Activity of Meropenem Combined with RPX7009, a Novel β-Lactamase Inhibitor, against Gram-Negative Clinical Isolates in New York City

Lapuebla, Amabel; Abdallah, Marie; Olafisoye, Olawole; Cortes, Christopher; Urban, Carl; Quale, John; Landman, David

doi:10.1128/aac.00843-15

Cited by 138 publications

(119 citation statements)

References 18 publications

(25 reference statements)

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“…In a recent study, for KPC-producing K. pneumoniae, E. cloacae, P. aeruginosa, and Acinetobacter spp. collected in a hospital located in New York City, meropenem-vaborbactam increased the activity of carbapenems; however, decreased expression of ompK36 also reduced the effect of the ␤-lactamase inhibitor 8-to 16-fold compared to the level for isolates producing the same ␤-lactamases (15).…”

Section: Discussionmentioning

confidence: 99%

Effect of the β-Lactamase Inhibitor Vaborbactam Combined with Meropenem against Serine Carbapenemase-Producing Enterobacteriaceae

Castanheira

Rhomberg

Flamm

et al. 2016

Antimicrob Agents Chemother

127

112

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Klebsiella pneumoniae carbapenemase (KPC)-producing isolates have become increasingly prevalent worldwide, and these organisms are often multidrug resistant, limiting the therapeutic options available for treating infections. We evaluated the activity of meropenem combined with the serine ␤-lactamase inhibitor vaborbactam (formerly RPX7009) against 315 serine carbapenemase-producing Enterobacteriaceae (CPE) isolates by use of checkerboard-designed panels to assess the optimal inhibitor concentration (range tested, 0.5 to 32 g/ml). Overall, meropenem alone (MIC 50 and MIC 90 , 16 and >64 g/ml, respectively) inhibited only 2.2% of the isolates at <1 g/ml (the CLSI susceptibility breakpoint) and 7.3% of the isolates at <2 g/ml (the EUCAST breakpoint). Vaborbactam restored meropenem activity for 72.7 to 98.1% of CPE isolates at <2 g/ml, and maximum potentiation was achieved with fixed concentrations of >8 g/ml of the inhibitor (>96.5% of isolates were inhibited at <2 g/ml of meropenem-vaborbactam). Meropenem-vaborbactam with a fixed concentration of 8 g/ml of the inhibitor (MIC 50 , <0.06 g/ml for all organisms) inhibited 93.7% of the CPE isolates displaying elevated meropenem MICs at <1 g/ml. Meropenem-vaborbactam MICs were elevated for isolates producing metallo-␤-lactamases (MIC, 16 to >64 g/ml) or displaying decreased expression of OmpK37 and/or elevated expression of the AcrAB-TolC efflux system (MIC, 16 g/ml). Vaborbactam showed no antibacterial activity alone (all MICs, >64 g/ml). Meropenem-vaborbactam appears to be a good candidate for further development and it could increase the options for treatment of serious infections caused by carbapenemase-producing pathogens.C arbapenem-resistant Enterobacteriaceae (CRE) isolates have been detected worldwide, and their increasing prevalence is mainly due to the dissemination of isolates producing carbapenemases, such as Klebsiella pneumoniae carbapenemase (KPC) and metallo-␤-lactamases (largely NDM but also IMP and VIM) (1). Infections caused by carbapenemase-producing Enterobacteriaceae (CPE) became a serious cause of concern among infectious diseases and clinical microbiology professionals worldwide because these infections are difficult to manage (2-4). CPE isolates are resistant to all or nearly all ␤-lactam agents, and these organisms may also be resistant to other antimicrobial classes, limiting the therapeutic options available for the treatment of CPE infections (3, 4). CPE isolates may be susceptible only to tigecycline and/or colistin, which have been widely used; however, there are limitations to the usage of both agents (4). Low plasma peak concentrations are achieved with tigecycline, and this antimicrobial agent is not recommended for the treatment of bloodstream infections. Furthermore, colistin use can be associated with nephrotoxicity and occasionally neurotoxicity. CPE isolates can display colistin or tigecycline resistance, a problem increasingly reported worldwide (3).The use of ␤-lactamase inhibitors combined with a potent ␤-lactam agent has bee...

