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Colloids and Surfaces. B, Biointerfaces Sep 2020The objective of this study is to investigate the feasibility of delivery of novel levofloxacin/ doxycycline (LEVO/DOX) combination to the brain by intranasal route to...
The objective of this study is to investigate the feasibility of delivery of novel levofloxacin/ doxycycline (LEVO/DOX) combination to the brain by intranasal route to achieve a significant local concentration in the brain and a direct nose-to-brain pathway. Solid lipid nanoparticles (SLN) were selected as a drug carrier and employed Box-Behnken design for optimizing LEVO/DOX-SLN to achieve minimum particle size and maximum apparent entrapment efficiency (EE). SLNs were prepared by hot emulsification and characterized. In vitro release of optimized formulations showed prolonged drug release from the optimized formulation. The results of pharmacokinetic study of the optimized SLN-HPMC gel in plasma and brain revealed significant increase in the brain peak concentration (420, 315 ng/g), the AUC min (57130 and 48693.13 ng. min/g) in comparison to intranasal LEVO/DOX free solution with the values of (160, 120) ng/g, (36850, 27637.5 ng⋅min/g) for LEVO and DOX, respectively. The optimized LD-SLN-HPMC gel gave a drug-targeting efficiency (DTE %) of 149.815 and 161.969 for LEVO and DOX, respectively, in comparison to the intravenous route. Moreover, the optimized formulation had a direct transport percentage (DTP %) of 33.285 and 40.236 for LEVO and DOX, respectively, which indicates a significant contribution of direct nose-to-brain pathway in brain drug delivery.
Topics: Animals; Brain; Camelus; Doxycycline; Drug Compounding; Drug Delivery Systems; Levofloxacin; Lipids; Nanoparticles; Nasal Mucosa; Particle Size; Surface Properties
PubMed: 32408259
DOI: 10.1016/j.colsurfb.2020.111076 -
Current Drug Delivery 2021Levofloxacin has been recommended by the WHO for the treatment of pulmonary tuberculosis and inhalable delivery of levofloxacin can be advantageous over conventional...
BACKGROUND
Levofloxacin has been recommended by the WHO for the treatment of pulmonary tuberculosis and inhalable delivery of levofloxacin can be advantageous over conventional delivery.
OBJECTIVE
This study aimed to develop and optimize inhalable levofloxacin Loaded Chitosan Nanoparticles (LCN). The objective was to achieve the mean particle size of LCN less than 300nm, sustain the drug release up to 24 h, and achieve MMAD of LCN of less than 5μm.
METHODS
LCN were prepared by ionic gelation of chitosan with sodium tripolyphosphate (STPP) and subsequent lyophilization. A Plackett Burman screening design, 32 full factorial design, and overlay plots were sequentially employed to optimize the formulation. The mean particle size, % entrapment efficiency, in vitro drug release, and minimum inhibitory concentration were all evaluated.
RESULTS
The Pareto chart from the Placket Burman screening design revealed that the concentrations of chitosan and STPP was found to be significant (p < 0.05). Further analysis by 32 full factorial design revealed that F-ratio for each model generated was found to be greater than the theoretical value (p < 0.05), confirming the significance of each model.
CONCLUSION
The optimized formulation showed a mean particle size of 171.5 nm, sustained the drug release up to 24 h in simulated lung fluid, and revealed MMAD of 3.18 μm, which can confirm delivery of the drug to the deep lung region. However, further in vivo studies are required to design a suitable dosage regimen and establish the fate of nanoparticles for safe and efficacious delivery of the drug.
Topics: Chitosan; Drug Carriers; Drug Liberation; Humans; Levofloxacin; Nanoparticles; Particle Size; Tuberculosis
PubMed: 33155907
DOI: 10.2174/1567201817999201103194626 -
PloS One 2023Minimizing antibiotic resistance is a key motivation strategy in designing and developing new and combination therapy. In this study, a combination of the antibiotics...
Minimizing antibiotic resistance is a key motivation strategy in designing and developing new and combination therapy. In this study, a combination of the antibiotics (cefixime, levofloxacin and gentamicin) with Lysobacter enzymogenes (L. enzymogenes) bioactive proteases present in the cell- free supernatant (CFS) have been investigated against the Gram-positive methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA) and the Gram-negative Escherichia coli (E. coli O157:H7). Results indicated that L. enzymogenes CFS had maximum proteolytic activity after 11 days of incubation and higher growth inhibitory properties against MSSA and MRSA compared to E. coli (O157:H7). The combination of L. enzymogenes CFS with cefixime, gentamicin and levofloxacin at sub-MIC levels, has potentiated their bacterial inhibition capacity. Interestingly, combining cefixime with L. enzymogenes CFS restored its antibacterial activity against MRSA. The MTT assay revealed that L. enzymogenes CFS has no significant reduction in human normal skin fibroblast (CCD-1064SK) cell viability. In conclusion, L. enzymogenes bioactive proteases are natural potentiators for antimicrobials with different bacterial targets including cefixime, gentamicin and levofloxacin representing the beginning of a modern and efficient era in the battle against multidrug-resistant pathogens.
