Spider chart, greenness and whiteness assessment of experimentally designed multivariate models for simultaneous determination of three drugs used as a combinatory antibiotic regimen in critical care units: Comparative study.

In this study, five earth-friendly spectrophotometric methods using multivariate techniques were developed to analyze levofloxacin, linezolid, and meropenem, which are utilized in critical care units as combination therapies. These techniques were used to determine the mentioned medications in laboratory-prepared mixtures, pharmaceutical products and spiked human plasma that had not been separated before handling. These methods were named classical least squares (CLS), principal component regression (PCR), partial least squares (PLS), genetic algorithm partial least squares (GA-PLS), and artificial neural network (ANN). The methods used a five-level, three-factor experimental design to make different concentrations of the antibiotics mentioned (based on how much of them are found in the plasma of critical care patients and their linearity ranges). The approaches used for levofloxacin, linezolid, and meropenem were in the ranges of 3-15, 8-20, and 5-25 µg/mL, respectively. Several analytical tools were used to test the proposed methods' performance. These included the root mean square error of prediction, the root mean square error of cross-validation, percentage recoveries, standard deviations, and correlation coefficients. The outcome was highly satisfactory. The study found that the root mean square errors of prediction for levofloxacin were 0.090, 0.079, 0.065, 0.027, and 0.001 for the CLS, PCR, PLS, GA-PLS, and ANN models, respectively. The corresponding values for linezolid were 0.127, 0.122, 0.108, 0.05, and 0.114, respectively. For meropenem, the values were 0.230, 0.222, 0.179, 0.097, and 0.099 for the same models, respectively. These results indicate that the developed models were highly accurate and precise. This study compared the efficiency of artificial neural networks and classical chemometric models in enhancing spectral data selectivity for quickly identifying three antimicrobials. The results from these five models were subjected to statistical analysis and compared with each other and with the previously published ones. Finally, the whiteness of the methods was assessed by the recently published white analytical chemistry (WAC) RGB 12, and the greenness of the proposed methods was assessed using AGREE, GAPI, NEMI, Raynie and Driver, and eco-scale, which showed that the suggested approaches had the least negative environmental impact. Furthermore, to demonstrate solvent sustainability, a greenness index using a spider chart methodology was employed.

[Contamination Characteristics and Ecological Risk Assessment of Pharmaceuticals and Personal Care Products in Drains Flowing into the Yellow River of Ningxia].

Pharmaceuticals and personal care products (PPCPs) are a group of emerging contaminants causing detrimental effects on aquatic living organisms even at low doses. To investigate the contamination characteristics and ecological risks of PPCPs in drains flowing into the Yellow River of Ningxia, 21 PPCPs were detected and analyzed using solid phase extraction and ultra-high performance liquid chromatography-mass spectrometry in this study. All 21 targeted compounds were detected in the drains, with total concentrations ranging from 47.52 to 1 700.96 ng·L-1. Ciprofloxacin, acetaminophen, benzophenone-3, and diethyltoluamide were the more commonly detected compounds, with detection frequencies exceeding 80%. The five highest-concentration PPCPs were acetaminophen, diethyltoluamide, caffeine, benzophenone-3, and levofloxacin, with the maximum concentrations of 597.21, 563.23, 559.00, 477.28, and 473.07 ng·L-1, respectively. Spatial analysis showed that the pollution levels of PPCPs in the drains of the four cities were different, with average concentrations of ∑PPCPs in the order of Yinchuan>Shizuishan>Wuzhong>Zhongwei. The total concentration of PPCPs before flowing into the Yellow River ranged from 124.82 to 1 046.61 ng·L-1. Source analysis showed that livestock and poultry breeding wastewater was the primary source for sulfadiazine and oxytetracycline, whereas medical wastewater was the primary source for levofloxacin and ciprofloxacin. The primary sources of triclocarban and triclosan were domestic sewage and industrial wastewater, whereas the primary source of caffeine and diethyltoluamide was domestic sewage. The pollution of diciofenac, cimetidine, triclocarban, and triclosan in the drains was positively correlated with the regional population and economic development level. The ecological risk assessment indicated that levofloxacin, diclofenac, gemfibrozil, benzophenone-3, and triclocarban posed high risks to aquatic organisms in drains flowing into the Yellow River. It is worthwhile to consider the mixture risk of the PPCPs that exhibited high risk at most sampling sites.

