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The greatest medical battle of all?

According to the World Health Organisation (WHO), a post-antibiotic era, far from being an apocalyptic fantasy, is now becoming a very real possibility for the 21st Century.

Our antibiotics are becoming less effective, fewer and fewer new ones are being developed, and new multi-resistant bacteria are emerging in both human and veterinary medicine.

Last year, in its landmark report, Antimicrobial Resistance: Global Report on Surveillance, the WHO made it clear that resistance to common bacteria has reached alarming levels in many parts of the world and that in some settings, few, if any, of the available treatment options remain effective for common infections. The report stated that ‘superbugs’ that are resistant to last-line carbapenem antibiotics have been found in all regions of the world. It further states that MRSA alone kills approximately 19,000 people every year in the US — far more than HIV and AIDS — and a similar number in Europe.

Another important finding of the report is that surveillance of antibacterial resistance is neither co-ordinated nor harmonised and there are many gaps in information on bacteria of major importance to public health.

Indeed, so grave is the situation that the WHO’s Assistant Director-General for Health Security Dr Keiji Fukuda has stated that “without urgent, co-ordinated action, the world is heading towards a post-antibiotic era in which common infections and minor injuries, which have been treatable for decades, can once again kill”.

Hospital-acquired infections (HAIs), in particular MRSA and C.difficile, have long been recognised as a major healthcare problem in this country. Since 1999, Irish hospitals have been voluntarily contributing data on HAIs to the European Antimicrobial Resistance Surveillance Network.

So grave is the situation that the WHO’s Assistant DG for Health Security Dr Keiji Fukuda stated that ‘without urgent, co-ordinated action, the world is heading towards a post-antibiotic era’

The Health Protection Surveillance Centre has confirmed that between 2006 and 2014, the number of incidences of MRSA bloodstream infections reported in Ireland decreased from 592 to 218, a reduction of 63 per cent. Indeed, in 2014, MRSA was at its lowest reported level since surveillance began, though rates are still high compared to the UK and other southern European countries.

However, while MRSA and C.difficile have reduced in hospitals in many countries, there has been an alarming increase in other types of bacteria, including new strains of E coli and Klebsiella, points out a 2013 report by the UK Chief Medical Officer. These gram-negative bacteria are particularly dangerous for older and frailer patients and have high treatment resistance rates. In the UK, 5,000 people die as a result of gram-negative sepsis each year, according to the report.

Meanwhile, the number of prescriptions for antibiotics written in the UK between 2010 and 2013 rose by 6 per cent, according to a 2014 Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR) report. UK GPs are now 40 per cent more likely to prescribe antibiotics for coughs and colds than they were a decade ago, according to research from Public Health England and University College London, which was published last year.

The WHO’s Antimicrobial Resistance: Global Report on Surveillance highlights high levels of resistance to third-generation cephalosporins in K.pneumoniae throughout the European region. Staphylococcus aureus infections are also problematic, having been found in the report to be methicillin-resistant in as many as 60 per cent of cases in some settings. The continuing threat of MRSA, as well as growing resistance to carbapenem antibiotics — the last resort for the treatment of life-threatening infections caused by Klebsiella pneumonia — was also noted to be spreading “to all regions of the world”.

The cost of antimicrobial resistance

A report this year by the UK National Risk Register of Civil Emergencies, which provides guidance on potential threats such as terror, flu and natural disasters, fuels more widespread concern. It states that superbugs are responsible for the deaths of approximately 50,000 people a year in the US and Europe, and that should a widespread outbreak of infections complicated by antimicrobial resistance occur, minor surgery and routine operations could become high-risk procedures.

Each year in the US, at least two million people become infected with bacteria that are resistant to antibiotics and at least 23,000 people die as a direct result of these infections, according to the US Centres for Disease Control and Prevention (CDC). The economic cost of this tragic human statistic is $20 billion (€17.8 billion) for extra medical costs and $30 billion (€26.7 billion) in lost productivity annually.

Approximately 25,000 patients die each year in the EU from infection caused by multi-drug resistant bacteria, according to a report from the European Centre for Disease Prevention and Control and the European Medicines Agency (ECDC/EMEA).

Developments

Some of the developments highlighted in the report The bacterial Challenge — Time to React (2009) include the lack of new agents being developed for the treatment of multi-drug resistant gram-negative bacteria.

