Strategies to stop the return of infectious diseases
Worldwide, resistant pathogens are gaining ground. Medical Microbiologist and Infection Control specialist Volkhard Kempf and his team are pinning their hopes on a new group of active ingredients, whose mode of action could make it more difficult for microorganisms to become insensitive to them.
The robotic arm clasps a thin wire with a tiny, glistening droplet at its lower end – part of a purulent sample diluted with buffer fluid. In a rapid zigzag pattern, the arm drips it over the nutrient in a Petri dish. A second arm picks the dish up and transports it to the incubator. Meanwhile, the robot is already busy with the next sample.
The Microbiology Laboratory at University Hospital Frankfurt is one of the largest of its kind in Germany. Year in, year out, over 170,000 samples – blood, saliva, fluids, swabs, stool – are tested here for microorganisms. Key steps in the work process, such as growing the bacteria detected in the samples on culture plates, are automated. Handling the vast number of assays would otherwise be impossible.
More and more often in the course of their work, staff at the laboratory encounter pathogens that are difficult to combat with antibiotics. This currently applies for one in every hundred samples. “In the past, these were mostly methicillin-resistant Staphylococcus aureus pathogens, commonly known as MRSA,” explains physician Volkhard Kempf. He is the director of the Institute of Medical Microbiology and Infection Control at University Hospital Frankfurt and in this capacity also responsible for the Microbiology Laboratory.
Less dangerous pathogens are also affected
For a long time now, MRSA in hospitals and care facilities has been a severe problem for doctors around the world. Not only do such staphylococci survive treatment with methicillin, penicillin and related antibiotics, they are mostly also insensitive to other groups of these once highly effective drugs. This multidrug-resistance makes MRSA infections difficult to treat, and it is estimated that they are accountable for more than 100,000 deaths worldwide every year.
“However, the number of severe MRSA infections in Germany and at our hospital has decreased in recent years,” says Kempf. “This is mainly thanks to the extensive hygiene measures that many hospitals have implemented to reduce their spread.” However, he finds another trend rather worrying – the increase in what are known as gram-negative bacteria with reduced sensitivity to last-resort antibiotics. This group includes, for instance, the intestinal bacteria Klebsiella pneumoniae and Escherichia coli as well as the pathogens Acinetobacter baumannii and Pseudomonas aeruginosa, which can cause pneumonia or infections of the urinary tract, for example.
“Some of these pathogens are now even multidrug-resistant, that is, they respond to practically none of the antibiotics available,” says Kempf. “In such cases, there is a risk that even harmless illnesses, such as a urinary tract infection, can turn into sepsis – the body’s extreme and potentially fatal reaction to an infection.”
War and hardship are drivers
Today, multidrug-resistant gram-negative bacteria are already becoming more common in Germany. “We do find them regularly in patients coming to us for treatment from countries with healthcare systems where these pathogens are more present,” explains Kempf. “Unfortunately, there have been increasing signs lately that the pathogens are becoming endemic in Germany, too. For example, we recently examined a young German patient with a urinary tract infection. Although she had never traveled overseas, she had contracted – not in a hospital but elsewhere – an infection with such a multidrug-resistant pathogen.”
So far, this is thankfully still an exception. When the staff at the Microbiology Laboratory detect such a bacterium in someone from Germany, the person concerned has usually just returned from a trip to foreign countries, including in Asia or the Near East. Among other things, medical tourism is one of the main reasons why multi-resistant pathogens are increasingly gaining ground worldwide, as some travelers, who for some reason or other undergo medical treatment abroad, bring them back home undetected.
War is another important factor: Doctors working in field hospitals have to treat the wounded in the most basic conditions without sophisticated hygiene measures, which makes it easy for pathogens to spread. Then there are other trends, such as our ageing society. More and more people are suffering from illnesses that require treatment in the last years of their lives and necessitate at least a temporary stay in hospital. “The possibility of contracting an infection during a complex operation cannot always be ruled out,” says Kempf. Even everyday procedures such as changing an infusion or a urinary catheter are potential routes of transmission and subsequent infection, which can, however, be countered by maintaining consistent basic hygiene measures.
Search for novel drugs
In addition, it is especially in hospitals that many different types of bacteria come together. This can also promote resistance because some microorganisms are able to transfer their resistance genes to bacteria of a completely different species. Metaphorically speaking, they “transmit” their antimicrobial resistance genes. All these factors will probably contribute to many diseases becoming significantly more dangerous again in the future that had largely lost their threat.
