Published: 13-06-2022 11:53 | Updated: 15-06-2022 11:10

Antibiotic resistance – the silent pandemic

Foto: Getty images

Antibiotic resistance is sometimes referred to as the silent pandemic – a contagion that spreads without us really knowing its extent or severity. But research is in progress to find new ways of fighting bacteria. And as with COVID-19, everyone can help to reduce the spread – and save lives.

Text: Annika Lund for Medicinsk Vetenskap no 2, 2022 | Spotlight on antibiotic resistance

Imagine an elderly patient who’s given a new hip joint. The operation goes well, and the patient becomes more mobile again. But then an infection develops around the prosthesis. The infection is difficult to cure and turns out to be caused by MRSA, methicillin-resistant staphylococcus aureus. The infection is treated with more potent antibiotics, but the bacteria eventually reach the bloodstream in an escalating process and the patient dies of sepsis.

Or imagine a person with cancer who’s starting to put the disease behind them following surgery and chemotherapy. The prognosis is good. But then they get a stubborn cold that develops into pneumonia. This turns out to be caused by PNSP, penicillin-non-susceptible pneumococcus. This is an infection that can be treated with other antibiotics, but it takes a few days to investigate and the bacteria get the upper hand in the meantime, eventually leading to the patient’s death.

Or imagine a person admitted to hospital and recovering from pneumonia, which is sensitive to antibiotics. But then they contract a urinary tract infection caused by E. coli bacteria that have found their way in through a urinary catheter during their hospital stay. The bacteria are of a variant that can produce the enzyme ESBL. This makes them resistant to many antibiotics, but there are still some that work. Unfortunately, it turns out that these particular bacteria produce an enzyme of the ESBL-CARBA subgroup, and doctors are effectively left with no treatment options. The infection reaches the blood and the outcome is fatal.

This is happening all over the world, right now. It happens in Sweden, too.

Difficult to obtain reliable figures

But it’s hard to say exactly how often it happens. According to one estimate, around 700,000 people globally die each year as a result of antibiotic-resistant bacteria. This estimate was presented in 2019 by the Interagency Coordination Group of Antimicrobial Resistance (IACG), an expert group led by WHO on behalf of the UN.

Other estimates suggest even higher death rates. For example, a study was published in The Lancet in February 2022 using a new model for making assessments from existing sources. According to this estimate, 1.27 million people died in 2019 from infections that they would have survived if the bacteria had been sensitive to antibiotics.

As I said, it’s difficult to obtain reliable figures. One reason for this is that statistics on causes of death indicate diseases, such as sepsis – but they don’t usually indicate what kind of bacteria caused the sepsis. Moreover, many countries have insufficient resources to examine the bacteria in more detail, which means that accurate diagnosis falls by the wayside.

According to estimate in The Lancet, 75 per cent of these deaths were caused by six particularly worrying infections, such as MRSA, resistant pneumococci and different variants of resistant intestinal bacteria, such as E. coli. But back in 2017, WHO presented a list of resistant bacteria that should be prioritised when it comes to the development of new antibiotic varieties, for example. These two lists only overlap to an extent – which indicates just how much we need to know about which bacteria will threaten us in the future.

Relatively favourable situation in Sweden

So – what’s the situation in Sweden? More favourable. Sweden has a low incidence of resistant bacteria compared to the rest of the world. This is reflected, for example, in the reporting requirements under the Communicable Disease Act when a laboratory detects any of the following four infections in a sample: MRSA, PNSP, the intestinal bacterium VRE or ESBL and ESBL-CARBA-forming intestinal bacteria.

According to the latest Swedres-Svarm report in which the development of antibiotic resistance in Sweden is summarised by the National Veterinary Institute and the Public Health Agency of Sweden, the problem is most widespread for ESBL-forming intestinal bacteria, mainly E. coli bacteria but also Klebsiella. In 2020, more than 8,200 cases of infection or carrying of ESBL-forming intestinal bacteria were reported in Sweden, leading to sepsis in 727 cases.

Saving lives in these contexts requires treatment with antibiotics that target the bacteria.

And that’s the dance, that eternal tug-of-war between the healthcare system and the bacteria that cause disease: a patient carrying bacteria that are insensitive to a particular antibiotic is instead treated with a variety that still works. But over time, the bacteria develop resistance to that variety as well. The healthcare system will then change the antibiotic again – until, in a worst-case scenario, there are no more antibiotics left to use. This situation is close to occurring in the case of gonorrhoea. There, the first choice is now what used to be the last effective option.

For decades, few new antibiotics have reached the market. And those that have arrived are mainly variants of existing substances. These new variants may be useful in the short term, but the bacteria often develop resistance quickly due to the fact they’re closely related to other antibiotics that have already been used in healthcare for a long time.

