Saving the World from Superbug Apocalypse Worldwide problem of antibiotic resistance.
2016 Person of the Year - Saving the World from Superbugs By Yisrael M Safeek, MD, MBA
SWEDEN October 9, 2016
Yisrael Safeek: Welcome Dr. Cars. You have spent more than 20 years spreading the word about the risks of antibiotic resistance around the world. You are one of the founders and the second president of the International Society of Anti-infective Pharmacology. You are also the founder of the international network ReAct – Action on Antibiotic Resistance. Through Science outreach, you have disseminated evidenced-based information driving the issue of antimicrobial resistance toward political decisions, both national and international. Your twenty plus year work on yielded tangible results when on September 21st, UN Member States convened for the first ever High-Level Meeting on Antimicrobial Resistance (AMR) during the 71st UN General Assembly (UNGA). AMR became the fourth ever health issue to make it onto the agenda of the UNGA, only preceded by major global health issues such as HIV/AIDS, non-communicable diseases, and Ebola. Heads of States adopted a Political Declaration calling for coordinated, global action. You were awarded H.M. The King’s Medal by King Carl XVI Gustaf for your contributions to the betterment of mankind. Antimicrobial resistance, conservatively calculated, causes more than 500,000 deaths every year with one third of neonatal sepsis deaths linked to resistant pathogens. Can you tell us, what is antibiotic resistance? Otto Cars: Ever since the 1940s we’ve been used to be able to treat common bacterial infections such as pneumonia, urinary tract infections, wound infections and sepsis with antibiotics both in the community and in hospitals. Today, successful treatment of these and many other infections is becoming more and more difficult, because of antibiotic resistance, which is a phenomenon that makes these medicines ineffective. But it is not only the successful treatment of individuals that is at stake. Antibiotics are indispensable components of any health system in the world and they’ve been a prerequisite for what we have achieved until today in modern medicine, like major surgery, transplants, cancer chemotherapy and the survival of pre-term babies just to give you a few examples. As you stated, we’re seeing a worrying increasing death toll of resistant bacterial infections worldwide. For too long, this problem has been neglected, and if the situation is not urgently dealt with by governments and international organizations we are facing a true global crisis - not only for public health, but also for global sustainable development and economic growth. YS:What causes antibiotic resistance? OC: Antibiotic resistance is a way for bacteria to avoid the effects of antibiotics. This can be accomplished through several mechanism e.g. by preventing the antibiotic to enter the bacterial cell, or pumping it out of the bacterium. Bacteria can also change the target molecule for the antibiotic, thus preventing it from exerting its effect and they can sometimes also destroy the antibiotic itself, in fact, they break it down. So there are many ways that they can resist effects of the antibiotics. And some bacteria are equipped with several of these mechanics simultaneously. Bacteria are all around us; in the environment, one gram of soil contains millions and millions of bacteria .They are also in us: bacteria are vital components of the human body! An adult person has on average 1.5 kilograms of bacteria in the normal bacterial flora, primarily in the gut and on the skin. In all bacterial populations there will always be some bacteria that have become resistant, and when we treat humans and animals with antibiotics, and disseminate these drugs into the environment, the resistant bacteria has an advantage – they can survive and will be selected. This evolutionary process has been driven by the millions of tons of antibiotics we have used during more than 70 years and as a result we are now facing multi-resistant bacteria spreading globally.
YS:You wrote in one of your papers that we’re seeing the “tip of the iceberg” with antibiotic resistance, what do you mean by that? OC: Well, I mean that, although antibiotic resistance undermines the safe treatment of many important diseases, the world has not reacted proportionally to this problem and has not dealt with it in the way it should have. Because antibiotic resistance is not a disease itself, it has not been visible, the major consequences have been emerging under the surface, and thus have not been properly measured and understood until the last five or six years. Today we have strong evidence of the attributable mortality of antibiotic resistance from the EU, US and globally. We can see today that burden of antibiotic resistance falls disproportionally on low-income countries with weak health and sanitary systems, but it has been hidden among many other major health challenges, again being an invisible threat. YS:Why is that important not to use antibiotics unless it’s absolutely necessary? OC: I think the analogy with climate change might be appropriate here. If we look upon effective antibiotics as a global public good, a common, scarce resource, all of us have the responsibility to preserve this resource, because it might not be easily renewable, like fossil fuels. Any antibiotic use will lead to more resistance, so everyone using antibiotics is contributing to resistance development. To slow down and manage this phenomenon, we must take a shared responsibility to avoid unnecessary antibiotic use, which is a big problem everywhere. I believe that continuous awareness- raising efforts toward the general population is really an important tool to make everyone part of the solution. In some countries, antibiotics are readily available over the counter, in pharmacies and in drug shops. If the public becomes aware of when antibiotics should be used or not, the unnecessary demand could be changed and that would be a very good contributions to the solution. YS:Are there clinical practice guidelines that can help healthcare professionals determine whether an antibiotic is needed? OC: Yes, absolutely. Because of increasing resistance among bacteria, the choice of antibiotics is becoming more