-
European Journal of Pharmacology Jan 2024Reperfusion therapy is currently the most effective treatment for acute ischemic stroke, but often results in secondary brain injury. Adipocyte fatty acid-binding...
Reperfusion therapy is currently the most effective treatment for acute ischemic stroke, but often results in secondary brain injury. Adipocyte fatty acid-binding protein (A-FABP, FABP4, or aP2) was shown to critically mediate cerebral ischemia/reperfusion (I/R) injury by exacerbating blood-brain barrier (BBB) disruption. However, no A-FABP inhibitors have been approved for clinical use due to safety issues. Here, we identified the therapeutic effect of levofloxacin, a widely used antibiotic displaying A-FABP inhibitory activity in vitro, on cerebral I/R injury and determined its target specificity and action mechanism in vivo. Using molecular docking and site-directed mutagenesis, we showed that levofloxacin inhibited A-FABP activity through interacting with the amino acid residue Asp76, Gln95, Arg126 of A-FABP. Accordingly, levofloxacin significantly inhibited A-FABP-induced JNK phosphorylation and expressions of proinflammatory factors and matrix metalloproteinase 9 (MMP-9) in mouse primary macrophages. In wild-type mice with transient middle cerebral artery occlusion, levofloxacin substantially mitigated BBB disruption and neuroinflammation, leading to reduced cerebral infarction, alleviated neurological outcomes, and improved survival. Mechanistically, levofloxacin decreased MMP-9 expression and activity, and thus reduced degradation of extracellular matrix and endothelial tight junction proteins. Importantly, the BBB- and neuro-protective effects of levofloxacin were abolished in A-FABP or MMP-9 knockout mice, suggesting that the therapeutic effects of levofloxacin highly depended on specific targeting of the A-FABP-MMP-9 axis. Overall, our study demonstrates that levofloxacin alleviates A-FABP-induced BBB disruption and neural tissue injury following cerebral I/R, and unveils its therapeutic potential for the treatment of ischemic stroke.
Topics: Animals; Mice; Rats; Blood-Brain Barrier; Brain Ischemia; Infarction, Middle Cerebral Artery; Ischemic Stroke; Levofloxacin; Matrix Metalloproteinase 9; Molecular Docking Simulation; Rats, Sprague-Dawley; Reperfusion; Reperfusion Injury; Fatty Acid-Binding Proteins
PubMed: 38113968
DOI: 10.1016/j.ejphar.2023.176275 -
International Journal of Molecular... Sep 2023Point mutations in the , , and genes can confer resistance to clarithromycin (CAM) and levofloxacin (LVX) by altering target sites or protein structure, thereby...
Point mutations in the , , and genes can confer resistance to clarithromycin (CAM) and levofloxacin (LVX) by altering target sites or protein structure, thereby reducing the efficacy of standard antibiotics in the treatment of infections. Considering the confirmed primary CAM and LVX resistance in infected patients from southern Croatia, we performed a molecular genetic analysis of three target genes (, and ) by PCR and sequencing, together with computational molecular docking analysis. In the CAM-resistant isolates, the mutation sites in the gene were A2142C, A2142G, and A2143G. In addition, the mutations D91G and D91N in GyrA and N481E and R484K in GyrB were associated with resistance to LVX. Molecular docking analyses revealed that mutant strains with resistance-related mutations exhibited a lower susceptibility to CAM and LVX compared with wild-type strains due to significant differences in non-covalent interactions (e.g., hydrogen bonds, ionic interactions) leading to destabilized antibiotic-protein binding, ultimately resulting in antibiotic resistance. Dual resistance to CAM and LVX was found, indicating the successful evolution of resistance to unrelated antimicrobials and thus an increased risk to human health.
Topics: Humans; Clarithromycin; Levofloxacin; Helicobacter pylori; Helicobacter Infections; RNA, Ribosomal, 23S; Molecular Docking Simulation; Croatia; Drug Resistance, Bacterial; Microbial Sensitivity Tests; Anti-Bacterial Agents; Biopsy
PubMed: 37834008
DOI: 10.3390/ijms241914560 -
Zhonghua Yi Xue Za Zhi Jul 2023To explore the rate of Helicobacter pylori (Hp) resistance to levofloxacin and clarithromycin and the common mutation patterns of resistance genes in Ningxia, and to...
