31.05.2017

Facing Antimicrobial Resistance - a 'Global Health' problem with future impact

Again and again we read about dangerous resistances against antibiotics. Many people are afraid of a future in which antibiotics will no longer help. Can we still stop the triumph of the bacteria?

Thomas K. has a great hobby - travelling. As soon as he has saved enough money and can take leave, he is out to see the world. Whether enjoying Niagara Falls, heli-skiing on Ruby Mountain or sunbathing on the beach in Hawaii, he always seeks special memorable experiences. One summer he decided to take a three-month tour through India with a good friend. The Taj Mahal, the Golden Temple, Delhi and Mumbai - all these places were on their list. But what began as an exciting sightseeing holiday nearly ended fatally. At first everything went according to plan. “But somehow I got this burning pain in my stomach”, remembers Thomas. “I tried painkillers and was given antibiotics in the hospital, but it just got worse and worse. It felt as if my whole body were on fire. ” The two men decided to return home to the USA. “The whole flight I was in pain. I thought I wouldn’t survive”, says Thomas. “When I arrived in California I immediately went to casualty.”

Nasty Holiday Souvenir

“There the doctor suddenly said to me: ‘I have bad news’”, the 45-year-old entrepreneur remembers as if it had been yesterday. “You’re not going home tonight. You’re going straight to the operating theatre.” Months later, Thomas is still trying to put his life back together after an antibiotic-resistant E. coli infection turned his world upside down. “I am still trying to understand how this could happen. I have lived a healthy lifestyle my whole life, with lots of sports and a good diet, but this small bacteria almost killed me.” So-called ESBL-forming E. coli bacteria, super-resistant germs, had infected his intestine and perforated his colon. Surgeons had to remove an 8-inch section of his colon. Since the bacteria were resistant to almost all available antibiotics, the doctors had to resort to repeated antiseptic flushing. Finally, his immune system managed to fight the pathogen and the infection did not return. “This was a blessing in disguise”, says Thomas. After missing almost six months of work and losing more than 20 pounds, he is now trying to get back into shape. “I pray that this nasty bacterium is out of my life for good.”

Nightmare bacteria

This is not an isolated case. Earlier this year American researchers announced the shocking case of a 70-year-old Nevada woman who died from the effects of infection with multiresistant pathogens. She had also spent some time in India, the country which accounts for nearly 70% of the world's antibiotics production, and is repeatedly hit by the emergence of new multiresistant bacteria. The 70-year-old woman broke her right hip - it would turn out to be a fatal injury. The fracture resulted in a hip infection and several stays in Indian hospitals. When the woman finally went to an American hospital in Reno, it was already too late. After a few tests, the doctors found out that she was infected with a so-called CRE, a carbapenem-resistant enterobacterium. These common bacteria live in the intestine of a person and have developed resistances against a particular class of antibiotics, which are an important reserve antibiotic when other drugs fail. The director of the CDC (Center for Disease Control and Prevention) Dr. Tom Frieden called these CREs “nightmare bacteria”, because of the danger they pose for spreading antibiotic resistance.

And it was a real nightmare for the 70-year-old American, because it turned out that the bacteria, which had now spread throughout her whole body, were resistant not only to one, but all antibiotics. As unbelievable as it sounds, the germ was unresponsive to all 14 different medicines that were available to the hospital to fight the infection. “This was the first time we've experienced such a thing” the researchers reported. A sample was sent to the American Center for Disease Control and Prevention for further testing, which revealed that nothing available to US doctors would have cured this infection. “I think it’s very concerning,” writes researcher Lei Chen. “We have relied for so long on just newer and newer antibiotics. But obviously the bugs can often develop resistance faster than we can make new ones”. The woman from Nevada experienced this first hand. Since the infection could not be contained, she finally died of a septic shock, the final stage of blood poisoning.

Magic weapon against killer bacteria

How could this happen? To understand this, you need to know how antibiotics actually work. It’s worth taking a brief look at their history.

