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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 -
Biomedicine & Pharmacotherapy =... Oct 2021Fluoroquinolones efficacy depend on both the drug exposure and the level of drug resistance of the bacteria responsible for the infection. Specifically for the...
Fluoroquinolones efficacy depend on both the drug exposure and the level of drug resistance of the bacteria responsible for the infection. Specifically for the Staphylococcus species, which is the microorganism mainly involved in osteoarticular infections (OAI), in-vitro data reported that an AUC/MIC ratio above 115 h maximizes drug efficacy. However, data on OAI patients are lacking and a simple approach to access AUCs is still a clinical issue. We conducted a prospective, single-center study in 30 OAI patients hospitalized in the Rennes University Hospital to model ofloxacin pharmacokinetics and to define a limited sampling strategy (LSS) suitable for ofloxacin and levofloxacin treatments. Modeling was conducted with the Monolix software. The final model was externally validated using levofloxacin data. Monte-Carlo simulations were used to evaluate the probability of target attainment (PTA) of different dosing regimens. Two hundred and ninety-seven (297) ofloxacin concentrations were available for the pharmacokinetic modeling. Ofloxacin pharmacokinetics was best described using a bicompartmental model with a first order elimination, and a transit compartment model absorption. CKD-EPI and sex explained half of ofloxacin pharmacokinetic variability. For LSS, the 0, 1 h and 3 h sampling scheme resulted in the best approach both for BID and TID dosages (R adjusted = 91.1% and 95.0%, outliers = 4.8% and 5.0%, respectively). PTA allows choosing the best drug and dosage according to various hypotheses. A simple 3-sample protocol (pre-dose, 1 h after intake and 3 h after intake) to estimate ofloxacin and levofloxacin AUC allows optimal drug dosage for the treatment of osteoarticular infections.
Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bone Diseases, Infectious; Female; Fluoroquinolones; Humans; Joint Diseases; Levofloxacin; Male; Middle Aged; Models, Biological; Monte Carlo Method; Ofloxacin; Prospective Studies; Staphylococcus; Young Adult
PubMed: 34435591
DOI: 10.1016/j.biopha.2021.112053 -
Chemosphere Dec 2021Here, the antibiotic levofloxacin (LFX) widely used and detected in the environment was degraded by photoelectrolysis using a new electrode based on zinc oxide (ZnO) and...
Here, the antibiotic levofloxacin (LFX) widely used and detected in the environment was degraded by photoelectrolysis using a new electrode based on zinc oxide (ZnO) and a mixture of mixed oxides of ruthenium and titanium (MMO). The influence of the potential and irradiation of UV light was investigated in the photostability of the Ti/MMO/ZnO electrode and in the degradation of the antibiotic. The experiments were conducted at different pH values (5.0, 7.0 and 9.0) in sodium sulfate solution in a glass reactor with central lighting. It was observed that the new Ti/MMO/ZnO electrode has good stability under light irradiation and potential, presenting excellent photocurrent and high photoactivity in LFX photoelectrolysis. The removal efficiency of the compound was directly related to the formation of oxidizing species in solution, the photo-generated charges on the electrode and the electrostatic characteristics of the molecule. The mineralization rate, the formation of reaction intermediates and short chain carboxylic acids (acetic, maleic, oxalic and oxamic acid), in addition to the formation of N-mineral species (NO and NH) was dependent on the pH of the solution and the investigated processes: photoelectrolysis was more efficient than photolysis, which, in turn, was more efficient than electrolysis. The synergistic effect and the high rate of degradation of LFX after 4.0 h of treatment (100%) observed in photoelectrolysis at alkaline pH, was associated with the high stability of the Ti/MMO/ZnO electrode at this pH, the photoactivation of sulfate ions and the ease generation of oxidizing radicals, such as OH.
Topics: Catalysis; Electrodes; Electrolysis; Levofloxacin; Titanium; Water Pollutants, Chemical; Zinc Oxide
PubMed: 34182289
DOI: 10.1016/j.chemosphere.2021.131303 -
Journal of Global Antimicrobial... Sep 2023The aim of the study was to update the classification of drugs used in multidrug-resistant tuberculosis (MDR-TB) regimens. Group A drugs (fluoroquinolones, bedaquiline... (Meta-Analysis)
Meta-Analysis Review
Evaluation of genetic mutations associated with phenotypic resistance to fluoroquinolones, bedaquiline, and linezolid in clinical Mycobacterium tuberculosis: A systematic review and meta-analysis.