To explore the rate of Helicobacter pylori (Hp) resistance to levofloxacin and clarithromycin and the common mutation patterns of resistance genes in Ningxia, and to assess the concordance between phenotypic resistance and genotypic resistance. Cross-sectional study. Patients diagnosed with Hp infection in 14 hospitals in Ningxia region from February 2020 to May 2022 were retrospectively selected. Hp strains were isolated from gastric biopsy specimens of Hp-infected patients and subjected to phenotypic drug sensitivity testing and detection of resistance genes to analyze the rate of Hp resistance to levofloxacin and clarithromycin and the common mutation patterns of resistance genes in Ningxia region; and the concordance rate and Kappa concordance test were used to assess the concordance between phenotypic resistance and genotypic resistance. A total of 1 942 Hp strains were isolated and cultured, and among the infections, 1 069 cases (55.0%) were male and 873 cases (45.0%) were female, aged (50.0±12.5) years (15-86 years). The rates of Hp resistance to levofloxacin and clarithromycin in Ningxia were 42.1% (818/1 942) and 40.1% (779/1 942), respectively, and the rate of dual resistance to both was 22.8% (443/1 942). The rate of resistance to levofloxacin and clarithromycin of Hp strains from female patients was higher than in male patients (levofloxacin: 50.4%(440/873) vs 35.4%(378/1 069); clarithromycin: 44.4%(388/873) vs 36.6%(391/1 069), both <0.001). Among the GyrA gene mutations associated with levofloxacin resistance, the differences in mutation rate of amino acid at positions 87 and 91 were statistically significant in both drug-resistant and sensitive strains(both <0.001), except for Asn87Thr. Hp strains were statistically significant for levofloxacin (Kappa=0.834, <0.001) and clarithromycin (Kappa=0.829, <0.001) had good concordance in resistance at the phenotypic and genotypic levels. The resistance of Hp to levofloxacin and clarithromycin in Ningxia region is severe, and there is good consistency between genotypic and phenotypic resistance.
Topics: Female; Humans; Male; Anti-Bacterial Agents; Clarithromycin; Cross-Sectional Studies; Drug Resistance, Bacterial; Helicobacter Infections; Helicobacter pylori; Levofloxacin; Microbial Sensitivity Tests; Retrospective Studies; Adolescent; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over
PubMed: 37482728
DOI: 10.3760/cma.j.cn112137-20230214-00206 -
Cancer Epidemiology May 2024Acute myeloid leukemia patients are at high risk for infections, which contribute to increased mortality rates of up to 70%. The use of antimicrobial prophylaxis has...
INTRODUCTION
Acute myeloid leukemia patients are at high risk for infections, which contribute to increased mortality rates of up to 70%. The use of antimicrobial prophylaxis has been shown to significantly lower rates of infection. Therefore, this retrospective study aimed to evaluate the effect of two agents that showed effective results in the literature, levofloxacin and fluconazole, as prophylaxis strategies in AML patients.
METHODOLOGY
A total of 85 AML patients' medical records treated with a 7+3 induction chemotherapy protocol in the Cancer Hospital of Uberlândia from 2017 to 2021 were screened and their data was collected. Within these patients, groups for analysis were created based on whether the acting physician included an antibacterial or antifungal prophylaxis protocol during induction. Contingency tables with χ² and odds ratio tests were realized to verify associations between prophylaxis and infection. Additionally, Kaplan-Meier curves with Cox regression were developed to analyze survival.
RESULTS
The use of prophylaxis with either fluconazole or levofloxacin did not lower rates of infection, as those who with prophylaxis did not demonstrate significant differences when compared to those without (20.3-29.7%, and 12.3-23.3%, respectively). Patients who suffered a bacterial infection during induction were shown to have lower overall survival, with a similar trend seen in fungal infections.
CONCLUSION
Bacterial and fungal infections were associated with higher rates of induction mortality and lower overall survival, and prophylaxis using fluconazole and levofloxacin did not present any significant difference in preventing these infections in this study, contrasting results found in the literature. The individuality of each treatment center should be taken into consideration and future studies should be realized to better determine the most effective methods and agents for prophylaxis.
