Antibacterial activity of WY-49605 compared with those of six other oral agents and selection of disk content for disk diffusion susceptibility testing

The high intrinsic penem resistance of Pseudomonas aeruginosa is due to the interplay among the outer membrane barrier, the active efflux system MexAB-OprM, and AmpC ␤-lactamase. We studied the roles of two other efflux systems, MexCD-OprJ and MexXY-OprM, in penem resistance by overexpressing each system in an AmpC-and MexAB-OprM-deficient background and found that MexAB-OprM is the most important among the three efflux systems for extrusion of penems from the cell interior.Pseudomonas aeruginosa is a clinically significant pathogen exhibiting intrinsic and acquired resistance to various antimicrobial agents. This resistance is attributable to the limited permeability of the outer membrane and the extrusion of a wide variety of antibiotics from the cell interior by a tripartite multidrug efflux system, which is composed of membrane fusion protein-type periplasmic, resistance-nodulation-cell division-type inner-membrane, and outer-membrane efflux proteins (10). Among these efflux systems, 9,19) and 11,14) contribute to both intrinsic resistance and acquired resistance, while and MexEF-OprN (8) contribute only to acquired resistance in P. aeruginosa. Recently, Masuda et al. (12) reported the substrate specificities of MexAB-OprM, MexXY-OprM, and MexCD-OprJ. Although most antimicrobial agents are substrates of all three efflux systems, these systems have slight but significant differences in substrate specificities to ␤-lactams. MexAB-OprM extrudes the broadest variety of ␤-lactams, including penicillins, cephems, and meropenem-type carbapenems. MexXY-OprM and MexCD-OprJ extrude most penicillins but not carbenicillin, sulbenicillin, various cephems, and many carbapenems. Penem antibiotics display potent activities against a variety of gram-positive and gram-negative bacteria but not against P. aeruginosa (2,3,4,13,15,16,17,21,24). Studies with mutants that overproduce or lack MexAB-OprM demonstrated that this efflux system extrudes penem antibiotics (18). However, it is unclear whether MexXY-OprM and MexCD-OprJ extrude penem antibiotics.We compared the susceptibilities of a series of previously described isogenic AmpC-lacking mutants, each of which constitutively overexpressed an individual efflux pump (12, 18) ( Table 1). We used AmpC-lacking P. aeruginosa mutants because the presence of chromosomal AmpC ␤-lactamase makes it difficult to interpret data on the MICs of ␤-lactams, including penems, due to the interplay between ␤-lactamase and the efflux system(s). The MICs of various penems, norfloxacin, and tetracycline for the mutants were determined by the twofold agar dilution method (23) with L agar with an inoculum of 10 4 cells. These results are shown in Table 2. Although the susceptibilities of the mutant KG5002, which lacked MexABOprM, MexCD-OprJ, and MexXY-OprM, to all penems tested were reduced by the overexpression of MexAB-OprM, MexCD-OprJ, or MexXY-OprM, as were those to norfloxacin and tetracycline, the degree of reduction resulting from the overexpression of MexAB-OprM (128-to 4,096-fold reduction ...

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confidence: 99%

Extrusion of Penem Antibiotics by Multicomponent Efflux Systems MexAB-OprM, MexCD-OprJ, and MexXY-OprM of Pseudomonas aeruginosa

Okamoto

Gotoh

Nishino

2002

“…Although recent studies have highlighted the broad-spectrum antibacterial activity of faropenem (previously known as SUN/SY 5555, ALP-201, or WY-49605) (8,9,15,(17)(18)(19), new attention has focused on its activity against the respiratory pathogens S. pneumoniae, H. influenzae, and M. catarrhalis (3). The aim of the present study was to benchmark the activity of faropenem against recent bacterial pathogens isolated from patients with respiratory tract infections.…”

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confidence: 99%

Activities of Faropenem, an Oral β-Lactam, against Recent U.S. Isolates of Streptococcus pneumoniae , Haemophilus influenzae , and Moraxella catarrhalis

