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
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.
This study compared the activity of finafloxacin, a novel fluoroquinolone which shows enhanced activity under acidic pH, and that of ciprofloxacin against Acinetobacter baumannii under standard conditions (pH 7.2) and at a pH of 5.8. Overall, finafloxacin demonstrated superior activity to ciprofloxacin under acidic conditions. Furthermore, finafloxacin showed comparable activity to ciprofloxacin at pH 7.2. Hence, finafloxacin could be a promising new antimicrobial agent for the treatment of A. baumannii infections at acidic body compartments.The continuing spread of multidrug-resistant Acinetobacter baumannii is of serious concern to health professionals and often leaves few therapeutic options (7). Fluoroquinolones have in the past shown good activity against A. baumannii (8); however, over the past decade there has been a constant rise in fluoroquinolone resistance (11). Resistance to fluoroquinolones in A. baumannii is mediated primarily by stepwise selection of mutations in the drug targets gyrA and parC. The first step is a gyrA mutation, most commonly leading to a Ser83-Leu substitution (18). This is often sufficient to render the isolate intermediate or fully resistant to ciprofloxacin. A second mutation, in parC, most often causing a Ser80-Leu substitution, usually leads to high-level resistance to all fluoroquinolones (17,19). In addition, drug efflux contributes to fluoroquinolone resistance (9, 13).Finafloxacin ( Fig. 1) is a novel fluoroquinolone currently undergoing phase II clinical trials. This drug shows enhanced activity under acidic pH, where other fluoroquinolones display decreased activity. Infected body sites can have a significantly lower pH than healthy tissue (Table 1). The objective of this study was to determine the activity of finafloxacin and ciprofloxacin against A. baumannii isolates with characterized gyrA and parC genes under standard testing conditions and under an acidic pH.A total of 68 previously characterized genotypically unrelated ciprofloxacin-sensitive and -resistant A. baumannii clinical isolates were investigated (Table 2) (9,13,19). Of these, 18 are wild-type GyrA/ParC, 26 have a GyrA substitution, and 24 have a double GyrA/ParC substitution. Two isolates overexpress the efflux pump adeB compared to their isogenic parent strains (9, 13). Ciprofloxacin and finafloxacin MICs were determined by agar dilution under standard conditions (pH 7.2) (5), and at a pH of 5.8. pH 5.8 was chosen as it is representative of a number of infected body sites (lower respiratory tract, skin, stomach mucosa) and is the mean pH of urine during urinary tract infection. Ciprofloxacin and finafloxacin powders were supplied by their respective manufacturers (Bayer AG, Wuppertal, Germany, and MerLion Pharmaceuticals GmbH, Berlin). Mueller-Hinton agar (Oxoid, Wesel, Germany) was prepared following the manufacturer's instructions, and the pH was adjusted by the addition of HCl prior to pouring antibiotic-containing plates. The pH of the agar was checked once solidified. Ciprofloxacin-and finafloxac...
Finafloxacin is a new fluoroquinolone antibiotic with the unique property of increasing antibacterial activity at pH values lower than neutral. Whereas its antibacterial activity at neutral pH matches that of other quinolones in clinical use, it is expected to surpass this activity in tissues and body fluids acidified by the infection or inflammation processes. Pharmacokinetic parameters of oral single and multiple doses of up to 800 mg of finafloxacin and safety/tolerability observations were assessed in a phase I study including 95 healthy volunteers. Finafloxacin is well absorbed after oral administration, generating maximum concentrations (C max s) in plasma at least comparable to those of other fluoroquinolones, with a half-life of around 10 h. About one-third of the dose is excreted unchanged in the urine. Renal elimination appears to be a saturable process leading to slight increases of the area under the concentration-time curve extrapolated to infinity and dose normalized (AUC ؕ,norm ) at dosages of 400 mg and above. Safety and tolerability data characterize finafloxacin as a drug with a favorable safety profile. In particular, adverse reactions regarded as class-typical of fluoroquinolones, such as, e.g., electrocardiogram (ECG) changes, neurotoxic effects, or hypoglycemia, were not observed in the study population.
