Abstract Rationale Drug development for nontuberculous mycobacterial (NTM) pulmonary disease (PD) is hindered by the lack of a reproducible evaluative framework. Though tuberculosis (TB) suffered similar challenges, drug and regimen development has been accelerated through complementary trial designs including the early bactericidal activity (EBA) study. This study aimed to describe the bactericidal activity of standard therapy against Mycobacterium avium complex (MAC) pulmonary disease (PD), adapting from TB EBA trial design. Methods This prospective single-arm trial enrolled adults starting on treatment for MAC-PD between 2021 and 2025. Participants received 2 weeks of azithromycin monotherapy, followed by addition of rifampin and ethambutol for an additional 6 weeks. Intensive microbiologic and pharmacokinetic sampling was conducted. Serial large-volume expectorated sputum samples were analyzed using both solid culture (for colony forming units (CFU) per mL) and liquid culture (for time to positivity (TTP)) to quantify mycobacterial burden. Results Ten participants enrolled in the study with median age 71 (SD 5), majority white (80%), and 60% female. Mean baseline mycobacterial burden was 2.66 log10 CFU/mL (SD 1.48) on solid culture and 127.0 (SD 44.6) hours on liquid culture media in MGIT. By day 15, mean log10 CFU/mL was measured as 2.48 (SD 1.60) and mean TTP had risen to 141.0 (SD 65.7) hours. Estimated EBA (change in CFU/mL) between days 0 and 15 was 0.5 log10 CFU/mL. By study end at week 8, there was a decline in mycobacterial burden to 1.41 log10 CFU/mL (SD 1.51) and rise in TTP to 316.0 hours (SD 275.0). Conclusions This data demonstrated a clear inverse relationship between two markers of bacterial load and an overall decline in mycobacterial burden at both days 14 (azithromycin monotherapy) and 56 (triple drug combination therapy). Further analysis is required to better understand the variance of TTP at later time points and address the inter-individual variability. These findings strongly support the use of TTP in tandem with CFU as a sensitive, early-phase PD biomarker. Such a biomarker captures treatment effect months before traditional culture conversion and may help advance novel NTM-PD drugs and regimens with an efficient and reproducible trial design. This abstract is funded by: K23 AI159145, Fisher Center Discovery Award, CHEST Foundation
Ignatius et al. (Fri,) studied this question.