Inhaled tigecycline induces change in immune cell modulation that synergizes with antimicrobial activity in chronic pulmonary Mycobacterium abscessus disease

Abstract

Abstract Pulmonary Mycobacterium abscesssus (pAMB) infection is particularly challenging to treat because this bacillus displays intrinsic antibiotic resistance to most front-line drugs. Tigecycline, a glycyclcycline tetracycline, shows potent bactericidal effects against pMAB, while successfully evading bacterial resistance mechanisms. Tigecycline is FDA approved as a twice daily IV administration but provokes intolerable side effects in patients. More than its potent antimicrobial effects, tigecycline has demonstrated immunomodulatory properties observed in preclinical animal models of bacterial infection. We hypothesized that inhaled therapy of tigecycline reduces side effects and improve efficacy against pMAB. GM-CSF knockout mice with pMAB were treated daily for 28 days with aerosols of tigecycline at 0.25, 1.25 and 2.50 mg/dose. Thereafter, bacterial burden was assessed, and samples were prepared for immunophenotyping of lymphocyte and myeloid cell populations through H&E staining and IHC techniques. The results demonstrated that treatment with aerosols of tigecycline to mice with pAMB was tolerated and highly effective at reducing bacterial burden. Furthermore, this therapy was associated with the influx of macrophages and lymphocytes in both perivascular zones and granulomatous-like formations. There was also an increase in alveoli lined by hypertrophied cells with vesicular nuclei, suggesting induced Type II cell hyperplasia. To summarize, inhaled tigecycline not only demonstrated bactericidal effects against pMAB, but it invokes unique immunomodulatory effects that appear to aid the significant reduction in pulmonary bacteria.