To explore candidate prognostic and predictive biomarkers identified in retrospective observational studies (interleukin-6, C-reactive protein, lactate dehydrogenase, ferritin, lymphocytes, monocytes, neutrophils, d-dimer, and platelets) in patients with coronavirus disease 2019 pneumonia after treatment with tocilizumab, an anti-interleukin-6 receptor antibody, using data from the COVACTA trial in patients hospitalized with severe coronavirus disease 2019 pneumonia.DESIGN: Exploratory analysis from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. SETTING: Hospitals in North America and Europe. PATIENTS:Adults hospitalized with severe coronavirus disease 2019 pneumonia receiving standard care. INTERVENTION:Randomly assigned 2:1 to IV tocilizumab 8 mg/kg or placebo. MEASUREMENTS AND MAIN RESULTS:Candidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomization) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. Modeling in the placebo arm showed all candidate biomarkers except lactate dehydrogenase and d-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modeling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction, p = 0.03), mechanical ventilation (predictive interaction, p = 0.01), and clinical status (predictive interaction, p = 0.02) compared with placebo. CONCLUSIONS:Multiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28.
Kill kinetics and MICs of finafloxacin and ciprofloxacin against 34 strains with defined resistance mechanisms grown in cation-adjusted Mueller-Hinton broth (CAMHB) at pH values of 7.2 and 5.8 and in synthetic urine at pH 5.8 were determined. In general, finafloxacin gained activity at low pH values in CAMHB and remained almost unchanged in artificial urine. Ciprofloxacin MICs increased and bactericidal activity decreased strain dependently in acidic CAMHB and particularly in artificial urine.Bacteria colonizing or infecting a host grow under hostile conditions, sense changing environmental stress via diverse quorum sensing, and other two-component systems, and respond by up-or downregulating the expression levels of appropriate proteins, which in turn can affect the susceptibility of the cell to antibiotics (2, 11). Examples of environmental stress include, e.g., growth at extreme temperatures, pH, osmotic pressure, and depletion of nutrients, etc.; Escherichia coli and Staphylococcus aureus causing uncomplicated cystitis or growing in urine or in biofilms on indwelling urethral catheters are such examples (3,8,24,28,31,34,35,38).Thus, it is physiologically relevant and clinically important to study the antibacterial activities of agents under test conditions which mimic the infectious focus most closely. Therefore, we used cation-adjusted Mueller-Hinton broth (CAMHB), pH 7.2 and pH 5.8 (Oxoid GmbH, Wesel, Germany), and synthetic urine, pH 5.8, containing 11 solutes each, in concentrations found in a 24-h period in the urine of healthy men (14) for the comparison of the bacteriostatic and -cidal activities of finafloxacin (batch CBC000288) and ciprofloxacin (batch CBC000290).(Part of the data presented in this paper were shown as a poster at the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, October 2008.)Thirty-four phenotyped and/or genotyped strains were used for the examination of MICs and kill kinetics, according to CLSI guidelines (6,7,19). S. aureus ATCC 29213, E. coli ATCC 25922, and Enterococcus faecalis ATCC 29212, as well as moxifloxacin as an external standard, served as controls. Tests were run in duplicate; the higher values were reported in case of deviation (1.2%). Kill kinetics were examined by using finafloxacin and ciprofloxacin at bioequivalent concentrations of 16ϫ, 4ϫ, and 1ϫ the individual MIC values, as measured in the corresponding media. Samples for determination of viable counts were taken at 0, 1, 2, 4, 6, 8, and 24 h. Drug carryover was minimized first by dilution and second by plating the aliquots on cation-enriched agar, thus inactivating the fluoroquinolones. In order to quantify the reduction of viable counts and the speed of kill, the times needed to reduce the inocula by 3-log 10 titers and kill rates were calculated as described recently (32). Furthermore, kill rates were normalized to a drug exposure of 1 mg/liter, as the drug concentration/isolate/media and pH associations vary considerably under the different growth conditions studie...
The spectrophotometric microplate method for determining PAEs may be a suitable alternative to the classical method for those antibiotics that do not induce bacterial cell lysis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.