Antibacterial activity of finafloxacin under different pH conditions against isogenic strains of Escherichia coli expressing combinations of defined mechanisms of fluoroquinolone resistance

Emrich, Nadine-C.; Heisig, Anke; Stubbings, Will; Labischinski, Harald; Heisig, Peter

doi:10.1093/jac/dkq375

Cited by 47 publications

(51 citation statements)

References 11 publications

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“…It possesses a unique pH activation profile where antibacterial activity is enhanced in acidified environments (pH 5.0 to 6.5) common in infection sites such as urine, abscesses, wounds, chronically infected tissues, and stomach mucosa (25) (http: //www.merlionpharma.com). MICs compared with those of other fluoroquinolones at pH 5.8 were lower by 2-to 256-fold (26). As one example, finafloxacin was superior to ciprofloxacin when tested in vitro against Acinetobacter baumannii strains under acidic conditions (27).…”

Section: Quinolonesmentioning

confidence: 96%

Investigational Antimicrobial Agents of 2013

Pucci

Bush

2013

Clin Microbiol Rev

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SUMMARY New antimicrobial agents are always needed to counteract the resistant pathogens that continue to be selected by current therapeutic regimens. This review provides a survey of known antimicrobial agents that were currently in clinical development in the fall of 2012 and spring of 2013. Data were collected from published literature primarily from 2010 to 2012, meeting abstracts (2011 to 2012), government websites, and company websites when appropriate. Compared to what was reported in previous surveys, a surprising number of new agents are currently in company pipelines, particularly in phase 3 clinical development. Familiar antibacterial classes of the quinolones, tetracyclines, oxazolidinones, glycopeptides, and cephalosporins are represented by entities with enhanced antimicrobial or pharmacological properties. More importantly, compounds of novel chemical structures targeting bacterial pathways not previously exploited are under development. Some of the most promising compounds include novel β-lactamase inhibitor combinations that target many multidrug-resistant Gram-negative bacteria, a critical medical need. Although new antimicrobial agents will continue to be needed to address increasing antibiotic resistance, there are novel agents in development to tackle at least some of the more worrisome pathogens in the current nosocomial setting.

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Section: Quinolonesmentioning

confidence: 96%

Investigational Antimicrobial Agents of 2013

Pucci

Bush

2013

Clin Microbiol Rev

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“…The plasmid-mediated quinolone resistance genes qnrA, qnrB, qnrS, and qepA, which encode three targetprotecting proteins and an efflux pump, respectively, were screened for by multiplexing existing and novel single PCRs, with a second PCR screen used to identify isolates containing aac(6Ј)-Ib. The primers and product sizes are listed in Table 1; controls were as described previously (11). PCR conditions were: 5 min of denaturation at 95°C; 30 cycles of 95°C for 30 s, 57°C for 30 s, and 72°C for 50 s; and then 10 min of elongation at 72°C.…”

Section: Bacterial Isolatesmentioning

confidence: 99%

Commonality among Fluoroquinolone-Resistant Sequence Type ST131 Extraintestinal Escherichia coli Isolates from Humans and Companion Animals in Australia

Platell

Cobbold

Johnson

et al. 2011

Antimicrob Agents Chemother

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Escherichia coli sequence type 131 (ST131), an emergent multidrug-resistant extraintestinal pathogen, has spread epidemically among humans and was recently isolated from companion animals. To assess for humancompanion animal commonality among ST131 isolates, 214 fluoroquinolone-resistant extraintestinal E. coli isolates (205 from humans, 9 from companion animals) from diagnostic laboratories in Australia, provisionally identified as ST131 by PCR, selectively underwent PCR-based O typing and bla CTX-M-15 detection. A subset then underwent multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE) analysis, extended virulence genotyping, antimicrobial susceptibility testing, and fluoroquinolone resistance genotyping. All isolates were O25b positive, except for two O16 isolates and one O157 isolate, which (along with six O25b-positive isolates) were confirmed by MLST to be ST131. Only 12% of isolates (25 human, 1 canine) exhibited bla CTX-M-15 . PFGE analysis of 20 randomly selected human and all 9 companion animal isolates showed multiple instances of >94% profile similarity across host species; 12 isolates (6 human, 6 companion animal) represented pulsotype 968, the most prevalent ST131 pulsotype in North America (representing 23% of a large ST131 reference collection). Virulence gene and antimicrobial resistance profiles differed minimally, without host species specificity. The analyzed ST131 isolates also exhibited a conserved, host species-independent pattern of chromosomal fluoroquinolone resistance mutations. However, eight (89%) companion animal isolates, versus two (10%) human isolates, possessed the plasmid-borne qnrB gene (P < 0.001). This extensive across-species strain commonality, plus the similarities between Australian and non-Australian ST131 isolates, suggest that ST131 isolates are exchanged between humans and companion animals both within Australia and intercontinentally.

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“…Finafloxacin was also highly effective when tested in in vivo infection models, perhaps more so than would have been predicted from its in vitro MIC (7,8). This effect was attributed, at least in part, to the enhancement of finafloxacin activity at slightly acidic pH (5,6,9), which is a distinctive property of finafloxacin in contrast to other marketed fluoro- quinolones, which generally lose activity at pH below neutral (4,15). The present study had two aims.…”

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confidence: 96%

In Vitro Spectrum of Activity of Finafloxacin, a Novel, pH-Activated Fluoroquinolone, under Standard and Acidic Conditions

Stubbings

Leow

Yong

et al. 2011

Antimicrob Agents Chemother

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Finafloxacin is a novel fluoroquinolone that exhibits enhanced antibacterial activity under acidic conditions. The aim of this study was to define the in vitro pH-activity relationship. Finafloxacin exhibited optimal antibacterial activity between pH 5.0 and 6.0 at which MICs were 4-to 8-fold lower than those determined at neutral pH. These observations were then confirmed against a larger collection of bacteria. These data suggest that finafloxacin could potentially offer a therapeutic advantage within acidic foci of infection.Fluoroquinolones are a widely utilized class of antibacterial agent. However, a number of attempts to develop new, more potent, members of this class have failed due to concerns over safety and tolerability that have resulted in a halt to development, withdrawal from the market, or restriction of the market (12). Finafloxacin is a new fluoroquinolone belonging to a novel 8-cyano subclass that exhibited a low potential for toxicity or tolerability issues in preclinical tests (14) and in later clinical trials (13). Finafloxacin was also highly effective when tested in in vivo infection models, perhaps more so than would have been predicted from its in vitro MIC (7,8). This effect was

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Antibacterial activity of finafloxacin under different pH conditions against isogenic strains of Escherichia coli expressing combinations of defined mechanisms of fluoroquinolone resistance

Abstract: Compared with ciprofloxacin, levofloxacin and moxifloxacin, finafloxacin shows higher activity especially at pH 5.8 against Escherichia coli mutants expressing known fluoroquinolone resistance determinants alone and in combinations.

Cited by 47 publications

References 11 publications

Investigational Antimicrobial Agents of 2013

Investigational Antimicrobial Agents of 2013

Commonality among Fluoroquinolone-Resistant Sequence Type ST131 Extraintestinal Escherichia coli Isolates from Humans and Companion Animals in Australia

In Vitro Spectrum of Activity of Finafloxacin, a Novel, pH-Activated Fluoroquinolone, under Standard and Acidic Conditions

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