Ceftazidime-Avibactam in Combination With Fosfomycin: A Novel Therapeutic Strategy Against Multidrug-Resistant Pseudomonas aeruginosa.

Previously, by targeting penicillin-binding protein 3, Pseudomonas-derived cephalosporinase (PDC), and MurA with ceftazidime-avibactam-fosfomycin, antimicrobial susceptibility was restored among multidrug-resistant (MDR) Pseudomonas aeruginosa. 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 ß-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-ß-lactamases.

Fosfomycin for Injection (ZTI-01) Versus Piperacillin-tazobactam for the Treatment of Complicated Urinary Tract Infection Including Acute Pyelonephritis: ZEUS, A Phase 2/3 Randomized Trial.

BACKGROUND: ZTI-01 (fosfomycin for injection) is an epoxide antibiotic with a differentiated mechanism of action (MOA) inhibiting an early step in bacterial cell wall synthesis. ZTI-01 has broad in vitro spectrum of activity, including multidrug-resistant Gram-negative pathogens, and is being developed for treatment of complicated urinary tract infection (cUTI) and acute pyelonephritis (AP) in the United States. METHODS: Hospitalized adults with suspected or microbiologically confirmed cUTI/AP were randomized 1:1 to 6 g ZTI-01 q8h or 4.5 g intravenous (IV) piperacillin-tazobactam (PIP-TAZ) q8h for a fixed 7-day course (no oral switch); patients with concomitant bacteremia could receive up to 14 days. RESULTS: Of 465 randomized patients, 233 and 231 were treated with ZTI-01 and PIP-TAZ, respectively. In the microbiologic modified intent-to-treat (m-MITT) population, ZTI-01 met the primary objective of noninferiority compared with PIP-TAZ with overall success rates of 64.7% (119/184 patients) vs 54.5% (97/178 patients), respectively; treatment difference was 10.2% (95% confidence interval [CI]: -0.4, 20.8). Clinical cure rates at test of cure (TOC, day 19-21) were high and similar between treatments (90.8% [167/184] vs 91.6% [163/178], respectively). In post hoc analysis using unique pathogens typed by pulsed-field gel electrophoresis, overall success rates at TOC in m-MITT were 69.0% (127/184) for ZTI-01 versus 57.3% (102/178) for PIP-TAZ (difference 11.7% 95% CI: 1.3, 22.1). ZTI-01 was well tolerated. Most treatment-emergent adverse events, including hypokalemia and elevated serum aminotransferases, were mild and transient. CONCLUSIONS: ZTI-01 was effective for treatment of cUTI including AP and offers a new IV therapeutic option with a differentiated MOA for patients with serious Gram-negative infections. CLINICAL TRIAL REGISTRATION: NCT02753946.