Use of epigenetically modified bacteriophage and dual beta-lactams to treat a Mycobacterium abscessus sternal wound infection

Madison Cristinziano, Elena Shashkina, Liang Chen, Jaime Xiao, Melissa B. Miller, Christina Doligalski, Raymond Coakley, Leonard Jason Lobo, Brent Footer, Luther Bartelt, Lawrence Abad, Daniel A. Russell, Rebecca Garlena, Michael J. Lauer, Maggie Viland, Ari Kaganovsky, Emily Mowry, Deborah Jacobs-Sera, David Duin, Barry N. Kreiswirth (), Graham F. Hatfull () and Anne Friedland ()
Additional contact information
Madison Cristinziano: University of Pittsburgh
Elena Shashkina: Center for Discovery and Innovation
Liang Chen: Center for Discovery and Innovation
Jaime Xiao: University of North Carolina School of Medicine
Melissa B. Miller: University of North Carolina
Christina Doligalski: University of North Carolina School of Medicine
Raymond Coakley: University of North Carolina
Leonard Jason Lobo: University of North Carolina
Brent Footer: University of North Carolina
Luther Bartelt: University of North Carolina
Lawrence Abad: University of Pittsburgh
Daniel A. Russell: University of Pittsburgh
Rebecca Garlena: University of Pittsburgh
Michael J. Lauer: University of Pittsburgh
Maggie Viland: University of Pittsburgh
Ari Kaganovsky: University of Pittsburgh
Emily Mowry: University of Pittsburgh
Deborah Jacobs-Sera: University of Pittsburgh
David Duin: University of North Carolina
Barry N. Kreiswirth: Center for Discovery and Innovation
Graham F. Hatfull: University of Pittsburgh
Anne Friedland: University of North Carolina

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Nontuberculous mycobacterium (NTM) infections are challenging to manage and are frequently non-responsive to aggressive but poorly-tolerated antibiotic therapies. Immunosuppressed lung transplant patients are susceptible to NTM infections and poor patient outcomes are common. Bacteriophages present an alternative treatment option and are associated with favorable clinical outcomes. Similarly, dual beta-lactam combinations show promise in vitro, but clinical use is sparse. We report here a patient with an uncontrolled Mycobacterium abscessus infection following a bilateral lung transplant and failed antibiotic therapy. Both smooth and rough colony morphotype strains were initially present, but treatment with two phages that kill the rough strain – including epigenetic-modification to overcome restriction – resulted in isolation of only the smooth strain. The rough and smooth strains have similar antibiotic susceptibilities suggesting that the phages specifically eliminated the rough strain. Dual beta-lactam therapy with meropenem and ceftazidime-avibactam provided further clinical improvement, and the phages act synergistically with meropenem in vitro.

Date: 2024
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DOI: 10.1038/s41467-024-54666-4

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