In vivo Pharmacokinetics and Pharmacodynamics of ZTI-01 (Fosfomycin for Injection) in the Neutropenic Murine Thigh Infection Model against E. coli, K. pneumoniae, and P. aeruginosa [PublishAheadOfPrint]

Fosfomycin is a broad-spectrum agent with activity against gram-positive and gram-negative bacteria, including drug-resistant strains, such as extended spectrum beta-lactamase (ESBL)-producing and carbapenem-resistant (CR) gram-negative rods. In the present study, the pharmacokinetic/pharmacodynamic (PK/PD) activity of ZTI-01 (fosfomycin for injection) was evaluated in the neutropenic murine thigh infection model against 5 E. coli (EC), 3 K. pneumoniae (KPN), and 2 P. aeruginosa (PSA) strains, including a subset with ESBL and CR phenotype. The pharmacokinetics of ZTI-01 were examined in mice after subcutaneous administration of 3.125, 12.5, 50, 200, 400 and 800 mg/kg. The half-life ranged from 0.51 to 1.1 h, area under the concentration-time curve (AUC_0-) ranged from 1.4 to 87 mg*h/L, and maximum concentrations ranged from 0.6 to 42.4 mg/L. Dose fractionation demonstrated AUC/MIC ratio to be the PK/PD index most closely linked to efficacy (R² = 0.70). Net stasis and cidal activity was observed against all strains. Net stasis was observed at 24 h AUC/MIC values of 24, 21, and 15 for EC, KPN and PSA, respectively. For the Enterobacteriaceae group stasis was noted at mean 24 h AUC/MIC targets of 23 and 1 log kill at 83. Survival in mice infected with EC 145 was maximal at 24 h AUC/MIC exposures of 9-43, which is comparable to the stasis exposures identified in the PK/PD studies. These results should prove useful for the design of clinical dosing regimens for ZTI-01 in the treatment of serious infections due to Enterobacteriaceae and Pseudomonas.

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