The threat of drug-resistant bacteria

antibiotic resistance1 superbug
Race against time

Anthony Harrington looks at the global threat posed by drug-resistant bacteria and asks whether the measures being implemented to alleviate challenges are sufficient

There is just about universal agreement among medical experts that the threat posed by drug-resistant bacteria – so-called ‘superbugs’ – is getting worse. The most frustrating thing about this problem, which has the potential to become catastrophic, is that the reasons it is intensifying are extremely well known, yet the problem is close to intractable.

Almost every paper and article surrounding the topic seems to end with a homily on the importance of hand-washing in a clinical setting. Of course, hand-washing and improving ward cleanliness in hospitals helps to combat the spread of bacteria from person to person. However, in the real world, where nursing staff have more duties than there are hours in the day to carry them out, slips are virtually inevitable.

This is true even when there are alcohol gels available on every ward. And when it comes to micro-organisms, the naked eye cannot discern when a particular surface has just been coated with toxic microbes by a careless hand. To be sure, there are now sprays that will stain bacteria and enable their presence to be seen, but these sprays are generally applied after the fact, and sometimes, quite a long time after the fact. In that timeframe, multiple hands could have touched that spot and gone on to touch patients. And even when nursing staff are extremely vigilant, hospital visitors, coming in droves each visiting hour to see their loved ones, are generally less aware about the spread of infection.

Impenetrable defences

Hospital acquired infections (HAI) – generally as a consequence of infection by one or another superbug – have become so common that there is now real cause for concern for anyone going into hospital for even minor surgery. This is not just a UK, US or a European problem. In a briefing note on HAI, the World Health Organization (WHO) comments: “Based on data from a number of countries, it can be estimated that each year hundreds of millions of patients around the world are affected by HAI.” (The WHO term is Healthcare-Associated-Infections, or HCAI). WHO goes on to point out that the burden of HCAI is seven-fold higher in low- and middle-income countries than in high-income ones.

The blatant overuse and over-free prescribing of antibiotics the world over, for both animal and human use, has brought us to this pass. Populations of bacteria have the ability, over time, to recognise antibiotic components to produce enzymes that can surround antibiotic molecules and eject them from the organism, leaving the bacteria free to thrive. How these enzymes are produced – how the ‘enzyme factories’ inside the bacterium work – is a focus for research, but much remains to be done.

Yet another defence some bacteria have is the ability to produce a myelin sheath that surrounds the colony once a sufficient population has formed. This protects the enclosed bacteria from both antibiotics and the body’s own immune cells. The medical profession and drug companies are still struggling to work out how to break through the defences that superbugs can throw up.

antibiotic resistance1 ecoli

Growing concerns

Professor Robin May, director of the Institute of Microbiology & Infection at the University of Birmingham, and professor of Infectious Diseases, points out that, on the positive side, research that is currently going forward on several fronts could result in a major breakthrough. “Very few of these studies have so far generated results that are ready to be used in medicine, but the signs are positive!” he stated. “The avenues being explored range from strategies to discover new antibiotics to novel approaches that aim to render current antibiotics more effective by, for example, blocking the so-called ‘efflux pumps’ which some bacteria use to get rid of antibiotics. Then there are completely different approaches, such as phage therapy which uses viruses that kill bacteria, or immunomodulation, which is all about stimulating the patient’s own immune system so that it can kill the infection.”

While he remains optimistic that the research currently going forward in multiple labs around the world will generate results, Professor May emphasises that the world is facing a serious problem. Overuse of antibiotics is endemic in many parts of the world. “Selected areas are making progress in terms of improved antibiotic stewardship, but this is a drop in the ocean relative to the global impact of widespread antibiotic use,” he said.

Professor May argues that the dangers presented by drug resistant bacteria are generating concern in at least three ways. First, the medical profession is already seeing individuals who are displaying ‘untreatable’ infections, which means that they are unresponsive to any antibiotics that doctors try on them. “Whilst the numbers displaying untreatable infections are still low, for the individuals concerned this is obviously a disastrous scenario,” he noted. The majority of these cases tend to involve patients with so-called ‘secondary’ infections following operations or who have underlying conditions such as cystic fibrosis.

Second, there is a serious concern that transmissible primary infections that are spread from person to person may gain antibiotic resistance. “This has already happened to some extent with TB, where multidrug resistant strains are spreading, but the prospect of widespread community acquired infections, such as streptococcal infections, for instance, becoming untreatable, is pretty apocalyptic,” Professor May explains.

