Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
What is antibiotic resistance and is it correct to describe it as a ‘looming global threat’?
Antibiotic resistance is a consequence of antibiotic use. Bacteria adapt to the threat of antibiotics using mechanisms to overcome the drug. These bacteria, which we call resistant bacteria, then survive. The more antibiotics we use, the more we generate resistant bacteria and therefore provide a definite advantage for these bacteria in overcoming antibiotics. The antibiotics become less effective the more we use them and eventually have no effect at all.
That's the evolutionary, sort of Darwinian perspective on antibiotic resistance – the view that this is a very natural process which occurs due to the adaptive capabilities of bacteria. Bacteria divide every 20 to 30 minutes and during this division mutations may arise, some of which generate resistant bacterial strains, providing a selective advantage in the presence of antibiotics.
The second aspect of antibiotic resistance is that the mutated, resistant genes sit inside the bacteria and these can spread. Some resistant strains are very good at spreading globally, with some leading to epidemics and pandemics. Therefore, the problems are antibiotic use, selection, and how we manage this spread.
Regarding the reference to a looming global threat – yes, antibiotic resistance is one of the greatest threats to healthcare worldwide because all health systems, even in the weakest countries, are building on effective antibiotics to treat patients with various different types of infections.
In modern medicine, procedures such as transplantation, catheter treatments and hip replacements all depend on antibiotic effectiveness. If we lose the effects of antibiotics, we will also lose some of these procedures as they would be associated with the risk of unacceptable consequences. In this sense, the threat of antibiotic resistance to global health really is underestimated.
Why has the use of antibiotics across medicine and agriculture seen vast increases in recent decades?
I think we are using antibiotics in different ways and much of the antibiotic use across the world is actually unnecessary.
There is a huge lack of knowledge about when antibiotics should be used. People believe they can have a quick “fix” when they have a cold, a cough or a simple infection such as an earache. People request antibiotics when it is simply unnecessary. Modern society is hectic and people have to be fit for work, which increases the demand for antibiotic prescription and in some countries people can simply buy them. People believe antibiotics can cure them, but using antibiotics in this way really is not doing any good, as overuse is one major driver of resistance.
In the animal sector, there is a drive to be competitive in mass production. Antibiotics are used heavily for prophylaxis to keep the animals healthy and infection free and also as growth promoters to make them grow more quickly. In a sense, they are used to cover up for improper or non-idyllic rearing systems.
The third factor may be heavy marketing. A lot of industries sell these drugs and there are strong financial incentives for prescribers and pharmacists in many countries. The system needs to be changed completely and the business and financial models altered, because otherwise this will not be sustainable. We cannot allow these precious drugs to continue being misused or overused the way they have been before.
The causes of antibiotic resistance have been described as complex. Please could you explain what is currently known about the causes?
The causes are not that complex and can be divided into three components. The first is the overuse and misuse of antibiotics. The second is the spread of resistant bacteria due to crowding, improper hygiene, and improper infection control in hospitals and poor sanitation. Finally, the third problem is almost a complete standstill in the research and development of novel antibiotics.
Aside from those three main areas, a fourth problem posed is the lack of rapid diagnostic testing. Sometimes, a prescriber is blinded somewhat by the difficulty in differentiating between an infection caused by a virus and a bacterial infection. When a mother presents her child with a fever, for example, it can be difficult to decide whether an antibiotic is needed or not, especially in poor countries where the healthcare systems are weak.
What is really needed to preserve antibiotic use and reduce misuse is a quick diagnostic test that can accurately differentiate a bacterial infection from a viral one and, ideally, indicate the correct antibiotic for treating the infection. This is another area of research that has been poorly promoted.
The issue of actually solving these problems is rather complex as, unlike a health problem such as tobacco use, which is clearly a dangerous threat to health and something people know they should stop, we actually need antibiotics to treat severe infections. On the one hand, we need them in order to treat infections and save lives but, at the same time, we don't want them to be misused.
Also, in terms of implementing policies, there is no one agency or ministry that is responsible and there needs to be a coordinated approach. The use of antibiotics needs to be tracked, resistance needs to be surveyed, the behaviour of bacteria needs to be observed and knowledge of the current issue of resistance needs to be promoted in society and in hospitals.
In addition, antibiotic use needs to be regulated, diagnostic tools need to be developed, infection control needs to be implemented and new drugs need to be researched and developed. There are many components that need to work in a coordinated way and this is not easy – it is not what governments are best at, but we need to get there.
