We demonstrated here the efficacy of the new sitafloxacin-arbekacin combination regimen. The regimen revealed that both sitafloxacin and arbekacin MICs reduction when the combination administration and significantly high synergistic effect against M. abscessus complex. The combination regimen showed a higher rate of susceptibility and synergistic effects against M. abscessus subsp. abscessus than M. abscessus subsp. Massiliense. These results might suggest that the combination therapy was more effective against M. abscessus subsp. abscessus, showing a high level of antimicrobial resistance. Furthermore, the combination revealed higher efficacy for the treatment of M. abscessus complex in rough morphotypes associated with aggressive infections.
In 2020, the new treatment guidelines for NTM pulmonary disease had been published , and new treatment strategies recommended changing the regimens based on macrolide resistance gene status. The systematic review described that treatment of macrolide containing regimens for M. abscessus subsp. massiliense led to a better culture conversion rate than M. abscessus subsp. abscessus . However, the treatment options for macrolide resistance species of M. abscessus complex were lacking. We focused on a novel, highly effective FQ, sitafloxacin, as a potential treatment option for the refractory M. abscessus infections.
Sitafloxacin is approved in Japan, and it has been clinically used against most mycobacterial infections, mainly MAC, by its exceedingly low MIC level compared to other FQs. Eighteen patients with pulmonary MAC disease who received sitafloxacin for at least 4 weeks for pulmonary MAC disease were evaluated; 10 patients (55.6%) showed improved radiological characteristics, and 8 patients (44.4%) showed negative sputum cultures at 6 months . Thirty-one patients with refractory MAC-lung disease, who received sitafloxacin-containing regimen for ≥ 4 weeks, were evaluated, 26% and 19% of patients showed symptomatic and radiological responses, respectively 12 months after receiving, and low sitafloxacin MIC (≤ 1 µg/mL) were significant predictors of negative sputum culture conversion . In a recent study, sitafloxacin efficacy against M. abscessus has been reported. Bedaquiline-clofazimine-sitafloxacin combination revealed a synergistic effect against 11 isolates of 70 M. abscessus subsp. abscessus (15.7%) . In a Japanese retrospective study of 13 M. abscessus pulmonary disease, all 4 patients who received sitafloxacin-containing regimens achieved negative sputum conversion after 1 year of treatment and improved radiological findings . Together with our data and previous reports, sitafloxacin could be an effective antimicrobial combination partner against refractory M. abscessus complex.
M. abscessus exist in two distinct morphotypes, smooth and rough, that differ in their gross colony appearances when grown on solid media due to their differing amounts of cell wall GPLs. The smooth morphotype initially colonizes the airway mucosa, and had generally lower pathogenicity in this state. Subsequently switching from smooth morphotypes to rough morphotypes, aggressive pulmonary disease cause. Smooth morphotypes have an advantage in survival due to biofilm formation, leading to inhibit bacteria-induced apoptosis . Conversely, rough morphotypes, without biofilms, induce the invasion ability mediated by apoptotic cell death [35, 36]. Several clinical data have revealed increased pathogenicity from the rough morphotype. The rates of isolation of rough morphotype is higher in the CF patients with clinical symptoms , and case reports describe that the CF patients with rough morphotypes lead to dramatic declines of respiratory function and/or death [26, 38]. Thus, the development of new treatment targeted rough morphotypes has become imperative. Our study revealed that sitafloxacin-arbekacin combination had the higher synergy in rough morphotypes, the combination could be useful treatment for the patients who are isolated with rough morphotypes and/or whose disease have progressed. On the other hands, the combination had the less synergy in smooth morphotypes by biofilm activity. Interestingly, in 17 out of 19 smooth morphotypes (89.5%), sitafloxacin susceptibility in the combination treatment improved as compared to alone. This data suggested that sitafloxacin-arbekacin combination could be also partially effective as the treatment for smooth morphotypes of M. abscessus.