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Pharmacodynamics of Ceftolozane plus Tazobactam Studied in an In Vitro Pharmacokinetic Model of Infection.
Antimicrob Agents Chemother. 2016 01; 60(1):515-21.AA

Abstract

Ceftolozane plus tazobactam is an antipseudomonal cephalosporin combined with tazobactam, an established beta-lactamase inhibitor, and has in vitro potency against a range of clinically important β-lactamase-producing bacteria, including most extended-spectrum-β-lactamase (ESBL)-positive Enterobacteriaceae. The pharmacodynamics of β-lactam-β-lactamase inhibitor combinations presents a number of theoretical and practical challenges, including modeling different half-lives of the compounds. In this study, we studied the pharmacodynamics of ceftolozane plus tazobactam against Escherichia coli and Pseudomonas aeruginosa using an in vitro pharmacokinetic model of infection. Five strains of E. coli, including three clinical strains plus two CTX-M-15 (one high and one moderate) producers, and five strains of P. aeruginosa, including two with OprD overexpression and AmpC β-lactamases, were employed. Ceftolozane MICs (E. coli, 0.12 to 0.25 mg/liter, and P. aeruginosa, 0.38 to 8 mg/liter) were determined in the presence of 4 mg/liter tazobactam. Dose ranging of ceftolozane (percentage of time in which the free-drug concentration exceeds the MIC [fT>MIC], 0 to 100%) plus tazobactam (human pharmacokinetics) was simulated every 8 hours, with half-lives (t1/2) of 2.5 and 1 h, respectively. Ceftolozane and tazobactam concentrations were confirmed by high-performance liquid chromatography (HPLC). The ceftolozane-plus-tazobactam fT>MIC values at 24 h for a static effect and a 1-log and 2-log drop in initial inoculum for E. coli were 27.8% ± 5.6%, 33.0% ± 5.6%, and 39.6% ± 8.5%, respectively. CTX-M-15 production did not affect the 24-h fT>MIC for E. coli strains. The ceftolozane-plus-tazobactam fT>MIC values for a 24-h static effect and a 1-log and 2-log drop for P. aeruginosa were 24.9% ± 3.0%, 26.6% ± 3.9%, and 31.2% ± 3.6%. Despite a wide range of absolute MICs, the killing remained predictable as long as the MICs were normalized to the corresponding fT>MIC. Emergence of resistance on 4× MIC plates and 8× MIC plates occurred maximally at an fT>MIC of 10 to 30% and increased as time of exposure increased. The fT>MIC for a static effect for ceftolozane plus tazobactam is less than that observed with other cephalosporins against E. coli and P. aeruginosa and is more similar to the fT>MIC reported for carbapenems.

Authors+Show Affiliations

Bristol Centre for Antimicrobial Research & Evaluation, University of Bristol, and North Bristol NHS Trust, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol, United Kingdom.Bristol Centre for Antimicrobial Research & Evaluation, University of Bristol, and North Bristol NHS Trust, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol, United Kingdom.Bristol Centre for Antimicrobial Research & Evaluation, University of Bristol, and North Bristol NHS Trust, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol, United Kingdom.Bristol Centre for Antimicrobial Research & Evaluation, University of Bristol, and North Bristol NHS Trust, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol, United Kingdom.Bristol Centre for Antimicrobial Research & Evaluation, University of Bristol, and North Bristol NHS Trust, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol, United Kingdom karen.bowker@nbt.nhs.uk.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26552975

