Sequence of Antibiotic Administration for the Treatment of Mycobacterium avium subsp. hominissuis Infection Might Influence the Response Outcome

Background/Objectives: Mycobacterium avium subsp. hominissuis is a cause of disseminated infections in immunosuppressed patients and pulmonary infections in individuals with chronic lung conditions. The treatment of this infection is prolonged, and ultimately associated with failure in a large percentage of patients. Previous studies have determined that the bacteria respond to antibiotic contact, altering pathways affecting metabolic and other functions, as well as structural aspects. Methods: Based on this assumption and the fact that the medication used to treat M. avium infection may encounter the target bacterium at different sequential times, we evaluated the effect of three antibiotics, clarithromycin, ethambutol and rifabutin, delivered together or separately in different orders. Results: The results showed no difference regarding the response of the bacterium to treatment with the three antibiotics when in planktonic state. However, in either the biofilm phenotype or inside macrophages, different orders of exposure to antibiotics led to different responses. In macrophages, the sequence of exposure when ethambutol was given first, followed by clarithromycin and rifabutin, was associated with bacterial count decrease, similar to the simultaneous exposure to the three antibiotics, whereas the other combinations showed a decreased effect. Conclusions: In summary, the study highlights an important aspect of bacterial response to combination therapies, and more specifically, the response of M. avium to therapy. The use of a cell wall-active antibiotic first appears to be linked to an improvement in therapy efficacy.