OR11

Despite global health efforts to eliminated tuberculosis (TB), minimal decline in TB numbers was realized in the past years. Moreover, TB infections are fueling the antibiotic resistance crisis, with about half a million new multidrug resistant (MDR) TB cases annually. Slow development of new and repurposed antibiotics, delayed diagnostics, and inefficient MDR-TB treatment regimens plus ongoing transmission of MDR Mycobacterium tuberculosis complex (Mtbc) strains accelerate this health crisis. We propose that in addition to the development of new drugs, alternative treatments strategies which have the potential to circumvent resistance evolution should be explored.

We established an in vitro model to investigate “cellular hysteresis”, a sequential treatment strategy where the exposure to one antibiotic enhances/reduces the susceptibility to a second antibiotic. This can re-direct the target of selection and reduce resistance evolution. Initial experiments examined the relationship between ethambutol (EMB) and rifampicin (RIF). We found that short-term exposure to EMB, followed by treatment with RIF enhanced bacterial killing. However, inversely when RIF was first applied before EMB, a reduced killing effect was observed as compared to no drug switching. This observation holds true across lineages, as similar effects were observed in both lineage 2 and 4 strains.

In conclusion, cellular hysteresis in Mtbc strains is strongly drug order dependent. Such sequential treatment strategies can potentially optimize TB therapy and should be further explored with more drug combinations and resistant/wild-type Mtbc strains. We hope that sequential treatments might limit resistance evolution and be a viable alternative treatment option.