Eravacycline for Mycobacterium abscessus infections: pharmacodynamic advantages of long-acting post-antibiotic effects and weekly dosing regimens

Mycobacterium abscessus (MAB) is one of the most common non-tuberculous mycobacteria with an extremely high resistance rate to classic anti-tuberculosis drugs. This study aimed to evaluate the activities of the novel Tetracycline agent eravacycline (ERC) against MAB using clinical isolates and mouse Infection models. We determined the minimum inhibitory concentration (MIC) of ERC against the MAB standard strain ATCC 19977 and 27 clinical isolates. The THP-1-derived macrophage Infection model was established to assess the intracellular inhibitory activity. The post-antibiotic effect (PAE) and post-antibiotic sub-MIC effect (PA-SME) of ERC were evaluated against ATCC 19977. Additionally, the efficacy and safety of treatment of ERC under different dosing intervals were compared with omadacycline (OMC) and tigecycline (TGC) in a BALB/c mouse model. The MIC₅₀ and MIC₉₀ of ERC were 0.03 and 0.5 μg/mL, respectively. In macrophages, 1 μg/mL ERC inhibited Bacterial growth by 21.65% after 24 h, outperforming both 5 μg/mL TGC (4.85%) and OMC (17.41%). ERC also exhibited a prolonged PAE (up to 10 days after 2 h exposure to 16 μg/mL) and PA-SME (>7 days, at 0.5 μg/mL), longer than those of TGC and OMC. In the intracellular model, ERC and OMC showed sustained Antibacterial activity for up to 1 week after drug removal, whereas TGC did not. In mice, ERC treatment reduced lung Bacterial burden by 3.34-3.74 log₁₀CFU after 2 weeks. Notably, a once-weekly high-dose regimen of ERC achieved therapeutic efficacy comparable to that of alternate-day dosing and significantly reduced inflammatory lung injury. ERC demonstrates potent in vitro and intracellular activity against MAB, supported by an exceptionally long PAE/PA-SME and promising in vivo efficacy and safety. The sustained Antibacterial effect supports the feasibility of a weekly dosing regimen, positioning ERC as an ideal candidate for the treatment of MAB infections.IMPORTANCEMycobacterium abscessus (MAB) infections are increasingly prevalent and notoriously difficult to treat due to intrinsic resistance to most Antibiotics. This study demonstrates that eravacycline-a novel tetracycline-exhibits exceptional potency against MAB, outperforming current therapies like tigecycline and omadacycline. Key findings include eravacycline's low minimum inhibitory concentration (MIC) values (MIC₅₀ = 0.03 µg/mL), strong intracellular activity, and uniquely prolonged post-antibiotic effects. Crucially, a weekly high-dose regimen in mice achieved Bacterial clearance comparable to daily dosing while reducing lung inflammation, leveraging eravacycline's sustained pharmacological impact. This challenges the need for frequent dosing, potentially minimizing toxicity and improving patient adherence.