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How do we tackle antibiotic resistance? Victor Torres/Stocksy
  • Bacterial resistance to antibiotics is a major global health issue.
  • Researchers have found that as some bacteria develop resistance to one antibiotic, they can develop sensitivity to another at the same time.
  • Switching between these antibiotics may be one way of responding to growing antibiotic resistance.
  • However, the researchers behind the present study show that very few bacteria operate in this way, suggesting that antibiotic cycling has a limited value.

In a new study, researchers have shown that antibiotic cycling — which involves doctors switching between antibiotics to overcome antibiotic resistance — may be an ineffective and unsustainable strategy.

However, in their study, which appears in The Lancet Microbe, the researchers did find that some subpopulations of bacteria may be appropriate for antibiotic cycling, in limited cases.

Antibiotics are crucial for treating and preventing bacterial infections.

The use of microorganisms to protect against infections has been documented in ancient China, Greece, and Egypt, while the modern use of antibiotics began following Alexander Fleming’s discovery of penicillin in 1928.

Today, however, bacterial resistance to antibiotics is a serious, growing health issue. The World Health Organization (WHO) describes antibiotic resistance as “one of the biggest threats to global health, food security, and development today.”

Bacteria are likely to develop resistance as antibiotics are used. However, the growing prevalence of resistant bacteria results from a range of modifiable factors.

Researchers have found that antibiotic resistance has been exacerbated by the overuse of antibiotics, inappropriate prescribing, and the extensive use of these drugs in intensive livestock farming.

There is also a lack of research into new antibiotics, driven by the profit motive of the pharmaceutical industry, which encourages research into treatments for chronic illnesses over curative treatments.

According to Antibiotic Resistance Threats in the United States, a 2019 report from the Centers for Disease Control and Prevention (CDC), bacteria and fungi resistant to antibiotics cause the deaths of around 35,000 people each year.

Dr. Robert R. Redfield, former director of the CDC, says that the report “shows us that our collective efforts to stop the spread of germs and preventing infections is saving lives.”

Referring to an earlier version of the paper, he notes that “The 2013 report propelled the nation toward critical action and investments against antibiotic resistance. Today’s report demonstrates notable progress, yet the threat is still real. Each of us has an important role in combating it. Lives here in the U.S. and around the world depend on it.”

Meanwhile, research from from Public Health England (PHE) shows that doctors diagnose 178 antimicrobial resistant infections each day.

Prof. Isabel Oliver, director of the National Infection Service at PHE, says, “We want the public to join us in tackling antimicrobial resistance — listen to your [family doctor], pharmacist, or nurse’s advice, and only take antibiotics when necessary.”

“It’s worrying that more infections are becoming resistant to these lifesaving medicines. Taking antibiotics when you don’t need them can have grave consequences for you and your family’s health, now and in the future.”

Researchers have suggested that one way to counter antibiotic resistance may be to identify strains of bacteria that become resistant to one antibiotic while becoming sensitive to another at the same time, due to the same evolutionary pressures.

In these circumstances, cycling between the two antibiotics may delay or inhibit bacterial resistance to the drugs.

However, research into this process has produced mixed results, and many studies that have identified this “collateral sensitivity” have been laboratoryinvestigations, not studies in live animals.

Scientists have highlighted how bacteria react differently to antibiotics depending on the metabolic conditions that they are in, and so bacterial resistance in the lab may differ from that in a human host.

Speaking to Medical News Today, Dr. Erik Wright, from the Department of Biomedical Informatics at the University of Pittsburgh, and the corresponding author of the present study, said:

“Antibiotic resistance is a common problem in the clinic. We originally set out to find antibiotic pairs displaying seesaw susceptibilities. That is, a pathogen [cannot] be resistant to both antibiotics in the pair at the same time. We called this disjoint resistance because a disjoint set is one that is mutually exclusive.”

“The existence of such antibiotic pairs is expected because of a phenomenon known as collateral sensitivity: When a pathogen adapts to one drug, it can become more sensitive to other drugs (collateral sensitivity), or it can become more resistant (cross-resistance).”

“Research had previously shown that collateral sensitivity exists between some antibiotic pairs [in laboratory studies]. The question is whether this leads to observing disjoint resistance in the clinic. If it does, then we could potentially use these pairs of antibiotics to avoid multidrug resistance.”

In the present paper, Dr. Wright and co-author Andrew Beckley, a doctoral student in the same department, wanted to gain better real-world information about which antibiotic pairs develop collateral sensitivity. To do so, they conducted a retrospective study of 448,563 antimicrobial susceptibility test results.

They drew the data from 23 hospitals between January 2015 and December 2018. All the hospitals were part of the University of Pittsburgh Medical Center system.

The researchers then developed a scoring method to identify antibiotics that were independently resistant, concurrently resistant, or disjointedly resistant — the latter offering the potential for antibiotic cycling.

The researchers found 69 pairs of antibiotics that had some of the properties of disjoint resistance for subpopulations of the six most common bacterial pathogens.

However, at a species level, this dropped to 6 out of 875 antibiotic pairs — or only 0.7%.

By contrast, more than half of the pairs of antibiotics showed concurrent resistance, meaning that bacteria were typically resistant to both antibiotics.

Further, this concurrent resistance extended to triplets of antibiotics to a greater extent than the researchers had predicted, based on the data for the pairs of antibiotics. This suggests that as bacteria develop resistance to one antibiotic, they are more likely to develop resistance to multiple others, the researchers believe.

Dr. Wright said to MNT, “We mostly found concurrent resistance between antibiotic pairs, which is the opposite of disjoint resistance. This means that the evolution of antibiotic resistance begets more antibiotic resistance. We also showed this was true for combinations of three antibiotics.”

“At this point in the study, it was not what we had set out to find. But we knew from previous [laboratory] experiments that collateral sensitivities are not always conserved across all strains of a species.”

“Unfortunately, bacteria are only classified to the species level in our dataset. However, we also knew that resistance is often clustered on phylogenetic trees, since it is heritable. So we could use resistance to an antibiotic as a marker for subspecies level classification.”

“We repeated our analysis on subpopulations of species that were resistant to one of the drugs in our set. When we did this, it revealed 69 antibiotic pairs displaying disjoint resistance.”

Dr. Wright told MNT that while fewer pairs of antibiotics maintained disjoint resistance, the 69 pairs identified at the subspecies level would make a good starting point for further research.

“One potential strategy to combat antibiotic resistance is to alternate between different antibiotics. Most often, this strategy has been employed by giving different antibiotics to different patients within the same hospital, either switching antibiotics every other patient or every other month.”

“These switching strategies have failed to curb resistance, but this might be because of the wrong choice of antibiotic pairs. We showed how to find antibiotic pairs that are most likely to be successful at mitigating antibiotic resistance. These are good antibiotic candidates for future clinical trials, but they will also require subspecies-level classification to be correctly applied.”

“Our study also revealed which antibiotic pairs display the worst concurrent resistance, and the use of these antibiotics together should be avoided.”