Topics: Humans; Methicillin-Resistant Staphylococcus aureus; Levofloxacin; Peptide Hydrolases; Cefixime; Escherichia coli; Virulence; Anti-Bacterial Agents; Methicillin; Staphylococcus aureus; Gentamicins; Microbial Sensitivity Tests
PubMed: 36893145
DOI: 10.1371/journal.pone.0282705 -
Alternative Therapies in Health and... Mar 2023Helicobacter pylori (H. pylori) infection has become a global public-health problem, and people living in low-resource settings may be more likely to be infected because... (Observational Study)
Observational Study
CONTEXT
Helicobacter pylori (H. pylori) infection has become a global public-health problem, and people living in low-resource settings may be more likely to be infected because of unhealthy life habits, poor sanitary conditions, and overuse of antibiotics without a prescription.
OBJECTIVES
The study intended to assess the susceptibility of H. pylori to nine antibiotics commonly prescribed for eradication of H. pylori infections among minority people in Yunnan province, China, to provide updated recommendations for H. pylori eradication therapy among adults.
DESIGN
The research team designed a cross-sectional observational study.
SETTING
The study took place in the First Affiliated Hospital of Kunming Medical University, Yunnan Province.
PARTICIPANTS
Participants were 276 people in the Mosuo or Pumi minority population who had lived on the shores of Lugu Lake in Ninglang county, Yunnan province in China for generations.
OUTCOME MEASURES
After completing a questionnaire, all participants underwent 13C-urea breath test, and those with a positive result participated in an antimicrobial-susceptibility test. For each H. pylori isolate, the research team tested the minimum inhibitory concentrations (MICs) of nine commonly used antibiotics: amoxicillin, azithromycin, levofloxacin, clarithromycin, metronidazole, tetracycline, rifampicin, gentamicin, and moxifloxacin.
RESULTS
The research team confirmed that 276 participants were resistant to at least one antibiotic. The resistances rates for moxifloxacin, metronidazole, and levofloxacin were the highest, while that for amoxicillin was the lowest, and no isolates were resistant to gentamicin. Double resistance (33.20%) had the highest proportion of all multiple-resistance patterns. Moreover, the metronidazole resistance rate was higher in females than in males and in nonsmokers than in smokers, and rifampicin resistance was higher in nondrinkers than in drinkers, suggesting that smoking and drinking might be protective against metronidazole and rifampicin resistance.
CONCLUSIONS
Most of the Mosuo and Pumi people in Yunnan were resistant to antibiotics. Moxifloxacin, metronidazole, and levofloxacin should no longer be the main medicines for H. pylori, whereas amoxicillin and gentamicin should be recommended to be the first-line clinical therapy for H. pylori eradication regimens.
Topics: Adult; Male; Female; Humans; Anti-Bacterial Agents; Metronidazole; Helicobacter pylori; Levofloxacin; Moxifloxacin; Rifampin; Cross-Sectional Studies; East Asian People; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; China; Helicobacter Infections; Amoxicillin; Gentamicins
PubMed: 36480681
DOI: No ID Found -
Future Microbiology Dec 2022Drug repurposing is a viable approach to expediting the tedious conventional drug discovery process, given rapidly increasing bacterial resistance. In this context, we...
Drug repurposing is a viable approach to expediting the tedious conventional drug discovery process, given rapidly increasing bacterial resistance. In this context, we have repurposed pyrvinium pamoate (PP) for its antibacterial activity against . US FDA-approved non-antibiotics were screened against clinically relevant bacterial pathogens to identify antibacterials. The hits were further evaluated utilizing a variety of preclinical parameters, following which efficacy was estimated in isolation and in combination in a murine neutropenic thigh infection model. The screening identified PP exhibiting potent activity against along with concentration-dependent killing. PP also showed a post-antibiotic effect of >22 h and significantly eradicated preformed biofilms and intracellular at 1× and 5× MIC, respectively. PP synergized with levofloxacin both and , resulting in ∼1.5 and ∼0.5 log CFU/g reduction against susceptible and resistant infections, respectively, as compared with untreated control. Pyrvinium potentiates levofloxacin against levofloxacin-resistant
Topics: Mice; Animals; Levofloxacin; Staphylococcus aureus; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Anti-Bacterial Agents
PubMed: 36314364
DOI: 10.2217/fmb-2022-0159 -
Current Microbiology May 2023Myroides spp. are rare opportunistic pathogens, but they can be life-threatening because of their multidrug-resistant drug properties and their potential to cause...
