P794 The efficacy of ceftazidime combined with NXL104, a novel β-lactamase inhibitor, in a mouse model of kidney infections induced by β-lactamase producing Enterobacteriaceae

Borgonovi, Monica; Miossec, Christine; Lowther, John

doi:10.1016/s0924-8579(07)70635-0

Cited by 8 publications

(12 citation statements)

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“…In these preclinical studies, the septicemia model did not show any significant differences between the 4:1 and 8:1 ratios of ceftazidime-avibactam. Ultimately, a 4:1 ratio of ceftazidime-avibactam was selected for clinical development based on a number of fac- tors, including in vitro, in vivo, and the hollow-fiber infection model data (8,9,12,13,20,21,(23)(24)(25)(26)34).…”

Section: Resultsmentioning

confidence: 99%

“…Both in vitro and in vivo studies of combinations of oxyimino-cephalosporins with avibactam have been reported to overcome these resistances (20)(21)(22). While there is an extensive body of literature on the in vitro activities of ceftazidime-avibactam combinations, only a few studies on the in vivo efficacy of this combination against Escherichia coli, K. pneumoniae, Enterobacter cloacae, Citrobacter freundii, and Pseudomonas aeruginosa have been published (20)(21)(22)(23)(24)(25)(26)(27).…”

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confidence: 99%

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Efficacy of a Ceftazidime-Avibactam Combination in a Murine Model of Septicemia Caused by Enterobacteriaceae Species Producing AmpC or Extended-Spectrum β-Lactamases

Levasseur¹,

Girard²,

Lavallade³

et al. 2014

Antimicrob Agents Chemother

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Avibactam is a novel non-␤-lactam ␤-lactamase inhibitor that has been shown in vitro to inhibit class A, class C, and some class D ␤-lactamases. It is currently in phase 3 of clinical development in combination with ceftazidime. In this study, the efficacy of ceftazidime-avibactam was evaluated in a murine septicemia model against five ceftazidime-susceptible (MICs of 0.06 to 0.25 g/ml) and 15 ceftazidime-resistant (MICs of 64 to >128 g/ml) species of Enterobacteriaceae, bearing either TEM, SHV, CTX-M extended-spectrum, or AmpC ␤-lactamases. In the first part of the study, ceftazidime-avibactam was administered at ratios of 4:1 and 8:1 (wt/wt) to evaluate the optimal ratio for efficacy. Against ceftazidime-susceptible isolates of Klebsiella pneumoniae and Escherichia coli, ceftazidime and ceftazidime-avibactam demonstrated similar efficacies (50% effective doses [ED 50 ] of <1.5 to 9 mg/kg of body weight), whereas against ceftazidime-resistant ␤-lactamase-producing strains (ceftazidime ED 50 of >90 mg/kg), the addition of avibactam restored efficacy to ceftazidime (ED 50 dropped to <5 to 65 mg/kg). In a subsequent study, eight isolates (two AmpC and six CTX-M producers) were studied in the septicemia model. Ceftazidime-avibactam was administered at a 4:1 (wt/wt) ratio, and the efficacy was compared to that of the 4:1 (wt/wt) ratio of either piperacillin-tazobactam or cefotaxime-avibactam. Against the eight isolates, ceftazidime-avibactam was the more effective combination, with ED 50 values ranging from 2 to 27 mg/kg compared to >90 mg/kg and 14 to >90 mg/kg for piperacillin-tazobactam and cefotaxime-avibactam, respectively. This study demonstrates that the potent in vitro activity observed with the ceftazidime-avibactam combination against ceftazidime-resistant Enterobacteriaceae species bearing class A and class C ␤-lactamases translated into good efficacy in the mouse septicemia model.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Efficacy of a Ceftazidime-Avibactam Combination in a Murine Model of Septicemia Caused by Enterobacteriaceae Species Producing AmpC or Extended-Spectrum β-Lactamases

Levasseur¹,

Girard²,

Lavallade³

et al. 2014

Antimicrob Agents Chemother

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“…Limited data suggest that the addition of avibactam does not improve the activity of ceftazidime versus Acinetobacter species (Table 2). Table 3 shows the activity of ceftazidime-avibactam compared with ceftazidime alone against E. coli and K. pneumoniae isolates producing specific b-lactamase enzymes [42,47,57,58,[67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83]. It should be noted that, except where indicated, MIC values are based on results from fewer than ten isolates.…”

Section: Mechanism Of Resistancementioning

confidence: 99%

“…In vitro activity of ceftazidime-avibactam and comparators against bacteria expressing specific b-lactamase enzymes[42,47,57,58,[67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83] …”

mentioning

confidence: 99%

Ceftazidime-Avibactam: a Novel Cephalosporin/β-lactamase Inhibitor Combination

Zhanel

Lawson

Adam

et al. 2013

Drugs

375

255

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Avibactam (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to β-lactamases. Very little is known about the potential for avibactam to select for resistance. The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of avibactam also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of avibactam does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, avibactam serves to broaden the spectrum of ceftazidime versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spect...

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“…A previously published direct inoculation model was used to establish UTIs in mice (7,8). Two transfers of the bacterial isolate were performed on Trypticase soy agar with 5% sheep blood (Becton, Dickinson & Co., Sparks, MD) and placed into an incubator at 37°C for approximately 24 h. A bacterial suspension of approximately 10 7 CFU/ml was prepared in sterile saline.…”

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confidence: 99%

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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P794 The efficacy of ceftazidime combined with NXL104, a novel β-lactamase inhibitor, in a mouse model of kidney infections induced by β-lactamase producing Enterobacteriaceae

Cited by 8 publications

References 0 publications

Efficacy of a Ceftazidime-Avibactam Combination in a Murine Model of Septicemia Caused by Enterobacteriaceae Species Producing AmpC or Extended-Spectrum β-Lactamases

Efficacy of a Ceftazidime-Avibactam Combination in a Murine Model of Septicemia Caused by Enterobacteriaceae Species Producing AmpC or Extended-Spectrum β-Lactamases

Ceftazidime-Avibactam: a Novel Cephalosporin/β-lactamase Inhibitor Combination

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

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