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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.).

SUBMITTER: Wagenlehner F

PROVIDER: S-EPMC5913919 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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

Wagenlehner F F Nowicki M M Bentley C C Lückermann M M Wohlert S S Fischer C C Vente A A Naber K K Dalhoff A A

Antimicrobial agents and chemotherapy 20180327 4

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 te ...[more]

PMID: 29339395

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Project description: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.).

Project description:Oral fosfomycin is approved in Canada for the treatment of acute uncomplicated cystitis. Several studies have reported "off label" use of oral fosfomycin in the treatment of patients with complicated lower urinary tract infection (cLUTI). This review summarizes the available literature describing the use of oral fosfomycin in the treatment of patients with cLUTI. Collectively, these studies support the use of a regimen of 3 grams of oral fosfomycin administered once every 48 or 72 hours for a total of 3 doses for patients who have previously failed treatment with another agent, are infected with a multidrug-resistant (MDR) pathogen, or cannot tolerate first-line treatment due to intolerance or adverse effects. Additionally, a Phase 2/3 clinical trial, known as the ZEUS study, assessed the efficacy and safety of intravenous (IV) fosfomycin versus piperacillin-tazobactam in the treatment of patients with complicated upper urinary tract infection (cUUTI) or acute pyelonephritis (AP) including in patients with concomitant bacteremia. IV fosfomycin was reported to be noninferior to piperacillin-tazobactam in treating patients with cUUTI and AP; however, when outcomes were independently evaluated according to baseline diagnosis (i.e., cUUTI versus AP), IV fosfomycin was superior to piperacillin-tazobactam in the treatment of patients with cUUTI and demonstrated superior microbiological eradication rates, across all resistant phenotypes including extended-spectrum β-lactamase- (ESBL-) producing Escherichia coli and Klebsiella spp. and carbapenem-resistant (CRE), aminoglycoside-resistant, and MDR Gram-negative bacilli (primarily Enterobacterales). Based on the ZEUS study, IV fosfomycin dosed at 6 grams every 8 hours for 7 days (14 days in patients with concurrent bacteremia) appears to be a safe and effective therapeutic option in treating patients with upper urinary tract infections, particularly those with cUUTI caused by antimicrobial-resistant Enterobacterales.

Project description:Background and Objectives. Numerous studies have been conducted to explore the epidemiological characteristics of urinary tract infections (UTI) and sepsis. However, there is still a lack of relevant bacteriological features and prognostic information regarding urosepsis based on bacteriological etiology. The current study aims to evaluate the bacterial etiology of complicated UTI (cUTI) and bacterial resistance to antibiotics and whether they present an intrinsic risk of developing urosepsis. Materials and Methods. A retrospective study was performed that included 102 patients who were diagnosed with cUTI and admitted to the urology department of the "Sfântul Apostol Andrei" County Emergency Clinical Hospital (GCH) from September 2019 to May 2022. Results. A considerable number of patients, n = 41 (40.2%), were diagnosed with multi drug-resistant (MDR) infection. Escherichia coli (E. coli) was identified as the prevailing pathogen, accounting for 51 patients. Klebsiella manifested itself as the subsequent causative agent in 27 instances. The presence of Enterococcus spp. infection was documented in 13 patients, whereas Pseudomonas emerged as the etiological perpetrator in the clinical context of 8 patients. The current study found a substantial prevalence of resistance to first-line antibiotics. The overall resistance rate was 74.5% for penicillin, 58.82% for trimethoprim-sulfamethoxazole and 49% for fluoroquinolones; cephalosporin resistance displayed an inverse correlation with antibiotic generation with fourth-generation cephalosporins exhibiting a resistance rate of 24.5%, and first-generation cephalosporins demonstrating a resistance rate of 35.29%. Conclusions. Age, comorbidities and indwelling urinary catheters are risk factors for developing MDR infections. While the intrinsic characteristics of the causative bacterial agent in cUTI may not be a risk factor for developing urosepsis, they can contribute to increased mortality risk. For empiric antibiotic treatment in patients with cUTI who are at a high risk of developing urosepsis and experiencing a potentially unfavorable clinical course, broad-spectrum antibiotic therapy is recommended. This may include antibiotics, such as amikacin, tigecycline, carbapenems and piperacillin-tazobactam.

Project description:The rise in resistant Gram-negative pathogens continues to challenge clinicians treating infections. These resistant infections have inspired the development of new antimicrobial agents, including ceftolozane-tazobactam, a novel ?-lactam/?-lactamase inhibitor combination approved by the US Food and Drug Administration for the treatment of complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) in combination with metronidazole. Ceftolozane exhibits bactericidal activity by inhibiting penicillin-binding proteins (PBPs), with high affinity for PBP1b, PBP1c, and PBP3. The addition of tazobactam protects ceftolozane from hydrolysis by irreversibly binding to some ?-lactamase enzymes. Ceftolozane-tazobactam is active against a wide range of Gram-negative pathogens, including extended-spectrum ?-lactamase (ESBL)-producing Enterobacteriaceae and multidrug-resistant (MDR) Pseudomonas aeruginosa, several streptococcal species, and Bacteroides fragilis. When anaerobic coverage is needed, it should be used in combination with metronidazole. Ceftolozane demonstrates linear pharmacokinetics, low protein binding, and minimal accumulation with repeated dosing. The major pharmacokinetic/pharmacodynamic index for ceftolozane is the percentage of the dosing interval in which the plasma free drug concentration remains higher than the minimum inhibitory concentration (%T.MIC). Phase III clinical trials for the treatment of cUTIs and cIAIs have been completed, showing that it is an effective and safe alternative for the treatment of these infections. The approved dose for cUTIs and cIAIs is 1.5 g (1 g ceftolozane and 500 mg tazobactam) infused over 1 hour every 8 hours. A higher 3 g dose is currently in Phase III trials for the treatment of ventilated nosocomial pneumonia. Dosage adjustments are necessary for patients with moderate-to-severe renal impairment. Current data suggest that ceftolozane-tazobactam is a promising carbapenem-sparing alternative agent for the treatment of cUTIs and cIAIs, including those caused by ESBL-producing Enterobacteriaceae and MDR P. aeruginosa.

Dataset Information

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

Publications

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

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