Why is there a lack of adequate regulatory controls, treatment guidelines and patient awareness with regards to antibiotic resistance?
I think this is a very good question because if we can come up with the answer there could be improvements. I think one answer is that the problem here is not the disease itself but rather the issue of undermining the effects of important drugs that cure the disease. If we undermine the effect of antibiotics by allowing resistance to develop, we prevent their curative effects.
The world has not been able to visualize this as a real consequence. Yet, if you consider who is being affected, we are talking about children in Africa with blood infections, about mothers that have died during childbirth because they have become infected and people with urinary tract infections for which they have no treatment, for example. This health burden is not visualized, nor is the economic burden on society and healthcare.
Another answer is that people are in a state of denial in as much as they believe new antibiotics will always be available. Until now, we have always been provided with new antibiotics by pharmaceutical companies when the current ones have stopped working, at least in high income countries which can afford new drugs and provide new treatment options. Now, this is not happening. Research has stalled and there has been a decrease in the development of new drugs.
Also, the awareness and understanding about antibiotics among the general population is poor, with people in many areas of the world buying antibiotics simply because they have always done so. This lack of knowledge needs to be addressed through an educational campaign to reduce the demand for antibiotics by helping people understand that unnecessary use is really doing a lot of harm.
There seems to be growing awareness of the problem of antibiotic resistance, but what hurdles still need to be overcome to tackle this issue on a global scale?
I think political awareness is one, because the ultimate responsibility lies with national governments. They need to secure effective treatments for their country but if they don't understand how serious the problem of antibiotic resistance is, they won't do anything about it.
Plenty of data demonstrate the health and economic burdens associated with this issue as well as how many deaths it is causing. For example, we know the estimated number of deaths caused by antibiotic resistance in the European Union (EU) is 25,000 per year and for the United States, the estimate is 23,000 per year.
Bearing in mind that these are likely to be significant underestimates, such figures provide strong evidence of a real health problem and more data should be obtained and presented in order to convince policy makers.
In addition, the issue of a general lack of awareness among the public is a very important one that needs to be addressed worldwide. In the majority of countries, antibiotic use is not controlled and you can even buy the drugs. If you can reduce demand by making people understand that antibiotics don't work for simple infections, this will reduce use.
In countries where doctors prescribe the drugs, you simply need to prevent sales without prescription. This could not be achieved in all parts of the world because in some low income countries, there are no prescribers and people can only obtain the drugs by purchasing them from pharmacies or drug dealers.
Although we cannot enforce this regulation globally, in countries where there are urban areas where doctors prescribe drugs, we need to take the antibiotics away from shops where prescriptions are not required. This is one area where governments could make agreements to put new policies in place.
We also need to stop the global use of antibiotics as growth promoters and as preventatives of infection in livestock production.
Lastly, we need to find a way to reinvigorate research and development. There needs to be collaboration between the pharmaceutical and academic sectors if the enormous challenges faced in making a new antibiotic are to be overcome.
Although the major pharmaceutical companies have played a significant role in the downwards trend in antibiotic development, the innovative capacity really lies with the academic sector. There needs to be a new business model where there is a public–private partnership to pull all the scientific plans together and try to fix this. This needs to be looked upon as a global issue, with governmental agreements between countries, because no country can address the problem alone.
Why has there been a lack of new antibiotic drugs developed in recent years?
I think the pharmaceutical industry has tried really hard, but if you look at the drugs in the pipeline, you can see that the last antibiotic with a specific mechanism of action was discovered in 1987. It was marketed later, but the discovery was made a long time ago.
Now, some existing antibiotics have been modified and amended which is good, but bacteria recognize these molecules very quickly and resistance evolves. What we really need is a new class of antibiotic for the most resistant bacteria.
I would say there are three explanations for the lack of development but the primary issue is that it is difficult. The resistant bacteria or "gram-negative" bacteria have a very complex outer layer that is difficult for antibiotics to enter. They also have a mechanism for destroying antibiotics that have entered them, as well as something called an "efflux mechanism" which ejects the antibiotic from the bacterium.
In addition, the return on investment is an important factor for pharmaceutical companies. Of course, they would like to get a return on investment as quickly as possible and an antibiotic is not the ideal drug to develop because the treatment course is so short. Compared with antibiotics, medicines that are used by patients for long durations and maybe even their whole lives offer a more secure investment. Also, even if antibiotics are used properly, resistance will still eventually develop and no one can really predict how quickly resistance will evolve.
