Infectious diseases cost millions of lives each year. In a few decades, bacteria could kill even more people than cancer. Researchers at University Hospital Cologne are focussing on antibiotic resistance and exploring new ways to defeat the deadly pathogens.

Anna Euteneuer

Bacteria live everywhere – in hot sulfur springs, in ice and even in and on our bodies. Most of the bacteria live in symbiosis with us and help us, for example, to ward off other bacteria on our skin or to digest our lunch.

But for over a hundred years, medicine has been trying to fight those bacteria that use humans as hosts to multiply and cause diseases. Bacteria make a copy of themselves and split in two, so they grow exponentially. Depending on the type of bacteria and external factors such as temperature or humidity, the number of bacteria doubles every twenty minutes, every hour or every day. Bacteria are masters of adaptation and interact with each other. They owe their robustness to certain genetic information, which is exchanged between the bacteria in the form of round DNA pieces called plasmids.

This exchange becomes dangerous when the DNA pieces contain the blueprints for proteins that make them resistant to antibiotics. Experts worldwide and the World Health Organization (WHO) are concerned about the growing antibiotic resistance of bacteria and call it a ‘silent’ or ‘creeping’ pandemic. In Germany, almost 9,700 deaths could be attributed to resistant pathogens in 2019. According to predictions of antimicrobial resistance, more people could die from resistant bacteria than from cancer by 2050. In figures, that means ten million deaths per year.

Staphylococcus aureus, which can lead to skin and soft tissue infections, pneumonia, meningitis or sepsis, Mycobacterium tuberculosis, which causes tuberculosis, or the hospital pathogens Pseudomonas aeruginosa and Acinetobacter baumannii are examples of such dangerous bacteria. In 2017, the WHO warned in particular of twelve bacterial families which pose the greatest risk to human health due to their antibiotic resistance.

In the absence of good hygiene, bacteria have an easy job multiplying

Acinetobacter baumannii is considered to be the most dangerous bacterium. It can cause pneumonia, as well as wound, urinary tract or bloodstream infections. Professor Dr Harald Seifert, former deputy director of the Institute for Medical Microbiology, Immunology and Hygiene at University Hospital Cologne and now retired, has been researching the small rod bacteria for more than thirty years with his research group. He is still working for the laboratory on a part-time basis. With nearly one hundred and fifty scientific publications, the working group is one of the world’s best-known groups dedicated to research on Acinetobacter baumannii. Today, it is headed by Dr Paul Higgins.

The researchers also deal with other antibiotic-resistant pathogens as well as bacterial infections that can occur in hospitals or in outpatient practices. They recently conducted a comprehensive study on the bacterium that is resistant to the broad-spectrum antibiotic group of carbapenems and has the highest priority in antibiotic research, according to the WHO. So-called ‘CRAB’ (Carbapenem-resistant Acinetobacter baumannii) pose a growing threat to public health, as carbapenems have long been considered last-resort antibiotics against these and other multi-resistant bacteria.

“Acinetobacter baumannii is relatively rare in western and northern Europe,” said Seifert. “However, it is very common in southern and eastern Europe, on the Indian subcontinent, in Southeast Asia and especially in China, where Acinetobacter baumannii is even the most common pathogen of respiratory pneumonia.” Acinetobacter baumannii was also called ‘Iraqibacter’ by Americans because severe wound infections were diagnosed in American soldiers in Iraq and Afghanistan in the early 2000s.

Infection with the bacterium rarely occurs outside the hospital. It often is a so-called nosocomial infection: Patients who are ventilated mechanically in the hospital can become infected due to the bacterium’s antibiotic resistance, contract pneumonia and often die. Good hygiene measures in the hospital are necessary to stop the spread of CRAB. The bacterium can survive on hospital furniture or bed linen and can be transferred if hygiene measures such as disinfecting hands or surfaces are not performed properly in patient rooms. In addition to ventilation, catheters that provide access to the bloodstream and open wounds can also cause infection.
Although many multi-resistant bacteria have so far been found only in certain regions of the world, they are not a local problem, but a global one. Holidays, business trips and globalization in general allow resistant pathogens to travel around the world quickly.

Dangerous clones

Bacteria of a certain species, such as Acinetobacter baumannii, are not all the same: Due to their rapid development and spread, there are always different lineages that show different properties and variances in terms of resistance. Back in 2010, Seifert’s team examined a worldwide collection of more than three-hundred CRAB samples for their molecular epidemiology, i.e. the dynamics between the bacterial populations, in order to understand their resistance. Eight large, globally dispersed groups were identified, which are referred to as ‘international high-risk clones (ICs)’.

A recent study with samples from 114 study centres in 47 countries on all continents shows that CRAB can be classified largely into the known ICs. The most widespread group, IC2, was found on all continents and has increased significantly since 2010. A new group, IC9, was also discovered. Samples from patients in regions that were considered completely unrelated until now, for example Brazil and Poland, can be assigned to the same ‘family group’. The study also revealed regional peculiarities: for example, IC5 dominates Latin and South America.

