Activity of the Investigational Fluoroquinolone Finafloxacin against Ciprofloxacin-Sensitive and -Resistant Acinetobacter baumannii Isolates

Abstract

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...

Contrasting Effects of Acidic pH on the Extracellular and Intracellular Activities of the Anti-Gram-Positive Fluoroquinolones Moxifloxacin and Delafloxacin againstStaphylococcus aureus

“…1 for chemical structural and main physicochemical properties). This property further increases delafloxacin's potency in acidic environments (35,43), as also observed for N-sulfanilylpiperazinyl fluoroquinolones (1,3) and finafloxacin (21). This could be an advantage with respect to S. aureus infections, since this bacterium, which shows a high tolerance to low pH, survives and multiplies in mild acidic environments (47), such as the skin, the vagina, or the urinary tract, and within the phagolysosomes of infected cells (6), where the pH is about 5 to 5.5 (19).…”

Investigational Antimicrobial Agents of 2013

“…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). Finafloxacin has been evaluated in phase 1 studies with oral and intravenous (i.v.)…”

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

“…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.…”