A24 Isolation and characterization of bacteriophages targeting extensively drug-resistant and pan-resistant klebsiella pneumoniae for phage support Ukraine

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Introduction As antimicrobial resistance continues to rise and the development of new antimicrobials lags, we face an urgent threat where routine infections could become life-threatening. Armed conflicts, like the war on Ukraine, intensify this crisis by accelerating the spread of resistant organisms across regions and borders. Phage therapy or the use of bacteriophages (phages), the viruses of bacteria, as a therapeutic has reemerged as a viable treatment for difficult to treat multidrug resistant (MDR) infections. Our Belgian consortium, led primarily by the Queen Astrid Military Hospital (QAMH), has been dedicated to treating patients, culminating in a landmark publication that documents 100 consecutive cases of phage therapy. 1 Phage Support Ukraine (Phage SP UKR) is a collaborative effort led by QAMH in partnership with our group at KU Leuven to provide phages targeting circulating pathogens and enable a military hospital in Kyiv to effectively deliver personalized phage therapies. Methods As part of this initiative, we received from this hospital in Kyiv bacterial isolates belonging to a number of species, but decided to focus here on Klebsiella pneumoniae , the most concerning pathogen with regard to prevalence, virulence and antibiotic resistance. Strains were sequenced using both Illumina (short-read) and Nanopore (long-read) technologies to characterize their genomic content, including antibiotic resistance and virulence factors. Antibiograms were also conducted in accordance with standard protocols. Strains were assessed for hypervirulence using Galleria mellonella and a mouse model of pneumonia. Phages were isolated from Ukrainian wastewater, sequenced and characterized for therapeutic effectiveness. Results Among these K. pneumoniae isolates we identified MDR sequence types (ST)39, 307 and 395 and one predominating clonal group—CG10146 first detected in Moscow, Russia—carrying a hybrid virulence and antibiotic resistance plasmid encoding the carbapenemase NDM-1 and aerobactin. When tested in virulence assays, only one isolate (ST395) was hypervirulent in a G. mellonella though not in a mouse model of infection. Several phages were isolated that could lyse these K. pneumoniae strains, including those isolated from soldiers displaced in Belgium, Germany, and Latvia. Bacterial resistance was observed during in vitro testing; however, some phage-resistant isolates had mutations in virulence factors, including one that lost its hybrid plasmid, resulting in re-sensitivity to antibiotics. As we continue to receive isolates for surveillance, new strains emerging from Ukraine this year have been identified as pan-drug resistant (PDR). However, they have also been found to be susceptible to the phages isolated to date. Conclusion These phages show high potential as a therapeutic against MDR and PDR strains of K. pneumoniae . As part of this initiative, QAMH will provide these phages as well as equipment for the group in Kyiv to work with these phages and the training needed to implement phage therapy in Ukraine. Strategies like Phage SP UKR are essential to prevent the selection, persistence, and global spread of these drug-resistant clones. Reference Pirnay JP, Djebara S, Steurs G, Griselain J, Cochez C, De Soir S, et al . Personalized bacteriophage therapy outcomes for 100 consecutive cases: a multicentre, multinational, retrospective observational study. Nat Microbiol . 2024; 9 (6):1434–53. Abstract A24 Figure 1 Phage SP UKR. A schematic outlining the goals of this project, which include: 1. Pathogen characterization, 2. Phage isolation and characterization, and 3. Delivery of phages to Ukraine Disclosures The authors declare no conflict of interest.

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