a weak dose, and that just helps weed out the non-resistant forms.”

Changing lifestyles have also contributed to AMR. The growing trend to urbanisation throughout the world’s developing nations, for instance, and the overcrowding and poor sanitation typically associated with it, makes an ideal breeding ground for disease while the explosion of global trade and travel facilitates its rapid spread. In 2008, for example, carbapenem-resistant specimens of klebsiella pneumoniae and escherichia coli were identified in a Swede who had fallen ill while visiting India. This was the first known instance of an entirely new drug resistance, subsequently named the New Delhi metallo-beta-lactamase (NDM-1) factor.

By 2010, the gene for this enzyme, which confers resistance to a wide range of beta-lactam antibiotics, had been reported in bacteria isolated from 77 patients in 13 countries and according to the European Centre for Disease Prevention and Control, its distribution continues to widen.

“There is little doubt that novel drugs must hold part of the answer.”

The use of antimicrobial agents in animal husbandry is another area that has been implicated in the ongoing rise of resistance, most recently in a paper published in January’s BioMed Central Microbiology journal, highlighting the risk of flies and cockroaches acting as vectors of transmission. It is a multifaceted challenge and combating it calls for an equally broad-based approach.

Mounting a response

While it is unlikely ever to be a return to the rapid rate of discovery of ever-new antimicrobial agents that characterised the antibiotic heyday decades between 1930 and 1970, there is little doubt that novel drugs must hold part of the answer.

Fortunately after a virtual 40-year standstill in development, the recent arrival of three new classes onto the clinical scene – cyclic lipopeptides, glycylcyclines and oxazolidinones – provides some renewed hope for the future on this score, but pharmaceutical innovation cannot be expected to solve the problem alone.

Advances in allied therapeutic technologies have a contribution to make, notably in the fields of medical coatings and nanotechnology, and the work is already underway. A €3m pan-European collaborative research programme is helping to fund pioneering work on antimicrobial polymers, the UCL Eastman Dental Institute have developed a novel, light-activated hard coating capable of destroying 99.9% of E coli, and Auburn University have produced a nano-composite material which prevents S aureus growth. Effective diagnostics also play a part in combating AMR. Without a swift and reliable diagnosis, healthcare workers may opt for a broad-acting medication to maximise the chance of successfully dealing with the pathogen, but this carries the risk of accelerating the emergence of resistant strains. Encouraging the development of rapid diagnostic tests that can be easily used in the field to identify a microbe and its antibiotic sensitivities could potentially prove one of the most successful strategies.

“Advances in allied therapeutic technologies have a contribution to make.”

Societal factors too, obviously need to be addressed and the WHO has picked combating AMR as the theme for this year’s World Health Day, making the point that achieving it calls for concerted action by all the key stakeholders, including policy-makers, practitioners, patients and the pharmaceutical industry. In the end, however, we may have to accept that some infections, particularly multiple-drug resistant ones, will always represent what Dr Miles calls a ‘biological arms-race which perhaps neither side – man, nor microbe – will ever definitively win’.

After the wonders antimicrobial drugs achieved against infectious diseases worldwide in the last century, that comes as a sobering thought.