Third, there is the awful possibility that antibiotic resistance will become so widespread that the use of antibiotics becomes pointless. Professor May points out that, at present, antibiotics are essential to the success of many surgical interventions. We could be looking at a near-term future in which many surgical procedures that are routine today, but essential to the patient’s survival or quality of life, will become impossible because the risk of infection would be too high for the procedure to be undertaken.

antibiotic resistance1

A holistic view

Professor Colin Garner, CEO of Antibiotic Research UK, points out that WHO recently took a long, hard look at R&D drug research related to drug-resistant bacteria. It produced a report on its findings, which concluded that there are insufficient drugs being developed to have a chance of making a significant difference to the downward spiral in the effectiveness of antibiotics. “Today, if you pick up an HAI, you have a reasonable chance of a good outcome. We still have quite a wide range of antibiotics that doctors can call on to treat most HAI instances. However, there is no doubt that the situation is getting worse,” he said.

One of the charity’s major concerns is its belief that the present situation could actually be much worse than reported figures suggest. “We think that there is widespread under-reporting of infections stemming from drug-resistant bacteria,” Professor Garner noted.

If a patient succumbs to a drug-resistant bacterial infection and dies of pneumonia or sepsis, the report on that death may well simply list it as a result of pneumonia or sepsis, and the role of drug-resistant bacteria in that instance will just not appear in the records. “It is estimated that about 10 per cent of the Earth’s population are walking around today with antibiotic resistant bacteria in their bodies. This doesn’t matter until they get ill or something affects their immune system. Then suddenly things can get bad very quickly and treatments can be hard to find,” said Professor Garner.

He believes what is needed is a holistic view of the problem, and this is something the charity is concerned to promote. “This needs tackling on several levels,” he notes. A general reduction in the use of antibiotics is needed. Using them only when absolutely necessary and using them properly, which means not abandoning a prescribed course, would drive down selective resistance. It is also necessary to look at repurposing or repositioning existing drugs to see if they can help break down a particular bacterial strain’s drug resistance.  “We also want to set up a one-stop-shop web site to provide the general public with detailed information about antibiotic resistance,” noted Professor Garner. “This would bring together all the links and leaflets that various laboratories and organisations are producing. That is part of our public education remit as a charity.”

The final piece of the jigsaw would be putting together a patient support network for those impacted by the consequences of drug resistant bacteria. “The main point for people to grasp is that bacteria have been on the planet for far longer than humans. They have fantastic survival mechanisms. We still do not understand the multiple resistant pathways that bacteria deploy,” warned Professor garner. “The danger is that so many of our major procedures, be it in cancer treatment, organ transplants or heart or bowel surgery, are absolutely dependent on antibiotics. They play a critical role even in childbirth, so to be without them would fundamentally degrade our medical capabilities.”

antibiotic resistance2

Prioritising R&D

On the positive side, for several years now there has been a firm, global realisation at government and national chief health officer level, that drug resistant bacteria represent a massive threat. The WHO’s global priority pathogens list (PPL), released earlier this year, was put together at the request of member states, specifically to help in prioritising R&D into new and more effective antibiotic treatments.

As the authors of the report note, the time has passed when such research could be left entirely to the market and to individual decisions by top pharmaceutical companies. Such decisions were always driven by a variety of factors, ranging from perceived unmet medical need, pressure from investors, market size, the potential of certain research lines to be rewarding and so on.

National PPLs, such as those drawn up by the US and Canada, tended to reflect the concerns of particular countries relative to the threats they saw themselves as facing. WHO’s list has the distinction of being global. It also used a very carefully thought through ranking system, with a number of checks and balances, to generate the list (see boxout).

The aim, as Professor Evelina Tacconelli, who chaired the group drawing up the report, notes, is to inform and shape policy initiatives, and to incentivise basic science and advanced R&D by encouraging public funding agencies and the private sector to channel antibiotic investment to where it is most needed.

Perhaps the only controversial thing about the WHO PPL is that it left off Mycobacteria, including mycobacterium tuberculosis, because the WHO decided that drug resistant TB was already sufficiently recognised globally as a threat. Malaria and HIV were also not included as they are caused by viruses, not bacteria.

Humankind’s war against lethal microbes continues. Although the issue of superbugs is universally recognised, the challenges they pose are numerous and intractable. So, who will emerge the victor is, at this point in time, anybody’s guess.

antibiotic resistance3