Urinary tract infections (UTIs) caused by antibiotic-resistant Gram-negative bacteria are a growing concern due to limited treatment options. Knowledge of the common uropathogens in addition to local susceptibility patterns is essential in determining appropriate empiric antibiotic therapy of UTIs. The recommended first-line empiric antibiotic therapy for acute uncomplicated bacterial cystitis in otherwise healthy adult nonpregnant females is a 5-day course of nitrofurantoin, a 3-g single dose of fosfomycin tromethamine, or a 5-day course of pivmecillinam. High rates of resistance for trimethoprim-sulfamethoxazole and ciprofloxacin preclude their use as empiric treatment of UTIs in several communities, particularly if patients who were recently exposed to them or in patients who are at risk of infections with extended-spectrum β-lactamases (ESBLs)-producing Enterobacteriales. Second-line options include oral cephalosporins such as cephalexin or cefixime, fluoroquinolones and β-lactams, such as amoxicillin-clavulanate. Current treatment options for UTIs due to AmpC- β -lactamase-producing Enterobacteriales include nitrofurantoin, fosfomycin, pivmecillinam, fluoroquinolones, cefepime, piperacillin-tazobactam and carbapenems. Treatment oral options for UTIs due to ESBLs-E coli include nitrofurantoin, fosfomycin, pivmecillinam, amoxicillin-clavulanate, finafloxacin, and sitafloxacin while pivmecillinam, fosfomycin, finafloxacin, and sitafloxacin are treatment oral options for ESBLs- Klebsiella pneumoniae. Parenteral treatment options for UTIs due to ESBLs-producing Enterobacteriales include piperacillin-tazobactam (for ESBL-E coli only), carbapenems including meropenem/vaborbactam, imipenem/cilastatin-relebactam, and sulopenem, ceftazidime-avibactam, ceftolozane-tazobactam, aminoglycosides including plazomicin, cefiderocol, fosfomycin, sitafloxacin, and finafloxacin. Ceftazidime-avibactam, meropenem/vaborbactam, imipenem/cilastatin-relebactam, colistin, fosfomycin, aztreonam and ceftazidime-avibactam, aztreonam and amoxicillin-clavulanate, aminoglycosides including plazomicin, cefiderocol, tigecycline are treatment options for UTIs caused by carbapenem-resistant Enterobacteriales (CRE). Treatment options for UTIs caused by multidrug resistant (MDR)-Pseudomonas spp. include fluoroquinolones, ceftazidime, cefepime, piperacillin-tazobactam, carbapenems including imipenem-cilastatin/relebactam, meropenem, and fosfomycin, ceftolozane-tazobactam, ceftazidime-avibactam, aminoglycosides including plazomicin, aztreonam and ceftazidime-avibactam, cefiderocol, and colistin. It is important to use the new antimicrobials wisely for treatment of UTIs caused by MDR-organisms to avoid resistance development.

This study investigated the in vitro activity of finafloxacin against panels of the biodefence pathogens. Broth microdilution assays were performed at neutral and acidic pH, to determine the effectiveness of the antibiotics in conditions typical of an intracellular environment. In all instances, finafloxacin demonstrated superior activity at low pH. These results highlight the importance of evaluating antimicrobial efficacy in conditions relevant to those encountered in vivo.

Fluoroquinolones are considered one of the widely utilized antibiotics, specifically, with the recent development of newer generations such as moxifloxacin, delafloxacin and finafloxacin which possess a wider spectrum of activity and improved bioavailability. However, alarming increase in bacterial resistance reports worldwide incites medicinal chemists to employ guided-biologically-oriented-synthesis-strategies toward the modulation of quinolones derivatives activity. At present, quinolone scaffold diverse biological activities prompted the fortuitous discovery of novel antimicrobial and anticancer derivatives. Herein, the opponent arguments (2013-2015) regarding the structure activity relationships of fluoroquinolones' antibacterial, anticancer, antifungal activities are inscribed.

