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Pharmacokinetics and Tissue Penetration of Ceftolozane-Tazobactam in Diabetic Patients with Lower Limb Infections and Healthy Adult Volunteers.
Antimicrob Agents Chemother. 2017 12; 61(12)AA

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 (n = 10) with DFI were compared with those in healthy volunteers (n = 6) using in vivo microdialysis. In the patient participants, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: maximum concentration (Cmax), 55.2 μg/ml (range, 40.9 to 169.3 μg/ml); half-life (t1/2), 3.5 h (range, 2.3 to 4.7 h); and area under the concentration-time curve (AUC) from time zero to 8 h (AUC0-8), 191.6 μg · h/ml (range, 147.1 to 286.6 μg · h/ml). The median AUC for tissue (AUCtissue; where AUCtissue was the AUC0-8 for tissue for ceftolozane)/AUC for plasma for each antibiotic corrected by the fraction of free drug (fAUCplasma) was 0.75 (range, 0.35 to 1.00), resulting in a mean free time above 4 μg/ml (the Pseudomonas aeruginosa 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: Cmax, 14.2 μg/ml (range, 7.6 to 64.2 μg/ml); t1/2, 2.0 h (range, 0.7 to 2.4 h); and AUC0-8, 27.1 μg · h/ml (range, 15.0 to 70.0 μg · h/ml). The AUCtissue (where AUCtissue was the AUC from time zero to the time of the last measureable concentration in tissue for tazobactam)/fAUCplasma 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: Cmax, 91.5 μg/ml (range, 65.7 to 110.7 μg/ml); t1/2, 1.9 h (range, 1.6 to 2.1 h); and AUC0-8, 191.3 μg · h/ml (range, 118.1 to 274.3 μg · h/ml). The median AUCtissue/fAUCplasma 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: Cmax, 17.5 μg/ml (range, 15.4 to 27.3 μg/ml); t1/2, 0.7 h (range, 0.6 to 0.8 h); and AUC0-8, 22.2 μg · h/ml (range, 19.2 to 36.4 μg · h/ml). The AUCtissue/fAUCplasma 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.).

Authors+Show Affiliations

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.Hartford Healthcare Medical Group, Podiatric Surgery, Hartford, Connecticut, USA.Hartford Healthcare Medical Group, Podiatric Surgery, Hartford, Connecticut, USA.Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA david.nicolau@hhchealth.org. Division of Infectious Diseases, Hartford Hospital, Hartford, Connecticut, USA.

Pub Type(s)

Clinical Trial
Journal Article

Language

eng

PubMed ID

28893779

Citation

Monogue, Marguerite L., et al. "Pharmacokinetics and Tissue Penetration of Ceftolozane-Tazobactam in Diabetic Patients With Lower Limb Infections and Healthy Adult Volunteers." Antimicrobial Agents and Chemotherapy, vol. 61, no. 12, 2017.
Monogue ML, Stainton SM, Baummer-Carr A, et al. Pharmacokinetics and Tissue Penetration of Ceftolozane-Tazobactam in Diabetic Patients with Lower Limb Infections and Healthy Adult Volunteers. Antimicrob Agents Chemother. 2017;61(12).
Monogue, M. L., Stainton, S. M., Baummer-Carr, A., Shepard, A. K., Nugent, J. F., Kuti, J. L., & Nicolau, D. P. (2017). Pharmacokinetics and Tissue Penetration of Ceftolozane-Tazobactam in Diabetic Patients with Lower Limb Infections and Healthy Adult Volunteers. Antimicrobial Agents and Chemotherapy, 61(12). https://doi.org/10.1128/AAC.01449-17
Monogue ML, et al. Pharmacokinetics and Tissue Penetration of Ceftolozane-Tazobactam in Diabetic Patients With Lower Limb Infections and Healthy Adult Volunteers. Antimicrob Agents Chemother. 2017;61(12) PubMed PMID: 28893779.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetics and Tissue Penetration of Ceftolozane-Tazobactam in Diabetic Patients with Lower Limb Infections and Healthy Adult Volunteers. AU - Monogue,Marguerite L, AU - Stainton,Sean M, AU - Baummer-Carr,Arlinda, AU - Shepard,Ashley K, AU - Nugent,James F, AU - Kuti,Joseph L, AU - Nicolau,David P, Y1 - 2017/11/22/ PY - 2017/07/16/received PY - 2017/09/02/accepted PY - 2017/9/13/pubmed PY - 2018/7/4/medline PY - 2017/9/13/entrez KW - ceftolozane-tazobactam KW - diabetes KW - microdialysis KW - pharmacokinetics KW - tissue penetration JF - Antimicrobial agents and chemotherapy JO - Antimicrob Agents Chemother VL - 61 IS - 12 N2 - 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 (n = 10) with DFI were compared with those in healthy volunteers (n = 6) using in vivo microdialysis. In the patient participants, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: maximum concentration (Cmax), 55.2 μg/ml (range, 40.9 to 169.3 μg/ml); half-life (t1/2), 3.5 h (range, 2.3 to 4.7 h); and area under the concentration-time curve (AUC) from time zero to 8 h (AUC0-8), 191.6 μg · h/ml (range, 147.1 to 286.6 μg · h/ml). The median AUC for tissue (AUCtissue; where AUCtissue was the AUC0-8 for tissue for ceftolozane)/AUC for plasma for each antibiotic corrected by the fraction of free drug (fAUCplasma) was 0.75 (range, 0.35 to 1.00), resulting in a mean free time above 4 μg/ml (the Pseudomonas aeruginosa 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: Cmax, 14.2 μg/ml (range, 7.6 to 64.2 μg/ml); t1/2, 2.0 h (range, 0.7 to 2.4 h); and AUC0-8, 27.1 μg · h/ml (range, 15.0 to 70.0 μg · h/ml). The AUCtissue (where AUCtissue was the AUC from time zero to the time of the last measureable concentration in tissue for tazobactam)/fAUCplasma 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: Cmax, 91.5 μg/ml (range, 65.7 to 110.7 μg/ml); t1/2, 1.9 h (range, 1.6 to 2.1 h); and AUC0-8, 191.3 μg · h/ml (range, 118.1 to 274.3 μg · h/ml). The median AUCtissue/fAUCplasma 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: Cmax, 17.5 μg/ml (range, 15.4 to 27.3 μg/ml); t1/2, 0.7 h (range, 0.6 to 0.8 h); and AUC0-8, 22.2 μg · h/ml (range, 19.2 to 36.4 μg · h/ml). The AUCtissue/fAUCplasma 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.). SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/28893779/Pharmacokinetics_and_Tissue_Penetration_of_Ceftolozane_Tazobactam_in_Diabetic_Patients_with_Lower_Limb_Infections_and_Healthy_Adult_Volunteers_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=28893779 DB - PRIME DP - Unbound Medicine ER -