1412. Clinical Epidemiology and Characteristics of Pulmonary Nontuberculous Mycobacterial Isolates from a Large Academic Military Treatment Facility

Abstract Background Non-tuberculous mycobacteria (NTM) are ubiquitous in the environment and include pathogenic and nonpathogenic species. Although prevalence appears to be increasing in the US, diagnosis and treatment can be challenging. This study describes the epidemiology and clinical characteristics of pulmonary NTM (pNTM) isolates at Brooke Army Medical Center (BAMC). Methods BAMC pulmonary NTM isolates from 2012-2020 were included. Corresponding electronic health records were reviewed for epidemiologic, microbiologic, and clinical data. Pulmonary NTM infection (pNTMi) was defined using 2020 NTM guidelines and patients were divided into 2 groups based on whether guideline criteria for pNTMi were met. Demographic, microbiologic, and clinical characteristics were compared between groups. Results A total of 813 isolates from 225 patients were analyzed (median 2 [IQR 1-4] isolates per patient). Approximately half (49.7%) were female with a median age of 71 years (IQR 62-79, Table 1), and the majority were current or former smokers (57.3%). Compared to those not meeting criteria (n=116; 51.6%), pNTMi patients (n=109; 48.4%) more commonly had bronchiectasis (47.7% vs 27.6; p=0.002) but were less likely to have solid organ malignancy (11.9% vs 23.3%; p=0.036). A higher proportion of pNTMi patients were female (58% vs 42%; p=0.005) and had lower median Body Mass Index (BMI, 22.6 vs 25.1; p=0.001). M. avium complex (MAC) was more common among pNTMi patients (75.2% vs 35.3%; p=0.001). In contrast, M. simiae and M. gordonae were more likely to be isolated from those not meeting criteria (25.9% vs. 10.1%; p=0.003 and 16.4% vs. 1.8%; p=0.001, respectively). Among pNTMi patients, 60 (55%) were offered therapy and were more likely to be younger (70 [IQR 63-76] vs. 73 [IQR 65-82] years; p=0.049), have chronic obstructive pulmonary disease (COPD; 51.7% vs 24.5%; p=0.006) and MAC (88.3% vs. 59.2%; p=0.001) compared to untreated patients (Table 2). Conclusion Approximately half of pNTM isolates were observed in patients who did not meet criteria for pNTMi diagnosis. Female patients, lower BMI, bronchiectasis, or MAC isolation were more likely to meet pNTMi criteria. Management of pNTMi remains a challenge, with younger patients with COPD and MAC more likely to receive treatment. Disclosures All Authors: No reported disclosures

undergoes identical PK and metabolism in vivo. Dynamic 18F-pretomanid PET/CT imaging was performed in validated preclinical models of tuberculosis following intravenous administration of 18F-pretomanid. (B) PET signal was quantified in multiple compartments to generate time activity curves (TACs) used to calculate area under the curve (AUC) over 0-60 minutes. A subset of animals also underwent PET/CT imaging of 18F-py-albumin to assess vascular supply to lung and brain lesions, and with 18F-FDG to confirm the presence of neuroinflammation in the mouse and rabbit models of TB meningitis. Tissue resection post-mortem was used to visualize the intralesional retention of 18F-pretomanid using high-resolution (10 µm) autoradiography. The efficacy of the BPaL regimen in TB meningitis was compared to that of standard treatment with rifampin, isoniazid, and pyrazinamide in the mouse model. Mass spectrometry was performed following oral administration of BPaL to determine brain drug levels. (C) These data provide multicompartment PK analysis, intralesional levels of pretomanid, and insights into the mechanism that govern pretomanid tissue distribution.
