The word ‘collateral’ elicits an unpleasant image of unintended damages in our minds. Sometimes though, the collateral effects could be welcome. At least that was the thought of the group of doctors and scientists at the Minneapolis Veterans Affairs Medical Center in the 80s. In a 10-year long experiment, this group employed a novel strategy to muffle the rising incidence of antibiotic resistance. Instead of using a single antibiotic for an extended period they cycled between different antibiotics, amikacin, and gentamycin, of the same class of antibiotics called aminoglycosides. The results were indeed encouraging as they observed fewer instances of antibiotic resistance. This idea of one drug reducing the effect of another stirred much interest amongst the scientists and came to be known as ‘collateral sensitivity.’

Another couple of trials of cyclic medication produced hopeful results. One was conducted on the patients with neutropenia. These patients are typically immunocompromised due to the lower repertoire of a certain type of white blood cells. In a second clinical study, patients admitted in ICU were also shown to be benefitted, to some extent, by cyclic antibiotic treatments.

In simple words, collateral sensitivity is incidental sensitivity developed by microbes towards an antibiotic during the resistance evolution towards some other antibiotic. Evolving resistance towards any antibiotic involves physiological changes in the microbe. These changes can include secretion of some substance against the antibiotic or modification of cell wall to avoid the uptake of the antibiotic or even the modification of the target of the antibiotic inside the cell. It is conceivable that some of these changes can render the microbe susceptible towards some other antibiotic from the same or unrelated class.

With this rationale, more systematic inquiries about the efficacy and underlying mechanisms of cyclic treatments were launched. Microbial cultures were evolved in the laboratory to be resistant to a certain antibiotic. The evolved microbes were then tested against many other antibiotics to check whether they have developed any sensitivity. The results showed that such sensitivities could develop.

Imamovic and colleagues identified one such pair in the form of gentamycin and cefuroxime where resistance to one results in the sensitivity towards the other. They further showed that cyclic regime demands lower concentrations of the drugs to be administered. This can result in lower antibiotic load inside our body as well as in the environment, and thus retard the rate of multi-drug evolution.

Another study went further to look at the underlying mechanisms of such collaterally sensitive pair of drugs. Again they conducted laboratory evolution of microbes in the presence of single or pairs of drugs. They tested the antibiotic resistance profiles of the evolved microbes as well as looked at the changes inside the evolved microbes. When microbes could produce resistance to both the drugs through a single change, collateral resistance evolved rather than sensitivity. But when the microbes needed two different kinds of changes to cope with the pair of drugs, collateral sensitivity could evolve.

In spite of these promising results, the current state of the field sounds a word of caution. Studies with a higher number of replicate microbial populations show that the outcomes of resistance evolution may not be identical. In some drug pairs, few populations display collateral sensitivity while few other populations of the same species of microbes evolve collateral resistance.

A recent 2019 article by Nichol and colleagues point out that the efficacy treatments based on collateral sensitivity highly depends on the repeatability of evolution. Unfortunately, resistance evolution to any antibiotic can typically take many different paths. The choice of the path taken by the microbes can depend on the population size, the concentration of antibiotic experienced, duration of the evolution, starting genetic composition of the microbes and sometimes just pure chance. With so many variables in play, it is hard if not impossible, to assure the effectiveness of treatments based on collaterally sensitivity. The authors instead propose a more cautious approach where we estimate the likelihood of evolution of collateral sensitivity based on more extensive data gathered through experiments.

We currently stand on the brink of antibiotic resistance apocalypse. Along with the new drugs we also need a long term approach which can fight the ability of the microbes to evolve resistance. Robust collateral sensitivity profiles might provide just that. Though we are far away from that point currently, with more data, we might be able to implement drug regimens based on collateral sensitivity profiles and fight the menace of antibiotic resistance.  

Dr. Shraddha Karve

@ShraddhaKB