It wasn’t until 1928 that the first antibiotic was found. And that was pure coincidence. At the time the Scotsman Alexander Fleming was experimenting with the bacterium Staphylococcus aureus, which can trigger a lung inflammation, in his laboratory. But he had an accident. One day he discovered that a mould had entered his bacterial cultures. Normally, scientists would have disposed of the damaged sample, as it had become unusable for bacterial experiments. Not so, however, Fleming. He noticed that no bacteria seemed to grow around the fungus - the bacterial layer was gone. This discovery prompted him to conduct further experiments, and soon he found that the mould was a bacterial-killing substance. Thus ‘Penicillin’ was discovered and in 1944 the first large-scale production started in the USA. But how does the mould work? All antibiotics are based on a mechanism which is targeted to attack bacterial structures, but leaves human cells alone. This works because bacteria and body cells differ in some significant aspects.

Penicillin, for example, attacks the bacterial cell walls, destroys them, and thus renders the bacteria harmless. Since human cells have no cell wall but only a cell membrane, they are spared. The antibiotic classes of cephalosporins and carbapenemes function similarly to penicillins. Macrolides, aminoglycosides, tetracyclines and lincosamides, on the other hand, use a different mechanism of action. These interfere with the protein production of the bacteria, which takes place on the ribosomes. Bacteria possess so-called 70S ribosomes, while human cells contain 80S ribosomes. Since the antibiotics only interfere with the 70S ribosomes of the bacteria, our body cells remain protected. The antibiotic groups of quinolones and nitroimidazoles, yet again, damage the DNA of the bacteria. This lies free inside the cell and requires certain enzymes which are different to those of human cells. There are also antibiotics such as cotrimoxazole which inhibit the bacterial folic acid synthesis. While bacteria need to produce this vitamin themselves in order to grow, we assimilate it through food and have an increased need, for example, during pregnancy.

Currently there are around 20 different classes of antibiotics. Most were developed in the second half of the 20th century, but research on new antibiotics gradually decreased in the late 1980s. Drug research has become quite costly. On average, pharmaceutical companies have to spend one billion euros and invest 13 years until a drug comes on the market. In contrast to drugs for chronic illnesses such as diabetes, which have to be taken for a lifetime and are therefore very profitable, the prospects for successfully discovering a new antibiotic and making money from it are much lower. While nearly 800 cancer drugs and vaccines are currently being investigated in the US, the number of potentially newly developed antibiotics is just 41. However, the increasing resistance against antibiotics makes development difficult.

Watch how a superbacterium is born

But how exactly do resistances arise?

Resistance basically means opposition. In the case of antibiotic resistance, the bacteria do not react to the administered drug. There are many different types of resistances. A primary resistance refers to a pre-existing resistance which bacteria have had all along. This means that the antibiotic has never been effective here; there is a gap of effectiveness against a certain bacterial species. For example, cephalosporins do not work against enterococci bacteria, which naturally occur in our intestines. This is referred to as the “enterococcal gap”. But there are also so-called secondary resistances. The bacteria spontaneously acquire the resistance, for example by mutation in the genotype of the germs. This can, for example, result in the bacterium being able to form an enzyme which cleaves the antibiotics, thus rendering them ineffective. It is also possible for bacteria to alter their cell membranes in such a way that the antibiotic substance can no longer pass through, or bacterial attack points such as the ribosome are changed so that the antibiotic can no longer work there. Bacteria can also transmit such resistances among themselves by exchanging genetic material, referred to as a “transfer”.

Resistance mainly occurs where many antibiotics are used. Even aggressive antibiotics never kill all germs, but only about 99 percent. This can be imagined as follows: The bacteria are a Viking army resisting an attack by an opposing village – the so called antibiotics. The antibiotics know exactly the weak points of the Vikings and manage to defeat them. But a few Vikings were clever enough to come up with a survival strategy (resistance mechanism) and survived the fight. Due to their fallen companions they now have a lot of space in their village, their community is able to grow. The Vikings pass on the survival tactics to their children, these to their grandchildren, and so on (transfer of resistance genes). In time, the community expands ever further, becoming a metropolis. In the next attack of the antibiotics the Viking bacteria finally win the fight - they have become resistant. The bacterial army can also pass on survival tactics to neighbouring villages (colonies) and even to foreign warriors (other species).