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Section: Discussionmentioning

confidence: 99%

Effect of the β-Lactamase Inhibitor Vaborbactam Combined with Meropenem against Serine Carbapenemase-Producing Enterobacteriaceae

Castanheira

Rhomberg

Flamm

et al. 2016

Antimicrob Agents Chemother

127

112

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“…Blood samples for the measurement of vaborbactam concentrations in plasma were obtained predose (time zero) and 1.5, 3, 3.167, 3.333, 3.5, 3.75, 4,5,6,7,8,12, and 24 h after the start of infusion. All blood samples (approximately 2 ml) were obtained via an indwelling intravenous cannula, collected into EDTA-containing tubes, immediately placed on ice, and centrifuged at 3,000 ϫ g for 15 min.…”

Section: Methodsmentioning

confidence: 99%

“…Vaborbactam is being developed in combination with meropenem. The combination has potent in vitro and in vivo activities against carbapenem-resistant KPC-producing strains of Enterobacteriaceae (3,4,5). Against a panel of 121 carbapenem-resistant KPC-producing strains of K. pneumoniae, the meropenem-vaborbactam MIC 90 was 0.5/8 g/ml (4), and in a neutropenic mouse thigh infection model, the addition of vaborbactam to meropenem produced significant bacterial killing compared to that produced by meropenem alone against carbapenem-resistant KPC-containing Escherichia coli, Enterobacter cloacae, and K. pneumoniae (5).…”

mentioning

confidence: 99%

Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of the β-Lactamase Inhibitor Vaborbactam (RPX7009) in Healthy Adult Subjects

Griffith

Loutit

Morgan

et al. 2016

Antimicrob Agents Chemother

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Vaborbactam (formerly RPX7009) is a member of a new class of ␤-lactamase inhibitor with pharmacokinetic properties similar to those of many ␤-lactams, including carbapenems. The pharmacokinetics and safety of vaborbactam were evaluated in 80 healthy adult subjects in a first-in-human randomized, placebo-controlled, double-blind, sequential single-and multiple-ascending-dose study. A total of 10 dose cohorts were enrolled in the study, with 6 subjects randomized to receive 250 to 2,000 mg of vaborbactam and 2 subjects randomized to receive placebo in each cohort.

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“…Despite the inhibitory activity of RPX7009 against many groups of serine b-lactamases (Hecker et al 2015), it is being developed in combination with meropenem to target pathogens producing serine carbapenemases (Lapuebla et al 2015).…”

Section: B-lactamase Inhibitorsmentioning

confidence: 99%

β-Lactams and β-Lactamase Inhibitors: An Overview

Bush

Bradford

2016

Cold Spring Harb Perspect Med

799

587

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b-Lactams are the most widely used class of antibiotics. Since the discovery of benzylpenicillin in the 1920s, thousands of new penicillin derivatives and related b-lactam classes of cephalosporins, cephamycins, monobactams, and carbapenems have been discovered. Each new class of b-lactam has been developed either to increase the spectrum of activity to include additional bacterial species or to address specific resistance mechanisms that have arisen in the targeted bacterial population. Resistance to b-lactams is primarily because of bacterially produced b-lactamase enzymes that hydrolyze the b-lactam ring, thereby inactivating the drug. The newest effort to circumvent resistance is the development of novel broad-spectrum b-lactamase inhibitors that work against many problematic b-lactamases, including cephalosporinases and serine-based carbapenemases, which severely limit therapeutic options. This work provides a comprehensive overview of b-lactam antibiotics that are currently in use, as well as a look ahead to several new compounds that are in the development pipeline.

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Activity of Meropenem Combined with RPX7009, a Novel β-Lactamase Inhibitor, against Gram-Negative Clinical Isolates in New York City

Cited by 138 publications

References 18 publications

Effect of the β-Lactamase Inhibitor Vaborbactam Combined with Meropenem against Serine Carbapenemase-Producing Enterobacteriaceae

Effect of the β-Lactamase Inhibitor Vaborbactam Combined with Meropenem against Serine Carbapenemase-Producing Enterobacteriaceae

Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of the β-Lactamase Inhibitor Vaborbactam (RPX7009) in Healthy Adult Subjects

β-Lactams and β-Lactamase Inhibitors: An Overview

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