Efficacy of ceftolozane/tazobactam versus levofloxacin in the treatment of complicated urinary tract infections (cUTIs) caused by levofloxacin-resistant pathogens: results from the ASPECT-cUTI trial

Huntington, Jennifer A.; Sakoulas, George; Umeh, Obiamiwe; Cloutier, Daniel; Steenbergen, Judith N.; Bliss, Caleb; Goldstein, Ellie J. C.

doi:10.1093/jac/dkw053

Cited by 40 publications

(16 citation statements)

References 29 publications

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“…Herein, using ESBL-and non-ESBL-producing organisms, we assessed the translational value of this murine UTI model and humanized exposures for several frequently employed antimicrobial regimens for cUTI in humans. Levofloxacin displays poor clinical and microbiologic outcomes in the face of phenotypic resistance (9,10). Similar to these clinical outcomes, data derived in the current study show a lack of efficacy in an organism defined as nonsusceptible when exposed to a humanized regimen.…”

supporting

confidence: 67%

Translational Efficacy of Humanized Exposures of Cefepime, Ertapenem, and Levofloxacin against Extended-Spectrum-β-Lactamase-Producing Escherichia coli in a Murine Model of Complicated Urinary Tract Infection

Monogue

Nicolau

2017

Antimicrob Agents Chemother

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Validated animal models are required as bridging tools to assess the utility of novel therapies and potential microbiologic outcomes. Herein, we utilized uropathogenic extended-spectrum-␤-lactamase (ESBL)-producing and non-ESBL-producing Escherichia coli in the neutropenic murine complicated urinary tract infection (cUTI) model with humanized exposures of cefepime, ertapenem, and levofloxacin to assess its translational value to human outcomes. Our data support the translational utility of this murine model to cUTI in humans as humanized exposures produced microbiologic outcomes consistent with the phenotypic profiles of the organisms.KEYWORDS ESBL, Escherichia coli, urinary tract infection, cefepime, ertapenem, levofloxacin U rinary tract infections (UTIs) are one of the most common types of communityacquired and nosocomial infections, impacting 150 million people per year globally (1). Escherichia coli is the leading cause of UTIs, and often displays resistance to currently available antibiotics due to the production of various enzymes, such as extended-spectrum ␤-lactamases (ESBLs) (1). ESBLs are enzymes produced by Gramnegative bacteria, namely, E. coli, and are responsible for the resistance against penicillins, cephalosporins, and aztreonam (2). Carbapenems, such as ertapenem, are standard for the treatment of infections caused by ESBL-producing organisms, although the potential clinical utility of extended-spectrum cephalosporins, notably cefepime, has yet to be clearly defined. Herein, we used humanized exposures of cefepime, 2 g every 8 h (q8h) (0.5-h infusion), ertapenem, 1 g every 24 h (q24h), and levofloxacin, 500 mg q24h, against uropathogenic ESBL-and non-ESBL-producing E. coli and assessed antimicrobial efficacy after 24 and 48 h of therapy in a neutropenic murine complicated UTI (cUTI) model.Commercially available cefepime 1g (lot no. 106014C), ertapenem 1g (lot no. m027105), and levofloxacin 500 mg (lot no. CLF150003) vials were acquired from Cardinal Health, Inc. Vials were reconstituted according to the package insert and further diluted with 0.9% normal saline solution (Hospira, Inc., Lake Forest, IL). Doses were administered as 0.2-ml subcutaneous injections to achieve humanized exposures of 2 g cefepime q8h (0.5-h infusion), 1 g ertapenem q24h, and 500 mg levofloxacin q24h, as previously described (3-5).Two clinical uropathogenic E. coli isolates (EC 429, ESBL; EC 430, non-ESBL) were used in this study. The MICs of cefepime, ertapenem, and levofloxacin were determined

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supporting

confidence: 67%

Translational Efficacy of Humanized Exposures of Cefepime, Ertapenem, and Levofloxacin against Extended-Spectrum-β-Lactamase-Producing Escherichia coli in a Murine Model of Complicated Urinary Tract Infection

Monogue

Nicolau

2017

Antimicrob Agents Chemother

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“…TOL/TAZ had a good safety profile and was superior to levofloxacin in terms of composite outcome (clinical cure and microbiological eradication) in 800 patients [24]. The difference was even greater in the subgroup of patients with levofloxacin-resistant bacteria [26]. In the CAZ/AVI trial, which enrolled a small sample (135 patients), microbiological and clinical responses were comparable in the active versus comparator arm, and CAZ/AVI was well tolerated [25].…”

Section: Role Of Tol/taz and Caz/avi In Therapymentioning

confidence: 99%

What is the role of the new β-lactam/β-lactamase inhibitors ceftolozane/tazobactam and ceftazidime/avibactam?

Gentile

Maraolo

Borgia

2016

Expert Review of Anti-infective Therapy

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“…The composite cure rates for ceftolozane/tazobactam were superior in both the microbiological intention-to-treat population (76.9% versus 68.4%) and the per protocol population (83.3% versus 75.4%). A sub-group analysis that included baseline susceptibility testing showed that 2.7% of Gram-negative pathogens were resistant to ceftolozane/ tazobactam, whereas 26.7% of Gram-negative pathogens were resistant to levofloxacin and that among patients with levofloxacinresistant pathogens at baseline, the composite cure rate at the testof-cure visit was significantly higher in the ceftolozane/tazobactam group than the levofloxacin group [72]. In a pooled analysis of patients in the cIAI and cUTI trials where ESBL-producing Enterobacteriaceae were isolated showed that ceftolozane/tazobactam was highly effective with clinical cure in 97% of these patients [73].…”

Section: Clinical Studiesmentioning

confidence: 99%

New agents for the treatment of infections with Gram-negative bacteria: restoring the miracle or false dawn?

Wright

Bonomo

Paterson

2017

Clinical Microbiology and Infection

231

150

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The development of new agents with activity against multidrug-resistant Gram-negative pathogens has provided important therapeutic options for clinicians. Polymyxins appear to have been supplanted by new agents as first-line therapy for Klebsiella pneumoniae carbapenemase producers. Cefiderocol and ceftazidime/avibactam/aztreonam are promising options for metallo-β-lactamase producers, and cefiderocol and ceftolozane/tazobactam for multiply resistant Pseudomonas aeruginosa, but definitive data showing clinical efficacy is as yet lacking. Reports of the development of resistance early after the release and use of new agents is of concern. Orally administered options and agents active effective against Acinetobacter baumannii are under-represented in clinical development.

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Efficacy of ceftolozane/tazobactam versus levofloxacin in the treatment of complicated urinary tract infections (cUTIs) caused by levofloxacin-resistant pathogens: results from the ASPECT-cUTI trial

Cited by 40 publications

References 29 publications

Translational Efficacy of Humanized Exposures of Cefepime, Ertapenem, and Levofloxacin against Extended-Spectrum-β-Lactamase-Producing Escherichia coli in a Murine Model of Complicated Urinary Tract Infection

Translational Efficacy of Humanized Exposures of Cefepime, Ertapenem, and Levofloxacin against Extended-Spectrum-β-Lactamase-Producing Escherichia coli in a Murine Model of Complicated Urinary Tract Infection

What is the role of the new β-lactam/β-lactamase inhibitors ceftolozane/tazobactam and ceftazidime/avibactam?

New agents for the treatment of infections with Gram-negative bacteria: restoring the miracle or false dawn?

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