Ca-EDTA restores the activity of ceftazidime-avibactam or aztreonam against carbapenemase-producing Klebsiella pneumoniae infections

Dhammika Leshan Wannigama, Aye Mya Sithu Shein, Cameron Hurst, Peter N. Monk, Parichart Hongsing, Phatthranit Phattharapornjaroen, William Graham Fox Ditcham, Puey Ounjai, Thammakorn Saethang, Naphat Chantaravisoot, Pattama Wapeesittipan, Sirirat Luk-in, Sasipen Sae-Joo, Sumanee Nilgate, Ubolrat Rirerm, Chanikan Tanasatitchai, Naris Kueakulpattana, Matchima Laowansiri, Tingting Liao, Rosalyn KupwiwatRojrit Rojanathanes, Natharin Ngamwongsatit, Somkanya Tungsanga, Asada Leelahavanichkul, Naveen Kumar Devanga Ragupathi, Vishnu Nayak Badavath, S. M.Ali Hosseini Rad, Talerngsak Kanjanabuch, Nattiya Hirankarn, Robin James Storer, Longzhu Cui, Mohan Amarasiri, Hitoshi Ishikawa, Paul G. Higgins, Stephen M. Stick, Anthony Kicic, Tanittha Chatsuwan, Shuichi Abe

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Abstract

Developing an effective therapy to overcome carbapenemase-positive Klebsiella pneumoniae (CPKp) is an important therapeutic challenge that must be addressed urgently. Here, we explored a Ca-EDTA combination with aztreonam or ceftazidime-avibactam in vitro and in vivo against diverse CPKp clinical isolates. The synergy testing of this study demonstrated that novel aztreonam-Ca-EDTA or ceftazidime-avibactam-Ca-EDTA combination was significantly effective in eliminating planktonic and mature biofilms in vitro, as well as eradicating CPKp infections in vivo. Both combinations revealed significant therapeutic efficacies in reducing bacterial load in internal organs and protecting treated mice from mortality. Conclusively, this is the first in vitro and in vivo study to demonstrate that novel aztreonam-Ca-EDTA or ceftazidime-avibactam-Ca-EDTA combinations provide favorable efficacy and safety for successful eradication of carbapenemase-producing Klebsiella pneumoniae planktonic and biofilm infections.

Original languageEnglish
Article number107215
Pages (from-to)1-24
Number of pages24
JournaliScience
Volume26
Issue number7
DOIs
Publication statusPublished - 21 Jul 2023

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