difficult and guidelines are important both to ensure maximum patient safety but also to avoid unnecessary antibiotic use. Guidelines need to build on good surveillance systems in the hospitals, monitoring dynamically the resistance trends so that physicians can target the treatment, the best way. A great help would be a rapid diagnostic test quickly could guide this decision. This has for too long been a neglected area for research and development, but more diagnostic tools are now becoming available, and it is important that these are implemented in health care since they will contribute both to cost-effectiveness of treatment and to patient safety. YS:Why are we so worried about these “nightmare bacteria”? Are they Gram-negatives? OC: Yes, what’s being called “nightmare bacteria” or “superbugs” in the media is today primarily the Gram-negatives, a group of bacteria that are present, for example, in the gut flora in humans and animals. They have a very complex outer shell which makes it very difficult for antibiotics to enter. They also are more and more equipped with other resistance mechanisms making them multi-resistant. This makes them really difficult to treat, and some of these Gram-negative bacteria that are now travelling around the world are resistance to almost all available antibiotics. This, coupled with the fact that for these specific Gram-negative bacteria, drug development has been standing still for more than 30-40 years, makes the situation really frightening. The pipeline of new antibiotics is definitely not meeting the needs. YS:Should hospital leaders be concerned? OC: Absolutely. Hospital leaders have the responsibility of course to create the safe environment for the patients and minimize the risk for emergence of nosocomial infections including those caused by resistant organisms. Safeguarding the effectiveness of existing antibiotics and minimizing the risk for hospital outbreaks is becoming increasingly important. We really need to see this as a quality issue in healthcare. Optimizing hygienic measures and compliance with infection control practices and supporting systems for prescribing decisions are key responsibilities for hospital leaders. YS:Which populations are at increased risk? OC: The most vulnerable are patient populations with weak immune defenses, for example patients undergoing transplantation or cancer chemotherapy and patients taking other kind of immune suppressive drugs for chronic diseases. Neonates or preterm babies with non-developed immune defenses are also more vulnerable, as are elderly people. When local barriers in the body are broken e.g. during surgery, bacteria from the normal flora could easily spread into the blood causing sepsis. In low-and middle-income countries malnourishment among children is another important factor.
YS:What are the real-world challenges facing practicing clinicians? OC: Today, clinicians all over the world are facing problems with increasing resistance and are becoming increasingly worried that the antibiotics currently available for treatment are not going to work. In high-income countries with well-developed health systems and with access to combinations of antibiotics to treat multi-drug resistant bacteria, the risk of treatment failure and serious consequences can still be minimized. The situation is much worse in low-income countries where the latest antibiotics are often not available or affordable and where weak infection control and lack of basic sanitation are paving the way for the spread and outbreaks of these bacteria. What has happened during the last 5 years or so, is that the world is waking up to see this is a truly global problem, which needs a global solution. Without this, we won’t succeed because resistant bacteria are developing and spreading in all regions. YS:You also wrote, “The world is accountable for the present-day crisis of ABR by a failing public policy, global governance, research prioritization, and market system.” What is being done to control ABR at the WHO? Can you also explain the Global Action Plan on Antimicrobial Resistance? OC: Yes, clearly the world has failed to understand the dimensions of the antibiotic crisis and the WHO has not been showing the leadership that was expected. Already in 2001, a global strategy was published, and although the expert knowledge was already there, it didn’t translate into governmental action, research prioritization, and the necessary financial resources. Coming back to what we discussed before, this inability was probably caused partly by the lack of data on the disease burden caused by antibiotic resistance. So we have been losing many, many years and the Global Action Plan on Antimicrobial Resistance, adopted by the World Health Assembly in May 2015 is an extremely important step forward. It’s a really important plan. It’s well-structured and it is a giving guidance to governments on actions in all the different areas needed to manage the problem. Of course all national governments need to do their part, but it is a major challenge for weak economies to deal with this complex problem where health systems, surveillance and regulation need to be strengthened and where funding is needed for this capacity building. Therefore, we need to create global mechanisms to support low-income countries and to fund research and development of new technologies. A high level meeting on antimicrobial resistance will be held in the United Nations General Assembly on September 21st. My hope is that in addition to the WHO, other UN agencies such as UNICEF, UNESCO, UNDP and the World Bank will now get truly involved in this global problem, and contribute with their knowledge and capacity. YS: That kind of leads me to my next question. Besides funding, what else can the UN do to combat ABR? Please discuss National Surveillance Programs. OC: Surveillance programs are key, without a good understanding of the magnitude of the problem we cannot prioritize our interventions, nor measure their effect, and we need them to regularly update treatment guidelines. There is now a program in development lead by WHO, the Global Antimicrobial Resistance Surveillance System (GLASS) which needs to be speeded up. It will take some time, because it builds on data from quality assured laboratories, and in some countries there