Also highlighted was that, at the time of the report, 15 systemically administered antibacterial agents with a new mechanism of action or directed against a new bacterial target were being developed, albeit for the most part for the treatment of bacteria for which other treatment options are available.

Part of the problem, according to the WHO, is that awareness of the impact of overusing and misusing antibiotics is high globally, but lower in countries where the drugs are less regulated and can be obtained over the counter without prescription.

The fact that over half of all medicines — including antibiotics — are prescribed, dispensed or sold inappropriately, while half of all patients fail to take medicines correctly, was noted in the 2012 WHO report The Pursuit of Responsible Use of Medicines.

Internationally, according to a 2014 Princeton University study, antibiotic use increased 36 per cent between 2000 and 2010. In India, specifically, the rise in that time period was 62 per cent.

The fact that MRSA is also now emerging in communities, as opposed to remaining a HAI, is confirmed by research carried out in the WHO’s South-East Asia region (home to one-quarter of the world’s population), where more than 25 per cent of Staphylococcus aureus infections are reported to be MRSA.

The WHO has confirmed that gonorrhoea is also hugely problematic, with treatment failure caused by resistance to last-resort antibiotics (third-generation cephalosporins) being reported in 10 countries last year. Gonorrhoea may soon become untreatable as no vaccines or new drugs are in development, the WHO says. There is also growing resistance in malaria, TB, and HIV.

According to its Antimicrobial Resistance: Global Report on Surveillance, failure of fluoroquinolones is also “very widespread” — more than 50 per cent in some countries. When they were introduced in the 1980s, the resistance rate was “virtually zero”.

The good news

For all the challenges posed by growing antimicrobial resistance and superbugs, there is hope in the form of scientific progress and ongoing research.

The discovery of teixobactin earlier this year is a landmark in the battle against infections caused by multi-drug resistant bacteria. The first truly ‘new’ class of antibiotic in 30 years that can kill these organisms, the properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.

Teixobactin has successfully treated many common bacterial infections such as TB and septicaemia in mice without resistance, and it is hoped it will eventually be successful in treating humans. While it is not effective against gram-negative bacteria, its method of discovery has the potential to be a huge advance, and could lead to more possible antibiotic candidates in the future.

The year 2014 also saw three ground-breaking advances in this field: A peptide that breaks up biofilms, which are responsible for two-thirds of human infections, was discovered by scientists at the University of British Columbia; oxadiazoles (antibiotics used to treat MRSA in mice) were discovered by University of Notre Dame chemists; and spectinamides (a new class of semisynthetic antituberculosis agents that overcome native drug efflux) were discovered by research scientists at St Jude Children’s Research Hospital in the US.

Meanwhile, faecal microbiota transplantation has been found to be successful in fighting C. Difficile infection in a study presented at the 2014 annual scientific meeting of the American College of Gastroenterology.

‘It is important to remember that no matter how successful drug development incentives are, there will never be enough new drugs. Bacteria will always find a way to become resistant’ — Dr Jean Patel, CDC  

On the natural remedy side, it was reported earlier this year that an unlikely concoction in the form of cow‘s bile, wine, garlic and onions has been found by Nottingham University researchers to be a 99 per cent effective treatment for MRSA-infected wounds on mice. The blend was initially used more than 1,000 years ago to treat eye infections.

Diagnostically, Duke University scientists made a further advance in the field when in 2013 they developed a rapid diagnostic test to differentiate viral from bacterial infections.

In Ireland, research scientist Mr Martin Hayes and his team are testing bioactive compounds from Irish fungi at Limerick Institute of Technology, to determine antimicrobial resistance against Escherichia coli, Pseudomonas aeruginosa, Bacillus cereus, Staphylococcus epidermidis, Staphylococcus aureus and Candida albicans.

“It is believed that fungi may still harbour numerous unknown compounds to be explored, as it is estimated that only about 7-to-10 per cent have been studied to date,” says Mr Hayes.

At NUI Galway, research teams led by scientists Dr Cyril Carroll and Dr Maria Tuohy have been investigating the use of seaweed for its bioactive properties. “Results to date have identified novel extracts which retard the growth of clinically-relevant bacterial pathogens,” reports Dr Tuohy. “Some of the same extracts have been shown to promote the growth of naturally-occurring, beneficial, commensal bacteria,” adds Dr Carroll.

