The empire strikes back
A contribution by Dr. Hannelore Meyer Resistance to antibiotics became alarming During the 1940s antibiotics were first discovered. They were and are used to fight bacterial infections successfully ever since. This is the first instance where the cause of bacterial infections could be tackled, which led to an unprecedented increase in life-span as well as to the development of modern medicine. Infections caused by bacteria that developed resistance against (almost) all existing antibiotics represent a massive threat jeopardizing health and life of many people. Media report 33,000 deaths caused by antibiotics-resistant bacteria in Europe every year. This number has doubled since 2007 and now equals the fatal crash of a Jumbo jet carrying 400 – 500 passengers every five days. Deaths caused by multi-resistant bacterial strains are globally expected to grow from currently 700,000 to approximately 10 million by 2050. This would exceed the current number of cancer-related deaths, which is standing at 8.2 million / year. On top of that, medical achievements such as transplantations, tumor-therapies, complex surgeries, or intensive care for prematurely born infants may be jeopardized. All of these treatments require effective antibiosis for success as the immune system of these patients is compromised. Therefore, they cannot effectively overcome bacterial infections without the help of powerful antibiotics. This already resulted in a drastic increase of the cost of medical care to about 20 to 35 billion US $ by 2013 in USA. By 2050 the global loss of productivity may equal today’s gross domestic product of Great Britain. Figure 1: Death cases by disease. Blue: 2013 data; orange: 2050 projection Multi-faceted strategies against bacterial antibiotics resistance The threat posed by AMR receives worldwide attention and was recognized in the declarations of the G7 and G20 summits during the last years. Due to the rapid global dissemination and inter-bacterial transfer of resistances against antibiotics will essential to implement monitored number of measures: i) monitoring the development of antibiotics resistances, ii) targeted and restrictedapplication of antibiotics in the clinic, iii) reduction of the use of antibiotics in farming, iv) improvement of hygiene, v) development of novel diagnostic tests allowing for identification remaining treatment options. Furthermore, the development of new therapeutic options is pivotal in that respect. The WHO published a list of bacteria in 2017 against which development of new therapies is most urgent. This list allows streamlining multiple approaches in order to speed up development of therapies against the most dangerous bacterial pathogens. Complementary, novel and personalized therapy concepts There are multiple developments augmenting the classical range of antibiotic therapies. “Prevention is better than therapy” is the motto inspiring the development of vaccines against malicious bacteria. The best weapons are prophylactic vaccinations preventing infections later on. Such vaccines are usually well tolerated, cost-effective and avoid the problem of subsequent development of resistances. Innovative antibody-therapies (i.e. utilizing specifically induced immune agents) are currently developed to enable application of antibiotics not yet used. The idea is to chemically link particular antibiotics to an antibody, which is supposed to shuttle to the target location, where it is enriched. This way a rather high local concentration of the antibiotics can be achieved, while much lower systemic concentrations are needed, which avoids side effects and toxicity. In addition, this approach is also feasible for antibiotics that would not reach the target sites upon oral or intravenous application. So called ‘lytic peptides’ are molecules, which only get incorporated into bacterial (but not into human) membranes and cause membrane perforation. These peptides are expected to be effective against a wide variety of bacterial pathogens, as they do not specifically block a particular cell function. Due to this unspecific mode of action, development of resistance is not expected. Bacteria themselves fall prey to viruses like us. These bacteria-specific viruses are called “phages” and, fortunately, they are harmless to humans. However, so far the western world took little notice of this approach, which recently gained more attention. The production of phages, which are highly specific for the disease-causing bacterial strain, is straight forward and comparatively cheap. For the first time, it becomes possible to provide each patient with a personalized antibacterial therapy based on this technology. This raises great hopes, but we still need to see how to ensure and proof that each new phage product will meet all criteria regarding quality, safety and efficacy. More than 1000 clinical trials have shown successful treatment of intestinal infections with antibiotics-resistant Chlostridia by transplanting the gut microbiome from healthy donors. This procedure restores the balance of the highly diverse bacterial community in the intestine which had been disturbed in previous antibiotic therapies.. However, our understanding of the interdependencies between the microbiome and certain diseases is currently rather limited. Therefore, microbiome transplantations are still restricted to patients, for who no other treatment options are left. Studies so far are very promising both regarding efficacy as well as avoidance of side effects. The classical drug development is still a major part of our anti-infections arsenal, despite the multitude of ideas and concepts. Bacterial infections can be typed rapidly by the latest state-of-the-art diagnostics and technologies