Resistant germs – How Swiss researchers are fighting antibiotic resistance – Knowledge

When antibiotics lose their effectiveness, even harmless infections can become life-threatening again. Even a cut on the finger could be fatal. Because resistance is increasingly becoming a problem.

What a group of international experts in the specialist magazine «The Lancet» published in January, makes you sit up and take notice: Using data from various sources such as specialist literature, hospital databases or monitoring systems, the research group calculated that in 2019 4.95 million deaths worldwide could be linked to resistant germs.

Over 1.2 million people have died directly from infection with resistant bacteria – more than from HIV/AIDS (864,000 deaths) and malaria (643,000).

Respiratory infections particularly common

According to the researchers, problems with resistant germs were particularly common in infections of the respiratory tract – such as pneumonia. This alone killed 400,000 people.

But even blood poisoning or appendicitis could often no longer be treated with antibiotics due to the resistant bacteria.

Modern medicine in jeopardy

Infectiologist Andreas Widmer has been fighting for years as a hospital hygienist and as president of the association Swissnoso against the spread of antibiotic resistance. He warns of the dangers posed by bacteria: “Half of the patients in the hospital receive antibiotics, because many of today’s therapies cannot be carried out without these drugs.”

The resistance mechanisms

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Bacteria multiply by cell division. This sometimes results in mutations. These random changes in the genome can lead to the development of resistance.

  • It can happen that a mutated bacterium forms new enzymes due to the change in its genetic material, which break down the antibiotic active ingredient and thus render it ineffective.
  • The mutation can also change the proteins of the bacterium that are targeted by the antibiotic.
  • Also possible: the mutated bacterium forms new openings through which it can expel the drug again.
  • Or it changes its cell envelope. This means that the antibiotic cannot penetrate at all.

Without antibiotics, the isolated, randomly mutated bacteria usually disappear again. That can change with antibiotics. Although the antibiotic kills the normal bacteria, the mutated bacterium can protect itself against the drug and survive.

Since the normal bacteria have been killed by the antibiotic, the mutated bacterium now has room to multiply unhindered. The use of an antibiotic has created a resistant family of bacteria.

Bacteria can not only transmit such resistance vertically to their offspring, but also spread the resistance horizontally across the bacterial family.

Because bacteria form a kind of small gene snippets, so-called plasmids, which they excrete. These are then taken up by other bacteria and incorporated into their genome. If such a plasmid carries the genetic information for a resistance, this resistance can be transferred from one bacterial species to another.

A caesarean section is only possible thanks to the administration of antibiotics to protect the mother from postnatal infections. Likewise, joint replacement operations or organ transplants cannot be carried out without antibiotics. Cancer patients can only be protected from life-threatening infections during chemotherapy thanks to antibiotics.

However, these achievements of modern medicine are in danger. In particular, the widespread and uncritical use of antibiotics worldwide means that this weapon is becoming less and less effective.

Uncanny speed

How quickly bacteria develop resistance is shown by an EHarvard Medical School experiment from 2016: The researchers divided a 1.2 meter field into several zones. There was a bacteria-friendly zone on the outside left and right. With each field towards the inside, the culture medium was mixed with an antibiotic in increasing doses – from the single dose on the outside to a 1000-fold dose in the middle.

When the Harvard researchers added Escherichia Coli bacteria to the field, the germs initially only colonized the outermost fields. The antibiotic was working.

Then the first successful mutation arose. The bacteria continued to spread. With each new strip, growth came to a brief halt. It did not take long for further mutations to form, with which the bacteria survived even a thousand-fold concentration of the antibiotic after eleven days.

Fight bacteria with viruses

Neuro-urologist Thomas M. Kessler is familiar with the problem of resistance from his everyday clinical work at Balgrist University Hospital: “Almost every consultation I see patients who suffer from recurring urinary tract infections, some with resistant germs.”

Since he has reached his limits when treating such infections with antibiotics, he is looking for new therapy options. He focuses his interest on the natural enemies of bacteria: bacteriophages. In other words, viruses that multiply in bacteria and destroy their host in the process.

They occur everywhere in nature. There are correspondingly many different types of phages, but each of them only attacks a specific type of bacteria. Phage therapy makes use of this mechanism of action by using the viruses specifically against the disease-causing bacteria. “Like a key, they only fit into one suitable keyhole,” explains Thomas M. Kessler.

Discontinued due to antibiotics

This therapeutic approach was discovered in Paris in 1917 by the French-Canadian Félix d’Herelle. In the years that followed, phages were used against typhus, cholera, dysentery, purulent infections and urinary tract infections with varying degrees of success.

However, with the discovery of antibiotics in the late 1930s, phage therapy was forgotten again. With antibiotics, doctors now had an extremely effective drug against most infectious diseases that was easy to produce.

From Tbilisi to Switzerland

Only in the former Eastern bloc, where access to antibiotics was more difficult, has the therapeutic approach continued to be researched and practiced over the past 60 years. Even today, for example, offers this Eliava Institute in Georgia phage therapies, among other things against chronic urinary tract infections or chronically inflamed wounds.

Thomas Kessler has been following the work in Georgia with great interest for a long time. He has been to Tbilisi himself and has one there study carried out for urinary tract infections. He compared the effect of bacteriophages with antibiotics and a dummy drug. “Although the bacteriophages were no better against bladder infections, they were no worse than antibiotics either,” the urologist summarizes his study results.

We now have to develop treatment methods – in case the antibiotics eventually stop working.

He also used such phages once here in Switzerland in an experimental test on a patient with a bladder infection with resistant germs.

The therapy worked well at first. But after five days the infection came back. “We believe that the bacteriophages did not kill all the bacteria present in the bladder and that is why the infection flared up again,” Thomas M. Kessler regrets.

Designer phages as an alternative

That is why the Zurich universities and university hospitals in the research project «immunophage» joined forces to revolutionize phage therapy. Customized bacteriophages for the treatment of urinary tract infections are to be created in the laboratory.

“We want to genetically modify the bacteriophages so that they can attack and kill the problem germs very effectively,” explains Martin Loessner, the microbiologist at the ETH who is responsible for the phages and their engineering.

Further information should even be able to eliminate and neutralize other bacteria that are common in these infections.

First human trials

In addition, the body’s own immune system is to be stimulated via the genetically modified phages. The phages are currently being developed in the laboratory.

The first tests on humans are scheduled to start at the end of 2022. “We have to develop the new treatment methods now in order to be ready when these diseases can no longer be cured with antibiotics,” says Martin Loessner, looking to the future.

There are still many hurdles on the way to this new therapy. “But if the designed phages achieve the desired effect, it would be a revolution in the treatment of infections,” Thomas M. Kessler is convinced.

Because phages modified in this way in the laboratory have the potential to be used in a wide variety of infections. The researchers expect the first meaningful results to be available in around five years.

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