The efficacy of the novel fluoroquinolone finafloxacin was evaluated as a potential therapeutic in vitro and in vivo, following an intranasal infection of Francisella tularensis strain SchuS4 in BALB/c mice. We demonstrated that short treatment courses of finafloxacin provide high levels of protection, with a single dose resulting in a significant increase in time to death when compared to ciprofloxacin. In addition, following investigation into the window of opportunity for treatment, we have shown that finafloxacin can provided protection when administered up to 96 h post-challenge. This is particularly encouraging since mice displayed severe signs of disease at this time point. In summary, finafloxacin may be a promising therapy for use in the event of exposure to F. tularensis, perhaps enabling the treatment regimen to be shortened or if therapy is delayed. The efficacy of finafloxacin against other biological threat agents also warrants investigation.

Introduction: The constantly increasing spread of severe infections due to multidrug-resistant (MDR) Gram-negative bacteria (GNB) is a critical threat to the global medical community. After a long period of antibiotic pipeline pause, new antibiotic compounds are commercially available or are at late stages of clinical evaluation, promising to augment the therapeutic armamentarium of clinicians against deadly pathogens. Areas covered: This review summarizes available data regarding agents with potent activity against critical MDR Gram-negative pathogens, which urgently require new efficient antibiotics. Recently approved antibiotic formulations; and agents in advanced stages of development, including combinations of β-lactam/β-lactamase inhibitor, novel cephalosporins (cefiderocol), tetracyclines (eravacycline), aminoglycosides (plazomicin), quinolones (delafloxacin and finafloxacin) and pleuromutilins (lefamulin) are discussed in this review. Expert opinion: The recent introduction of new antibiotics into clinical practice is an encouraging step after a long period of pipeline stagnation. New formulations will be a useful option for clinicians to treat serious infections caused by several MDR Gram-negative pathogens. However, most of the new compounds are based on modifications of traditional antibiotic structures challenging their longevity as therapeutic options. More investment is needed for the discovery and clinical development of truly innovative and effective antibiotics without cross-resistance to currently used antibiotics.

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.).

Finafloxacin is a novel fluoroquinolone with increased antibacterial activity at acidic pH and reduced susceptibility to several resistance mechanisms. A phase II study revealed a good efficacy/safety profile in patients with complicated urinary tract infections (cUTIs), while the pharmacokinetics was characterized by highly variable concentration-versus-time profiles, suggesting the need for an elaborated pharmacokinetic model. Data from three clinical trials were evaluated: 127 healthy volunteers were dosed orally (n = 77) or intravenously (n = 50), and 139 patients with cUTI received finafloxacin intravenously. Plasma (2,824 samples from volunteers and 414 samples from patients) and urine (496 samples from volunteers and 135 samples patients) concentrations were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). NONMEM was used to build a population pharmacokinetic model, and pharmacokinetic/pharmacodynamic relationships were investigated via simulations and logistic regression. A two-compartment model with first-order elimination described the data best (central volume of distribution [Vc] and peripheral volume of distribution [Vp] of 47 liters [20%] and 43 liters [67%], respectively, and elimination clearance and intercompartmental clearance of 21 liters/h [54%] and 2.8 liters/h [57%], respectively [median bootstrap estimates {coefficients of variation}]). Vc increased with body surface area, and clearance was reduced in patients (-29%). Oral absorption was described best by parallel first- and zero-order processes (bioavailability of 75%). No pharmacodynamic surrogate parameter of clinical/microbiological outcome could be identified, which depended exclusively on the MIC of the causative pathogens. Despite the interindividual variability, the present data set does not support covariate-based dose adjustments. Based on the favorable safety and efficacy data, the clinical relevance of the observed variability appears to be limited. (This study has been registered at ClinicalTrials.gov under identifier NCT01928433.).