At the same time, we’ve increased their use – which has given the bacteria more of a chance to develop resistance to them.

How resistance develops

Some bacteria are naturally resistant to antibiotics. Other bacteria acquire resistance to antibiotics. This can happen through mutations, where the bacterium develops resistance by chance as it divides, giving it a survival advantage. It can also happen when bacteria transfer resistance genes between one another via what are known as plasmids, tiny DNA molecules that bacteria usually share with one another.

Sources: Christian G. Giske et al.

However, the Swedres-Svarm report describes a decreasing number of cases of most notifiable bacteria in 2020. The amount of antibiotics dispensed at pharmacies also fell by 17 per cent between 2019 and 2020. The reduction was 28 per cent for just the varieties used for respiratory infections.

According to the report, this is probably due to the change in our behaviour during the pandemic. Social distancing and staying at home when we feel ill may have reduced the spread of other infections, such as resistant bacteria. Another important reason is that people’s travel was restricted. This in itself may have reduced the spread of infection – but it also meant that fewer screening tests were done on admission to hospital.

The problem is expected to worsen

However, although the figures for 2020 were lower, the problem with resistance is expected to worsen in the future. And to dramatic levels, from a global perspective.

According to one forecast, we risk being in a situation within a generation, by 2050, where 10 million people a year worldwide die from infections involving resistant bacteria. This forecast is taken from the 2019 report of the WHO-led expert group IACG. But the same figure was already disseminated in 2014 from a report commissioned by the British government. According to that report, death rates at those levels will affect the global economy, stating that we can reasonably expect a drop in global GDP of up to 3.5 per cent.

10 million deaths a year is comparable to the nearly 6.2 million people who’ve died so far as a result of COVID-19, according to statistics released by WHO in April 2022. Or compare this to the 1.5 million or so people who die each year from tuberculosis, the most deadly bacterial infectious disease globally.

But the problem has more dimensions than can be expressed purely in terms of death rates. If there are no drugs that can be used to deal with serious infections, it becomes less self-evident that people should expose themselves to situations in which the risk of contracting an infection is heightened.

Such situations include all surgeries, cancer treatments and immunosuppressive therapies, to name but a few. Or, to take the argument to its logical conclusion, it may be risky to even visit a hospital, where resistant bacteria are naturally more prevalent than in many other settings. In short, everything that’s part of modern healthcare may become more difficult to perform if there are no drugs that can be used to control infections; from caesarean sections and hip replacements to organ transplants and care for premature babies.

Virus against bacteria

But the gloomy forecast, where 10 million people a year are at risk of dying on account of resistant bacteria, is just that – a forecast. It’s based on the assumption that no action will be taken to counter the threat.

Christian Giske. Photo: Stefan Zimmerman.
Christian Giske. Photo: Stefan Zimmerman.

And this is not the case. Attempts are being made to prevent this development. For instance, research is being conducted into new ways of fighting bacteria. One of the people grappling with this issue is Christian G. Giske, Professor at the Department of Laboratory Medicine at Karolinska Institutet. He and his colleagues are investigating the possibility of making bacteria succumb to infection – with viruses. The principle is easy to explain. Some viruses, known as bacteriophages, or phages, attack only bacteria. Once inside the bacterium, the virus reproduces and then tries to get back out of the bacterium, but in the process the bacterium bursts and dies. The virus then seeks out new bacteria, which also die.

However, it’s more difficult to make this work in a clinical situation. The phages are extremely targeted, attacking only one or a few strains of bacteria – they can kill one strain of E. coli, for example, but leave others alone. This makes it difficult to find the particular bacteriophage that would work for a specific patient. At the same time, that’s why they’re gentle – they only kill unwelcome bacteria.

“This is both the advantage and disadvantage of phage therapy. On the one hand, we need to isolate extremely large numbers of bacteriophages if we are to have a large enough bank to be useful. But on the other hand, this is gentle on the patient,” says Christian G. Giske.

He’s currently planning animal trials where they’ll be trying to cure carriers of resistant Klebsiella bacteria in the intestines of mice. If it proves effective, it could be used to treat carriers in nursing homes, for example, or other settings where many people are living with resistant gut bacteria that regularly flourish to cause urinary tract infections that are difficult to treat.

“This isn’t an option for acute infections, but it could be used to get rid of long-standing, sub-acute infections that are difficult to treat. It takes time to find the right phage therapy for a specific patient,” says Christian G. Giske.

Infections around joint replacements, such as around the hip, are another application. One approach would be to take a sample from the infected area and then expose it to a plethora of different phages. This would reveal which bacteriophages are attacking the bacteria in question. These would then be prepared in large quantities and administered to the patient.