Antibacterial and Antibiofilm Activities of Ceragenins Alone and in Combination with Levofloxacin Against Multidrug Resistant Myroides spp. Clinical Isolates from Patients with Urinary Tract Infections.
Myroides spp. are rare opportunistic pathogens, but they can be life-threatening because of their multidrug-resistant drug properties and their potential to cause outbreaks, especially in immunosuppressed patients. In this study, 33 isolates isolated from intensive care patients with urinary tract infections were examined for drug susceptibility. All isolates except three proved to be resistant to the tested conventional antibiotics. The effects of ceragenins, a class of compounds developed to mimic endogenous antimicrobial peptides, were evaluated against these organisms. The MIC values of nine ceragenins were determined, and the most effective ceragenins were CSA-131 and CSA-138. Three isolates that were susceptible to levofloxacin and two isolates resistant to all antibiotics underwent 16 s rDNA analysis, and whereas resistant isolates were identified as M. odoratus, susceptible isolates were identified as M. odoratimimus. CSA-131 and CSA-138 showed rapid antimicrobial effects observed in time-kill analyses. Combinations of ceragenins and levofloxacin caused a significant increase in antimicrobial and antibiofilm activities against M. odoratimimus isolates. In this study, Myroides spp. were found to be multidrug-resistant and have biofilm forming capacity, and ceragenins CSA-131 and CSA-138 were found to be especially effective on both planktonic and biofilm forms of Myroides spp.
Topics: Humans; Levofloxacin; Microbial Sensitivity Tests; Anti-Bacterial Agents; Anti-Infective Agents; Urinary Tract Infections; Flavobacteriaceae; Biofilms
PubMed: 37191731
DOI: 10.1007/s00284-023-03321-0 -
Scientific Reports Aug 2023Drug-induced liver injury induced by already approved substances is a major threat to human patients, potentially resulting in drug withdrawal and substantial loss of...
Drug-induced liver injury induced by already approved substances is a major threat to human patients, potentially resulting in drug withdrawal and substantial loss of financial resources in the pharmaceutical industry. Trovafloxacin, a broad-spectrum fluoroquinolone, was found to have unexpected side effects of severe hepatotoxicity, which was not detected by preclinical testing. To address the limitations of current drug testing strategies mainly involving 2D cell cultures and animal testing, a three-dimensional microphysiological model of the human liver containing expandable human liver sinusoidal endothelial cells, monocyte-derived macrophages and differentiated HepaRG cells was utilized to investigate the toxicity of trovafloxacin and compared it to the structurally-related non-toxic drug levofloxacin. In the model, trovafloxacin elicited vascular and hepatocellular toxicity associated with pro-inflammatory cytokine release already at clinically relevant concentrations, whereas levofloxacin did not provoke tissue injury. Similar to in vivo, cytokine secretion was dependent on a multicellular immune response, highlighting the potential of the complex microphysiological liver model for reliably detecting drug-related cytotoxicity in preclinical testing. Moreover, hepatic glutathione depletion and mitochondrial ROS formation were elucidated as intrinsic toxicity mechanisms contributing to trovafloxacin toxicity.
Topics: Animals; Humans; Levofloxacin; Endothelial Cells; Hepatitis; Fluoroquinolones; Drug-Related Side Effects and Adverse Reactions; Cytokines
PubMed: 37587168
DOI: 10.1038/s41598-023-40004-z -
Antimicrobial Agents and Chemotherapy May 2021The Clinical and Laboratory Standards Institute (CLSI) revised the fluoroquinolone MIC breakpoints for in 2019, based on pharmacokinetic/pharmacodynamic analyses....
