Vancomycin-arginine (STM-001) abrogates ESBL carrier and carbapenem-resistant Escherichia coli burden in a murine complicated urinary tract infection model

Abstract

Abstract Objectives STM-001, a retargeted glycopeptide, is active against MDR E. coli expressing ESBLs including carbapenemases. Herein, we assessed its capability to combat E. coli complicated urinary tract infections (cUTI) in mice driven by clinically important serine (CTX-M-15) and metallo-β-lactamases (NDM-1). Methods Plasma and urine pharmacokinetics following IV administration of STM-001 (1–50 mg/kg) were determined in mice via LC-MS/MS. The effects on bacterial burden (kidney, bladder and urine) were determined in a 7 day mouse cUTI model whereby STM-001 was administered q12h or q24h at 2–100 mg/kg/day from Day 4. Efficacy was assessed by the change in log10 cfu/g or log10 cfu/mL from vehicle-treated infected mice. Results MICs of STM-001 for CTX-M-15 and NDM-1 E. coli were 8 and 16 mg/L, respectively. Blood pharmacokinetic profile was linear and dose-dependent with low clearance of 9.49 ± 0.31 mL/min/kg, V = 0.63 ± 0.02 L/kg and t½ = 1.16 ± 0.03 h. High STM-001 concentrations were recovered in urine 0–8 h post-administration, reaching up to 120-fold above its MIC. In cUTI efficacy studies, STM-001 (1–50 mg/kg, q12h) reduced CTX-M-15 burden by log10 4.31 (kidney), 3.95 (bladder) and 4.82 (urine) compared with vehicle-treated animals (P < 0.0001). STM-001 also reduced NDM-1 burden by log10 3.89 (kidney), 3.76 (bladder) and 3.08 (urine) (P < 0.0001), with similar inhibitory effects following q24h dosing. Conclusions STM-001 was highly effective in reducing E. coli burden in kidney, bladder and urine in mouse cUTI models. The observed efficacy with either dosing regimen indicates potential low humanized doses of 1–5 mg/kg. These data support further development of STM-001 as an innovative, carbapenem-sparing antibiotic to combat human cUTIs.