Both scientists agree that the results “are very promising” and the next step involves acquiring research funding to develop their findings for clinical, human food chain and animal production applications.

Addressing the question as to why so few of the larger pharmaceutical companies are researching new antibiotics, Prof Martin Cormican, Professor of Bacteriology at NUI Galway, says he is “not really convinced” that the offering of incentives to pharmaceutical companies to encourage them to research and develop new antibiotics will play a major part in solving the global problem of antibiotic resistance: “The problem is more fundamental, in that the nature of biology makes finding new antibiotics inherently difficult,” he says. “There was a limited number of really good targets for antibiotic action, most of which were found in the 1940s and 1950s, and many of which were wasted. The idea that there is a whole new batch of antibiotics waiting to be discovered is to me just another excuse for the utter failure at a national, European and global level to deal with this issue in a serious way.”

Prof Cormican is not optimistic about the likelihood of consensus being achieved internationally for what he describes as “purposeful action”.

“Achieving such consensus is difficult, given the competing perspectives of powerful stakeholders and conflicting perceived short-term and long-term objectives at an individual level,” he says.

Incentives

Many Governments believe, however, that incentives are key in tackling antimicrobial resistance. On remarking last year that no new classes of antibiotics had come on the market for 25 years, British Prime Minister David Cameron said: “There is a market failure; the pharmaceutical industry hasn’t been developing new classes of antibiotics, so we need to create incentives.”

The European Commission agrees. European Commissioner for Research, Science and Innovation Mr Carlos Moedas confirmed that growing resistance to antibiotics is one of the biggest challenges to public health today. “We need to bring new classes of antibiotics to market and we need to take preventative measures to stop antibiotics being over-prescribed and over-used,” Commissioner Moedas commented.

In February, the European Commission announced that a €1 million prize will be awarded to the person or team that develops a rapid test to tell whether a patient needs to be treated with antibiotics or not.

Meanwhile, in July 2014 the £10 million Longitude Prize for the creation of an inexpensive point-of-care test for bacterial infections was launched in the UK. The organisers noted that in the UK, over 50 million antibacterial items were dispensed in the community in 2013.

Two months later, a $20 million prize was promoted for a similar innovation in the US. Also in the US, a $1.2 billion plan to combat drug-resistant bacteria has been launched.

Speaking with WebMD in March of this year, US President Barack Obama confirmed that five-out-of-six Americans are prescribed antibiotics each year, with 262 million antibiotic prescriptions being written annually. Noting that drug-resistant infections are on the rise, with two million infections each year resulting in 23,000 deaths, he said: “Studies have consistently shown that a lot of America’s antibiotic use is unnecessary.”

Action plans

The five-year US National Action Plan for Combating Antibiotic-Resistant Bacteria was released in March of this year. Its goals include slowing the emergence of resistant bacteria and the spread of resistant infections and accelerating the rate of R&D for new antibiotics.

The US goal is to cut antibiotic use in hospitals by 20 per cent and in communities by 50 per cent by 2020, and to cut hospital infection rates from the most dangerous bacteria in half during that same period. To counter the built-in disincentives to antibiotic development, the US 2012 Generating Antibiotic Incentives Now (GAIN) Act was passed. This statute gives promising new antibiotics priority review and doubles their period of market exclusivity to 10 years.

In addition, in September 2014 the US FDA announced that it had approved three new antibiotics to treat MRSA infections. However, the Infectious Diseases Society of America has higher ambitions — in the form of 10 new antibiotics being developed by 2020. Initiatives designed to help this goal become a reality include the creation of an Antibacterial Drug Development Task Force in the US, the extension by five years of drug patent exclusivity clauses, the acceleration of the FDA approval process, and the introduction of mandatory trial guidance by the FDA.

Speaking with the Medical Independent (MI), Dr Jean Patel, acting Director of the CDC’s Office of Antimicrobial Resistance, says that antibiotic development is desperately needed for treating infections caused by the most resistant bacteria, such as carbapenem-resistant Enterobacteriaceae, Mycobacterium tuberculosis, and resistant Neisseria gonorrhoeae.

