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Minerva Urology and Nephrology Jun 2023On March 11 2019, European Medicines Agency (EMA) issues a warning after a review of serious, disabling and potentially permanent adverse events (AEs), particularly on... (Review)
Review
BACKGROUND
On March 11 2019, European Medicines Agency (EMA) issues a warning after a review of serious, disabling and potentially permanent adverse events (AEs), particularly on musculoskeletal and nervous system, with quinolone (QN) and fluoroquinolone (FQ) antibiotics. Aim of this study was to evaluate the effect of the EMA warning on the rate of AEs after QN and FQ treatments, reported in the EudraVigilance (EV) database.
METHODS
EV database is the system for managing and analyzing information on suspected AEs to medicines which have been authorized or being studied in clinical trials in the European Economic Area (EEA). We retrospectively explored the effect of FQs and QNs on musculoskeletal and nervous system from the EMA warning up to now (21 months) and compared these results with the 21 months before the EMA warning.
RESULTS
Main part of AEs in EV database were reported for ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin. Ciprofloxacin total AEs before 21 months till 12 months of EMA warning were 2763. 12 months before EMA Warning they were 2935. Twelve months after EMA Warning they were 3419. Between 12 months till 21 months they were 3174. Musculoskeletal disorders were respectively 574 (21% of the total) 21 months before, 558 (19%) 12 months before, 1048 (31%) after 12 months, 540 (17%) after 21 months of EMA Warning. Nervous system disorders were respectively 606 (22% of the total) 21 months before, 517 (18%) 12 months before, 680 (20%) after 12 months, 560 (18%) after 21 months of EMA Warning (respectively OR 1,16 95%CI 1,10 -1,22, P 0,12 ; OR 0,76 95%CI 0,69-0,83, P 0,27 ; OR 1,01 95%CI 0,96-1,06 P 0,05).
CONCLUSIONS
Our analysis clearly showed no significant differences before and after EMA warning, opening new insights in the role of the EMA warning in clinical practice.
Topics: Fluoroquinolones; Quinolones; Retrospective Studies; Ciprofloxacin; Levofloxacin
PubMed: 36940165
DOI: 10.23736/S2724-6051.23.05169-8 -
Antimicrobial Agents and Chemotherapy 2015A better understanding of second-line drug (SLD) pharmacokinetics, including cavitary penetration, may help optimize SLD dosing. Patients with pulmonary... (Clinical Trial)
Clinical Trial
A better understanding of second-line drug (SLD) pharmacokinetics, including cavitary penetration, may help optimize SLD dosing. Patients with pulmonary multidrug-resistant tuberculosis (MDR-TB) undergoing adjunctive surgery were enrolled in Tbilisi, Georgia. Serum was obtained at 0, 1, 4, and 8 h and at the time of cavitary removal to measure levofloxacin concentrations. After surgery, microdialysis was performed using the ex vivo cavity, and levofloxacin concentrations in the collected dialysate fluid were measured. Noncompartmental analysis was performed, and a cavitary-to-serum levofloxacin concentration ratio was calculated. Twelve patients received levofloxacin for a median of 373 days before surgery (median dose, 11.8 mg/kg). The median levofloxacin concentration in serum (Cmax) was 6.5 μg/ml, and it was <2 μg/ml in 3 (25%) patients. Among 11 patients with complete data, the median cavitary concentration of levofloxacin was 4.36 μg/ml (range, 0.46 to 8.82). The median cavitary/serum levofloxacin ratio was 1.33 (range, 0.63 to 2.36), and 7 patients (64%) had a ratio of >1. There was a significant correlation between serum and cavitary concentrations (r = 0.71; P = 0.01). Levofloxacin had excellent penetration into chronic cavitary TB lesions, and there was a good correlation between serum and cavitary concentrations. Optimizing serum concentrations will help ensure optimal cavitary concentrations of levofloxacin, which may enhance treatment outcomes.