Two phase II studies were performed with patients with uncomplicated urinary tract infections (uUTIs) and complicated urinary tract infections (cUTIs) or acute pyelonephritis (PN) to compare finafloxacin (300 mg twice a day [b.i.d.] orally for uUTI and 800 mg once a day [q.d.] intravenously [i.v.] for cUTI/PN) and ciprofloxacin (250 mg b.i.d. orally for uUTI and 400 mg b.i.d. i.v. for cUTI/PN). The early response to the study medications was evaluated in the microbiological intent-to-treat population (mITT) at day 3. A total of 21% of the isolates were ciprofloxacin resistant, 13.7% were primed pathogens carrying a mutation(s) potentially fostering fluoroquinolone resistance development, and 7.1% produced extended-spectrum β-lactamases (ESBLs). Finafloxacin demonstrated very good early clinical activity, with microbiological eradication rates of 88.6% (n = 132), compared to 78.7% (n = 61) for ciprofloxacin, and 69.6% (n = 23), compared to 35.7% (n = 14) for ciprofloxacin, in patients with ciprofloxacin-resistant uropathogens; 94.1% (n = 17), compared to 80.0% (n = 10) for ciprofloxacin, in patients infected with uropathogens primed for fluoroquinolone resistance uropathogens; and 91.7% (n = 11), compared to 0% for ciprofloxacin, in patients infected with ESBL producers. Finafloxacin demonstrated early and rapid activity against uropathogens, including fluoroquinolone-resistant and/or multiresistant pathogens or ESBL producers, while ciprofloxacin was less active against this subset of resistant pathogens. Susceptibilities of pathogens were quantitated by broth microdilution. Isolates were subgrouped according to their susceptibility patterns, in particular first-step quinolone resistance, quinolone resistance, and ESBL production. Eradication was defined as the elimination or reduction of study entry pathogens to <103 CFU/ml in urine culture. (The studies described in this paper have been registered at ClinicalTrials.gov under identifiers NCT00722735 and NCT01928433.).

Finafloxacin is a novel fluoroquinolone exhibiting enhanced activity under acidic conditions and a broad-spectrum antibacterial profile. The present study assessed the pharmacokinetic properties and the safety and tolerability of finafloxacin following intravenous infusions. In this mixed-parallel-group, crossover study, healthy male and female volunteers received single ascending doses (18 volunteers, 200 to 1,000 mg) or multiple ascending doses (40 volunteers, 600 to 1,000 mg) of finafloxacin or placebo. Plasma and urine samples were collected by a dense sampling scheme to determine the pharmacokinetics of finafloxacin using a noncompartmental approach. Standard safety and tolerability data were documented. Finafloxacin had a volume of distribution of 90 to 127 liters (range) at steady state and 446 to 550 liters at pseudoequilibrium, indicating the elimination of a large fraction before pseudoequilibrium was reached. Areas under the concentration-time curves and maximum plasma concentrations (geometric means) increased slightly more than proportionally (6.73 to 45.9 μg · h/ml and 2.56 to 20.2 μg/ml, respectively), the terminal elimination half-life increased (10.6 to 17.1 h), and the urinary recovery decreased (44.2% to 31.7%) with increasing finafloxacin doses (single doses of 200 to 1,000 mg). The pharmacokinetic profiles suggested multiphasic elimination by both glomerular filtration and saturable tubular secretion. The values of the parameters were similar for single and multiple administrations. The coefficient of variation for the between-subject variability of exposure ranged from 10% (≤600 mg) to 38% (>600 mg). Adverse events were mild and nonspecific, with no dependence of adverse events on dose or treatment (including placebo) being detected. Despite a relatively high interindividual variability at higher doses, the level of exposure following intravenous administration of finafloxacin appears to be predictable. Individual elimination processes should be evaluated in more detail. Finafloxacin exhibited a favorable safety and tolerability profile. (This study has been registered at ClinicalTrials.gov under registration no. NCT01910883.).