The Clinical and Laboratory Standards Institute (CLSI) revised the fluoroquinolone MIC breakpoints for in 2019, based on pharmacokinetic/pharmacodynamic analyses. However, clinical evidence supporting these breakpoint revisions is limited. A retrospective study was conducted at 3 hospitals in Taiwan between January 2017 and March 2019. Patients treated with levofloxacin for bacteremia caused by members of the with high MICs (1 or 2 μg/ml; levofloxacin susceptible by pre-2019 CLSI breakpoints) were compared with those with low-MIC bacteremia (≤0.5 μg/ml; levofloxacin susceptible by 2019 CLSI breakpoints) to assess therapeutic effectiveness by multivariable logistic regression. The primary outcome was 30-day mortality, and the secondary outcome was the emergence of levofloxacin-resistant isolates within 90 days after levofloxacin initiation. A total of 308 patients were eligible for the study. Kaplan-Meier analysis showed that patients infected with high-MIC isolates ( = 63) had a significantly lower survival rate than those infected with low-MIC isolates ( = 245) ( = 0.001). Multivariable logistic regression revealed that high levofloxacin MIC was a predictor of 30-day mortality (odds ratio [OR], 6.05; 95% confidence interval [CI], 1.51 to 24.18; = 0.011). We consistently found similar results in a propensity score-matched cohort (OR, 5.38; 95% CI, 1.06 to 27.39; = 0.043). The emergence of levofloxacin-resistant isolates was more common in the high-MIC group than the low-MIC group (25.0% versus 7.5%; = 0.065). An estimated area under the concentration-time curve/MIC ratio of ≥87 was significantly associated with better survival ( = 0.002). In conclusion, patients infected with isolates with levofloxacin MICs within the pre-2019 CLSI susceptible range of 1 or 2 μg/ml exhibited higher mortality than those infected with isolates with MICs of ≤0.5 μg/ml.
Topics: Anti-Bacterial Agents; Bacteremia; Humans; Laboratories; Levofloxacin; Microbial Sensitivity Tests; Retrospective Studies; Taiwan
PubMed: 33782006
DOI: 10.1128/AAC.00074-21 -
Scientific Reports May 2022Although levofloxacin has been used for the last 25 years, there are limited pharmacokinetic data to guide levofloxacin dosing in adult patients. This study aimed to...
Although levofloxacin has been used for the last 25 years, there are limited pharmacokinetic data to guide levofloxacin dosing in adult patients. This study aimed to develop a population pharmacokinetic model of levofloxacin for adult hospitalized patients and define dosing regimens that attain pharmacokinetic/pharmacodynamic target associated with maximum effectiveness. Blood samples were drawn from 26 patients during one dosing interval. Population pharmacokinetic modelling and dosign simulations were performed using Pmetrics®. Pathogen minimum inhibition concentration (MIC) distribution data from the European Committee on Antimicrobial Susceptibility Testing database was used to analyse fractional target attainment (FTA). A two-compartment model adequately described the data. The final model included estimated glomerular filtration rate (eGFR) to describe clearance. The population estimate for clearance was 1.12 L/h, while the volume of distribution in the central compartment and peripheral compartments were 27.6 L and 28.2 L, respectively. Our simulation demonstrated that an area under free concentration-time curve to MIC ≥ 80 was hardly achieved for pathogens with MIC ≥ 1 mg/L. Low FTA against Pseudomonas aeruginosa and Streptococcus pneumoniae were observed for patients with higher eGFR (≥ 80 mL/min/1.73m). A daily levofloxacin dose of 1000 mg is suggested to maximise the likelihood of efficacy for adult patients.
Topics: Administration, Intravenous; Adult; Computer Simulation; Databases, Factual; Humans; Kinetics; Levofloxacin
PubMed: 35624222
DOI: 10.1038/s41598-022-12627-1 -
International Journal of Infectious... Sep 2022To evaluate the pharmacokinetic parameters of the 2020 World Health Organization (WHO)-recommended pediatric dosage of levofloxacin and the higher-than-WHO dosage.
OBJECTIVES
To evaluate the pharmacokinetic parameters of the 2020 World Health Organization (WHO)-recommended pediatric dosage of levofloxacin and the higher-than-WHO dosage.
METHODS
Children aged 1-15 years with tuberculosis who received levofloxacin-based treatment for at least 7 days were enrolled. First, five children were enrolled to receive the WHO-recommended dosage (15-20 mg/kg/day), then an additional five children received a dosage higher than the WHO-recommended dosage (20-30 mg/kg/day). Blood samples were collected at predose and postdose 1, 2, 4, 6, 8, and 12 hours. A target of the ratio of the free area under the concentration-time curve to minimum inhibitory concentration (fAUC/MIC) was 100.
RESULTS
The median (interquartile range) age was 9.6 (4.9-10.5) and 12.0 (10.1-12.3) years in the WHO dosage and higher-than-WHO dosage groups, respectively. The median (interquartile range) duration of antituberculosis treatment was 24 (8-24) weeks. The geometric mean (95% confidence interval) of fAUC/MIC was 60.4 (43.5-84.0) and 103.2 (70.1-151.8) in the WHO and higher-than-WHO dosage groups, respectively. There was no adverse event of QT prolongation or any other grade 3 or 4 adverse events.
CONCLUSION
Levofloxacin at a higher dose of 20-30 mg/kg/day could achieve the fAUC/MIC target in children.
Topics: Antitubercular Agents; Child; Humans; Levofloxacin; Pilot Projects; Tuberculosis; World Health Organization
PubMed: 35842213
DOI: 10.1016/j.ijid.2022.07.029