Multi-resistance is the insensitivity to several antibiotics of different classes. Over time the Vikings have not only developed one, but many different strategies to overcome the antibiotic attacks. Multi-resistant bacteria, such as MRSA (methicillin-resistant Staphylococcus aureus), are problem bacteria, since only very few drugs help against them (so-called reserve antibiotics). Meanwhile, however, there are also germs against which no known antibiotics have any effect. As early as 1945, penicillin discoverer Alexander Fleming sounded a warning in his speech at the Nobel Prize ceremony about the consequences of an uncontrolled use of his miracle cure: “The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.”

Secret weapon against nasty microbes

Whilst less and less new effective antibiotics are being discovered, high-risk germs are growing rapidly all over the world. It is becoming a global health problem with a potentially great future impact. But what can we do about it? In Germany, the so-called ‘Dart 2020 concept’ has been established to find solutions in cooperation with the WHO. The Global Action Plan to fight antimicrobial resistances was revised in 2015 and includes, among other things, stricter laws on the reporting requirements of resistant microorganisms. Since last year, doctors in Germany have to report antibiotic-resistant pathogens as soon as they are detected. Previously, the germs didn’t have to be reported until the outbreak. This should help keep an overview of the development of resistances and contribute to a more meaningful use of antibiotics according to the resistance situation. In addition, a further goal is to prevent the mere emergence of infections, for example by means of better hygienic measures in hospitals. In particular, disinfection of the hands is often underestimated by hospital staff, as well as the hygiene necessary in operating theatres or at patients’ bedsides.

It is also part of the plan to use antibiotics only upon strict indication and to critically question every application. Worldwide, huge amounts of antibiotics and other antimicrobial drugs are currently distributed to people who do not need them. Antibiotics are still prescribed too frequently and stopped too early, which greatly promotes the development of resistance. Antibiotics are even used against harmless viral infections, although they do not help against them.

Sensible use of antibiotics instead of swallowing them like sweets

However, an even greater problem is the use of antibiotics in farm animals. Without any regard, approximately 1500 tons of antibiotics are fed to pigs, cows and other fattening animals every year, almost twice as much as used in human medicine. On the one hand, this is to keep the rates of infection low in stables where the animals live in a confined space. On the other hand it promotes fattening and thus guarantees low meat prices. This senseless application helps neither animals nor humans. On the contrary, a resistance to antibiotics can be transmitted to the human body through eating meat containing antibiotics. By this method, bacteria in the body can become resistant to certain antibiotics without previous contact. However, the ‘Dart 2020 concept’ remains very vague on the question of strict legislation to control the use of antibiotics in animal fattening: “It will be examined whether and to what extent a more binding setting could increase the benefits for consumer protection and animal health”, the German Federal Ministry for Food and Agriculture stated. According to the British economist Jim O’Neil, as early as 2050 10 million people a year could die of infections against which antibiotics are powerless. People should stop swallowing antibiotics like sweets, O’Neil told BBC. Already today, 700,000 people die each year from the results of infection with resistant germs. According to the German Society for Hospital Hygiene, 40,000 people are affected in Germany alone. If this development continues, this could mean one death every three seconds in 2050. “If we do not solve the problem, we will be cast back into the dark ages when many people died of banal infections” states O’Neil. “Then important operations like cesarean sections could become life-threatening”.

Back to the future - Time travel into the post-antibiotic age?

“People have asked me many times ‘How scared should we be?’ … ‘How close are we to the edge of the cliff?’ And I tell them: We’re already falling off the cliff. It’s happening. It’s just happening — so far — on a relatively small scale and mostly far away from us. People that we don’t see … so it doesn’t have the same emotional impact.’’
Dr. James Johnson, University of Minnesota

Dr. James Johnson, Professor of Infectious Diseases at the University of Minnesota and specialist at the Minnesota VA Medical Center, sees our future quite gloomily. But is the increasing antibiotic resistance really a harbinger of a medieval era without any possibility of fighting infections? Even Keiji Fukuda, General Director for Health Security at the WHO, warns of the consequences: “The fallback to such an era is by no means an apocalyptic fantasy, but a very real threat to the 21st century.”