are no such laboratories at all. So, I think what we need, while awaiting the results from this system, is a quick global sentinel-based study with representative samples from different regions to get a picture of the resistance levels to guide therapy in countries where there is no data. Because today in many countries, physicians, pharmacists and other healthcare workers do not really know which antibiotics really work. YS:How about education among health-care professionals, the general public, hospital leaders etc.? OC: As said before, I think everyone has a role to manage the problem, so increasing the understanding through education and awareness-raising is a key factor. This could be done through targeted campaigns towards different stakeholders, but news media also has a significant role. Antibiotic resistance should be a compulsory component in schools and in all curricula of healthcare students, which is still not the case. Of course it need to be contextualized, I mean the messages couldn’t be the same in Ghana as in Sweden or the US, they need to be adapted to the local situation and culture. But in the end, we need to change behavior and social norms with regard to antibiotics everywhere. It should not be acceptable to take an antibiotic course for a viral infection where the only effect is to drive resistance. It took a long time for us to realize the severe effect of climate change, hopefully we will act quicker on the antibiotic crisis. It is not somebody else´s problem, we all are responsible for our part of the solution. YS:“Interagency task forces”, “intersectional collaborations” are bodies you believe are needed to ensure implementations of action on antibiotic resistance on a national level. What sort of agency do you see that can collaborate to bring more awareness and provide resources to antibiotic resistance? OC: I think one of the problems with antibiotic resistance is that it has been confined to the health area and therefore a responsibility primarily of health ministers. Of course, in its core, it’s a health issue but both the causes and the consequences of antibiotic resistance reaches far beyond the health sector, it’s a societal issue. Today there is also a better understanding of the ecological dimensions of the problem, we are talking about the one health concept, which includes humans, animals and the environment. But on the governmental level this is not sufficient, we need to broaden the responsibility even more, including not only the ministers of health, agriculture and environment, but also others such as ministers of research and education, development aid ,foreign affairs, and the not the least ministers of finance. There need to be a broad intergovernmental action plan and sufficient human and financial resources allocated for its implementation. And similarly, as we just discussed, on the global level a broad collaboration between UN agencies and other international bodies need to be formed to manage this problem.
YS: You’ve used the term “political courage”. What do you mean by that? OC: What we need is political will and political courage. During the last five years lot of documents and declarations have been produced, a lot of meetings have been organized but tangible global collaboration is still missing. We cannot solve antibiotic resistance, it will stay with us as long we are using these medicines. Thus we can only manage it, achieving a balance between supply and demand. This will cost a lot of money, but much less if we act today than if we allow the problem to continue to grow. The resource-rich countries need to take responsibility and must be willing take the risk of financing much of what is needed to be done. But all countries must be willing to take unpopular decisions such as stronger regulations, targets for antibiotic use, removing misaligned financial incentives etc. This is a difficult political issue, which needs courageous politicians. YS:I know for global warming it took some well noted politicians, including the former U.S Vice-President Al Gore, to bridge the gap between science and policy. How do you envision this for antibiotic resistance? OC: Yes, bridging the gap between science and policy is exactly what has been missing for many years. But in fact, we are now in a situation where scientists, health activists and champions in many countries have helped to “translate” a technically complex issue into political understanding and action. The AMR Review, commissioned by the UK Prime Minister, has contributed significantly to this. So, hopefully we can move from awareness-raising to policy implementation and what we need now is and international group of champions with the mandate and capacity to coordinate this on the global scale and mobilize the resources needed. YS:Let’s turn our attention to the international network ReAct. Can tell our readers about it? OC: I think it’s quite a unique network, it’s 10 years old, initiated in 2005. The primary reason for its establishment was that not much really happened after the publication of the global strategy to contain antimicrobial resistance by the WHO in 2001. We were building on experience from Sweden and some EU countries of the consequences and nature of the problem and how to deal with it, and started to engage policy makers, health activists and civil society organization in different regions of the world. ReAct has since the beginning been in close contact with the WHO and supported the organization in many projects. We aim for profound change in awareness and action to manage the interacting social, political, ecological and technical forces that drive the rising rate and rapid spread of resistant infections. ReAct, still a small network building on much voluntary work, is today organized in five regional nodes: Europe, United States, Latin America, South East Asia and Africa. The major funding comes from the Swedish International Development Cooperation Agency, SIDA. A core part of our work has been gathering evidence on the global consequences of antibiotic resistance, to translate this to into a broader understanding and supporting other groups and organizations to take actions. In this way, ReAct is a growing network of networks. We have also been working quite strongly and consistently to make the world aware of