Results. 18 F-Pretomanid PET provided detailed concentration-time profiles in infected tissues demonstrating excellent lung and brain tissue penetration (AUC ratio to plasma > 1) in both animal species, which was spatially compartmentalized, likely due to differential vascular supply ( 18 F-py-albumin PET) ( Figure 2). Brain lesions (identified by 18 F-FDG PET) demonstrated localized leakiness on 18 F-py-albumin PET. Autoradiography and mass spectrometry corroborated the imaging findings. The efficacy of the BPaL regimen in TB meningitis was substantially lower than standard TB treatment (Figure 3), likely due to restricted penetration of bedaquiline and linezolid into the brain parenchyma. Figure 2. Spatial heterogeneity of 18F-Pretomanid penetration and vascular supply to pulmonary TB lesions.
(A) A novel synthetic was devised to obtain 18F-pretomanid, which is chemically identical to pretomanid. (B) Maximum intensity projection (MIP) of 18F-Pretomanid PET/CT in M.tb.-infected mice over 3 hrs shows hepatobiliary and renal excretion, high uptake into brown fat, brain, and lungs. (C) Resection of infected lungs 30 minutes post intravenous administration of 18F-pretomanid shows heterogenous distribution of 18F-pretomanid into the lungs visible by high resolution autoradiography. Areas of pneumonia are identifiable by hematoxylin and eosin (H&E) staining of the same tissue section used for autoradiography. (D) Time-activity curves of 18F-Pretomanid in infected mouse lung (0-3 hours) and derived area under the curve (AUC) ratios to plasma (E) in infected mouse lung. Representative MIP of 18F-pretomanid (F) and 18F-py-albumin (H) PET/ CT in a rabbit with cavitary TB and quantification of the AUC ratios to plasma show reduced penetration into lung lesions and cavitary wall compared to areas of unaffected lung (G and I). Data are represented as median ± interquartile range, n=3-4 group. Figure 3. Exposure levels of 18/19F-pretomanid in models of TB meningitis.
(A) Experimental timeline used to assess the penetration of pretomanid into infected mouse brain before and during treatment with antimicrobials bedaquiline (B), pretomanid (Pa), and linezolid (L), and corticosteroid dexamethasone (D). (B) Representative three-dimensional MIP of 18F-pretomanid PET/CT in the CNS-TB model, 10 min post-injection, and transverse section showing high and heterogeneous brain uptake. (C) High-resolution autoradiography was performed to confirm heterogeneous penetration of 18F-pretomanid into infected brain lesions in the mouse. (D). 8F-pretomanid AUC ratios of tissue to plasma in mouse brain before (day 0) and two weeks into treatment show a reduction in penetration at week 2. (E). Pretomanid concentrations (µg/mL) in mouse plasma and brain, at day 0 and two weeks into treatment, measured by mass spectrometry and derived concentration ratios of brain to plasma (F) suggest drug accumulation due to the long half-life. (G) While 18F-pyalbumin and 18F-FDG PET/CT show vascular leakage and neuroinflammation in the rabbit model of TB meningitis, the penetration of 18F-pretomanid is heterogeneous and reduced at the lesion site (indicated by white arrow). (H) Quantification of the PET signal shows variability within the same animal. Data are represented as median ± interquartile range, n=3-5 group. Figure 4. Evaluation of a pretomanid-containing regimen in TB meningitis.
Conclusion. Dynamic 18 F-pretomanid PET provided holistic data on pretomanid exposures showing excellent penetration into infected lung and brain tissues. The BPaL regimen was inferior to standard TB treatment for TB meningitis. Thus, new pretomanid-containing regimens need to be developed for the treatment of MDR-TB meningitis.
Disclosures Background. Non-tuberculous mycobacteria (NTM) are ubiquitous in the environment and include pathogenic and nonpathogenic species. Although prevalence appears to be increasing in the US, diagnosis and treatment can be challenging. This study describes the epidemiology and clinical characteristics of pulmonary NTM (pNTM) isolates at Brooke Army Medical Center (BAMC).
Methods. BAMC pulmonary NTM isolates from 2012-2020 were included. Corresponding electronic health records were reviewed for epidemiologic, microbiologic, and clinical data. Pulmonary NTM infection (pNTMi) was defined using 2020 NTM guidelines and patients were divided into 2 groups based on whether guideline criteria for pNTMi were met. Demographic, microbiologic, and clinical characteristics were compared between groups.