“CRAB is a major threat worldwide, especially for seriously ill patients in intensive care units. In addition to the search for new medical compounds, we must make every effort to ensure the compliance with the necessary hygiene measures in hospitals in order to prevent the further spread of the dangerous pathogens,” said Dr Carina Müller, first author of the study.

“Bacterial research has suffered greatly during the coronavirus pandemic,” added Seifert. “The resistance problem increased disproportionately in the first two years of the pandemic, because bacterial infections were additionally assumed in cases of COVID-19 infections due to the lack of experience with and the severity of the symptoms.” This led to an increased use of antibiotics. Around eighty percent of all coronavirus patients treated in hospitals received antibiotics. “Antibiotics cannot be used to treat viruses; but the patients have a viral infection that makes the mucous membranes susceptible to a secondary attack by bacteria – and we can do something about that, so that’s what we do,” said Seifert, explaining the doctors’ actions. On the downside, the use of antibiotics, preferably broad-spectrum antibiotics, has increased bacterial resistance in hospitals that treated many COVID-patients.

With viruses against bacteria

In the fight against these multi-resistant bacteria, the researchers at University Hospital Cologne are breaking new ground: For example, Higgins’ team regularly tests new antibiotics for their effectiveness against CRAB, but also pursues new approaches, such as the treatment method with bacteriophages. Bacteriophages are small viruses that infect bacteria. Similar to how human cells can be infected by bacteria, bacteriophages can infect and destroy bacteria. The small, crab-like viruses specifically detect their target bacterium and insert their own genetic material. The bacterium is forced to produce more phages (‘bacteria eliminators’) until it bursts. The phages then look for new bacteria. If no bacteria are available as a host, the phages die off. Annika Claßen, a doctoral researcher with a scholarship from the German Center for Infection Research (DZIF) in the working group of Harald Seifert and Paul Higgins, develops CRAB-specific bacteriophages. However, their development is still in its infancy. In addition, bacteriophages are currently only approved for individual treatments. According to the German Medicinal Products Act, further randomized, controlled trials are necessary for the general approval of bacteriophages as a treatment of infections with multi-resistant bacteria. This includes data confirming efficacy and safety.

What to do if antibiotics no longer work?

In addition to the use of phages, there are other promising approaches. The team led by Dr Dr Jan Rybniker and Dr Alexander Simonis from University Hospital Cologne’s Infectiology Department of the Department I of Internal Medicine has adapted a form of therapy that is successfully used especially against viruses. They have developed so-called neutralizing antibodies for the treatment of infections with the bacterium Pseudomonas aeruginosa. Pseudomonas aeruginosa, like Acinetobacter baumannii, is another of the carbapenem-resistant bacteria that is considered a top priority for antibiotic research by the WHO. The bacterium also causes severe bloodstream infections as well as pneumonia, especially in mechanically ventilated patients. The often very resistant pathogen is also detected in wound and urinary tract infections.

Neutralizing antibodies – These proteins are an important part of immunity after an infection and protect against re-infection. All vertebrates possess the ability to form them. They can be isolated from the blood of recovered individuals for various diseases and used therapeutically, or produced synthetically.

For the study, antibodies were isolated from immune cells of patients suffering from chronic infection with Pseudomonas aeruginosa. The antibodies block an important virulence factor of the bacterium, the type III secretion system. This system allows bacteria to secrete bacterial proteins into the host’s cells through a needle-like structure. In extensive tests in cell cultures and animal models, blocking the secretion system with antibodies proved to be just as effective as conventional antibiotics. Since the activity of these antibodies does not depend on the mechanisms of action and resistance of conventional antibiotics, they could also be effective against highly resistant bacteria.

The team is now planning to further test and develop these antibodies in clinical trials so that they can be used as a new treatment option for infections with Pseudomonas aeruginosa in the long term. “The findings and the new experimental approaches can also be used for other bacterial pathogens,” said Rybniker. This approach thus represents a promising new way to treat infections with multi-resistant bacteria.

Intensive research into the spread of the pathogens and novel approaches such as bacteriophages therapy and the development of neutralizing antibodies provide new hope in the fight against multi-resistant bacteria. Rybniker summarized: “We will continue to rely on conventional antibiotics. However, we will only be able to reduce resistant bacteria in the future if we use all available resources and further advance alternative therapeutic approaches. The problem requires a comprehensive solution using state-of-the-art methods of prevention, diagnosis and therapy.”

In order to successfully implement such an approach at the Cologne campus, the Center for Infectious Dieseases (CIM) was founded in December 2022. It brings together the relevant specialist disciplines and forms a network for physicians and scientists focussing on infectious diseases in order to combine optimal patient care with the research and development of innovative prevention and treatment methods. Rybniker: “At our campus, we have the necessary resources and can only hope that the problem of the silent pandemic will be heard and tackled globally – especially in regions of our planet with less resources, which need our support.”