PubMed: 38815484
DOI: 10.1016/j.canep.2024.102593 -
The Science of the Total Environment Jul 2023In recent times, the need to make water safer and cleaner through the elimination of recalcitrant pharmaceutical residues has been the aim of many studies.... (Review)
Review
In recent times, the need to make water safer and cleaner through the elimination of recalcitrant pharmaceutical residues has been the aim of many studies. Fluoroquinolone antibiotics such as ciprofloxacin, norfloxacin, enrofloxacin, and levofloxacin are among the commonly detected pharmaceuticals in wastewater. Since the presence of these pharmaceuticals in water bodies poses serious risks to living organisms, it is vital to adopt effective wastewater treatment techniques for their complete removal. Electrochemical technologies such as photoelectrocatalysis, electro-Fenton, electrocoagulation, and electrochemical oxidation have been established as techniques capable of the complete removal of organics including pharmaceuticals from wastewater. Hence, this review presents discussions on the recent progress (literature within 2018-2022) in the applications of common electrochemical processes for the degradation of fluoroquinolone antibiotics from wastewater. The fundamentals of these processes are highlighted while the results obtained using the processes are critically discussed. Furthermore, the inherent advantages and limitations of these processes in the mineralization of fluoroquinolone antibiotics are clearly emphasized. Additionally, appropriate recommendations are made toward improving electrochemical technologies for the complete removal of these pharmaceuticals with minimal energy consumption. Therefore, this review will serve as a bedrock for future researchers concerned with wastewater treatments to make informed decisions in the selection of suitable electrochemical techniques for the removal of pharmaceuticals from wastewater.
Topics: Wastewater; Fluoroquinolones; Oxidation-Reduction; Water; Water Purification; Anti-Bacterial Agents; Pharmaceutical Preparations; Water Pollutants, Chemical; Hydrogen Peroxide
PubMed: 37068672
DOI: 10.1016/j.scitotenv.2023.163522 -
MBio Oct 2023Concerns over resistance and safety have been identified in the current treatment regimen for complicated urinary tract infections. Fosfomycin is a drug that is...
Concerns over resistance and safety have been identified in the current treatment regimen for complicated urinary tract infections. Fosfomycin is a drug that is routinely used for the treatment of uncomplicated cystitis. This study shows that fosfomycin could be an oral alternative as step-down therapy for the treatment of complicated urinary tract infections, with a clinical cure rate comparable to levofloxacin but a lower microbiological success rate 3 weeks from start of antibiotics.
Topics: Humans; Fosfomycin; Levofloxacin; Urinary Tract Infections; Anti-Bacterial Agents; Cystitis
PubMed: 37698412
DOI: 10.1128/mbio.01677-23 -
Pediatrics Sep 2023A 20-year-old female with depression presented to the emergency department with chronic weight loss, weakness, fatigue, hair loss, rash, palpitations, and 2 weeks of...
A 20-year-old female with depression presented to the emergency department with chronic weight loss, weakness, fatigue, hair loss, rash, palpitations, and 2 weeks of cough. Initial history revealed that she had disordered eating habits with dietary restriction, experienced a 50-pound unintentional weight loss over 2 years despite reported adherence to nutritional supplementation, and had a normal gastrointestinal workup. On examination, she was markedly cachectic with a BMI of 10.3kg/m2 and hypotensive (84/69 mmHg). Her cardiovascular examination revealed a regular rate and rhythm without a murmur. Her breath sounds were diminished in the upper lobes bilaterally. A skin examination showed diffuse hair loss, skin breakdown, and peeling with a tender, erythematous, papular rash over the bilateral ankles, and nonpitting edema. A chest radiograph showed a right upper lobe opacity and lucent lesions in the left proximal humerus. A focused assessment with sonography for trauma examination showed a large pericardial effusion. Chest computed tomography revealed a right upper lobe opacity with an associated cavitation. Though she began improving with rifampin, isoniazid, pyrazinamide, ethambutol, levofloxacin, azithromycin, and nutritional rehabilitation, her clinical course was complicated by an acute worsening nearly 1 month into her hospitalization with persistent high fevers, worsening cough, development of a murmur, and worsening consolidation on chest computed tomography. Adolescent Medicine, Infectious Diseases, Gastroenterology, and Allergy and Immunology were consulted to guide the diagnostic evaluation and management of this patient's complex clinical course.
Topics: Humans; Female; Adolescent; Young Adult; Adult; Cough; Malnutrition; Alopecia Areata; Weight Loss; Exanthema; Disease Progression
PubMed: 37525975
DOI: 10.1542/peds.2022-060983 -
Scientific Reports Feb 2024The spread of fluoroquinolone (FQ) resistance in Acinetobacter baumannii represents a critical health threat. This study aims to overcome FQ resistance in A. baumannii...