such as mass spectrometry, PCR-based or NGS-driven analyses. On top of that bacterial resistances to a host of antibiotics can be spotted paving the way for tailor-made drugs. So-called pathoblockers allow personalization of therapies based on the respective specifc bacterial infection. Pathoblockers aim to interfere with the intercations between bacterium and patient, but - in contrast to classical antibiotics - do not aim to kill the bacteria. Pathological processes can be blocked without harming the bacteria. Spontaneously occurring resistances are, thus, no longer a selection advantage. Mechanisms responsible for adhesion, virulence, or immune evasion are very specific for each bacterial strain or group of strains. Any drugs interfering with such mechanisms will, therefore, affect only a few pathologic bacteria sparing our symbiotic gut bacteria. This is ecpected to substantially reduce potential side effects. Furthermoer, even if some resistances appear, the number of other bacteria acquiring and maintaining such resistances will remain small as these resistances cannot be transferred to other bacterial species. Thus, pathoblockers are personalized medicine against bacterial infections, personalized not with respect to the patients but the bacteria attacking them. Innovative RNA- and immunology-based approaches are already used routinely in cancer therapies. Similar approaches will be applied both for diagnostics and therapy in infectious diseases. They will also provide the basis for more targeted personalized developments including anti-infection strategies. Our enemies, pathological bacteria, will also in future develop means to neutralize our medical arsenal. In order not to lose this rat race, we need to come up with more and new weapons. This does require increased effort in research, including an increase in personalized concepts.
HARMONY in personalized Medicine
The availability of huge amounts of personalized data from many patients becomes even more important when medicine becomes more personal. Cross-analysis of this data is a prerequisite for gaining new insights and devising helpful approaches. There is a news item from the university of Ulm that highlights this aspect: (Translated from the original news:) Big Data, i.e. huge amounts of data is regarded as an excellent opportunity for medical research. Patients with diseases of the hematopoietic system (generating blood cells) might profit from a unique data collection: 51 partners from 11 European countries collect anonymized patient data in the project HARMONY (Healthcare Alliance for Resourceful Medicines Offensive against Neoplasms in HematologY) funded with several million EUROs. Analysis of this huge amount of data shall yield valuable insights into diseases such as leukemias (AML, CLL, ALL), lymphomas, multiple myeloma, myelodysplastic syndrome, or malign diseases of the hematopoietic system in children. A thorough discussion of data protection guidelines and their necessary adaptations is meaningful and required in this respect. It is mandatory to prevent data protection guidelines from harming the very patients they should protect. Our member Dr. E. Precht alerted us to this news. Many thanks for that! Framework text by Thomas Werner, Chairman of the executive committee
Definitions - scientific background - examples Personalized Medicine is a relatively new field joining molecular biology, computer science, information technology, and medicine. The overarching aim is to optimize consulting, diagnosis, and treatment based on the individual characteristics of each patient (or sometimes patient group). I am currently the chairman of the association m4 Personalized Medicine and we defined it as our goal to support the essential discussion of personalized medicine aiming to foster a consensus regarding some key issues in our society. This includes scientists and specialists but should ideally also include ethics, health care providers, and patients. However, the basic knowledge, explanations of the circulating terms, as well as hard facts about pilot projects and other things are currently spread over the internet. All accessible in principle, but sometimes hard to find, apparently contradictory in part, and entirely unordered. I will try in this blog to collect and explain the most common terms simultaneously adding them to a framework hopefully facilitating understanding. There is no doubt that this will be a collection biased by my personal knowledge and experience, some things might even be missing entirely. That is the reason why this in my personal blog and neither the association nor any other individual has to assume any responsibility for the content. This is absolutely intended as this blog is meant as a mere starting point for a targeted discussion, and by leaving comments that contribute to the overall aim everybody can help to shape this into a more common consensus. The blog will be published every Friday each week, except for a few breaks. It will appear in its own location marked in the menu as “TW’s PM Blog E” (only this announcement is published on the other blog pages as well). It is published in parallel in German and English as it is placed on the publicly accessible part of our web page. This English version is no direct translation from the German text but I intend to adapt it to international aspects wherever I see this fit. What’s coming up next? Next week the first part of the introduction will be published
Randomized personalized medicine?
Lancet Oncology published an article in 2015 about a fully randomized study in personalized medicine. The comment highlights a few aspects with respect to how meaningful such an approach is. Full comment can be found in our download area (Download).