Topics: Adolescent; Adult; Antitubercular Agents; Female; Humans; Levofloxacin; Male; Middle Aged; Tuberculosis, Multidrug-Resistant; Young Adult
PubMed: 25779583
DOI: 10.1128/AAC.00379-15 -
American Journal of Veterinary Research Oct 2019To determine the pharmacokinetics of levofloxacin following oral administration of a generic levofloxacin tablet and IV administration to dogs and whether the achieved...
OBJECTIVE
To determine the pharmacokinetics of levofloxacin following oral administration of a generic levofloxacin tablet and IV administration to dogs and whether the achieved plasma levofloxacin concentration would be sufficient to treat susceptible bacterial infections.
ANIMALS
6 healthy adult Beagles.
PROCEDURES
Levofloxacin was administered orally as a generic 250-mg tablet (mean dose, 23.7 mg/kg) or IV as a solution (15 mg/kg) to each dog in a crossover study design, with treatments separated by a minimum 2-day washout period. Blood samples were collected at various points for measurement of plasma levofloxacin concentration via high-pressure liquid chromatography. Pharmacokinetic analysis was performed with compartmental modeling.
RESULTS
After oral administration of the levofloxacin tablet, mean (coefficient of variation) peak plasma concentration was 15.5 μg/mL (23.8%), mean elimination half-life was 5.84 hours (20.0%), and mean bioavailability was 104% (29.0%). After IV administration, mean elimination half-life (coefficient of variation) was 6.23 hours (14.7%), systemic clearance was 145.0 mL/kg/h (22.2%), and volume of distribution was 1.19 L/kg (17.1%).
CONCLUSIONS AND CLINICAL RELEVANCE
In these dogs, levofloxacin was well absorbed when administered orally, and a dose of approximately 25 mg/kg was sufficient to reach pharmacokinetic-pharmacodynamic targets for treating infections with susceptible Enterobacteriaceae (ie, ≤ 0.5 μg/mL) or (ie, ≤ 1 μg/mL) according to clinical breakpoints established by the Clinical and Laboratory Standards Institute.
Topics: Administration, Intravenous; Administration, Oral; Animals; Anti-Bacterial Agents; Area Under Curve; Biological Availability; Chromatography, High Pressure Liquid; Cross-Over Studies; Dogs; Female; Half-Life; Levofloxacin; Male; Tablets
PubMed: 31556716
DOI: 10.2460/ajvr.80.10.957 -
Scientific Reports Nov 2020The study aimed to investigate the antibacterial effect and potential mechanisms of chlorogenic acid (CA) in Klebsiella pneumonia (KPN) induced infection in vitro and in...
The study aimed to investigate the antibacterial effect and potential mechanisms of chlorogenic acid (CA) in Klebsiella pneumonia (KPN) induced infection in vitro and in vivo. 62 KPN strains were collected from the First People's Hospital of Yunnan Province. CA and CA combined Levofloxacin (LFX) were detected for KPN biofilm (BF) formation in vitro. The lung infection mice model were established by KPN. The effect of CA (500 mg/kg), LFX (50 mg/kg) and CA combined LFX (250 mg/kg + 25 mg/kg) were evaluated through the survival of mice, the changes of inflammation factors of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β and IL-6 in serum, the histopathological analysis of lung and the protein expression of NLRP3 signaling pathway in vivo. A total of 62 KPNs were isolated and identified, of which 13 (21%) strains were BF positive. 8 (13%) strains were extended spectrum β-lactamase strains (ESBLs), and 20 (32%) strains are ESBLs biofilm positive. In vitro study, CA and LFX showed a synergistic effect on KPN biofilm formation. In vivo mice experiment, CA, especially CA + LFX treated group significantly decreased the serum levels of TNF-α, IL-1β and IL-6, improved the survival ratio and lung pathology changes, and also reduced the protein expression of ASC, caspase 1 p20, IL-1β and phosphor NF-κB p65. CA could effectively alleviate lung infection of KPN infected mice, and the antibacterial effection is strengthened by combined with LFX. The study provide a theroy basis for making rational and scientific antibacterial therapy strategy in clinic.