“To do this, we need robust and innovative research to identify new antibiotic candidates and novel therapeutic options like vaccines and more effective probiotics,” she says. “Bringing new drugs to market is long, expensive and risky. Encouraging companies to take on this venture will require multiple incentive options; no one incentive will fill the antibiotic pipeline.

“In the United States, there is an inter-agency working group analysing different options to identify the best approach. It is important to remember that no matter how successful drug development incentives are, there will never be enough new drugs. Bacteria will always find a way to become resistant. For this reason, we need to improve our ability to track resistant bacteria, prevent transmission, and implement stewardship programmes to ensure that all drugs — new and old — are used appropriately.”

The EU launched an Action Plan against Antimicrobial Resistance in 2011, and supported the initiative with investment of €650 million for the conservation and stewardship of existing antimicrobials and for the development of new drugs.

The need for more prudent prescribing practices on the part of GPs was advocated in February of this year by the UK’s National Institute for Health and Care Excellence (NICE), which called for a reduction in the number of antimicrobial prescriptions. A significant 40 per cent of all Europeans still wrongly believe that antibiotics work against colds and flus, according to the CDC.

Ireland

Ireland has a relatively high rate of antimicrobial resistance in human health compared to most European countries and antibiotics are used more frequently than the European average, the Department of Health acknowledges. “While there are now some new drugs in development, it is important to realise that new antibiotics alone cannot be the answer to antibiotic resistance,” a spokesperson for the Department told MI.

“We need to use the antibiotics we currently have and any new antibiotics that are developed, prudently. That is, we need to avoid unnecessary or excessive use in human and animal health settings. We also need to strengthen infection control precautions in human and animal settings, to minimise the transmission of resistant bacteria. To this end, the Department of Health and the Department of Agriculture, Food and Fisheries have established a joint working group on antimicrobial resistance to see how the human and animal health sectors can work together to tackle this problem,” the spokesperson added.

The Department and HSE, as well as numerous professional training bodies and organisations, have a number of specific initiatives in place to tackle antimicrobial resistance. For example, the National Clinical Programme on HAIs and Antimicrobial Resistance Prevention oversees implementation of a number of programmes across the health system. To date, the Programme has concentrated on three main areas, namely antimicrobial stewardship, hand hygiene and prevention of infections associated with medical devices such as intravascular lines and urinary catheters.

The National Clinical Advisory Group on HAIs and Antimicrobial Resistance (established under HSE and RCPI governance) is tasked with providing expert policy advice, while the National Clinical Effectiveness Committee (NCEC) published national guidelines for the prevention and control of MRSA in December 2013 and the NCEC C.difficile Guideline was published in June 2014. HIQA’s National Standards for the Prevention and Control of HAIs in healthcare settings were published and mandated in 2009 and a monitoring process against these is in place, with reports published on the HIQA website. This year, HIQA will begin to monitor antibiotic prescribing as part of its hospital hygiene inspection process.

Speaking at the launch of the 2014 annual antibiotic awareness campaign last November, Dr Robert Cunney, Clinical Lead of the RCPI/HSE National Clinical Programme for Healthcare-Associated Infection and Antimicrobial Resistance, said that ongoing, urgent action is needed to preserve antibiotics.

“In addition to informing the public about the risks to their own health, and the ongoing viability of antibiotics, if we continue to overuse and overprescribe them, the medical profession has a key role to play in ensuring all appropriate measures are followed to protect and preserve antibiotics, which are a precious resource. We must take all measures to ensure that safe and effective use becomes the norm,” he concluded.

The pharmaceutical challenges

Research published in December of last year by The Pew Charitable Trusts reported that an estimated 37 new antibiotics that have the potential to treat serious bacterial infections are in clinical development for the US market. However, the majority are being researched by small companies, half of which currently have no products on the market.

It is clear that the pharmaceutical industry faces difficulties in making new antibiotics to fight the spread of antimicrobial resistance.

What some of those issues are was described for MI by an AstraZeneca spokesperson as “significant generic competition, scientific difficulties surrounding antibacterial development, the acute nature of patient needs and the changing regulatory environment and restrictions on antibacterial use”.

Lack of data in relation to the usage of antibiotics in animals adds to the challenge of fighting antimicrobial resistant bacteria.

 

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