Fabrication of levofloxacin-loaded porcine acellular dermal matrix hydrogel and functional assessment in urinary tract infection.

Bacterial cystitis, a commonly occurring urinary tract infection (UTI), is renowned for its extensive prevalence and tendency to recur. Despite the extensive utilization of levofloxacin as a conventional therapeutic approach for bacterial cystitis, its effectiveness is impeded by adverse toxic effects, drug resistance concerns, and its influence on the gut microbiota. This study introduces Lev@PADM, a hydrogel with antibacterial properties that demonstrates efficacy in the treatment of bacterial cystitis. Lev@PADM is produced by combining levofloxacin with decellularized porcine acellular dermal matrix hydrogel and exhibits remarkable biocompatibility. Lev@PADM demonstrates excellent stability as a hydrogel at body temperature, enabling direct administration to the site of infection through intravesical injection. This localized delivery route circumvents the systemic circulation of levofloxacin, resulting in a swift and substantial elevation of the antimicrobial agent's concentration specifically at the site of infection. The in vivo experimental findings provide evidence that Lev@PADM effectively prolongs the duration of levofloxacin's action, impedes the retention and invasion of E.coli in the urinary tract, diminishes the infiltration of innate immune cells into infected tissues, and simultaneously preserves the composition of the intestinal microbiota. These results indicate that, in comparison to the exclusive administration of levofloxacin, Lev@PADM offers notable benefits in terms of preserving the integrity of the bladder epithelial barrier and suppressing the recurrence of urinary tract infections.

Population pharmacokinetics and dose optimization of levofloxacin in elderly patients with pneumonia.

AIMS: Levofloxacin is a quinolone antibiotic with a broad antibacterial spectrum. It is frequently used in elderly patients with pneumonia. The pharmacokinetic profile of elderly patients changes with age, but data on the pharmacokinetics of levofloxacin in these patients are limited. The aim of this study was to establish a population pharmacokinetic model of levofloxacin in elderly patients with pneumonia and to optimize individualized dosing regimens based on this newly developed model. METHODS: This is a prospective, open-label pharmacokinetic study in elderly patients with pneumonia. Blood samples were collected using an opportunistic approach. The plasma concentrations of levofloxacin were determined by high-performance liquid chromatography. A population pharmacokinetic model was established using nonlinear mixed-effect model software. Monte Carlo simulations were used for dose simulation and dose optimization. RESULTS: Data from 51 elderly patients with pneumonia were used for the population pharmacokinetic analysis. A one-compartment model with first-order elimination was most suitable for describing the data, and the estimated glomerular filtration rate was the only covariate that had a significant impact on the model. The final model estimated that the mean clearance of levofloxacin in elderly patients with pneumonia was 5.26 L/h. Monte Carlo simulation results showed that the optimal dosing regimen for levofloxacin was 750 mg once a day in elderly patients with pneumonia, with a minimum inhibitory concentration of 2 mg/L. CONCLUSIONS: The population pharmacokinetic model of levofloxacin in elderly patients with pneumonia was established, and the dose optimization of levofloxacin was completed through Monte Carlo simulation.

Pharmacokinetic/pharmacodynamic comparison between generic and brand-name levofloxacin based on Monte Carlo simulation.

OBJECTIVE: Generic medications are widely used because of their low cost. However, some generic medications show lower quality and clinical efficacy compared with brand-name medications, especially for antimicrobial drugs. Levofloxacin is a fluoroquinolone antimicrobial drug with excellent antimicrobial activity and wide antimicrobial spectrum, while it is susceptible to drug resistance. Our study aims to evaluate the bioequivalence of generic and brand-name levofloxacin. METHODS: The pharmacokinetic (PK) parameters (Cmax, AUC0∼24, Tmax, and t1/2), pharmacodynamic (PD) parameters (in vitro antibacterial activity and the inhibition of resistant mutation), and PK/PD analysis (the probability of target attainment; the cumulative fraction of response) calculated by Monte Carlo simulation were investigated. RESULTS: Our results demonstrated that compared with generics, brand-name levofloxacin not only had higher drug content, it also showed higher antimicrobial susceptibility, higher resistance to mutation ability, and higher percentage of each dosage interval wherein plasma concentration of antimicrobial agents exceeded the MPC90 (mutant prevention concentration to prevent the mutation of 90% strains) against various clinical isolates. Although the differences in AUC0∼24 between brand-name levofloxacin and generics were not statistically significant (P > 0.05, F test), Monte Carlo simulation results showed cumulative fraction of response values for PK/PD of brand-name medications were higher than generics. CONCLUSION: Our results indicated that PK or PD equivalence did not imply therapeutic equivalence; thus, we suggest including PK/PD analysis in the bioequivalence evaluation system, which benefits prediction of clinical outcome with high application value.