Topics: Animals; Anti-Bacterial Agents; Biofilms; Chlorogenic Acid; Drug Resistance, Bacterial; Drug Synergism; Inflammation Mediators; Klebsiella Infections; Klebsiella pneumoniae; Levofloxacin; Lung; Male; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Pneumonia, Bacterial
PubMed: 33203903
DOI: 10.1038/s41598-020-76895-5 -
Ecotoxicology and Environmental Safety Jul 2023Excessive antibiotics transferred into the aquatic environment may affect the development of amphibians. Previous studies on the aquatic ecological risk of ofloxacin...
Excessive antibiotics transferred into the aquatic environment may affect the development of amphibians. Previous studies on the aquatic ecological risk of ofloxacin generally ignored its enantiomers. The purpose of this study was to compare the effects and mechanisms of ofloxacin (OFL) and levofloxacin (LEV) on the early development of Rana nigromaculata. After 28-day exposure at environmental levels, we found that LEV exerted more severe inhibitory effects on the development of tadpoles than OFL. According to the enrichment results of differentially expressed genes in the LEV and OFL treatments, LEV and OFL had different effects on the thyroid development of tadpoles. dio2 and trh were affected by the regulation of dexofloxacin instead of LEV. At the protein level, LEV was the main component that affected thyroid development-related protein, while dexofloxacin in OFL had little effect on thyroid development. Furthermore, molecular docking results further confirmed that LEV was a major component affecting thyroid development-related proteins, including DIO and TSH. In summary, OFL and LEV regulated the thyroid axis by differential binding to DIO and TSH proteins, thereby exerting differential effects on the thyroid development of tadpoles. Our research is of great significance for comprehensive assessment of chiral antibiotics aquatic ecological risk.
Topics: Animals; Ofloxacin; Levofloxacin; Larva; Thyroid Gland; Molecular Docking Simulation; Anti-Bacterial Agents; Ranidae; Hypothalamus; Thyrotropin
PubMed: 37178612
DOI: 10.1016/j.ecoenv.2023.114985 -
BMC Cancer Feb 2024Advanced pancreatic cancer is one of the leading causes of cancer-related deaths. For patients with advanced pancreatic cancer, gemcitabine and nanoparticle...
Efficacy of adding levofloxacin to gemcitabine and nanoparticle-albumin-binding paclitaxel combination therapy in patients with advanced pancreatic cancer: study protocol for a multicenter, randomized phase 2 trial (T-CORE2201).
BACKGROUND
Advanced pancreatic cancer is one of the leading causes of cancer-related deaths. For patients with advanced pancreatic cancer, gemcitabine and nanoparticle albumin-binding paclitaxel (nabPTX) combination (GEM/nabPTX) therapy is one of the recommended first-line treatments. Several retrospective studies have suggested that the addition of levofloxacin improves the efficacy of GEM/nabPTX therapy in patients with advanced pancreatic cancer. This prospective study aims to evaluate whether the addition of antibiotics improves the treatment efficacy of GEM/nabPTX as a first-line chemotherapy in patients with advanced pancreatic cancer.
METHODS
This multicenter, prospective, randomized, phase 2 trial will included 140 patients. Patients with advanced pancreatic cancer will be randomized in a 1:1 ratio to either the GEM/nabPTX therapy group or the GEM/nabPTX plus levofloxacin group. The primary endpoint for the two groups is median progression-free survival time (mPFS) for the full analysis set (FAS). The secondary endpoints for the two groups are median overall survival (mOS), response rate (RR), disease control rate (DCR), and adverse event (AE) for the FAS and mPFS, mOS, RR, DCR, and AE for the per-protocol set. This study will enroll patients treated with GEM/nabPTX as the first-line chemotherapy for stage IV pancreatic adenocarcinoma.
