Abstract
Biofilm-related vascular graft infections (VGIs) pose major therapeutic challenges due to persistent, antibiotic-resistant bacteria often residing in retained grafts. Phage therapy offers a promising alternative treatment strategy against biofilm-associated infections, though its use remains mostly ad hoc and typically considered a last-resort intervention. We report here the treatment of a refractory, fluoroquinolone non-susceptible Pseudomonas aeruginosa VGI using a systematically planned and synergistic phage-antibiotic combination approach. Adjunctive phage therapy led to radiological improvement, as seen by reduced 18F-FDG PET/CT tracer uptake around the graft. The patient was transitioned to oral fluoroquinolone suppression therapy with no recurrence of bacteremia to-date, after a year. Our workflow led to the selection of phages that sensitized Pseudomonas aeruginosa to killing by levofloxacin and piperacillin-tazobactam. We established that this phage-driven antibiotic sensitization was due to the ability of our phages to use the MexAB-OprM efflux pump as a receptor. We also showed that our phages had potent anti-biofilm activity. We advocate a systematic, multi-pronged management strategy for refractory VGIs, including early therapeutic drug monitoring (TDM), in vitro antibiotic combination testing (iACT), and timely adjunctive phage therapy. This case illustrates the utility of individualized, strategic approaches and highlights adjunctive phage therapy’s potential in treating complex biofilm-related infections.
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Data availability
All data that support the findings of this study are provided in the article and Supplementary Information/Source Data files. WGS raw reads have been deposited in the NCBI Sequence Read Archive (SRA) under accession numbers listed in the Supplementary Information. Source data are provided with this paper.
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Acknowledgements
We would like to thank the department of infectious diseases, department of microbiology, the antimicrobial stewardship team and the nursing team for the clinical support rendered to the phage team and the patient. This publication was supported in parts by SingHealth Group Allied Health/SingHealth Group Pharmacy. This work was supported by Singapore Ministry of Health National Medical Research Council NMRC IRG (MOH-000957, A.L-H. K.), NMRC SMART III (CG21APR1011, A.L-H. K.), NMRC CoSTAR-HS (CG21APR2005, A.L-H. K.), Clinical Scientist Awards (MOH-001293-01, MOH-001278-01, MOH-001168-00 and MOH-000018-00, A.L-H. K.), NMRC– Open Fund Young Individual Research Grant (MOH-OFYIRG25jan-0007, T.T.A.), SingHealth Duke-NUS Academic Medicine Philanthropic Funds & Singapore General Hospital Academic Medicine General Fund (AMSGH/03-09/FY2024/EX/55-A116(a), A.L-H. K.), Open Fund Individual Research Grant (MOH-OFIRG21jun0038, W.M.). We also acknowledged financial support from institutional grants: Singapore General Hospital Research Grant (SRG-OPN-02-2024, S.T.) and (SRG-OPN-03-2025, S.T.), and from the Ministry of Education, Singapore, under its Research Center of Excellence award to the Institute for Digital Molecular Analytics & Science, NTU (IDMxS, grant: EDUNC-33-18-279-V12, W.M.) and the Singapore Center for Environmental Life Sciences Engineering, NTU (SCELSE, grant: EDUN C33-62-036-V4, W.M.).
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A.L-H. K., W.M., and S.J.C. designed and supervised the work. S.J.C., Y.L., W.M., and A.L-H.K. were involved in the conception and writing of the manuscript. S.T., T.T.A., A.L., S.T., Z. L. M.G.K., W.M., and A.L-H.K. were part of the Singapore Phage Repository group and provided therapeutic phages. S.J.C., D.H.L.N., N.G.S.C., W.H.L., T.P.L., and A.L.K., L.W., T.Y.C., T.H.W.N., L.Y.J., T.T.E., and T.T.T. provided the relevant clinical data and perspectives, while Y.L., S.T., Z.S.C., J.H.Y., Y.Z., Z.L., S.T., M.G.K., B.H.T., P.H.E.Y., T.T.A., R.T.O., K.K.K.K., T.H.N.W., W.M., and A.L-H.K. contributed microbiological and laboratory data to the laboratory workup, analysis and interpretation of laboratory data. S.T., Z.S.C., Z.L., S.T., S.K., and J.H.Y. performed all phage related experimental work. K.K.K.K., M.G., S.K., and Y.Z. performed WGS and bioinformatic analyses. W.M. provided data on biofilm assays and antibiotic-sensitization mechanism. All authors provided critical feedback and helped shape the study, analysis, and manuscript.
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Chung, S.J., Liu, Y., Thong, S. et al. Timely bespoke phage-antibiotic combination to treat refractory Pseudomonas aeruginosa mediastinitis and vascular graft infection. Nat Commun (2026). https://doi.org/10.1038/s41467-025-68136-y
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DOI: https://doi.org/10.1038/s41467-025-68136-y
