Conor O’Donovan
Contributor
The retribution for our profligate use of antimicrobial drugs, warns Conor O’Donovan, could send us back in time. Raising awareness of this is not a scare tactic but a strategy to safeguard what we have, while governments must increase investment to discover new drugs.
Pathogens continue to mutate and overcome our most effective antimicrobial agents, and we are quickly running out of new drugs, as the impetus behind pharmaceutical research and development to find new ones lags far behind.
Cast your eye back to the days before antibiotics, and take a long, hard look. The average life expectancy was about 60 years. The most common causes of death in the developed world included major infectious diseases, such as tuberculosis, diphtheria, various types of pneumonia and enteritis. The risk of life-threatening infection made surgical treatments too dangerous to undertake. People generally lived short and sickly lives.
Among other developments, the discovery and mass availability of antimicrobial drugs (antibiotics, antifungals and others) have played a pivotal role in accelerating the vast improvements in human health over the past 80 years. The availability of safe and effective treatments for infectious disease has permitted great strides in virtually every field of medicine and has shaped modern society as we know it. Without effective antimicrobial drugs, many current sophisticated medical practices that we now take for granted, such as cancer chemotherapy, modern surgical treatment, and obstetric and perinatal care would have been impossible.
However, according to Dr Margaret Chan, the director general of the World Health Organisation (WHO), speaking in March 2012, these interventions could once again become “far more difficult or too dangerous to undertake … Things as common as strep throat or a child’s scratched knee could once again kill.” That is, if we do not prepare for what is arguably the most pressing healthcare challenge we face in present times: antimicrobial resistance (AMR).
“Those microbes which are not killed by the drugs live on within patients and spread their resistant traits to newly infected individuals, in a real-time example of natural selection in action.”
The root cause behind AMR is straightforward. By the natural process of random, uncontrolled mutation, microbes like bacteria and fungi that are exposed to antimicrobial drugs – as occurs during treatment of infections – pick up traits that confer resistance to the killing effect of these drugs, such as an altered drug target, a different metabolic pathway, a drug-metabolising enzyme or a drug-efflux pump. Those microbes which are not killed by the drugs live on within patients and spread their resistant traits to newly infected individuals, in a real-time example of natural selection in action.
A phenomenon shown to occur for many micro-organisms is conjugation, or horizontal transfer of resistance traits, where one mature bacterium transfers the gene(s) it uses to survive antibiotic treatment to another mature bacterium. This occurs separately to passing on its resistance trait to its progeny, which happens directly when the bacterium grows and divides.
Resistant organisms tend to collect in hospitals, because these are the places where the use of antimicrobial drugs is most concentrated, as are the most infectious and most vulnerable patients. After it is known that the microbe causing a patient’s infection is resistant to the front-line drug of choice, second- or third-line agents may be used instead. Pathogens may then gradually acquire resistance to multiple drugs, by both mutation and conjugation, until all the effective drugs essentially become useless. The pan-resistant microbes that result are the true “superbugs”, and pose the biggest threat to human health.
These are not merely scare tactics, but cold, sobering reality. We are familiar with the frequent headliners MRSA (meticillin-resistant Staphylococcus aureus) and VRE (vancomycin-resistant Enterococci), but less so with the more recently emerged VRSA (vancomycin-resistant S aureus) and the bacteria that produce ESBL (extended-spectrum beta-lactamase). CRE (carbapenem-resistant Enterococci) present one of our greatest forthcoming challenges. Furthermore, some current strains of Mycobacterium tuberculosis are resistant to multiple (MDR-TB) or virtually all known useful antibiotics (XDR-TB).
“Coupled with the increased clinical difficulty in treating resistant infections, the associated costs are also much greater. For example, the cost of treating one case of MDR-TB can be about 100 times the cost of treating a case that responds to standard drugs.”
Despite our best efforts at preventing the emergence of AMR here in Ireland, we are still not safe. According to the chair of clinical microbiology at Trinity, Professor Thomas Rogers: “With international travel being so easy, the possibility of importing resistant bugs from countries where antibiotics are not used prudently is ever present, as is the potential for new antibiotic resistance threats in Ireland.” The modern world is very much smaller than it used to be for the microbes that infect its human inhabitants.
Infections with resistant organisms are associated with increased morbidity (people are sicker), mortality (people are more likely to die) and cost. Reserve antibiotics are usually less effective than the front-line drugs, and more toxic; they may require prolonged duration or alternative methods of administration, and they may even require directly-observed therapy. Coupled with the increased clinical difficulty in treating resistant infections, the associated costs are also much greater. For example, the cost of treating one case of MDR-TB can be about 100 times the cost of treating a case that responds to standard drugs. The need for effective agents to treat these infections is huge.
Consider, on the other hand, the deterring factors towards the development of new antibiotics. It already costs hundreds of millions of euros to develop a new drug and to bring it to market; when this is a new, reserve antimicrobial agent, the use of the drug is going to be restricted to a very small, select group of gravely ill patients, namely those in whom many other antimicrobials have failed. The opportunities for pharmaceutical companies to recoup the huge costs of developing new antimicrobials are unimpressive.
Indeed, the number of new antibiotics in development has fallen considerably in recent decades. According to Rogers: “The locker is almost devoid of new antibiotics to fight the emerging infectious challenges. It has become too expensive for pharma to develop new agents alone, so government investment in drug discovery is urgently needed.”
However, there is still time and great potential to curtail the spread of AMR, and limit its further development. The WHO global strategy for containment of AMR, published over a decade ago, details the responsibilities that each player in healthcare must each keep: patients, prescribers, dispensers, hospitals, food-producers, national governments, drug and vaccine developers, pharmaceutical companies and international organisations. The continued fight by trained experts and researchers against AMR must be supported by wide public awareness and understanding of the challenges it poses.
“The number of new antibiotics in development has fallen considerably in recent decades. According to Rogers: ‘The locker is almost devoid of new antibiotics to fight the emerging infectious challenges. It has become too expensive for pharma to develop new agents alone, so government investment in drug discovery is urgently needed.’”
For years, with its clinical microbiologists at the forefront, Ireland has implemented anti-AMR policies in line with best international practice. We have, according to Rogers, “good systems for surveillance of antibiotic resistance, both nationally through www.hpsc.ie and at local hospital levels.” The priorities for now include, among others, the prudent use of currently available antimicrobials to preserve their effectiveness for as long as possible. This is a core principle in current education for medical students and practising clinicians. Another step in the right direction has been the employment of specialist antimicrobial pharmacists to work alongside clinicians, ensuring that antimicrobials are used in the most clinically- and cost-effective manner.
However, broader public education and awareness about AMR and an appreciation of the seriousness of this issue in political circles are required to secure the proper support and resources necessary to prevent further emergence of resistance, or a return to the time when we had no effective ways of treating infectious disease. For patients and the general public, it must be made clear when and why antibiotics are ineffective and when they must not be prescribed, such as for the common cold and the flu, both caused by viruses. A prescribed course of antibiotics should be completed as per the prescriber’s instructions. Without widespread commitment to fighting AMR, we may yet return to those dark days we lived before the golden scientific breakthrough of antibiotics.
European Antibiotic Awareness Day was held on 18th November 2012.