OBJECTIVES
The aim of the study was to update the classification of drugs used in multidrug-resistant tuberculosis (MDR-TB) regimens. Group A drugs (fluoroquinolones, bedaquiline (BDQ), and linezolid (LZD)) are crucial drugs for the control of MDR-TB. Molecular drug resistance assays could facilitate the effective use of Group A drugs.
METHODS
We summarised the evidence implicating specific genetic mutations in resistance to Group A drugs. We searched PubMed, Embase, MEDLINE, and the Cochrane Library for studies published from the inception of each database until July 1, 2022. Using a random-effects model, we calculated the odds ratios and 95% confidence intervals as our measures of association.
RESULTS
A total of 5001 clinical isolates were included in 47 studies. Mutations in gyrA A90V, D94G, D94N, and D94Y were significantly associated with an increased risk of a levofloxacin (LFX)-resistant phenotype. In addition, mutations in gyrA G88C, A90V, D94G, D94H, D94N, and D94Y were significantly associated with an increased risk of a moxifloxacin (MFX)-resistant phenotype. In only one study, the majority of gene loci (n = 126, 90.65%) in BDQ-resistant isolates were observed to have unique mutations in atpE, Rv0678, mmpL5, pepQ, and Rv1979c. The most common mutations occurred at four sites in the rrl gene (g2061t, g2270c, g2270t, and g2814t) and at one site in rplC (C154R) in LZD-resistant isolates. Our meta-analysis demonstrated that there were no mutations associated with BDQ- or LZD-resistant phenotypes.
CONCLUSION
The mutations detected by rapid molecular assay were correlated with phenotypic resistance to LFX and MFX. The absence of mutation-phenotype associations for BDQ and LZD hindered the development of a rapid molecular assay.
Topics: Humans; Mycobacterium tuberculosis; Linezolid; Fluoroquinolones; Antitubercular Agents; Tuberculosis, Multidrug-Resistant; Levofloxacin; Phenotype
PubMed: 37172764
DOI: 10.1016/j.jgar.2023.05.001 -
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 -
Molecules (Basel, Switzerland) Mar 2022This research dealt with the composition, structure determination, stability, and antibiotic potency of a novel organic salt composed of levofloxacin (LF) and citric...
This research dealt with the composition, structure determination, stability, and antibiotic potency of a novel organic salt composed of levofloxacin (LF) and citric acid (CA), named levofloxacin-citrate (LC). After a stoichiometric proportion screening, the antibiotic-antioxidant reaction was conducted by slow and fast evaporation methods. A series of characterizations using thermal analysis, powder X-ray diffractometry, vibrational spectroscopy, and nuclear magnetic resonance confirmed LC formation. The new organic salt showed a distinct thermogram and diffractogram. Next, Fourier transform infrared indicated the change in -methylamine and carboxylic stretching, confirmed by H nuclear magnetic resonance spectra to elucidate the 2D structure. Finally, single-crystal diffractometry determined LC as a new salt structure three-dimensionally. The attributive improvements were demonstrated on the stability toward the humidity and lighting of LC compared to LF alone. Moreover, the antibiotic potency of LF against (Gram-positive) and (Gram-negative) enhanced ~1.5-2-fold by LC. Hereafter, LC is a potential salt antibiotic-antioxidant combination for dosage formulas development.
Topics: Anti-Bacterial Agents; Antioxidants; Citric Acid; Levofloxacin; Spectroscopy, Fourier Transform Infrared
PubMed: 35408567
DOI: 10.3390/molecules27072166 -
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 -
Antimicrobial Agents and Chemotherapy May 2014Limited data on fluoroquinolone pharmacokinetics and cardiac effects in children exist. Among 22 children receiving drug-resistant tuberculosis prophylaxis or treatment,...
Limited data on fluoroquinolone pharmacokinetics and cardiac effects in children exist. Among 22 children receiving drug-resistant tuberculosis prophylaxis or treatment, serum concentrations following oral doses of levofloxacin (15 mg/kg of body weight) and ofloxacin (20 mg/kg) were lower than those expected from existing pediatric data, possibly due to differences in the formulations (crushed tablets). Drug exposures were lower than those in adults following standard doses and below the proposed pharmacodynamic targets, likely due to more rapid elimination in children. No QT prolongation was observed.
Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; Female; Humans; Infant; Levofloxacin; Male; Ofloxacin; Prospective Studies; Tuberculosis, Multidrug-Resistant
PubMed: 24550337
DOI: 10.1128/AAC.02755-13 -
Respiratory Research May 2013Mechanical ventilation can promote lung injury by triggering a pro-inflammatory response. Macrolides may exert some immunomodulatory effects and have shown significant...
BACKGROUND
Mechanical ventilation can promote lung injury by triggering a pro-inflammatory response. Macrolides may exert some immunomodulatory effects and have shown significant benefits over other antibiotics in ventilated patients. We hypothesized that macrolides could decrease ventilator-induced lung injury.
METHODS
Adult mice were treated with vehicle, clarithromycin or levofloxacin, and randomized to receive mechanical ventilation with low (12 cmH2O, PEEP 2 cmH2O) or high (20 cmH2O, ZEEP) inspiratory pressures for 150 minutes. Histological lung injury, neutrophil infiltration, inflammatory mediators (NFκB activation, Cxcl2, IL-10) and levels of adhesion molecules (E-selectin, ICAM) and proteases (MMP-9 and MMP-2) were analyzed.
RESULTS
There were no differences among groups after low-pressure ventilation. Clarithromycin significantly decreased lung injury score and neutrophil count, compared to vehicle or levofloxacin, after high-pressure ventilation. Cxcl2 expression and MMP-2 and MMP-9 levels increased and IL-10 decreased after injurious ventilation, with no significant differences among treatment groups. Both clarithromycin and levofloxacin dampened the increase in NFκB activation observed in non-treated animals submitted to injurious ventilation. E-selectin levels increased after high pressure ventilation in vehicle- and levofloxacin-treated mice, but not in those receiving clarithromycin.
CONCLUSIONS
Clarithromycin ameliorates ventilator-induced lung injury and decreases neutrophil recruitment into the alveolar spaces. This could explain the advantages of macrolides in patients with acute lung injury and mechanical ventilation.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Clarithromycin; Inflammation Mediators; Levofloxacin; Lung; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Ventilator-Induced Lung Injury
PubMed: 23663489
DOI: 10.1186/1465-9921-14-52 -
Medical Archives (Sarajevo, Bosnia and... Apr 2021infections induce chronic gastric mucosal inflammation and peptic ulcer disease, and eradication is recommended. (Comparative Study)
Comparative Study
BACKGROUND
infections induce chronic gastric mucosal inflammation and peptic ulcer disease, and eradication is recommended.
OBJECTIVE
To investigate antibiotic resistance and eradication rates in children with gastroduodenal ulcers in Vietnam.
METHODS
We performed gastroduodenal endoscopies, cultures, and antimicrobial susceptibility testing (clarithromycin, amoxicillin, metronidazole, tetracycline, and levofloxacin) In children with gastroduodenal ulcers at Children's Hospital 2 from November 1, 2019, to June 30, 2020.
RESULTS
A total of 76 participants were studied, with an average age of 9.3 ± 2.8 years (range: 4-15 years), including 52.6% males and 47.4% females. The antibiotic resistance rates were clarithromycin, 92.1%; amoxicillin, 50%; levofloxacin, 31.6%; metronidazole, 14.5%; and tetracycline, 0%. The successful eradication rate was 44.7%. Bismuth increased the eradication rate by 3.69-fold that without bismuth (p = 0.030). The eradication rate of levofloxacin was high (100%, p = 0.038) compared with other antibiotics. The effectiveness of high-dose amoxicillin in cases with >50% amoxicillin resistance was only 32.6% (p = 0.015).
CONCLUSION
Increased antibiotic resistance among resulted in decreased eradication efficacy, which was 44.7% in this study. Drug combinations, such as levofloxacin and bismuth, can increase the eradication efficacy in children.
Topics: Adolescent; Amoxicillin; Anti-Bacterial Agents; Asian People; Child; Child, Preschool; Clarithromycin; Disease Eradication; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Helicobacter Infections; Humans; Levofloxacin; Male; Metronidazole; Microbial Sensitivity Tests; Peptic Ulcer; Tetracycline
PubMed: 34219870
DOI: 10.5455/medarh.2021.75.112-115