Herein, we evaluated sustainability of humanized exposures of cefiderocol in vivo over 72 h against pathogens with cefiderocol MICs of 0.5 to 16 μg/ml in the neutropenic murine thigh model. In Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae displaying MICs of 0.5 to 8 μg/ml (n = 11), sustained kill was observed at 72 h among 9 isolates.

SPR741 is a novel agent with structural similarity to polymyxins that is capable of potentiating the activities of various classes of antibiotics. Previously published studies indicated that although isolates had minimal susceptibilities to azithromycin (AZM), the antimicrobial activity of AZM against was enhanced when it was combined with SPR741. The current study evaluated the activity of human-simulated regimens (HSR) of AZM equivalent to clinical doses of 500 mg given intravenously (i.v.) every 24 h (q24h) and SPR741 equivalent to clinical doses of 400 mg q8h i.v. (1-h infusion), alone and in combination, against multidrug-resistant (MDR) We studied 30 MDR isolates expressing a wide spectrum of β-lactamases (ESBL, NDM, VIM, and KPC), including a subset of isolates positive for genes conferring macrolide resistance (, ,, and ). activity was assessed as the change in log CFU per thigh at 24 h compared with 0 h. Treatment with AZM alone was associated with net growth of 2.60 ± 0.83 log CFU/thigh. Among isolates with AZM MICs of ≤16 mg/liter, treatment with AZM-SPR741was associated with an average reduction in bacterial burden of -0.53 ± 0.82 log CFU/thigh, and stasis to 1-log kill was observed in 9/11 isolates (81.8%). Combination therapy with an AZM-SPR741 HSR showed promising activity against MDR isolates with AZM MICs of ≤16 mg/liter, including those producing a variety of β-lactamases. These data support a potential role for AZM-SPR741 in the treatment of infections due to MDR .

Ceftibuten-clavulanate (CTB-CLA) is a novel ␤-lactam-␤-lactamase combination with potential utility for the management of urinary tract infections caused by extended-spectrum-␤-lactamase (ESBL)-producing organisms. We examined the pharmacodynamics of the combination against 25 Enterobacteriaceae expressing ␤-lactamases (CTX-M, TEM, and SHV wild types and SHV-ESBL) in the murine thigh infection model. MIC values of CTB and CTB-CLA ranged from 1 to Ͼ32 mg/liter and 0.125 to 8 mg/liter, respectively. Human-simulated regimens of CTB and CLA equivalent to clinical doses of 400 mg orally (p.o.) every 8 h (q8h) and 187 mg q8h, respectively, were developed. CLA dose fractionation studies were undertaken to characterize the driver of efficacy. CLA dose-ranging studies were undertaken to assess the activity of the CTB human-simulated regimen in combination with escalating CLA exposures. The relationships between the percentage of the dosing interval during which the free CLA plasma concentrations remained above a threshold concentration (%fTϾC T ) and the change in log 10 CFU per thigh at 24 h were examined across different threshold concentrations. Additionally, the efficacy of a human-simulated regimen of CTB-CLA was assessed against isolates with various susceptibilities to the combination. The pharmacokinetic/pharmacodynamic index that best correlated with the efficacy of the combination was %fT Ͼ threshold CLA plasma concentration of 0.5 mg/liter. The plasma %fTϾ0.5 mg/liter associated with the static endpoint was 20.59%. For isolates with CTB-CLA MICs of Յ4 mg/liter, stasis was achieved with a human-simulated regimen of CTB-CLA against 20/22 isolates (90.9%), while for isolates with MICs of 8 mg/liter, only 1/3 tested isolates (33.3%) displayed stasis. Results suggest a susceptibility breakpoint of 4 mg/liter for CTB-CLA. These data support the consideration of the CTB-CLA combination for the treatment of urinary tract infections due to ESBL-producing Enterobacteriaceae.

Herein, we present pharmacokinetic and tissue penetration data for oral tedizolid in hospitalized patients with diabetic foot infections (DFI) compared with healthy volunteers. Participants received oral tedizolid phosphate 200 mg every 24 h for 3 doses to achieve steady state. A microdialysis catheter was inserted into the subcutaneous tissue near the margin of the wound for patients or into thigh tissue of volunteers. Following the third dose, 12 blood and 14 dialysate fluid samples were collected over 24 h to characterize tedizolid concentrations in plasma and interstitial extracellular fluid of soft tissue. Mean ± standard deviation (SD) tedizolid pharmacokinetic parameters in plasma for patients compared with volunteers, respectively, were as follows: maximum concentration (), 1.5 ± 0.5 versus 2.7 ± 1.1 mg/liter ( = 0.005); time to () (median [range]), 5.9 (1.2 to 8.0) versus 2.5 (2.0 to 3.0 h) ( = 0.003); half-life (t), 9.1 ± 3.6 versus 8.9 ± 2.2 h ( = 0.932); and plasma area under the concentration-time curve for the dosing interval (AUC ), 18.5 ± 9.7 versus 28.7 ± 9.6 mg · h/liter ( = 0.004). The tissue area under the concentration-time curve (AUC ) for the dosing interval was 3.4 ± 1.5 versus 5.2 ± 1.6 mg · h/liter ( = 0.075). Tissue penetration median (range) was 1.1 (0.3 to 1.6) versus 0.8 (0.7 to 1.0) ( = 0.351). Despite lower plasma and delayed values for patients with DFI relative to healthy volunteers, the penetration into and exposure to tissue were similar. Based on available pharmacodynamic thresholds for tedizolid, the plasma and tissue exposures using the oral 200 mg once-daily regimen are suitable for further study in treatment of DFI.