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

Overview

Journal Antimicrob Agents Chemother

Publisher American Society for Microbiology

Specialty Pharmacology

Date 2015 Jun 3

PMID 26033723

Citations 75

Authors

Amabel Lapuebla

Marie Abdallah

Olawole Olafisoye

Christopher Cortes

Carl Urban

John Quale

David Landman

Affiliations

Soon will be listed here.

Abstract

Multidrug-resistant Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae are endemic to hospitals in New York City and other regions. RPX7009 is a novel β-lactamase inhibitor with activity against serine carbapenemases. We tested the activity of meropenem plus RPX7009 against 4,500 recent Gram-negative clinical isolates from 11 New York City hospitals. The meropenem-RPX7009 combination was found to have excellent in vitro activity against Escherichia coli, K. pneumoniae, and Enterobacter spp., including multidrug-resistant (MDR) KPC-producing strains. Overall, 131/133 (98.5%) KPC-producing Enterobacteriaceae strains were inhibited by meropenem (≤1 μg/ml) plus RPX7009 (8 μg/ml). In a limited number of strains, the combination appeared to have reduced activity against KPC-producing K. pneumoniae isolates with diminished ompK35 and ompK36 expression. The addition of RPX7009 did not affect the activity of meropenem against Acinetobacter baumannii and Pseudomonas aeruginosa. The meropenem-RPX7009 combination shows promise as a novel agent against KPC-producing Enterobacteriaceae and deserves further study. Other approaches will be needed to address multidrug-resistant A. baumannii and P. aeruginosa, which typically possess different mechanisms of carbapenem resistance.

Citing Articles

Multidrug Resistant in Clinical Settings: A Review of Resistance Mechanisms and Treatment Strategies.

Schwartz B, Klamer K, Zimmerman J, Kale-Pradhan P, Bhargava A Pathogens. 2024; 13(11).

PMID: 39599528 PMC: 11597786. DOI: 10.3390/pathogens13110975.

Activity of Organoboron Compounds against Biofilm-Forming Pathogens.

Konaklieva M, Plotkin B Antibiotics (Basel). 2024; 13(10).

PMID: 39452196 PMC: 11504661. DOI: 10.3390/antibiotics13100929.

The burden of antibiotic resistance of the main microorganisms causing infections in humans - review of the literature.

Baciu A, Baciu C, Baciu G, Gurau G J Med Life. 2024; 17(3):246-260.

PMID: 39044924 PMC: 11262613. DOI: 10.25122/jml-2023-0404.

Role of β-Lactamase Inhibitors as Potentiators in Antimicrobial Chemotherapy Targeting Gram-Negative Bacteria.

Zhang S, Liao X, Ding T, Ahn J Antibiotics (Basel). 2024; 13(3).

PMID: 38534695 PMC: 10967447. DOI: 10.3390/antibiotics13030260.

New Antibiotics Against Multidrug-Resistant Gram-Negative Bacteria in Liver Transplantation: Clinical Perspectives, Toxicity, and PK/PD Properties.

Lombardi A, Alagna L, Palomba E, Viero G, Tonizzo A, Mangioni D Transpl Int. 2024; 37:11692.

PMID: 38362283 PMC: 10867129. DOI: 10.3389/ti.2024.11692.

References

Logan L . Carbapenem-resistant enterobacteriaceae: an emerging problem in children. Clin Infect Dis. 2012; 55(6):852-9. DOI: 10.1093/cid/cis543. View

Livermore D, Mushtaq S, Barker K, Hope R, Warner M, Woodford N . Characterization of β-lactamase and porin mutants of Enterobacteriaceae selected with ceftaroline + avibactam (NXL104). J Antimicrob Chemother. 2012; 67(6):1354-8. DOI: 10.1093/jac/dks079. View

Castanheira M, Deshpande L, Costello A, Davies T, Jones R . Epidemiology and carbapenem resistance mechanisms of carbapenem-non-susceptible Pseudomonas aeruginosa collected during 2009-11 in 14 European and Mediterranean countries. J Antimicrob Chemother. 2014; 69(7):1804-14. DOI: 10.1093/jac/dku048. View