the problem with the innovation failure regarding new and urgently needed antibiotics, and the need for a radically new economic model to be able to deal with this crisis. In 2009, we worked together with the European Medicines Agency and the European Center for Disease Preventions and Control on a report that analyzed for the first time the health and economic burden of antibiotic resistance and the status of the pipeline of antibiotic development. I think that was very valuable report, because it laid down clear evidence of the situation. I think we have also been quite successful in making people understand that public and private sectors need to collaborate, and that the return of investment for newly developed antibiotics must be de-linked from volume sales, to conserve new drugs by avoiding rapid resistance development. YS:What is status of the development of new antibiotics? OC: We have an innovation crisis. Its major cause is the scientific challenges related to finding antibiotic candidates for treatment of multi-resistant Gram-negatives. Many major pharmaceutical companies have abandoned the field, and the global infrastructure for research and development of new antibiotics is weak, few scientists today are experts in the field. What we need is completely new chemical classes of antibiotics, but this is not easy. Following an EU conference in Sweden in 2009, the European Commission launched an action plan including significant funding for a public private partnership for antibiotic development, New Drugs for Bad Bugs (ND4BB). Recently a collaboration (CARB-X) was launched between the US National Institute of Allergy and Infectious Diseases (NIAID) and the Biomedical Advanced Research and Development Authority (BARDA) and four life science accelerators in the US and UK. We are now hopefully moving towards an open global collaboration to facilitate knowledge-sharing and avoiding duplication of expensive mistakes. However, these initiatives will not be sufficient, more will be needed to solve the antibiotic innovation crisis. YS:How about plans to promote new vaccines? OC: Of course pevention is much better than treatment. First of all we have to increase the implementation of the vaccines that already available! The pneumococcal vaccine is a great success, it has significantly reduced the numbers cases of pneumonia in children, but it’s not implemented globally the way it should. It is still too costly for many low-income countries, despite the fact that it could save numerous lives and avoid unnecessary antibiotic treatments. We also need more bacterial vaccines, but the pipline is unfortunately not very promising. This is another research area that has been neglected for long and needs to be strenthened significantly. YS:Is there a role for bacteriophage in the fight against antibiotic resistance? OC: There is an increasing interest for bacteriophages and other alternatives antibiotics, but they have so far only been promising for local application, such as wound infections. Also, they are very bacteria-specific, which means that we need precise diagnostic tools that can identify the pathogens rapidly to be able to make optimal use of them. I think therefore, that for many years to come, we need to rely on “classical” antibiotics for severe infections. YS:What are the main myths of antibiotic resistances that you’d like to dispel? OC: The first myth, or misconception I am thinking of, which is also one of the major causes of the resistance problem, is that all infections giving you fever should be treated with antibiotics. Here there are still major knowledge gaps to overcome worlds-wide. A second myth is the statement in numerous articles and policy documents that you have to take the full course of antibiotics to minimize the risk for resistance development. Although it is clearly true for a very special type of infection, tuberculosis, which requires many months of treatment, it is not relevant for other bacterial infections. Instead, long treatments periods will select more resistant bacteria in the normal commensal bacterial flora and the treatment period needs to be as short as possible. Of course, patients should complete the course recommended by the prescribing physician, but more studies are needed to find the optimal treatment times. What is true however, is that too low antibiotic doses, such as could be the case when substandard or counterfeit drugs are given, is an increased risk factor for resistance development. Thirdly, many people still believe that the pharmaceutical industry will continue to deliver new antibiotics when the old ones have become useless because of resistance. This is definitely not the case and a dangerous self-deception. YS:In all your years working with antibiotic resistance, what surprised you the most? OC: What actually has surprised me the most, and a question I am often asked, is why the WHO, who produced a very good strategy in 2001 was not able to generate momentum for the issue. I still don’t have the answer, but it was a great frustration, that became the incentive for starting ReAct. YS: How optimistic are you about securing a world free from fear of untreatable infections? OC: We have to be realistic. Although the nature of the problem, its causes and consequences are now much better known than ever before, it is a great challenge to mobilize the funding and global collaborations needed, where national interests need to be put aside for the global public good. If the scientific challenges for development of new antibiotics can be solved, it will still take many years to develop a novel antibiotic and make it available to patients. So, I believe that during the next 5-10 years, health care globally will face increasing problems with antibiotic resistance. Securing a world free from fear of untreatable infections is still ReAct´s vision. The increasing awareness and actions on the political level during the last few years gives some optimism that we are now moving in that direction. YS:Dr. Cars, on behalf of The SafeCare Group and SafeCare magazine, I thank you for devoting the last two decades contributing to the betterment of mankind as you spread the word about the risk of antibiotic resistance and we tackle the problem head-on.
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