An 81-year-old immunocompetent patient with bronchiectasis and refractory Mycobacterium abscessus lung disease was treated for 6 months with a three-phage cocktail active against the strain. In this case study of phage to lower infectious burden, intravenous administration was safe and reduced the M. abscessus sputum load tenfold within one month. However, after two months, M. abscessus counts increased as the patient mounted a robust IgM- and IgG-mediated neutralizing antibody response to the phages, which was associated with limited therapeutic efficacy.
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The GD82, GD01A and GD01B sequence data are available under accession nos. JADWXT000000000, CP035923 and CP035924, respectively. All phage information can be found at https://phagesdb.org/. Sequence information for Muddy, BPs and ZoeJ is available under accession nos. KF024728, EU568876 and KJ510412, respectively. ELISA raw data are available in the supplementary Excel file ‘Raw Data Fig2ab’.
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We thank D. Jacobs-Sera and H. G. Aull for the phage cocktail preparation, R. Garlena and D. Russell at the University of Pittsburgh for DNA sequencing and analysis and M. Ramsay, C. Lippincott, J. Zenilman, K. Dooley and E. Ignatius at Johns Hopkins University School of Medicine for their clinical discussions regarding the care of this patient. This work was funded by a Cystic Fibrosis Foundation grant no. HATFUL19GO, a National Institutes of Health (NIH) grant no. GM131729, a Howard Hughes Medical Institute grant no. GT12053 and by the Fowler Fund for Phage Research to G.F.H. as well as grants from the National Heart, Lung, and Blood Institute/NIH (no. K08 HL139994) and the Burroughs Wellcome Fund Career Award for Medical Scientists to K.A.C. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. We thank R. Schooley, E. Rubin and B. Bishai for comments on the manuscript.
J.A.N. has received consulting fees from AstraZeneca. G.F.H. is a compensated consultant for Janssen. K.A.C. has received consulting fees from Insmed, Hillrom and Merck. The other authors declare no competing interests.
Peer review information Nature Medicine thanks Nina Chanishvili, Laurent Kremer and Jeremy Barr for their contribution to the peer review of this work. Alison Farrell was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Quantitative MAC counts in expectorated sputum (log CFU mL−1) pre- and post-treatment. The observed decline in MAC treatment during phage therapy is likely attributable to the addition of anti-MAC antibiotics, azithromycin and ethambutol, to the multidrug regimen. MAC colony morphology appeared smooth and opaque.
Non-contrast high resolution chest CT scans were performed immediately prior to phage treatment, and repeated after phage treatment initiation at two- and six-months. The majority of chronic airway changes such as bronchiectasis and bronchial wall thickening (white arrows) were stable throughout phage therapy. However, there was slightly increased cavitation in the right upper lobe (black arrows) noted at two months post-phage treatment, and interval development of peripheral left lower lobe consolidations and right lower lobe nodularity (black arrow heads) at six months post-phage treatment.
Antibiotic minimum inhibitory concentration (MIC) determinations (in μg/mL) active against M. abscessus GD82 were determined pre-phage therapy initiation and monthly during phage therapy using a standard antibiotic panel for rapidly growing mycobacteria (Sensititre RAPMYCOTM).
a, 1 ml of 2 ×108 CFU GD82 was mixed with 2 ×109 PFU of each phage used in the cocktail or with all three phages, and incubated at 37 °C with shaking. After 48 hours, 0.1 ml of the mix was spread on solid media and incubated for 5 days at 37 °C. b, Four surviving colonies of each phage challenge were grown and retested for phage sensitivity by spotting 10-fold serial dilutions of phages as indicated. GD82-M_RM2 and GD82-Z_RM2 could not be propagated and were not tested further. BPsΔ33HTH_HRM10 RMs were not tested.
Safety assessments during phage treatment included regular monitoring of complete blood counts with differential, comprehensive metabolic panels, and inflammatory markers. During six-months of intravenous phage treatment there were no clinically significant differences observed in a, white blood cell (WBC) total counts and differentials, b, hemoglobin and platelets, c, liver function (alanine transaminase, ALT; aspartate transaminase, AST; and total bilirubin) or kidney function (creatinine), and d, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR).
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Dedrick, R.M., Freeman, K.G., Nguyen, J.A. et al. Potent antibody-mediated neutralization limits bacteriophage treatment of a pulmonary Mycobacterium abscessus infection. Nat Med 27, 1357–1361 (2021). https://doi.org/10.1038/s41591-021-01403-9