Toussaint K, Gallagher J . β-lactam/β-lactamase inhibitor combinations: from then to now. Ann Pharmacother. 2014; 49(1):86-98. DOI: 10.1177/1060028014556652. View

Hecker S, Reddy K, Totrov M, Hirst G, Lomovskaya O, Griffith D . Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases. J Med Chem. 2015; 58(9):3682-92. DOI: 10.1021/acs.jmedchem.5b00127. View

Nordmann P, Poirel L . Emerging carbapenemases in Gram-negative aerobes. Clin Microbiol Infect. 2002; 8(6):321-31. DOI: 10.1046/j.1469-0691.2002.00401.x. View

Poirel L, Heritier C, Tolun V, Nordmann P . Emergence of oxacillinase-mediated resistance to imipenem in Klebsiella pneumoniae. Antimicrob Agents Chemother. 2003; 48(1):15-22. PMC: 310167. DOI: 10.1128/AAC.48.1.15-22.2004. View

Bradford P, Bratu S, Urban C, Visalli M, Mariano N, Landman D . Emergence of carbapenem-resistant Klebsiella species possessing the class A carbapenem-hydrolyzing KPC-2 and inhibitor-resistant TEM-30 beta-lactamases in New York City. Clin Infect Dis. 2004; 39(1):55-60. DOI: 10.1086/421495. View

Woodford N, Ellington M, Coelho J, Turton J, Ward M, Brown S . Multiplex PCR for genes encoding prevalent OXA carbapenemases in Acinetobacter spp. Int J Antimicrob Agents. 2006; 27(4):351-3. DOI: 10.1016/j.ijantimicag.2006.01.004. View

10.

Quale J, Bratu S, Gupta J, Landman D . Interplay of efflux system, ampC, and oprD expression in carbapenem resistance of Pseudomonas aeruginosa clinical isolates. Antimicrob Agents Chemother. 2006; 50(5):1633-41. PMC: 1472219. DOI: 10.1128/AAC.50.5.1633-1641.2006. View

11.

Perez F, Hujer A, Hujer K, Decker B, Rather P, Bonomo R . Global challenge of multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2007; 51(10):3471-84. PMC: 2043292. DOI: 10.1128/AAC.01464-06. View

12.

Bratu S, Landman D, Martin D, Georgescu C, Quale J . Correlation of antimicrobial resistance with beta-lactamases, the OmpA-like porin, and efflux pumps in clinical isolates of Acinetobacter baumannii endemic to New York City. Antimicrob Agents Chemother. 2008; 52(9):2999-3005. PMC: 2533509. DOI: 10.1128/AAC.01684-07. View

13.

Doumith M, Ellington M, Livermore D, Woodford N . Molecular mechanisms disrupting porin expression in ertapenem-resistant Klebsiella and Enterobacter spp. clinical isolates from the UK. J Antimicrob Chemother. 2009; 63(4):659-67. DOI: 10.1093/jac/dkp029. View

14.

Landman D, Bratu S, Quale J . Contribution of OmpK36 to carbapenem susceptibility in KPC-producing Klebsiella pneumoniae. J Med Microbiol. 2009; 58(Pt 10):1303-1308. PMC: 2887543. DOI: 10.1099/jmm.0.012575-0. View

15.

Nordmann P, Naas T, Poirel L . Global spread of Carbapenemase-producing Enterobacteriaceae. Emerg Infect Dis. 2011; 17(10):1791-8. PMC: 3310682. DOI: 10.3201/eid1710.110655. View

16.

Livermore D, Mushtaq S . Activity of biapenem (RPX2003) combined with the boronate β-lactamase inhibitor RPX7009 against carbapenem-resistant Enterobacteriaceae. J Antimicrob Chemother. 2013; 68(8):1825-31. DOI: 10.1093/jac/dkt118. View