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Herein, ceftazidime-avibactam-fosfomycin combination therapy against MDR P. aeruginosa clinical isolate CL232 was further evaluated. Checkerboard susceptibility analysis revealed synergy between ceftazidime-avibactam and fosfomycin. Accordingly, the resistance elements present and expressed in P. aeruginosa were analyzed using whole-genome sequencing and transcriptome profiling. Mutations in genes that are known to contribute to \u03b2-lactam resistance were identified. Moreover, expression of blaPDC, the mexAB-oprM efflux pump, and murA were upregulated. When fosfomycin was administered alone, the frequency of mutations conferring resistance was high; however, coadministration of fosfomycin with ceftazidime-avibactam yielded a lower frequency of resistance mutations. In a murine infection model using a high bacterial burden, ceftazidime-avibactam-fosfomycin significantly reduced the P. aeruginosa colony-forming units (CFUs), by approximately 2 and 5 logs, compared with stasis and in the vehicle-treated control, respectively. Administration of ceftazidime-avibactam and fosfomycin separately significantly increased CFUs, by approximately 3 logs and 1 log, respectively, compared with the number at stasis, and only reduced CFUs by approximately 1 log and 2 logs, respectively, compared with the number in the vehicle-treated control. Thus, the combination of ceftazidime-avibactam-fosfomycin was superior to either drug alone. By employing a \"mechanism-based approach\" to combination chemotherapy, we show that ceftazidime-avibactam-fosfomycin has the potential to offer infected patients with high bacterial burdens a therapeutic hope against infection with MDR P. aeruginosa that lack metallo-\u03b2-lactamases.<\/jats:p>","DOI":"10.1093\/infdis\/jiz149","type":"journal-article","created":{"date-parts":[[2019,4,12]],"date-time":"2019-04-12T15:13:42Z","timestamp":1555082022000},"page":"666-676","source":"Crossref","is-referenced-by-count":73,"title":["Ceftazidime-Avibactam in Combination With Fosfomycin: A Novel Therapeutic Strategy Against Multidrug-Resistant Pseudomonas aeruginosa"],"prefix":"10.1093","volume":"220","author":[{"given":"Krisztina M","family":"Papp-Wallace","sequence":"first","affiliation":[{"name":"Research Service, Louis Stokes Cleveland VA Medical Center"},{"name":"Department of Medicine, Case Western Reserve University (CWRU), Cleveland, Ohio"},{"name":"Department of Biochemistry, Case Western Reserve University (CWRU), Cleveland, Ohio"},{"name":"Center for Proteomics and Bioinformatics, Case Western Reserve University (CWRU), Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise T","family":"Zeiser","sequence":"additional","affiliation":[{"name":"Research Service, Louis Stokes Cleveland VA Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott A","family":"Becka","sequence":"additional","affiliation":[{"name":"Research Service, Louis Stokes Cleveland VA Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Park","sequence":"additional","affiliation":[{"name":"Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigid M","family":"Wilson","sequence":"additional","affiliation":[{"name":"Research Service, Louis Stokes Cleveland VA Medical Center"},{"name":"Geriatric Research Education and Clinical Center, Louis Stokes Cleveland VA Medical Center"},{"name":"Department of Medicine, Case Western Reserve University (CWRU), Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa L","family":"Winkler","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roshan","family":"D\u2019Souza","sequence":"additional","affiliation":[{"name":"J. Craig Venter Institute, Rockville, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indresh","family":"Singh","sequence":"additional","affiliation":[{"name":"J. Craig Venter Institute, Rockville, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Granger","family":"Sutton","sequence":"additional","affiliation":[{"name":"J. Craig Venter Institute, Rockville, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derrick E","family":"Fouts","sequence":"additional","affiliation":[{"name":"J. Craig Venter Institute, Rockville, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Chen","sequence":"additional","affiliation":[{"name":"Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry N","family":"Kreiswirth","sequence":"additional","affiliation":[{"name":"Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn J","family":"Ellis-Grosse","sequence":"additional","affiliation":[{"name":"Nabriva Therapeutics, King of Prussia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George L","family":"Drusano","sequence":"additional","affiliation":[{"name":"Institute for Therapeutic Innovation, University of Florida, Orlando"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David 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