Switch from IV to SC Administration of Vancomycin-D-Arginine (STM-001) Maintains Effectivity to Combat NDM-1 E. Coli Burden in a Murine Model of Complicated Urinary Tract Infection (cUTI)

Abstract

Intravenous (IV)-bolus administered vancomycin-D-arginine (STM-001) was previously shown to be effective against E. coli in a mouse model of complicated urinary tract infection (cUTI) at a putative low, humanized-dose. Herein, we investigated if a switch in its route of administration from IV to SC during a 3-day treatment window, could still maintain the conjugate's antimicrobial effects. Mice were treated with IV STM-001, BID at 50 mg/kg four days following infection driven by a carbapenem-resistant E. coli (NDM-1 positive) strain. Thereafter, identical treatment was maintained with IV or switched to SC on days 5 and 6 or just during day 6. Bacterial burdens in urine were determined kinetically as well as in various organs on day 7. As compared to vehicle groups which ranged throughout from log10 mean (± SEM) of 4.79 ± 0.51 to log10 mean (± SEM) of 5.56 ± 0.53 CFU/mL urine), SC STM-001 treatment groups reduced urinary burden to log10 mean (± SEM) from of 1.89 ± 0.33 to log10 mean (± SEM) 2.47 ± 0.47 CFU/mL, (p < 0.05 Cf. to vehicle), very similar to IV treatment throughout. In kidney, bladder, liver and spleen, irrespective of the mode of administration, STM-001 was highly effective in lowering bacterial load from baseline, ranging from mean log10 1.4 to 2.65 CFU/tissue reductions (p < 0.05). These data underscore the promise of SC-administered STM-001 as an alternative parenteral route to IV administration in the effective targeting of highly resistant E. coli strains. STM-001 could represent an attractive clinical candidate for outpatient subcutaneous antimicrobial therapy (OSCAT) in contrast with demanding outpatient parenteral antimicrobial therapy (OPAT) to treat cUTIs in the clinic.