DISCUSSION
GEM/nabPTX is a standard first-line chemotherapy regimen for patients with advanced pancreatic cancer. Recently, the superiority of 5-fluorouracil, liposomal irinotecan, and oxaliplatin combination therapy (NALIRIFOX) to GEM/nabPTX as first-line therapy for pancreatic cancer has been reported. However, the efficacy of NALIRIFOX is inadequate. Based on previous retrospective studies, it is hypothesized that treatment efficacy will improve when levofloxacin is added to GEM/nabPTX therapy. If the AEs (such as leukopenia, neutropenia, and peripheral neuropathy) that occur at an increased rate with levofloxacin and GEM/nabPTX combination therapy can be carefully monitored and properly managed, this simple intervention can be expected to improve the prognosis of patients with advanced pancreatic cancer.
TRIAL REGISTRATION
This study was registered with the Japan Registry of Clinical Trials (jRCT; registry number: jRCTs021230005).
Topics: Humans; Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Gemcitabine; Levofloxacin; Multicenter Studies as Topic; Nanoparticles; Paclitaxel; Pancreatic Neoplasms; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies
PubMed: 38402399
DOI: 10.1186/s12885-024-11973-9 -
Health Technology Assessment... Nov 2019Myeloma causes profound immunodeficiency and recurrent serious infections. There are approximately 5500 new UK cases of myeloma per annum, and one-quarter of patients... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Myeloma causes profound immunodeficiency and recurrent serious infections. There are approximately 5500 new UK cases of myeloma per annum, and one-quarter of patients will have a serious infection within 3 months of diagnosis. Newly diagnosed patients may benefit from antibiotic prophylaxis to prevent infection. However, the use of prophylaxis has not been established in myeloma and may be associated with health-care-associated infections (HCAIs), such as . There is a need to assess the benefits and cost-effectiveness of the use of antibacterial prophylaxis against any risks in a double-blind, placebo-controlled, randomised clinical trial.
OBJECTIVES
To assess the risks, benefits and cost-effectiveness of prophylactic levofloxacin in newly diagnosed symptomatic myeloma patients.
DESIGN
Multicentre, randomised, double-blind, placebo-controlled trial. A central telephone randomisation service used a minimisation computer algorithm to allocate treatments in a 1 : 1 ratio.
SETTING
A total of 93 NHS hospitals throughout England, Northern Ireland and Wales.
PARTICIPANTS
A total of 977 patients with newly diagnosed symptomatic myeloma.
INTERVENTION
Patients were randomised to receive levofloxacin or placebo tablets for 12 weeks at the start of antimyeloma treatment. Treatment allocation was blinded and balanced by centre, estimated glomerular filtration rate and intention to give high-dose chemotherapy with autologous stem cell transplantation. Follow-up was at 4-week intervals up to 16 weeks, with a further follow-up at 1 year.
MAIN OUTCOME MEASURES
The primary outcome was to assess the number of febrile episodes (or deaths) in the first 12 weeks from randomisation. Secondary outcomes included number of deaths and infection-related deaths, days in hospital, carriage and invasive infections, response to antimyeloma treatment and its relation to infection, quality of life and overall survival within the first 12 weeks and beyond.
RESULTS
In total, 977 patients were randomised (levofloxacin, = 489; placebo, = 488). A total of 134 (27%) events (febrile episodes, = 119; deaths, = 15) occurred in the placebo arm and 95 (19%) events (febrile episodes, = 91; deaths, = 4) occurred in the levofloxacin arm; the hazard ratio for time to first event (febrile episode or death) within the first 12 weeks was 0.66 (95% confidence interval 0.51 to 0.86; = 0.002). Levofloxacin also reduced other infections (144 infections from 116 patients) compared with placebo (179 infections from 133 patients; -trend of 0.06). There was no difference in new acquisitions of , methicillin-resistant and extended-spectrum beta-lactamase Gram-negative organisms when assessed up to 16 weeks. Levofloxacin produced slightly higher quality-adjusted life-year gains over 16 weeks, but had associated higher costs for health resource use. With a median follow-up of 52 weeks, there was no significant difference in overall survival ( = 0.94).
LIMITATIONS
Short duration of prophylactic antibiotics and cost-effectiveness.
