Pharmacokinetics and Tissue Penetration of Ceftolozane-Tazobactam in Diabetic Patients with Lower Limb Infections and Healthy Adult Volunteers

Abstract

Ceftolozane-tazobactam displays potent activity against Gram-negative bacteria that can cause diabetic foot infections (DFI), making it an attractive treatment option when few alternatives exist. The pharmacokinetics and tissue penetration of ceftolozane-tazobactam at 1.5 g every 8 h (q8h) in patients ( = 10) with DFI were compared with those in healthy volunteers ( = 6) using microdialysis. In the patient participants, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: maximum concentration (), 55.2 μg/ml (range, 40.9 to 169.3 μg/ml); half-life (), 3.5 h (range, 2.3 to 4.7 h); and area under the concentration-time curve (AUC) from time zero to 8 h (AUC), 191.6 μg · h/ml (range, 147.1 to 286.6 μg · h/ml). The median AUC for tissue (AUC; where AUC was the AUC for tissue for ceftolozane)/AUC for plasma for each antibiotic corrected by the fraction of free drug (AUC) was 0.75 (range, 0.35 to 1.00), resulting in a mean free time above 4 μg/ml (the susceptibility breakpoint) in tissue of 99.8% (range, 87.5 to 100%). In the patient participants, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows:, 14.2 μg/ml (range, 7.6 to 64.2 μg/ml); , 2.0 h (range, 0.7 to 2.4 h); and AUC, 27.1 μg · h/ml (range, 15.0 to 70.0 μg · h/ml). The AUC (where AUC was the AUC from time zero to the time of the last measureable concentration in tissue for tazobactam)/AUC for tazobactam was 1.18 (range, 0.54 to 1.44). In the healthy volunteers, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: , 91.5 μg/ml (range, 65.7 to 110.7 μg/ml);, 1.9 h (range, 1.6 to 2.1 h); and AUC, 191.3 μg · h/ml (range, 118.1 to 274.3 μg · h/ml). The median AUC/AUC was 0.87 (range, 0.54 to 2.20), resulting in a mean free time above 4 μg/ml in tissue of 93.8% (range, 87.5 to 100%). In the healthy volunteers, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows: , 17.5 μg/ml (range, 15.4 to 27.3 μg/ml);, 0.7 h (range, 0.6 to 0.8 h); and AUC, 22.2 μg · h/ml (range, 19.2 to 36.4 μg · h/ml). The AUC/AUC for tazobactam was 0.85 (range, 0.63 to 2.10). Both ceftolozane and tazobactam penetrated into subcutaneous tissue with exposures similar to those of free drug in plasma in both patients with DFI and healthy volunteers. These data suggest that ceftolozane-tazobactam at 1.5 g q8h can achieve the optimal exposure with activity against susceptible Gram-negative pathogens in the tissue of patients with DFI. (This study has been registered at ClinicalTrials.gov under identifier NCT02620774.).

Expression of CTX-M-15 limits the efficacy of ceftolozane/tazobactam against Escherichia coli in a high-inoculum murine peritonitis model

“…The unitary dose that best reproduced the peak concentration obtained in humans with ceftolozane/tazobactam 1 g/500 mg (median concentrations in humans (range), 91.5 (65.7e110.7) and 17.5 (15.4e27.3) mg/L, respectively [12]) was 100/50 mg/kg, which led to median (range) ceftolozane and tazobactam peak concentrations at 30 minutes of 115.6 (95.9e201.2) and 13.85 (8.6e18.2) mg/L, respectively. The rate of injections every 2 hours was chosen according to the elimination half-lives of ceftolozane and tazobactam, which were approximately 15 minutes for each component.…”

Microdialysis as a tool for antibiotic assessment in patients with diabetic foot: a review

“…With regard to the use of microdialysis in DFI patients treated with ATBs, several parameters are useful when assessing ATB efficacy and concentrations in peripheral tissue. These pharmacokinetic/pharmacodynamic (PK/PD) indices include maximum ATB concentration ( C max ), biological half-life ( t 1/2 ), the area under the concentration-time curve (AUC), the AUC tissue (where AUC tissue is the AUC from time zero to the time of the last measureable concentration in tissue for certain ATB/AUC plasma for certain ATB) ( 61 ), MIC = 100 (area under the concentration-time curve/minimum inhibitory concentration (MIC), and fT (the percentage of a 24-hour period where the unbound drug concentration exceeds the MIC) ( 62 ).…”

“…Ceftolozane-tazobactam is another promising antibiotic agent with potent activity against DFI, especially infections caused by Gram-negative bacteria. In a study by Monogue et al., the pharmacokinetics and tissue penetration of ceftolozane-tazobactam were evaluated using in vivo microdialysis in 10 diabetic subjects and 6 healthy volunteers ( 61 ). The authors have confirmed that in the case of Pseudomonas aeruginosa , ceftolozane-tazobactam is the most potent (highest AUC in peripheral tissue) agent.…”

Antibiotics in Necrotizing Soft Tissue Infections

“…While ceftazidime penetration was not affected by diabetes, it highly depended on tissue perfusion in another work [101], and employing high doses is suggested for cefepime [100]. Maximal concentration in soft tissue was both reduced and delayed when compared to healthy-volunteers for tedizolid and ceftolozane-tazobactam [114,115]. Interestingly, tissue diffusion of linezolid in two patients was reported to improve after hyperbaric oxygen therapy, a therapeutic intervention sometimes employed in NSTIs [116].…”