But plenty of problems remain to be resolved – for instance, there has to be a bank of phages that can be tried out. And a bank of this kind must be maintained gradually. There are also legal barriers, with each individual bacteriophage currently requiring approval from pharmaceutical authorities.

“Theoretically, it’s possible to produce phages with a more widespread impact so that they can be used in more situations. But this will end up causing phage resistance. As I see it, we mustn’t fritter away this solution by starting to use it in the same way as we’ve used antibiotics. I view this as precision medicine, something to be used after individual testing. This will allow us to develop a method to treat long-lasting infections that are currently treated with antibiotics,” says Christian G. Giske.

What does “infected” mean?

Carriers: People can have resistant bacteria on their skin, in their noses or in their intestines without knowing it. If the bacterial flora is otherwise healthy, the resistant bacteria are usually unable to compete with all the other bacteria around them.

Infected: Carrying resistant bacteria increases the risk of them causing an infection. A wound can give skin bacteria an opportunity to get past the protection provided by the skin, and a catheter can give intestinal bacteria a chance to enter the urinary tract.

Incurable? No, recovery from an infection with resistant bacteria is possible. And even people who are carrying resistant bacteria without knowing it usually manage to get rid of them, but it can take many months; and the bacteria can spread to others or cause an infection in the meantime.

Staffan Normark Foto: Fredrik Person

Vaccines and small molecules

Targeted, narrow treatments are the way forward, according to Staffan Normark, Professor of Medical Microbiology at the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet.

“In our research, we’re trying to find new types of ways of attacking bacteria where you don’t violently knock out lots of bacteria in the intestinal tract. This broad-spectrum approach is what’s led to the problems we have now, where we’ve helped bacteria to develop resistance,” says Staffan Normark.

Did you know…

... more than one in two cells in your body is a bacterium? Or, to put it another way, more than half of your body isn’t human.

Source: Ron Sender et al. Cell, January 2016

He and his colleagues are working on a number of projects. Among other things, they’re hunting for new vaccines against pneumococci because the existing vaccines have been so effective in eliminating several strains, leading to other strains taking over as the cause of disease.

“We’re trying to develop new vaccines to fight the pneumococcus strains that are now in circulation. Or preferably against all strains,” says Staffan Normark.

In another project, they’re trying to develop antibiotics with a partially new mechanism of action. They’re targeting the bacterial cell wall, as is the case for most antibiotics used in healthcare today. For instance, penicillin works by blocking a particular protein that’s essential for the bacteria to form and hold together their cell walls. The bacteria burst, or lyse, when the cell wall breaks.

Staffan Normark and his colleagues are researching other ways of accessing the cell wall. They’ve targeted a substance known as lipid II, a fat molecule that plays a crucial role in the bacteria’s continuous maintenance of their cell walls. New building blocks for the cell wall will be delivered from this molecule. Blocking lipid II prevents this – leading to lysis of the bacteria.

A lipid II-targeted antibiotic, daptomycin, is already in clinical use and can be used for blood infections caused by MRSA, resistant skin bacteria. Another, teixobactin, is undergoing trials and has shown efficacy against both MRSA and the intestinal bacterium VRE.

Researchers at Karolinska Institutet, together with colleagues in Umeå and Germany, have now discovered a group of molecules known as THCz that block lipid II.

THCz are very tiny molecules, unlike other substances that target lipid II.

Their small size offers great advantages. A small molecule can find its way past protective membranes that some resistant bacteria acquire. A small molecule is also easier to modify – it can be developed in research for use in different situations, against different bacteria.

In laboratory trials, there have been varying degrees of efficacy for THCz on several bacteria such as MRSA, VRE and pneumococci, where the need for new antibiotics is high. Researchers have also seen effects on gonococci, which cause gonorrhoea, and on mycobacteria, a group of bacteria that includes the tubercle bacillus.

“We want to try to modify these molecules so that they have an effect on tuberculosis. Say what you will about antibiotic resistance, but multidrug-resistant tuberculosis is one of the nastiest things we have to deal with,” says Staffan Normark.

But even here, there are still many problems to be resolved before the lab trials might lead to a drug that can help patients. For example, the molecule is also likely to bind to some human cells that may have molecules similar to lipid II. In plain language, this means that THCz today can have serious side effects, that the substance is toxic.

“Our goal is to increase efficacy and reduce toxicity. And then we have the tuberculosis bacterium in our sights,” says Staffan Normark.

If successful, the target lipid II appears to have several advantages, one of which being that it’s a fat molecule. It’s less mutable than a protein, less prone to change with mutations. This means that bacteria are likely to find it more difficult to develop resistance to a drug that targets lipid II.

