Multicenter, Double-Blind, Randomized, Phase II Trial To Assess the Safety and Efficacy of Ceftolozane-Tazobactam plus Metronidazole Compared with Meropenem in Adult Patients with Complicated Intra-Abdominal Infections

Lucasti, Christopher; Hershberger, Ellie; Miller, Benjamin; Yankelev, Sara; Steenbergen, Judith N.; Friedland, Ian R.; Solomkin, Joseph S.

doi:10.1128/aac.00049-14

Cited by 91 publications

(82 citation statements)

References 27 publications

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“…Ceftolozane-tazobactam (in combination with metronidazole) was compared to meropenem for the treatment of complicated intra-abdominal infections in phase 2 [58] and phase 3 [59] trials that included 4 and 50 people, respectively, with ESBL-producing Enterobacteriaceae. Although the limited number of ESBLs precluded a robust analysis, this compound performed similarly against ESBL-producing and non-ESBL producing isolates.…”

Section: Newer β-Lactam-β-lactamase Inhibitorsmentioning

confidence: 99%

The Use of Noncarbapenem β-Lactams for the Treatment of Extended-Spectrum β-Lactamase Infections

Tamma¹,

Rodríguez‐Baño

2017

Clinical Infectious Diseases

151

117

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The continued rise in infections caused by extended-spectrum β-lactamase (ESBL)-producing pathogens is recognized globally as one of the most pressing concerns facing the healthcare community. Carbapenems are widely regarded as the antibiotics of choice for the treatment of ESBL-producing infections, even when in vitro activity to other β-lactams has been demonstrated. However, indiscriminant carbapenem use is not without consequence, and carbapenem overuse has contributed to the emergence of carbapenem-resistant Enterobacteriaceae. The use of non-carbapenem β-lactams for the treatment of ESBL infections has yielded conflicting results. In this review, we discuss the available data for the use of cephamycins, cefepime, piperacillin-tazobactam, ceftolozane-tazobactam, and ceftazidime-avibactam for the treatment of ESBL infections.

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Section: Newer β-Lactam-β-lactamase Inhibitorsmentioning

confidence: 99%

The Use of Noncarbapenem β-Lactams for the Treatment of Extended-Spectrum β-Lactamase Infections

Tamma¹,

Rodríguez‐Baño

2017

Clinical Infectious Diseases

151

117

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“…The carbapenemase neutralized ceftolozane up to a concentration of 50 g/ml. Aliquots of 1 ml each were taken from the central compartment at 0, 1,2,3,4,5,6,7,12,24,25,26,27,28,29,30,31,36,48,60, and 72 h, treated with 10 l of carbapenemase, left for 20 min, and then plated on nutrient agar plates using a spiral plater (Don Whitley Scientific, Yorkshire, United Kingdom) for determination of total bacterial counts. A second aliquot not treated with carbapenemase was plated on nutrient agar plates containing 1ϫ, 2ϫ, 4ϫ, and 8ϫ the MIC of ceftolozane and tazobactam (4 mg/liter) for the strain tested to detect changes in population profile.…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…The combination has completed phase 3 clinical trials for complicated intra-abdominal and complicated urinary tract infections (1,2). It was recently approved in the United States for these indications and is undergoing regulatory review in the European Union.…”

mentioning

confidence: 99%

Pharmacodynamics of Ceftolozane plus Tazobactam Studied in an In Vitro Pharmacokinetic Model of Infection

MacGowan

Noel

Tomaselli

et al. 2016

Antimicrob Agents Chemother

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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 ␤-lactamase-producing bacteria, including most extended-spectrum-␤-lactamase (ESBL)-positive Enterobacteriaceae. The pharmacodynamics of ␤-lactam-␤-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 ␤-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 (t 1/2 ) 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. Ceftolozane plus tazobactam is a novel antibacterial consisting of a combination of the new cephalosporin ceftolozane with a well-established ␤-lactamase inhibitor, i.e., tazobactam. The combination has completed phase 3 clinical trials for complicated intra-abdominal and complicated urinary tract infections (1, 2). It was recently approved in the United States for these indications and is undergoing regulatory review in the European Union.The in vitro potency of ceftolozane plus 4 mg/liter tazobactam has been studied against Pseudomonas aeruginosa and members of the Enterobacteriaceae from the United States and Europe (3-5). Ceftolozane plus tazobactam was the most active ␤-lactam agent when tested against multidrug-...

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“…A number of phase 1 and phase 2 studies have reported that ceftolozane has a good safety and tolerability profile, one that is consistent with that of other cephalosporins [13][14][15].…”

Section: Ceftolozane/tazobactammentioning

confidence: 67%

Light and Shade of New Antibiotics

Bassetti

Siega

Pecori

2015

Annual Update in Intensive Care and Emergency Medicine

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Multicenter, Double-Blind, Randomized, Phase II Trial To Assess the Safety and Efficacy of Ceftolozane-Tazobactam plus Metronidazole Compared with Meropenem in Adult Patients with Complicated Intra-Abdominal Infections

Cited by 91 publications

References 27 publications

The Use of Noncarbapenem β-Lactams for the Treatment of Extended-Spectrum β-Lactamase Infections

The Use of Noncarbapenem β-Lactams for the Treatment of Extended-Spectrum β-Lactamase Infections

Pharmacodynamics of Ceftolozane plus Tazobactam Studied in an In Vitro Pharmacokinetic Model of Infection

Light and Shade of New Antibiotics

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