Antimicrobial Activity of Ceftolozane-Tazobactam Tested against Enterobacteriaceae and Pseudomonas aeruginosa with Various Resistance Patterns Isolated in U.S. Hospitals (2011-2012)

Farrell, David J.; Flamm, Robert K.; Sader, Hélio S.; Jones, Ronald N.

doi:10.1128/aac.01802-13

Cited by 180 publications

(130 citation statements)

References 17 publications

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“…Tazobactam is a potent, irreversible inhibitor of most ESBLs. The MIC 50 /MIC 90 of this agent for ESBL-producing E. coli and K. pneumoniae are 0.5/4 µg/mL and 4/>32 µg/mL, respectively [56,57]. Differences in MIC distributions may be reflective of discrepancies in ESBL genes present.…”

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

143

106

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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

143

106

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“…A total of 998 P. aeruginosa clinical isolates were collected during 2012 in 27 U.S. hospitals and tested against ceftolozanetazobactam and comparator antimicrobial agents as part of a surveillance initiative (8). The surveillance study included one isolate per patient per episode that was deemed by the participant investigator to be the cause of infection.…”

Section: Methodsmentioning

confidence: 99%

“…Ceftolozane-tazobactam is an antibacterial consisting of ceftolozane, an antipseudomonal cephalosporin that has improved stability against the chromosomal AmpC produced by P. aeruginosa, and tazobactam, a penicillanic acid-sulfone ␤-lactamase inhibitor that has activity against constitutive Ambler class C and various class A enzymes (7,8). Ceftolozane-tazobactam was at least 4-fold more potent than ceftazidime against a large collection of global P. aeruginosa isolates, including multidrug-resistant and extremely drug-resistant isolates (7)(8)(9).…”

mentioning

confidence: 99%

Mutation-Driven β-Lactam Resistance Mechanisms among Contemporary Ceftazidime-Nonsusceptible Pseudomonas aeruginosa Isolates from U.S. Hospitals

Castanheira

Mills

Farrell

et al. 2014

Antimicrob Agents Chemother

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122

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OprD loss and hyperexpression of AmpC, MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM were evaluated among 120 Pseudomonas aeruginosa isolates collected during 2012 in U.S. hospitals and selected based on ceftazidime MIC values (1 to >32 g/ml). AmpC derepression (10-fold greater than that with the control) and OprD loss (decreased/no band) were the most prevalent resistance mechanisms: 47.5 and 45.8% of the isolates were considered positive, respectively. Elevated expression of the efflux pumps MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM was observed in 32.5, 8.3, 0.0, and 28.4% of the isolates, respectively. A total of 21 different combinations of resistance mechanisms were noted, and the most prevalent included AmpC derepression with OprD loss with and without efflux hyperexpression (38 and 10 isolates, respectively). A total of 26 isolates had no changes in the resistance mechanisms tested and had lower MIC values for all ␤-lactams or ␤-lactam/ ␤-lactamase inhibitor combinations analyzed. OprD loss had a strong correlation with elevated MIC results for imipenem and meropenem (median MIC values of 8 and 4 g/ml, respectively), with all combinations displaying OprD loss also displaying elevated median MIC values for these carbapenems (4 to >8 g/ml). AmpC expression levels were greater in isolates displaying elevated cefepime, ceftazidime, or piperacillin-tazobactam MIC values (>4, >4, and >16 g/ml, respectively). Isolates displaying derepressed AmpC had ceftolozane-tazobactam MIC values ranging from 1 to 16 g/ml. No strong correlation was noticed with MIC values for this ␤-lactam/␤-lactamase inhibitor combination and OprD loss or hyperexpression of efflux systems. Two KPC-producing isolates were detected among 16 isolates displaying ceftolozane-tazobactam MIC values of >8 g/ml.