“It’s not possible to imagine better or worse lipid II, the bacterium has no reason to mutate to provide better functions here. So it’s probably difficult to develop resistance to the mechanism of action that we’re trying to target,” says Staffan Normark.

Georgios Sotiriou Photo: Johannes Frandsén

Nanomaterials may help

The research team he’s part of is collaborating with Georgios Sotiriou, a civil engineer and researcher at the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet. This collaboration is looking at a number of aspects, one of them being how to deliver a drug more directly to the harmful bacteria and spare all other cells.

“We’re seeing how we can use nanomaterials that are about the same size as many proteins. That’s how they can interact with the body in different ways. We can use these materials to transport drugs, for example, but they can also have an effect on their own. The aim is to achieve higher efficacy with lower doses,” says Georgios Sotiriou.

He has a number of other projects in the pipeline on this kind of materials research. For instance, his research team has shown that a special patch can deliver antibiotics locally into the skin via tiny, tiny needles, directly into the wound, and kill MRSA bacteria.

But direct delivery of drugs is only one of several fields that his lab is looking at. Another involves trying to reduce the spread of resistant bacteria, particularly in elderly or frail patients who are already receiving care in hospitals or nursing homes.

It’s a well-known fact that different types of entrances to the body provide shortcuts for resistant bacteria. Georgios Sotiriou and his colleagues are investigating how urinary catheters can be coated with antibacterial substances to make them safer to use.

One substance described as particularly interesting in this context is silver.

The antibacterial properties of silver are nothing new. On the contrary: it’s been used for many hundreds of years to treat various kinds of wounds and burns. But exactly how it should be used – exactly what quantities are needed for what situations – has still not been investigated. This is evident from several SBU reports, where the message is repeatedly “more knowledge is needed.”

But silver isn’t a drug. It’s a metal that any manufacturer can add to their products. It’s then possible to claim that the jumper or towel has an antibacterial effect and convince buyers that this justifies higher prices.

This is how silver has found its way into all sorts of industries. Moreover, large quantities of colloidal silver are sold as a general wonder drug.

“I’m quite indignant about this. Silver, or rather silver ions, have a potent antimicrobial effect. But it can’t be added to everything without knowing the right proportions and the right application. Irresponsible overuse is what increases the risk of bacteria developing resistance to silver. It’s absolutely unnecessary,” says Georgios Sotiriou.

The fight against harmful bacteria

Here are some of the things that are being done or should be done to continue to fight dangerous infections.

Use antibiotics sparingly

Using fewer antibiotics gives bacteria fewer exposure opportunities, which delays the development of resistance. Today, the food industry uses as many antibiotics as the healthcare sector, according to an estimate by the International Association of Consumer Groups (IACG). Another important aspect is to reduce the release of antibiotics into the environment from sewage, for example, or from factories that manufacture them.
How you can contribute: Return leftover antibiotics to your pharmacy. Follow the course of treatment exactly as prescribed by your doctor. Choose meat and dairy products from countries with low antibiotic use, even when eating out. Routine administration of antibiotics through animal feed is now banned throughout the EU. But antibiotics are still used to treat infections in animals in the EU. This practice isn’t widespread in Sweden.

Reduce proliferation

Awareness needs to be raised among travellers about how to
avoid carrying resistant bacteria home. Research into treating carriers is ongoing.
How you can contribute: When travelling abroad: eat cooked vegetables, peel fruit, don’t eat ice lollies or ice cream, eat well done meat and only pasteurised cheeses and dairy products. Avoid seeking medical care if you can. When you’re in contact with healthcare services in Sweden, tell us if you’ve been abroad recently. Always: Stay at home when you are ill, make sure you wash your hands thoroughly.

Vaccinate to eliminate bacteria

A more effective vaccine against tuberculosis would save many lives. Around 230,000 people die from resistant TB each year, according to a 2019 report by the IACG expert group. That’s about a third of people who die as a result of antibiotic-resistant bacteria, according to this report.<
How you can contribute: Follow recommendations on vaccinations.

New ways to fight bacteria

Research is underway to find new approaches in the fight against harmful bacteria. Here are two examples:

  • Infect the bacteria with viruses known as bacteriophages.
  • Exploiting the bacteria’s own warfare, what’s known as the TYP6 secretion system. This system, which only some bacteria have, is used to damage other bacteria and cells in the fight for nutrition and living space.

Make insensitive bacteria sensitive again

Bacteria that have become insensitive to certain antibiotics may become sensitive to this treatment if it’s combined with heat or light therapy, for example. Silver ions can also increase the sensitivity of insensitive bacteria, according to studies.

Sources: Christian G. Giske, Malin Grape, Bodil Lund, Staffan Normark, Georgios Sotiriou et al.