Ceftriaxone efficacy for Mycobacterium avium complex lung disease in the hollow fiber and translation to sustained sputum culture conversion in patients.

ABSTRACT

BACKGROUND: Only 35.6%-50.8% of patients with Mycobacterium avium complex (MAC) pulmonary disease achieve sustained sputum culture conversion (SSCC) on treatment with the azithromycin-ethambutol-rifabutin standard of care (SOC). We tested the efficacy of ceftriaxone, a ß-lactam with a lung penetration ratio of 12.18-fold. METHODS: We mimicked lung concentration-time profiles of seven ceftriaxone once-daily doses for 28 days in the hollow fiber system model of intracellular MAC (HFS- MAC). Monte Carlo experiments were used for dose selection.We also compared the once-daily ceftriaxone monotherapy to three-drug SOC against five MAC clinical isolates in HFS-MAC using γ (kill)-slopes. Results were translated to SSCC rates. RESULTS: Ceftriaxone killed 1.02-3.82 log10 cfu/mL in dose-response studies. Ceftriaxone 2G once-daily was identified as the optimal dose. Ceftriaxone killed all five strains below day 0 versus 2/5 for SOC. The median γ (95% confidence interval) was 0.49(0.47-0.52) log10 cfu/mL/day for ceftriaxone and 0.38(0.34-0.43) log10 cfu/mL/day for SOC. In patients, the SOC was predicted to achieve SSCC rates of 39.3%(36%-42%) at 6 months (similar to meta-analyses results). The SOC SSCC was 50% at 8.18(3.64-27.66) months versus 3.58(2.20-7.23) months for ceftriaxone. Thus, ceftriaxone shortened time-to-SSCC 2.35-fold compared to SOC. CONCLUSION: Ceftriaxone is a promising agent for creation of short-course chemotherapy.