Critchley¹,

Karlowsky²,

Draghi³

et al. 2002

The in vitro activities of faropenem and other antimicrobial agents were determined against 4,725 Streptococcus pneumoniae isolates, 2,614 Haemophilus influenzae isolates, and 1,193 Moraxella catarrhalis isolates collected from 273 U.S. laboratories during 1999. Faropenem MICs at which 90% of isolates are inhibited were 0.008, 0.25, and 1 g/ml for penicillin-susceptible, -intermediate, and -resistant S. pneumoniae strains, respectively; 0.5 and 1 g/ml for ␤-lactamase-positive and -negative H. influenzae strains, respectively; and 0.12 and 0.5 g/ml for ␤-lactamase-negative and -positive M. catarrhalis strains, respectively. Faropenem holds promise as an oral therapy for community-acquired respiratory tract infections.The increasing levels of antimicrobial resistance among community-acquired respiratory tract pathogens limit the options for empirical therapy (2). Penicillin resistance among Streptococcus pneumoniae strains is now widely accepted as a global problem (1,7,10), and the widespread dissemination of plasmid-encoded ␤-lactamases in Haemophilus influenzae and Moraxella catarrhalis has eliminated amoxicillin as a treatment option for infections caused by ␤-lactamase-producing isolates (6). Although penem antimicrobials have broad-spectrum activities, remarkable potencies, and stabilities against ␤-lactamases, none are available, to date, for oral administration. The parenteral carbapenems imipenem (14) and meropenem (5) are prescribed in the United States, and a number of new oral carbapenems are now in development, including L-084 (11) and DU-6681a (16).Faropenem is a novel ␤-lactam antimicrobial with a penem (furanem) structure that is being developed for use as an oral therapy for community-acquired respiratory tract infections. Although recent studies have highlighted the broad-spectrum antibacterial activity of faropenem (previously known as SUN/SY 5555, ALP-201, or WY-49605) (8,9,15,(17)(18)(19), new attention has focused on its activity against the respiratory pathogens S. pneumoniae, H. influenzae, and M. catarrhalis (3). The aim of the present study was to benchmark the activity of faropenem against recent bacterial pathogens isolated from patients with respiratory tract infections.Respiratory tract isolates were collected from 273 hospital laboratories distributed throughout the United States during 1999 as part of the LIBRA surveillance program. Isolates were limited to one per patient and were collected from clinical samples derived from various upper and lower respiratory tract sites, blood, ears, and eyes. All isolates were shipped to the central laboratory of Focus Technologies, Inc. (Herndon, Va.), where each isolate was subcultured and reidentified by standard methods (12).A total of 4,725 isolates of S. pneumoniae were available for antimicrobial susceptibility testing; 58.9% (2,783 isolates) originated from respiratory specimens, 32.1% (1,517 isolates) originated from blood or cerebrospinal fluid, 4.7% (220 isolates) originated from eye specimens, and 4.3% (205 isolates) originated from ...

“…Penem antibiotics such as faropenem (formerly SUN5555 or WY-49605) (8,16,34), ritipenem (formerly FCE22101) (4,31,51), AMA3176 (K. Okonogi, T. Iwahi, M. Nakao, and Y. Noji, Program Abstr. 33rd Intersci.…”

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confidence: 99%

Pseudomonas aeruginosa Reveals High Intrinsic Resistance to Penem Antibiotics: Penem Resistance Mechanisms and Their Interplay

Okamoto

Gotoh

Nishino

2001

109

Pseudomonas aeruginosa exhibits high intrinsic resistance to penem antibiotics such as faropenem, ritipenem, AMA3176, sulopenem, Sch29482, and Sch34343. To investigate the mechanisms contributing to penem resistance, we used the laboratory strain PAO1 to construct a series of isogenic mutants with an impaired multidrug efflux system MexAB-OprM and/or impaired chromosomal AmpC ␤-lactamase. The outer membrane barrier of PAO1 was partially eliminated by inducing the expression of the plasmid-encoded Escherichia coli major porin OmpF. Susceptibility tests using the mutants and the OmpF expression plasmid showed that MexAB-OprM and the outer membrane barrier, but not AmpC ␤-lactamase, are the main mechanisms involved in the high intrinsic penem resistance of PAO1. However, reducing the high intrinsic penem resistance of PAO1 to the same level as that of penem-susceptible gram-negative bacteria such as E. coli required the loss of either both MexAB-OprM and AmpC ␤-lactamase or both MexAB-OprM and the outer membrane barrier. Competition experiments for penicillin-binding proteins (PBPs) revealed that the affinity of PBP 1b and PBP 2 for faropenem were about 1.8-and 1.5-fold lower, than the respective affinity for imipenem. Loss of the outer membrane barrier, MexAB, and AmpC ␤-lactamase increased the susceptibility of PAO1 to almost all penems tested compared to the susceptibility of the AmpC-deficient PAO1 mutants to imipenem. Thus, it is suggested that the high intrinsic penem resistance of P. aeruginosa is generated from the interplay among the outer membrane barrier, the active efflux system, and AmpC ␤-lactamase but not from the lower affinity of PBPs for penems.Penem antibiotics such as faropenem (formerly SUN5555 or