But what do we do without antibiotics? This question is the focus of many people around the world, all united in a vision of a medicine that does not need traditional antibiotics. There are currently many efforts to solve the resistance problem. Research is carried out not only on the development of new antibiotics, but also on finding alternative possibilities for germ elimination.

Bacterial mailbox glue     

A brand new approach to the fight against bacteria focuses on not destroying them completely, but instead to render them harmless, for example by preventing their communication. The bacterial species ‘Pseudomonas aeruginosa’, which sounds like a spell from Harry Potter, produces, among other things, the toxic dye pyocyanine, which attacks human tissue. The moisture loving bacterium is mainly found in air humidifiers, washbasins, vases and soap dishes, and can lead to infections of the respiratory and urinary tracts, as well as to wound infections and blood poisoning in people with a weakened immune system. However, the bacteria produce the dye only in a common group - it helps them to communicate with each other and plan attacks against human cells, so to speak. Researchers from the Helmholtz Institute for Pharmaceutical Research in the Saarland have recently succeeded in stopping the spread of the toxic product. They taped up the bacteria’s mailbox and thus prevented an exchange among the germs. In animal experiments the trick was successful: the bacteria with the administered glue actually produced less pyocyanine and the survival rate of worms and larvae infected with Pseudomonas increased. Although this research is still in its infancy, the researchers hope one day to use it to develop a medicine for humans. "In contrast to antibiotics, our active ingredient does not interfere with the pathways of the bacteria, but only blocks their pathogenicity," says Rolf Hartmann of the Helmholtz Institute. Because the bacteria are not killed, they do not give mutant pathogens any survival advantage and the probability of resistance development is much lower.

How plastic morning stars save lives       

An only 25-year-old Australian student, Shu Lam, recently caused quite an international stir with her research on alternative antibiotic treatments. In the laboratory, she produced a kind of morning star called ‘SNAPP’ (structurally nanoengineered antimicrobial peptide polymer), which is a star-shaped small plastic particle that can be used as a weapon against multiresistant bacteria. The sharp edges of the polymer star slash the bacterial membrane and cause so much stress in the microbes that they kill themselves. With this method, Shu Lam was able to render six different super-resistant strains harmless without the use of antibiotics. The paper, published in Nature Microbiology, caused great waves in the world of science, and was celebrated as a breakthrough that could change the world of medicine. “We found the polymers to be really good at wiping out bacterial infections“, the student explains. “They are actually effective in treating mice infected by antibiotic-resistant bacteria. At the same time, they are quite non-toxic to the healthy cells in the body“. SNAPPs are small enough to slice bacteria but too big to harm healthy body cells. So far, they have been able to destroy the corresponding bacteria in all experiments. And the germs do not seem to develop any resistance to it either. However, it is still far too early to hope for an early deployment in humans. Many experiments and studies are still necessary. Yet Shu Lam remains optimistic “I really hope that the polymers we are trying to develop here could eventually be a solution.“

Attack of the order killers: Bacterial eater ahoy!     

Scientists at the Leibniz Institute Braunschweig recently developed one of the most promising new weapons against multiresistant organisms. This weapon consists of thousands of small bacteria-eating pirates, the so-called phages (Greek ‘phagos’ means ‘eating’). Phages are special types of viruses which specialise in the destruction of bacteria and occur naturally wherever there are bacteria, such as in our human bodies. Their favourite food is bacteria - one could describe them as a kind of contract killer. They are built like a small space ship: a head-like protein structure protects the essential interior - their genetic code - and huge spider-like feet serve for attachment to surfaces. The phages, which are only 2000 nanometres in size, dock on to bacterial walls with their tentacles and thus capture them. The viruses then inject their genome into the bacteria and thereby take full control over the entire bacterial cell. It is transformed into a kind of laying battery, which clones the phages genetic material and then releases hundreds of new small offspring. The bacterium breaks down and the baby phages start looking for new victims. This cycle continues until there are no more bacteria: the ideal weapon in the fight against killer bacteria.