CONCLUSIONS
During the 12 weeks from new diagnosis, the addition of prophylactic levofloxacin to active myeloma treatment significantly reduced febrile episodes and deaths without increasing HCAIs or carriage. Future work should aim to establish the optimal duration of antibiotic prophylaxis and should involve the laboratory investigation of immunity, inflammation and disease activity on stored samples funded by the TEAMM (Tackling Early Morbidity and Mortality in Myeloma) National Institute for Health Research Efficacy and Mechanism Evaluation grant (reference number 14/24/04).
TRIAL REGISTRATION
Current Controlled Trials ISRCTN51731976.
FUNDING DETAILS
This project was funded by the NIHR Health Technology Assessment programme and will be published in full in ; Vol. 23, No. 62. See the NIHR Journals Library website for further project information.
Topics: Anti-Bacterial Agents; Antibiotic Prophylaxis; Clostridioides difficile; Cost-Benefit Analysis; Cross Infection; England; Female; Humans; Levofloxacin; Male; Middle Aged; Multiple Myeloma; Northern Ireland; Technology Assessment, Biomedical; Wales
PubMed: 31690402
DOI: 10.3310/hta23620 -
Internal Medicine (Tokyo, Japan) May 2019A 64-year-old woman with no previous mental illness took a single 500 mg tablet of levofloxacin for cystitis. Two hours later, she developed psychosis with involuntary...
A 64-year-old woman with no previous mental illness took a single 500 mg tablet of levofloxacin for cystitis. Two hours later, she developed psychosis with involuntary movement and severe hyperventilation with respiratory alkalosis. Cranial magnetic resonance imaging findings were unremarkable, and an electroencephalogram revealed no epileptiform discharge. Her symptoms improved on the third day after levofloxacin was discontinued. Levofloxacin-associated encephalopathy with psychotic features is a rare adverse event. Disturbance of gamma-aminobutyric acid-ergic (GABAergic) interneurons by levofloxacin may lead to hyperventilation via dysfunction of the brainstem respiratory network. Physicians should be aware of hyperventilation as an additional serious symptom of levofloxacin-associated encephalopathy in acute settings.
Topics: Anti-Infective Agents, Urinary; Brain Diseases; Cystitis; Female; Humans; Hyperventilation; Levofloxacin; Middle Aged; Treatment Outcome
PubMed: 30713304
DOI: 10.2169/internalmedicine.1619-18 -
Molecular Pharmaceutics Jun 2024Levofloxacin hemihydrate (LVXh) is a complex fluoroquinolone drug that exists in both hydrated and anhydrous/dehydrated forms. Due to the complexity of such a compound,...
Levofloxacin hemihydrate (LVXh) is a complex fluoroquinolone drug that exists in both hydrated and anhydrous/dehydrated forms. Due to the complexity of such a compound, the primary aim of this study was to investigate the amorphization capabilities and solid-state transformations of LVXh when exposed to mechanical treatment using ball milling. Spray drying was utilized as a comparative method for investigating the capabilities of complete LVX amorphous (LVXam) formation. The solid states of the samples produced were comprehensively characterized by powder X-ray diffraction, thermal analysis, infrared spectroscopy, Rietveld method, and dynamic vapor sorption. The kinetics of the process and the quantification of phases at different time points were conducted by Rietveld refinement. The impact of the different mills, milling conditions, and parameters on the composition of the resulting powders was examined. A kinetic investigation of samples produced using both mills disclosed that it was in fact possible to partially amorphize LVXh upon mechanical treatment. It was discovered that LVXh first transformed to the anhydrous/dehydrated form γ (LVXγ), as an intermediate phase, before converting to LVXam. The mechanism of LVXam formation by ball milling was successfully revealed, and a new method of forming LVXγ and LVXam by mechanical forces was developed. Spray drying from water depicted that complete amorphization of LVXh was possible. The amorphous form of LVX had a glass transition temperature of 80 °C. The comparison of methods highlighted that the formation of LVXam is thus both mechanism- and process-dependent. Dynamic vapor sorption studies of both LVXam samples showed comparable stability properties and crystallized to the most stable hemihydrate form upon analysis. In summary, this work contributed to the detailed understanding of solid-state transformations of essential fluoroquinolones while employing greener and more sustainable manufacturing methods.
