805. Amikacin Liposome Inhalation Suspension (ALIS) Add-on Therapy for Refractory Mycobacterium avium Complex (MAC) Lung Disease: Effect of In Vitro Amikacin Susceptibility on Sputum Culture Conversion
Session: Poster Abstract Session: Tuberculosis and Other Mycobacterial Infections
Thursday, October 4, 2018
Room: S Poster Hall

Background: ALIS (590 mg amikacin base) is liposome-encapsulated amikacin for inhalation, which delivers amikacin directly to the lung and limits systemic exposure. In the CONVERT phase 3 trial, significantly more adults with treatment-refractory MAC lung disease receiving ALIS plus guideline-based therapy (GBT) vs GBT alone achieved sputum culture conversion by month 6 (29.0% vs 8.9%, p<0.0001). Amikacin treatment failure has previously been reported in patients with amikacin minimum inhibitory concentrations (MIC) >64 µg/mL. We analyzed the impact of amikacin MIC on culture conversion during treatment with add-on ALIS.

Methods: In CONVERT, patients were randomly assigned (2:1) to receive once daily ALIS+GBT (n=224) or GBT alone (n=112). Patients with amikacin-resistant MAC isolates (MICs >64 μg/mL by broth microdilution) were excluded prior to randomization. The primary endpoint was culture conversion, defined as 3 consecutive monthly MAC-negative sputum cultures by month 6. Amikacin MICs were correlated with culture conversion rates.

Results: Amikacin MIC distributions at baseline (day 1) were similar in both groups (Fig 1). Conversion rates in the ALIS+GBT arm were 28.6–34.5% for MAC with amikacin MICs of 8–64 µg/mL (Fig 2). Overall, 28 patients developed post-screening amikacin MIC >64 µg/mL, 4/112 in the GBT alone arm (post-baseline), and 24/224 in the ALIS+GBT arm (1 at baseline, and 23 post-baseline after adding ALIS). Most of these (18/24) had MAC isolates with persistent amikacin MIC >64 µg/mL. Only 1/24 patients in the ALIS+GBT arm with amikacin MIC >64 µg/mL achieved culture conversion. No patient with both macrolide resistance and persistent amikacin MIC >64 µg/mL (8/24) converted.

Conclusion: In the ALIS+GBT arm of CONVERT, culture conversion rates were similar for amikacin MICs ranging from 8-64 µg/mL at baseline. Amikacin MIC >64 µg/mL emerged in 10.3% of patients after initiation of add-on ALIS treatment, and 3.6% in the GBT alone arm. Emergent amikacin MIC >64 µg/mL was associated with failure to convert, particularly with concurrent macrolide resistance. Determining amikacin susceptibility at both treatment initiation and during treatment may have utility for guiding treatment decisions.

 

Barbara A. Brown-Elliott, MS, MT(ASCP)SM1, Gina Eagle, MD2, Richard J. Wallace, MD1, Jakko Van Ingen, MD, PhD3, Lian J. Pennings, Mr.3, Brooke Berry, MBA4, Sushil Pandey, PhD, MBA4, Chris Coulter, MBBS, FRACP, FRCPA4, Melanie Syrmis, PhD4,5, Kevin L. Winthrop, MD, MPH6 and David E. Griffith, MD1, (1)University of Texas Health Science Center, Tyler, TX, (2)Insmed Incorporated, Bridgewater, NJ, (3)Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, Netherlands, (4)Queensland Mycobacterium Reference Laboratory, Pathology Queensland, Brisbane, Australia, (5)Faculty of Medicine, UQ Centre for Clinical Research, University of Queensland, Brisbane, Australia, (6)School of Public Health, Oregon Health & Science University-PSU, Portland, OR

Disclosures:

B. A. Brown-Elliott, Insmed: Investigator , Research support .

G. Eagle, Insmed Incorporated: Employee , Salary .

R. J. Wallace, Insmed: Investigator , Research support .

J. Van Ingen, Insmed: Investigator , Research support .

L. J. Pennings, Insmed: Investigator , Research support .

B. Berry, Insmed: Investigator , Research support .

S. Pandey, Insmed: Investigator , Research support .

C. Coulter, Insmed: Investigator , Research support .

M. Syrmis, Insmed: Investigator , Research support .

K. L. Winthrop, Insmed Incorporated: Consultant and Scientific Advisor , Consulting fee and Research grant .

D. E. Griffith, Aradigm Corporation: Advisor/consultant and Speaker's Bureau , Consulting fee and Speaker honorarium . Bayer Healthcare Pharmaceuticals: Advisor/consultant , Consulting fee . Grifols: Advisor/consultant and Speaker's Bureau , Consulting fee and Speaker honorarium . Insmed Incorporated: Advisor/consultant , Grant Investigator and Speaker's Bureau , Consulting fee , Grant recipient and Speaker honorarium .

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