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                <term xml:lang="en">delafloxacin</term>
                <term xml:lang="en">fluoroquinolones</term>
                <term xml:lang="en">Escherichia coli</term>
                <term xml:lang="en">urinary tract infection</term>
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              <p>&lt;div&gt;&lt;p&gt;The aim of this study is to evaluate the pH-dependent antimicrobial activities of delafloxacin against isogenic Escherichia coli strains carrying diverse fluoroquinolone resistance mechanisms. Eighty-one isogenic E. coli strains derived from ATCC 25922 were tested, carrying various combinations of chromosomal mutations (gyrA, parC), efflux pump overexpression (marR), and plasmid-mediated quinolone resistance (PMQR) determinants (qnrA1, qnrB1, qnrC, qnrD1, qnrS1, qepA2, aac(6')-Ib-cr). Minimum inhibitory concentrations (MICs) were determined using broth microdilution at pH 7.3, 6.0, and 5.0. Time-killing assays were performed on three representative strains. Semi-mechanism-based mathematical modeling using Monolix quantified bactericidal activity through EC 50 parameters. Ciprofloxacin MIC 90 increased from 8 mg/L at pH 7.3 to 128 mg/L at pH 5.0, while delafloxacin MIC 90 decreased from 64 mg/L to 16 mg/L. At physiological pH, ciprofloxacin demonstrated superior activity (median MIC: 1 mg/L vs 8 mg/L for delafloxacin, P &amp;lt; 0.001), while at pH 5.0, delafloxacin median MIC was 2 mg/L versus 64 mg/L for ciprofloxacin (P &amp;lt; 0.001). According to EUCAST breakpoints, susceptibility frequencies at pH 5.0 were 25.9% (21/81) for delafloxacin versus 2.5% (2/81) for ciprofloxacin (P &amp;lt; 0.001). Among PMQR, qnr genes led to 0% delafloxacin susceptibility across all conditions (0/150 strain-pH combinations), while qepA2 (8/30 strain-pH combinations, 26.7%) and aac(6')-Ib-cr (16/30 strain-pH combinations, 53.3%) showed comparable susceptibility frequencies to isogenic strains not carrying PMQR (15/33 strain-pH combinations, 45.5%). Simulated clinical exposures against chromoso mal mutant EC02 (GyrA-S83L) demonstrated that ciprofloxacin would fail at pH 5.0, while delafloxacin would maintain antimicrobial activity. Environmental pH deeply modulates fluoroquinolone activity and resistance mechanism impact. Delafloxacin demonstrates clinically relevant activity in acidic infection environments. IMPORTANCE Fluoroquinolones face increasing resistance challenges, particularly in acidic infection sites, such as the urinary tract, abscesses, and biofilms, where pH can drop below 6.0. This study reveals a critical pH-dependent reversal in antimicrobial effectiveness between ciprofloxacin and delafloxacin against resistant Escherichia coli. While ciprofloxacin loses substantial activity in acidic conditions (90% of strains showing 16-fold minimum inhibitory concentration increases at pH 5.0), delafloxacin maintains and even enhances its antimicrobial potency, with susceptibility rates increasing from 25.9% to over 50% as pH decreases. Using comprehensive resistance profiling across 81 isogenic strains and pharmacokinetic modeling, we demonstrate that delafloxa cin could overcome treatment failures in acidic infection sites where conventional fluoroquinolones fail. These findings could have immediate clinical implications for treating urinary tract infections, abscesses, and biofilmassociated infections, poten tially expanding therapeutic options against multidrug-resistant bacteria in previously challenging anatomical sites.&lt;/p&gt;&lt;/div&gt;</p>
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