Explorative Randomized Phase II Clinical Study of the Efficacy and Safety of Finafloxacin versus Ciprofloxacin for Treatment of Complicated Urinary Tract Infections

Abstract

The broad-spectrum C-8-cyano-fluoroquinolone finafloxacin displays enhanced activity under acidic conditions. This phase II clinical study compared the efficacies and safeties of finafloxacin and ciprofloxacin in patients with complicated urinary tract infection and/or pyelonephritis. A 5-day regimen with 800 mg finafloxacin once a day (q.d.) (FINA05) had results similar to those of a 10-day regimen with 800 mg finafloxacin q.d. (FINA10). Combined microbiological and clinical responses at the test-of-cure (TOC) visit were 70% for FINA05, 68% for FINA10, and 57% for a 10-day ciprofloxacin regimen (CIPRO10) in 193 patients (64 for FINA05, 68 for FINA10, and 61 for CIPRO10) of the microbiological intent-to-treat (mITT) population. Additionally, the clinical effects of ciprofloxacin on patients with an acidic urine pH (80% of patients) were reduced, whereas the effects of finafloxacin were unchanged. Finafloxacin was safe and well tolerated. Overall, 43.4% of the patients in the FINA05 group, 42.7% in the FINA10 group, and 54.2% in the CIPRO10 group experienced mostly mild and treatment-emergent but unrelated adverse events. A short-course regimen of 5 days of finafloxacin resulted in high eradication and improved clinical outcome rates compared to those for treatment with ciprofloxacin for 10 days. In contrast to those of ciprofloxacin, the clinical effects of finafloxacin were not reduced by acidic urine pH. Hospitalized adults were randomized 1:1:1 to finafloxacin treatment (800 mg q.d.) for either 5 or 10 days or to ciprofloxacin treatment (400 mg/500 mg b.i.d.) for 10 days with an optional switch from intravenous (i.v.) to oral administration at day 3. The primary endpoint was the combined microbiological and clinical response at the TOC visit in the microbiological intent-to-treat population. (This study has been registered at ClinicalTrials.gov under identifier NCT01928433.).

The Fluoroquinolone Finafloxacin Protects BALB/c Mice Against an Intranasal Infection With Francisella tularensis Strain SchuS4

“…It is also available in oral and intravenously delivered formulations, and is currently being developed for the treatment of urinary tract infections in hospitalized patients. Phase 2 trials have demonstrated that 800 mg of finafloxacin, administered for 5 days is as efficient as a 10 day regimen and that 800 mg of finafloxacin administered for 5 days is more efficient than the standard treatment (10 days of ciprofloxacin) (Wagenlehner et al, 2018). Efficacy in these trials was determined according to guidelines published by the FDA regarding the development of drugs for the treatment of complicated urinary tract infections (FDA, 2018 guidelines).…”

Pharmacodynamics of Finafloxacin, Ciprofloxacin, and Levofloxacin in Serum and Urine against TEM- and SHV-Type Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae Isolates from Patients with Urinary Tract Infections

“…These agents should be most active at the corresponding pH value, since the uncharged fraction only passes through prokaryotic and eukaryotic membranes, thus enhancing antibacterial activities against extracellular as well as intracellular bacteria. Dissociated in vitro activities (44, 48–50) and accumulation in eukaryotic cells (45) at acidic or alkaline pH values have been confirmed for finafloxacin and ciprofloxacin, respectively. However, the isoelectric points of finafloxacin and levofloxacin are almost identical, although the two agents are affected differently by pH changes.…”

“…The level of urinary excretion of finafloxacin is high (47), and its activity is impaired neither by an acidic pH nor by high concentrations of divalent cations, which prevail in UTIs (48–50). In contrast, the activities of expanded-spectrum fluoroquinolones are diminished under such growth conditions (48, 49).…”

Demonstration of the Broad-Spectrum In Vitro Activity of Finafloxacin against Pathogens of Biodefense Interest

“…It has been shown previously that the activity of certain classes of antibiotics (including fluoroquinolones) can be affected by a reduction in pH (1–4). Finafloxacin is a fluoroquinolone derivative with an 8-cyano substituent and 7-pyrrolo-oxazinyl moiety that is being developed for the treatment of urinary tract infections in hospitalized patients (5, 6). This modification has conferred activity in low-pH environments, which has resulted in superior in vitro activity against a range of organisms, including Staphylococcus aureus and Acinetobacter baumannii (7, 8).…”