The spread of fluoroquinolone (FQ) resistance in Acinetobacter baumannii represents a critical health threat. This study aims to overcome FQ resistance in A. baumannii via the formulation of polymeric nanoFQs. Herein, 80 A. baumannii isolates were obtained from diverse clinical sources. All A. baumannii isolates showed high resistance to most of the investigated antimicrobials, including ciprofloxacin (CIP) and levofloxacin (LEV) (97.5%). FQ resistance-determining regions of the gyrA and parC genes were the most predominant resistant mechanism, harbored by 69 (86.3%) and 75 (93.8%) of the isolates, respectively. Additionally, plasmid-mediated quinolone resistance genes aac(6')-Ib and qnrS were detected in 61 (76.3%) and 2 (2.5%) of the 80 isolates, respectively. The CIP- and LEV-loaded poly ε-caprolactone (PCL) nanoparticles, F and F, respectively, showed a 1.5-6- and 6-12-fold decrease in the MIC, respectively, against the tested isolates. Interestingly, the time kill assay demonstrated that MICs of F and F completely killed A. baumannii isolates after 5-6 h of treatment. Furthermore, F and F were found to be efficient in overcoming the FQ resistance mediated by the efflux pumps in A. baumannii isolates as revealed by decreasing the MIC four-fold lower than that of free CIP and LEV, respectively. Moreover, F and F at 1/2 and 1/4 MIC significantly decreased biofilm formation by 47-93% and 69-91%, respectively. These findings suggest that polymeric nanoparticles can restore the effectiveness of FQs and represent a paradigm shift in the fight against A. baumannii isolates.
Topics: Ciprofloxacin; Fluoroquinolones; Levofloxacin; Acinetobacter baumannii; Anti-Bacterial Agents; Microbial Sensitivity Tests; Biofilms; Drug Resistance, Bacterial; DNA Gyrase
PubMed: 38326515
DOI: 10.1038/s41598-024-53441-1 -
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 -
Auris, Nasus, Larynx Aug 2023The present study aimed to evaluate the efficacy and safety of 1.5% levofloxacin (LVFX) otic solution for the treatment of patients with otitis media. (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of 1.5% levofloxacin otic solution for the treatment of otitis media in a multicenter, randomized, double-blind, parallel-group, placebo-controlled, phase III study.
OBJECTIVE
The present study aimed to evaluate the efficacy and safety of 1.5% levofloxacin (LVFX) otic solution for the treatment of patients with otitis media.
METHODS
This multicenter, randomized, double-blind, parallel-group, placebo-controlled phase 3 trial was conducted at 34 institutions in Japan. A total of 202 patients with chronic suppurative otitis media (CSOM) or acute otitis media (AOM) were randomized into either the LVFX group or placebo group. A total of 6-10 drops of 1.5% otic solution of LVFX or its matching placebo were administered in the diseased ear twice daily, in the morning and evening for up to 10 days. Images corresponding to three clinical findings-purulent otorrhea, hyperemia (redness), and granulation tissue formation in the middle ear and tympanic membrane-for each diseased ear were evaluated using digital endoscopy by a blinded central independent review committee (BICRC) at each visit after treatment administration.
RESULTS
In total, the data of 201 participants (LVFX group, 99; placebo group, 102) were analyzed. The proportion of patients with disappearance (improvement rate) of all three clinical findings at the end of treatment or discontinuation by the BICRC was 46.5% (46/99) in the LVFX group and 23.5% (24/102) in the placebo group, and the difference (95% confidence interval) between the groups was 22.0% (8.7, 34.2), with a significantly higher improvement rate in the LVFX group than in the placebo group (p = 0.001; Cochran-Mantel-Haenszel test), demonstrating the efficacy of LVFX. The bacterial eradication rates were 93.9% (77/82) and 12.5% (11/88) in the LVFX and placebo groups, respectively, and the rate was significantly higher in the LVFX group than in the placebo group (p < 0.001). Treatment-related adverse events (AEs) occurred in 5.1% (5/99) and 7.8% (8/102) of the patients in the LVFX and placebo groups, respectively, and no significant difference was noted in incidence rate between the groups.
CONCLUSION
The clinical efficacy of 1.5% LVFX otic solution for CSOM and AOM was demonstrated by the resolution of inflammation in the middle ear and tympanic membrane as well as through the high bacterial eradication rate observed. No deaths or serious treatment-related AEs were observed. The study provided confirmation that 1.5% LVFX otic solution is a safe, well-tolerated, and effective treatment for CSOM and AOM.
Topics: Humans; Anti-Bacterial Agents; Levofloxacin; Otitis Media; Otitis Media, Suppurative; Ear, Middle
PubMed: 36599786
DOI: 10.1016/j.anl.2022.12.013