Eravacycline pharmacokinetics/pharmacodynamics in the hollow fiber system model of Mycobacterium abscessus lung disease

ABSTRACT Treatment of Mycobacterium abscessus (MAB) pulmonary diseases is challenging due to intrinsic resistance to many antibiotics and requires prolonged intravenous therapy with drugs that have severe side effects. The treatment guidelines include tetracyclines as part of the combination. We tested a 3rd generation tetracycline, eravacycline, for its potential role in MAB pulmonary disease. Eravacycline minimum inhibitory concentration (MIC) (ATCC#19977 strain and 59 clinical isolates) ranged between 0.0075 and 0.3 mg/L, and the MIC 50 and MIC 90 were 0.15 and 0.3 mg/L, respectively. In the static concentration-response studies, eravacycline killed 5.58 + 0.34 log 10 CFU/mL MAB, and EC 50 (concentration associated with 50% of the maximal effect [ E max ]) was 0.05 ± 0.01 mg/L. In the hollow fiber system model of Mycobacterium abscessus (HFS-MAB), examining eight eravacycline human-equivalent lung exposures, the ratio of area under the concentration-time curve to MIC (AUC 0-24 /MIC) of 3,588 was identified as EC 80 or the optimal exposure target for MAB kill. The probability of target attainment even with eravacycline doses of 4 mg/kg twice a day (8 mg/kg/day) falls below 90% at an MIC of 0.125 mg/L, and the cumulative fraction of response was only 30.56% in the 10,000 virtual patient trial. In summary, a MIC pattern does not accurately inform whether a tetracycline (in this study, eravacycline) has good efficacy, which must be determined using preclinical models applying a pharmacokinetics/pharmacodynamics study design. The HFS-MAB results suggest that, despite low MICs, the probability of better therapeutic outcomes with eravacycline is limited. IMPORTANCE Treatment of Mycobacterium abscessus (MAB) pulmonary diseases is challenging due to intrinsic resistance to many antibiotics. The ATS/IDSA guidelines include tetracyclines as part of the combination. Eravacycline is a new tetracycline approved for the treatment of complicated intra-abdominal bacterial infections with better tolerability and low gastrointestinal adverse events compared to tigecycline. We performed an eravacycline pharmacokinetics (PK)-pharmacodynamics (PD) study for dose optimization with respect to the MAB pulmonary disease mimicking the intrapulmonary PKs in the hollow fiber model system of MAB (HFS-MAB). While eravacycline MICs and static concentrations suggest great potential and even activity better than omadacycline and tigecycline, the drug only killed 0.56 log 10 CFU/mL below stasis in the HFS-MAB. Monte Carlo simulation experiments suggested that optimal doses for MAB pulmonary disease are likely in the range that would not be tolerated by patients.