“Every disadvantage has an advantage” is one of the many brilliant quotes from the late Dutch philosopher Johan Cruijff. This now also seems to hold for antibiotic resistance. The conventional belief is that resistance development is unidirectional: pathogens cumulatively acquire resistance traits, until being a multidrug resistant superbug. This now seems not always true; resistance development to antibiotic A, may – at the same time – increase susceptibility to antibiotic B, a phenomenon called “collateral sensitivity” that may help us in treating chronic infections.
You need to leave the beaten path in your library for this knowledge, as the latest was published in Cell. We are talking about bacteria in which antibiotic resistance is driven by activation of chromosomally encoded resistance mechanisms, such as changes in outer membrane porins, inducible β-lactamase AmpC or overexpression of efflux pumps. Morten Sommer and colleagues nicely demonstrated how this works in Pseudomonas aeruginosa. In the lab they demonstrated how exposing individual strains to an antibiotic created resistance (as expected), but also that this resulted in lower MICs for other antibiotics, and how this was linked to certain (predicted) mutations in the chromosome. Next, they confirmed their findings in cystic fibrosis patients with chronic pulmonary P. aeruginosa infection. Treatment with β-lactams and aminoglycosides rapidly induced resistance, but also sensitivity to colistin. Importantly, the antibiotic treatment modified the initially heterogeneous bacterial population into a phenotypically uniform population of susceptible isolates. So, after a first strike with β-lactams and aminoglycosides, all remaining bacteria are more susceptible to colistin. The occurrence of this change in susceptibility can be easily monitored, say the investigators, by measuring the chromosomal mutations by PCR. A simple mind like me would say: why not just determine MICs?
This principle of “collateral sensitivity” also appears to exist in cancer cell lines, and was recently tested (successfully) in an animal model with acute lymphoblastic leukemia. In bacteria, it has also been demonstrated in E. coli and S. aureus. This new knowledge has led to “a rational drug treatment paradigm termed collateral sensitivity cycling, in which sequential drug treatments are designed to exploit collateral sensitivity resulting from resistance evolution, see.” Yet wait a minute: that sounds not totally new. That is what has been attempted in multiple studies, especially in ICUs, termed antibiotic cycling, mixing or rotation. In these studies, antibiotics were cycled at the unit-level between patients, but not within patients. The collateral novelty is that this concept is used in individual patients, with (very) chronic infections, such as those with cystic fibrosis. Other groups that may benefit are those with bronchiectasis, prosthetic joint infections or chronic UTIs. So, if you have suitable cohorts, go and seek confirmation of this new biological phenomena.