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

• DOI: 10.1016/j.isci.2023.107215
• Publication Date: 2023-06-28T06:44:11Z
• Authors: Dhammika Leshan W...; Aye Mya Sithu Shein; Cameron Hurst; Peter N. Monk; Parichart Hongsing; Phatthranit Phatt...; William Graham Fo...; Puey Ounjai; Thammakorn Saethang; Naphat Chantaravi...; Pattama Wapeesitt...; Sirirat Luk-in; Sasipen Sae-Joo; Sumanee Nilgate; Ubolrat Rirerm; Chanikan Tanasati...; Naris Kueakulpattana; Matchima Laowansiri; Tingting Liao; Rosalyn Kupwiwat; Rojrit Rojanathanes; Natharin Ngamwong...; Somkanya Tungsanga; Asada Leelahavani...; Naveen Kumar Deva...; Vishnu Nayak Bada...; S.M. Ali Hosseini...; Talerngsak Kanjan...; Nattiya Hirankarn; Robin James Storer; Longzhu Cui; Mohan Amarasiri; Hitoshi Ishikawa; Paul G. Higgins; Stephen M. Stick; Anthony Kicic; Tanittha Chatsuwan; Shuichi Abe
• Keywords: 0303 health sciences; 572; Science; Immunology; Q; Medical specialty; Health sciences; Medical microbiology; Article; 3. Good health; Biological sciences; 03 medical and health sciences; Medicine

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.