Citation

MacGowan, Alasdair P., et al. "Pharmacodynamics of Ceftolozane Plus Tazobactam Studied in an in Vitro Pharmacokinetic Model of Infection." Antimicrobial Agents and Chemotherapy, vol. 60, no. 1, 2016, pp. 515-21.
MacGowan AP, Noel AR, Tomaselli SG, et al. Pharmacodynamics of Ceftolozane plus Tazobactam Studied in an In Vitro Pharmacokinetic Model of Infection. Antimicrob Agents Chemother. 2016;60(1):515-21.
MacGowan, A. P., Noel, A. R., Tomaselli, S. G., Nicholls, D., & Bowker, K. E. (2016). Pharmacodynamics of Ceftolozane plus Tazobactam Studied in an In Vitro Pharmacokinetic Model of Infection. Antimicrobial Agents and Chemotherapy, 60(1), 515-21. https://doi.org/10.1128/AAC.00727-15
MacGowan AP, et al. Pharmacodynamics of Ceftolozane Plus Tazobactam Studied in an in Vitro Pharmacokinetic Model of Infection. Antimicrob Agents Chemother. 2016;60(1):515-21. PubMed PMID: 26552975.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacodynamics of Ceftolozane plus Tazobactam Studied in an In Vitro Pharmacokinetic Model of Infection. AU - MacGowan,Alasdair P, AU - Noel,Alan R, AU - Tomaselli,Sharon G, AU - Nicholls,Donna, AU - Bowker,Karen E, Y1 - 2015/11/09/ PY - 2015/03/27/received PY - 2015/11/01/accepted PY - 2015/11/11/entrez PY - 2015/11/11/pubmed PY - 2016/10/12/medline SP - 515 EP - 21 JF - Antimicrobial agents and chemotherapy JO - Antimicrob Agents Chemother VL - 60 IS - 1 N2 - Ceftolozane plus tazobactam is an antipseudomonal cephalosporin combined with tazobactam, an established beta-lactamase inhibitor, and has in vitro potency against a range of clinically important β-lactamase-producing bacteria, including most extended-spectrum-β-lactamase (ESBL)-positive Enterobacteriaceae. The pharmacodynamics of β-lactam-β-lactamase inhibitor combinations presents a number of theoretical and practical challenges, including modeling different half-lives of the compounds. In this study, we studied the pharmacodynamics of ceftolozane plus tazobactam against Escherichia coli and Pseudomonas aeruginosa using an in vitro pharmacokinetic model of infection. Five strains of E. coli, including three clinical strains plus two CTX-M-15 (one high and one moderate) producers, and five strains of P. aeruginosa, including two with OprD overexpression and AmpC β-lactamases, were employed. Ceftolozane MICs (E. coli, 0.12 to 0.25 mg/liter, and P. aeruginosa, 0.38 to 8 mg/liter) were determined in the presence of 4 mg/liter tazobactam. Dose ranging of ceftolozane (percentage of time in which the free-drug concentration exceeds the MIC [fT>MIC], 0 to 100%) plus tazobactam (human pharmacokinetics) was simulated every 8 hours, with half-lives (t1/2) of 2.5 and 1 h, respectively. Ceftolozane and tazobactam concentrations were confirmed by high-performance liquid chromatography (HPLC). The ceftolozane-plus-tazobactam fT>MIC values at 24 h for a static effect and a 1-log and 2-log drop in initial inoculum for E. coli were 27.8% ± 5.6%, 33.0% ± 5.6%, and 39.6% ± 8.5%, respectively. CTX-M-15 production did not affect the 24-h fT>MIC for E. coli strains. The ceftolozane-plus-tazobactam fT>MIC values for a 24-h static effect and a 1-log and 2-log drop for P. aeruginosa were 24.9% ± 3.0%, 26.6% ± 3.9%, and 31.2% ± 3.6%. Despite a wide range of absolute MICs, the killing remained predictable as long as the MICs were normalized to the corresponding fT>MIC. Emergence of resistance on 4× MIC plates and 8× MIC plates occurred maximally at an fT>MIC of 10 to 30% and increased as time of exposure increased. The fT>MIC for a static effect for ceftolozane plus tazobactam is less than that observed with other cephalosporins against E. coli and P. aeruginosa and is more similar to the fT>MIC reported for carbapenems. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/26552975/Pharmacodynamics_of_Ceftolozane_plus_Tazobactam_Studied_in_an_In_Vitro_Pharmacokinetic_Model_of_Infection_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=26552975 DB - PRIME DP - Unbound Medicine ER -