Topics: Levofloxacin; X-Ray Diffraction; Powders; Kinetics; Drug Compounding; Anti-Bacterial Agents; Calorimetry, Differential Scanning; Crystallization; Chemistry, Pharmaceutical
PubMed: 38662637
DOI: 10.1021/acs.molpharmaceut.4c00008 -
Journal of Infection and Public Health May 2024With the global increase in antibacterial resistance, the challenge faced by developing countries is to utilize the available antibiotics, alone or in combination,...
BACKGROUND
With the global increase in antibacterial resistance, the challenge faced by developing countries is to utilize the available antibiotics, alone or in combination, against resistant bacterial strains. We aimed to encapsulate the levofloxacin (LVX) into polymeric nanoparticles using biodegradable polymers i.e. Chitosan and PLGA, estimating their physicochemical characteristics followed by functional assessment as nanocarriers of levofloxacin against the different resistant strains of bacteria isolated from biological samples collected from tertiary care hospital in Lahore, Pakistan.
METHODS
LVX-NPs were synthesized using ion gelation and double emulsion solvent-evaporation method employing chitosan (CS) and poly-lactic-co-glycolic acid (PLGA), characterized via FTIR, XRD, SEM, and invitro drug release studies, while antibacterial activity was assessed using Kirby-Bauer disc-diffusion method.
RESULTS
Data revealed that the levofloxacin-loaded chitosan nanoparticles showed entrapment efficiency of 57.14% ± 0.03 (CS-I), 77.30% ± 0.08(CS-II) and 87.47% ± 0.08 (CS-III). The drug content, particle size, and polydispersity index of CS-I were 52.22% ± 0.2, 559 nm ± 31 nm, and 0.030, respectively, whereas it was 66.86% ± 0.17, 595 nm ± 52.3 nm and 0.057, respectively for CS-II and 82.65% ± 0.36, 758 nm ± 24 nm and 0.1, respectively for CS-III. The PLGA-levofloxacin nanoparticles showed an entrapment efficiency of 42.80% ± 0.4 (PLGA I) and 23.80% ± 0.4 (PLGA II). The drug content, particle size and polydispersity index of PLGA-I were 86% ± 0.21, 92 nm ± 10 nm, and 0.058, respectively, whereas it was 52.41% ± 0.45, 313 nm ± 32 nm and 0.076, respectively for PLGA-II. The XRD patterns of both polymeric nanoparticles showed an amorphous nature. SEM analysis reflects the circular-shaped agglomerated nanoparticles with PLGA polymer and dense spherical nanoparticles with chitosan polymer. The in-vitro release profile of PLGA-I nanoparticles showed a sustained release of 82% in 120 h and it was 58.40% for CS-III. Both types of polymeric nanoparticles were found to be stable for up to 6 months without losing any major drug content. Among the selected formulations, CS-III and PLGA-I, CS-III had better antibacterial potency against gram+ve and gram-ve bacteria, except for K. pneumonia, yet, PLGA-I demonstrated efficacy against K. pneumonia as per CSLI guidelines. All formulations did not exhibit any signs of hemotoxicity, nonetheless, the CS-NPs tend to bind on the surface of RBCs.
CONCLUSION
These data suggested that available antibiotics can effectively be utilized as nano-antibiotics against resistant bacterial strains, causing severe infections, for improved antibiotic sensitivity without compromising patient safety.
Topics: Humans; Polylactic Acid-Polyglycolic Acid Copolymer; Polyglycolic Acid; Levofloxacin; Chitosan; Glycols; Drug Carriers; Lactic Acid; Anti-Bacterial Agents; Bacteria; Pneumonia; Nanoparticles; Glycolates
PubMed: 38569270
DOI: 10.1016/j.jiph.2024.03.023