Forgotten Cure

Phages, however, have certain preferences. Each phage has its own favourite food - a specific bacterial species or even a particular strain. This can be a blessing and a curse at the same time. On the one hand, it is possible to selectively kill certain bacteria and at the same time protect the useful microflora of humans. On the other hand, it is difficult and non-lucrative to find the right phages for every bacterial species. However, the idea is not new. Phage therapy was developed around the same time as the discovery of antibiotics at the beginning of the 20th century, but soon fell into oblivion in the western world. But phages are still known in the eastern countries. There they are used as a medicine for wounds, diarrhoea or bladder infections in the form of juice, tablets, ointments and even tampons. The Georgian Eliava Institute is the largest centre of phage production and research. Patients can have their pathogenic bacteria analysed there and get a suitable virus cocktail shortly afterwards. In Germany, however, people are much more cautious: the viruses are not officially approved as drugs, although they are not forbidden. The pharmaceutical industry also shows little interest in the small bacteria grains, but this could soon change. The US Institute of Allergy and Infectious Disease has already put phage therapy on the list of the most promising strategies against the growing number of resistant germs in 2014. Belgian and French researchers have also begun initial clinical studies on the effectiveness of phage therapy with ‘phagoburn’. They have already shown successes in the therapy of heart disease by Pseudomonas aeruginosa. If German policy follows and creates the legal basis for the use of phages, this methodology could soon be used in Germany as well.

Nanomedicine: small vampires as helper     

Another research group around Liangfang Zhang is trying to use methods of nanomedicine against bacteria. The idea is to use a precise tailor-made weapon against microbes. Nano comes from the Greek ‘nanos’ and means dwarf. It corresponds a billionth of a meter, one nanometre (nm) being defined as 10-9 m = 0.00000001 m. The dimensions in which nanomedicine operates are really small. Scientists have now developed tiny, tiny sponges of nanoparticles, which are supposed to soak up pathogenic toxins from out of the bacterial pathogens Staphylococcus and Streptococcus. The toxins of these bacterial species usually dig small holes the cells of our blood-cells and destroy them in this way. If, however, nanoparticles camouflaged with a coating of red blood cells are injected into the body of mice which are then infected with the bacterial poison, the following happens: the toxic particles are injected into the nano-sponges disguised as erythrocytes which then soak up the poison, thus preventing damage. Subsequently, the fully saturated balls are removed from the body without damage. In this experiment, approximately 90 percent of the laboratory mice survived a normally fatal dose of toxin. If, however, the small nano-vampires are administered after the poison, only about the half of the mice survive. Although this technique is far from mature, it is an interesting approach, since it would be possible to render many different bacterial toxins harmless, even those of multiresistant pathogens.

Research revolution wanted: only together they are strong

Still, none of these new active therapies can be found in pharmacies. At first, further studies have to show that the drugs can be administered not only in animal experiments but also in the human body and do not cause any other damage. In addition, it must also be clarified whether they also help with actual infections which have already broken out. However, great hope is also put into so-called host-based therapies such as vaccinations, which are supposed to boost the patient's immune system. "There will probably never be that one new miracle medicine that replaces antibiotics once and for all," explains Winfried Kern, who was chairman of the German Society of Infectious Diseases until 2013 and is currently the spokesman for the working group of scientific specialists in infectious diseases. "But perhaps a lot of different forms of therapy, which can be used more specifically against the pathogenic effect of different bacteria.” New drugs are urgently needed so that patients like Thomas K. can be treated effectively in the future. We relied a very long time on the preparatory work of the pharmaceutical industry in the golden age of the 1950s to 1970s, but now we need to wake up. We urgently need more measures to avoid antibiotic resistance and explore alternative drugs so that in the end we will not lose the race against time in the bacterial superfight.

Useful links:

The ‘Dart 2020 concept’ of the German Federal Government: http://www.bundesgesundheitsministerium.de/fileadmin/Dateien/Publikationen/Ministerium/Broschueren/BMG_DART_2020_Bericht_dt.pdf

Report by the British economist Jim O’Neil on antibiotic resistance: https://amr-review.org/sites/default/files/160518_Final%20paper_with%20cover.pdf

Assessment of the German Society for Hospital Hygiene: http://www.krankenhaushygiene.de/pdfdata/presse/2012/2012_03_22_pressemitteilung.pdf

This article was originally published on DocCheck.