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“…However, the compound is susceptible to degradation by extended-spectrum beta-lactamases (ESBLs); therefore, the compound is combined with tazobactam, a potent beta-lactamase inhibitor, to broaden its activity. The combination had been shown to be active in vitro against a wide variety of microorganisms with different resistance mechanisms (1)(2)(3)(4)(5). The combination has also been shown to be active in vivo, in particular in animal models, against both P. aeruginosa and Enterobacteriaceae (6,7).…”

mentioning

confidence: 99%

Plasma and Epithelial Lining Fluid Pharmacokinetics of Ceftolozane and Tazobactam Alone and in Combination in Mice

Melchers

Mavridou

Seyedmousavi

et al. 2015

Antimicrob Agents Chemother

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cCeftolozane is a new cephalosporin with activity against Gram-negative and Gram-positive microorganisms. However, the compound is susceptible to degradation by extended-spectrum beta-lactamases (ESBLs). Tazobactam is an ESBL inhibitor and is combined with ceftolozane to broaden its activity. Surprisingly, although tazobactam has been available for over 20 years, few if any reliable data exist on the tazobactam pharmacokinetic (PK) properties in mice. To evaluate the PK and pharmacodynamic (PD) relationships in mice, the PK properties of tazobactam and ceftolozane were extensively investigated. Thigh-infected neutropenic CD-1 mice were injected intraperitoneally with a single 0.1-ml dose containing ceftolozane, tazobactam, or both compounds. Ceftolozane was applied in 2-fold-increasing doses of 4 mg/kg of body weight to 64 mg/kg alone or in combination. Tazobactam was combined in reverse doses (thus, 64/4 mg/kg, 32/8 mg/kg, etc.) (n ‫؍‬ 2 per time point). In separate validation experiments, ceftolozane-tazobactam was given alone or in combination at 32/8 mg/kg and 8/32 mg/kg (n ‫؍‬ 4 per time point). Plasma samples (one per mouse) and bronchoalveolar lavage samples were collected at up to 12 time points until 6 h after administration. There were no significant differences in the ceftolozane and tazobactam PK alone versus combined, indicating no PK interaction. The PKs were linear and dose proportional for both compounds and showed a good penetration in the epithelial lining fluid. The estimated mean (standard deviation) half-life of ceftolozane was 0.287 h (0.031 h), and that of tazobactam was 0.176 h (0.026), and the V was 0.43 liter/kg and 1.14 liter/kg, respectively. The estimates of tazobactam parameters can also be used to (re)interpret PD data. Ceftolozane is a novel cephalosporin with activity against Pseudomonas aeruginosa and other Gram-negative microorganisms. However, the compound is susceptible to degradation by extended-spectrum beta-lactamases (ESBLs); therefore, the compound is combined with tazobactam, a potent beta-lactamase inhibitor, to broaden its activity. The combination had been shown to be active in vitro against a wide variety of microorganisms with different resistance mechanisms (1-5). The combination has also been shown to be active in vivo, in particular in animal models, against both P. aeruginosa and Enterobacteriaceae (6, 7). However, the pharmacodynamics of tazobactam in vivo have not been fully identified, despite being available for over 20 years in the combination piperacillin-tazobactam. Indeed few, if any, reliable data exist on the tazobactam pharmacokinetic (PK) properties in mice, including its penetration in lung epithelial lining fluid (ELF), precluding pharmacodynamic analyses. In addition, it is not clear whether pharmacokinetic interactions exist between cephalosporins and tazobactam. In one earlier, limited study, such a pharmacokinetic interaction was observed between these two compounds (8) in mice, although it was not observed in men (9). Thus, the primary object...

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Antimicrobial Activity of Ceftolozane-Tazobactam Tested against Enterobacteriaceae and Pseudomonas aeruginosa with Various Resistance Patterns Isolated in U.S. Hospitals (2011-2012)

Cited by 180 publications

References 17 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

Mutation-Driven β-Lactam Resistance Mechanisms among Contemporary Ceftazidime-Nonsusceptible Pseudomonas aeruginosa Isolates from U.S. Hospitals

Plasma and Epithelial Lining Fluid Pharmacokinetics of Ceftolozane and Tazobactam Alone and in Combination in Mice

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