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In Vitro Determination of Inhaled NO Regimen for Treatment of Pulmonary Non-Tuberculous Mycobacteria Infection
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A7668 - In Vitro Determination of Inhaled NO Regimen for Treatment of Pulmonary Non-Tuberculous Mycobacteria Infection
Author Block: C. Miller, J. Martins, T. A. Miller, B. McMullin, G. Regev; Division of Respiratory Medicine, University of British Columbia, Vancouver, BC, Canada.
INTRODUCTION: We’ve previously published evidence that interval delivery of 160ppm Inhaled NO (gNO) is safe and may be an effective antimicrobial. We’ve reported a small cohort of cystic fibrosis (CF) patients receiving 160 ppm gNO for 30-minutes, three times daily for 10 days, who clinically benefited and that gNO was safe. We observed that gram-negative and -positive bacteria; and aspergillus could be eradicated by gNO. Two of the eight subjects had Mycobaterium abscessus identified in their sputum, and had only a 4 log10 CFU/mL reduction in bacterial load following gNO treatments without complete eradication. To plan a clinical trial to treat patients with NTM using gNO, we studied the duration of NO exposure required to eradicate clinical strains of NTM and then designed a NO treatment plan. METHODS: We calculated the NO exposure to the lungs during the CF pilot study that did not eradicate NTM, a total NO dose-duration of 3,600 ppm-hours. We obtained clinical isolates of NTM collected and prepared from subjects that were refractory to the conventional 16 month multiple antibiotic treatment regimen. NO gas exposure was performed in our previously validated exposure incubator. Following continuous exposure to 160 ppm ± 5 ppm NO, complete killing (LD100) of M. abscessus was achieved by 8 hours or 1,280 ppm-hours, while M. avium required 28 hours of exposure or 4,480 ppm-hours. For cyclic exposures, twelve 30-minute cycles of 160 ppm gNO over 48 hours demonstrated complete killing of M. abscessus corresponding to 6 hours or 960 ppm-hours of gNO exposure. M. avium required sixty 30-minute gNO treatments over 240 hours of exposure to achieve complete killing, which equals 30 hours or 4,800 ppm-hours of exposure to gNO. In each of the experiments, the M. abscessus and M. avium control samples exposed to medical air remained viable at time points corresponding to the LD100 for the gNO groups. CONCLUSION: Using these data, the dose-duration of 4,800 ppm-hours required to eradicate the apparently more resilient species of M. abscessus, a dosing regimen was used. A 20% margin increase was used to account for translation into an in vivo scenario. It was decided to deliver gNO for 50 minutes, three-times a day for 15 days in order to ensure the possibility of eradicating NTM in patients with bronchiectasis and CF. This study in currently on-going (ClinicalTrials.gov Identifier: NCT03331445). Preliminary results indicate subjects are tolerating regimen with reduced CFQ-R scores and NTM loads.
Author Block: C. Miller, J. Martins, T. A. Miller, B. McMullin, G. Regev; Division of Respiratory Medicine, University of British Columbia, Vancouver, BC, Canada.
INTRODUCTION: We’ve previously published evidence that interval delivery of 160ppm Inhaled NO (gNO) is safe and may be an effective antimicrobial. We’ve reported a small cohort of cystic fibrosis (CF) patients receiving 160 ppm gNO for 30-minutes, three times daily for 10 days, who clinically benefited and that gNO was safe. We observed that gram-negative and -positive bacteria; and aspergillus could be eradicated by gNO. Two of the eight subjects had Mycobaterium abscessus identified in their sputum, and had only a 4 log10 CFU/mL reduction in bacterial load following gNO treatments without complete eradication. To plan a clinical trial to treat patients with NTM using gNO, we studied the duration of NO exposure required to eradicate clinical strains of NTM and then designed a NO treatment plan. METHODS: We calculated the NO exposure to the lungs during the CF pilot study that did not eradicate NTM, a total NO dose-duration of 3,600 ppm-hours. We obtained clinical isolates of NTM collected and prepared from subjects that were refractory to the conventional 16 month multiple antibiotic treatment regimen. NO gas exposure was performed in our previously validated exposure incubator. Following continuous exposure to 160 ppm ± 5 ppm NO, complete killing (LD100) of M. abscessus was achieved by 8 hours or 1,280 ppm-hours, while M. avium required 28 hours of exposure or 4,480 ppm-hours. For cyclic exposures, twelve 30-minute cycles of 160 ppm gNO over 48 hours demonstrated complete killing of M. abscessus corresponding to 6 hours or 960 ppm-hours of gNO exposure. M. avium required sixty 30-minute gNO treatments over 240 hours of exposure to achieve complete killing, which equals 30 hours or 4,800 ppm-hours of exposure to gNO. In each of the experiments, the M. abscessus and M. avium control samples exposed to medical air remained viable at time points corresponding to the LD100 for the gNO groups. CONCLUSION: Using these data, the dose-duration of 4,800 ppm-hours required to eradicate the apparently more resilient species of M. abscessus, a dosing regimen was used. A 20% margin increase was used to account for translation into an in vivo scenario. It was decided to deliver gNO for 50 minutes, three-times a day for 15 days in order to ensure the possibility of eradicating NTM in patients with bronchiectasis and CF. This study in currently on-going (ClinicalTrials.gov Identifier: NCT03331445). Preliminary results indicate subjects are tolerating regimen with reduced CFQ-R scores and NTM loads.
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