Lastly, we want the market size to shrink and be directed towards the patients that really need to use antibiotics. In this respect, the present marketing system does not work and a new business model needs to be composed where return on investment is disconnected from the volume of sales, to ensure sustainability. We need to find a better way to preserve these precious drugs.
What changes need to be made to the way antibiotics are prescribed?
We need a new, controlled way of prescribing and distributing these drugs, but without anyone being denied access to the drugs. If a new system is developed through a public–private partnership, we will get new, important antibiotics that rich countries may be able to pay more for than poor countries.
There needs to be a pricing system which makes antibiotics affordable and accessible to low-income countries. This is important not only because everybody should have the right to access effective medicine, but also because in order to protect the world from generating unnecessary resistance, infection needs to combated worldwide because resistance can emerge anywhere.
Are there plans to introduce new ways of financing antibiotic drug development?
The strongest and best example of this happening was when Sweden hosted the presidency of the EU in 2009. There was an expert conference held on the specific issues of why the drug pipeline is always empty of antibiotics, how we can deal with this, and whether there is a need for a public involvement in the process. That was quite a successful meeting which led to EU health ministers agreeing that this is a problem and the EU commission was tasked to produce an action plan. That action plan materialized in 2011 and included a component of antibiotic drug development and this is now moving into a concrete project.
The EU is providing a lot of funding to put into a collaboration with the pharmaceutical industry to try and overcome the scientific problems standing in the way of producing urgently needed antibiotics. This example needs to be adopted in other countries and a global consortium held to speed up this process.
How do you think non-therapeutic uses of antibiotics in animals can be curbed and what problems might this raise?
A good example of how this use can be safely reduced or eliminated is again provided by Sweden, which was the first country to ban the use of antibiotics as growth promoters, in 1986. Initially, there were some problems with the animals’ health that lasted a few years but these were eventually overcome. Based on this example, the EU eliminated the use of antibiotics as growth promoters and since 2006, this has been banned in the EU.
I therefore think the use of antibiotics as growth promoters in livestock production can be eliminated, but globally, it needs to be addressed in a stepwise fashion because in unhygienic breeding systems, eliminating prophylactic antibiotics could cause serious problems. In China, for example, you could help the farmers by offering insurance to cover any loss they may incur if they stop antibiotic use, losses that could be covered by the public sector.
Although it’s complicated to implement, we need to agree that the approach works in a stepwise fashion, with unnecessary use eliminated carefully because in many countries, the prophylactic use of antibiotics in the animals sector accounts for up to 80% of the total consumption.
What do you think the future holds with regards to antibiotic resistance?
Personally, I am worried about the speed with which some of the antibiotic resistance spreads around the world and causes hospital outbreaks in Europe, in the US, and also significant problems in Latin America, China and Asia.
Although we don't have the full picture, we are in a hurry to make a much stronger global governance on this issue. I think in the next 5 to 10 years, health systems will inherit significant problems, even in the richest countries. There is too little space, improper hygiene and irrational use of antibiotics still continues.
My prediction is that we will see more outbreaks and deaths from antibiotic resistance in years to come and a significant burden on healthcare systems and the economy while we try to reinvigorate antibiotic development and obtain new treatment options.
In the future, I think control will become an even more important part of the solution in terms of preventing initial infection and spread. However, a lot of focus is required since we know there are few drugs in the pipeline.
Where can readers find more information?
There is a lot of information available from different agencies:
There is also a lot of information on the problem and ideas on solutions from our website which is equipped with a resource centre: http://www.reactgroup.org/
About Professor Otto Cars
Otto Cars became a specialist in infectious diseases in the early 1970’s at the Medical Faculty, Uppsala University where he holds a position as Professor of Infectious Diseases since 2003. His research has focussed on pharmacokinetics and pharmacodynamics of antibiotics, optimal antibiotic dosing regimens, rational use of antibiotics and resistance epidemiology.
He was one of the founders and the second president of the International Society of Anti-infective pharmacology (ISAP). Otto Cars was the chair of Strama (the Swedish strategic programme against antibiotic resistance) since its inception in 1995 until 2011. He has been actively involved in numerous European and international initiatives in the area of antimicrobial resistance.
Since 2004 Otto Cars has been engaged in building an international network with focus on the global aspects and consequences of antibacterial resistance React, Action on Antibiotic Resistance (www.reactgroup.org).