That is the reason why researchers worldwide are looking for new, more effective drugs – including Volkhard Kempf. He and his team are pinning their hopes on substances based on a completely new mode of action. “Antibiotics such as penicillin stop bacteria from multiplying,” he says: “For example, they prevent the microorganisms from forming a stable cell.” The pathogens can undermine this mechanism by altering the molecular machinery responsible for building the cell wall, for example.
Bacteria, however, can overcome this therapeutic principle: Cell wall synthesis can be modified, making bacteria resistant to cell-wall-active antibiotics, for example. Kempf’s team, by contrast, is looking for antibiotics that bind, for instance, to structures that the bacteria urgently need to infect their target cells. To become insensitive to such “anti-virulence compounds”, the microorganisms would have to alter these pathogenicity factors. This, however, would jeopardize their “business model” because they need these factors to infect patients.
Attack on the business model of pathogenicity
Researchers call this an “anti-virulence strategy”: The active substance targets mechanisms that the pathogens require to cause an infection. “We therefore hope that drugs based on this principle will maintain their effectiveness for much longer,” says Kempf. His group is primarily working on adhesins, molecules via which bacteria adhere to patients. However, these adhesins are often highly specific: They can bind to the cells in the human body that are the respective pathogen’s niche.
“We have already found active substances against certain adhesins that are present on the surface of many gram-negative bacteria,” explains Kempf. Via these structures, the pathogens bind to a surface molecule that is present, for example, on the endothelial cells that line the blood vessels – the glycoprotein fibronectin. “Using an antibody, we managed to significantly reduce the binding of the bacteria to the endothelial cells.”
Alongside immunization, antibiotics are still a powerful weapon against bacterial infections. But this weapon has become blunted over the last decades. This can also be attributed to our own behavior. For a long time, antibiotics were prescribed all too rashly, especially in industrialized but also in developing countries – for viral infections, for example, that do not respond to antibiotics at all. In addition, some patients do not take them until they have finished the course of treatment but instead stop as soon as the symptoms subside. This enables some of the more resistant types of bacteria to survive and multiply all the faster, as their non-resistant conspecifics can no longer compete with them.
Manual for the prudent use of antibiotics
Over the last decades, however, the use of antimicrobial agents has changed. Doctors no longer prescribe them without further ado, as was partly the case twenty or thirty years ago, and they explain more clearly to patients when they are necessary and when not. University Hospital Frankfurt helps: For several years now, the Institute of Medical Microbiology and Infection Control and the Department of Medicine II, Infectious Diseases, have published a reference booklet with information on the use and dosage of antibiotics for various diseases – the “Frankfurter Infektionsfibel”, a diagnostic, therapeutic and infection prevention and control manual.
However, greater discipline when issuing prescriptions will not solve the problem of bacterial resistance by itself. In the search for new active substances, university hospitals play a particularly important role because developing such drugs is time-consuming and costs run into billions. “At the same time, pharmaceutical companies don’t earn much from them,” says Kempf. “After all, the new antibiotics should only be used when there is no other way to prevent the pathogens from developing resistance to these, too.” For the pharmaceutical industry, the risk is high that its development work will not pay off in the end.
By contrast, university-based research institutions can afford to be patient. “Understanding the infection biology of a bacterium and working out how it can best be disrupted often takes many years,” says Kempf, who knows what he is talking about: It took almost 20 years to develop such an anti-virulence compound – from the finding of the bacterial target structures to successful experimental infection experiments.
About / Volkhard Kempf, , born in 1969, has been a professor at University Hospital Frankfurt since 2009, where he heads the Institute of Medical Microbiology and Infection Control. Kempf studied medicine in Würzburg and Oxford and earned his doctoral degree in medicine in Würzburg. Among other things, he is a member of the Commission for Hospital Hygiene and Infection Prevention (KRINKO) of the Federal Ministry of Health at the Robert Koch Institute. He is also the chairperson of the permanent working group “Conciliary and Reference Laboratories” of the German Society for Hygiene and Microbiology.
volkhard.kempf@ukffm.de
The author / Frank Luerweg, born in 1969, graduated in biology. He was previously Deputy Press Spokesperson at the University of Bonn and has been working as a freelance science journalist for 13 years. www.wissenschaftsgeschichten.de