Efficacy And Cost-Effectiveness, Comparison Of 7-Days Vonoprazan Versus 14-Days Esomeprazole Based Triple Therapies For Treating Helicobacter Pylori Infection In Pakistani Population: A Randomized Clinical Trial.

Background: Helicobacter pylori (H. pylori) is a gram-negative bacterium which usually resides in the mucoid lining of the stomach and may cause different gastric pathologies e.g., Gastritis, peptic ulcer disease, adenocarcinoma of the gastric system and mucoid associated lymphoma (MALT). The Objective was to compare the effect of 7-days Vonoprazan based triple therapy and 14-days Esomeprazole based triple therapy on eradication rate, compliance and cost effectiveness in Helicobacter pylori infected patients. Methods: This clinical trial was performed in the Department of Pharmacology Army Medical College, National University of Medical Sciences (NUMS) in collaboration with the Gastroenterology Department, Pak Emirates Military Hospital (PEMH) Rawalpindi from December 2022 to March 2023. A total of one hundred and twenty-two patients with dyspepsia symptoms and yielding lab results positive for Helicobacter pylori by stool antigen test were enrolled in the study. They were randomly allocated into two groups. The Esomeprazole group received 14 days of triple therapy orally with Esomeprazole 20 mg twice a day; Amoxicillin 1000 mg twice a day; and Levofloxacin 500 mg one time a day. The comparative Vonoprazan group was given 7-days triple therapy orally with Vonoprazan 20 mg twice a day; Amoxicillin 1000 mg twice a day; and Levofloxacin 500 mg one time a day. Eradication success was evaluated by stool antigen test four weeks later, as counted from the start of treatment. compliance and cost-effectiveness of both therapies were also assessed. Results: The eradication rate was (95.1%) in the Vonoprazan group with 58 out of 61 patients negative for H. pylori and (93.1%) in Esomeprazole group with 54 patients out of 58 yielding a negative result demonstrating p-value of 0.64. Compliance was 95.0% in the Esomeprazole group with p-value of 0.07. Cost effective ratio for Vonoprazan triple therapy was lower (731.8PKR) than the Esomeprazole group. Conclusion: One two-week Vonoprazan regimen demonstrated improved eradication rate, good compliance, and better tolerability in patients with less cost and a half duration of treatment in comparison with two weeks Esomeprazole regimen, attesting that one week Vonoprazan therapy is more cost efficacious in producing better results.

Development and Assessment of a Novel Whole-Gene-Based Targeted Next-Generation Sequencing Assay for Detecting the Susceptibility of Mycobacterium tuberculosis to 14 Drugs.

Targeted next-generation sequencing (tNGS) has emerged as an alternative method for detecting drug-resistant tuberculosis (DR-TB). To provide comprehensive drug susceptibility information and to address mutations missed by available commercial molecular diagnostics, we developed and evaluated a tNGS panel with 22 whole-gene targets using the Ion Torrent platform to predict drug resistance to 14 drugs, namely, rifampicin (RIF), isoniazid (INH), ethambutol (EMB), pyrazinamide (PZA), moxifloxacin (MFX), levofloxacin (LFX), amikacin (AMK), capreomycin (CM), kanamycin (KM), streptomycin (SM), bedaquiline (BDQ), clofazimine (CFZ), linezolid (LZD), and delamanid (DLM). We selected 50 and 35 Mycobacterium tuberculosis isolates with various DR profiles as the training set and the challenge set, respectively. Comparative variant analyses of the DR genes were performed using Sanger sequencing and whole-genome sequencing (WGS). Phenotypic drug susceptibility testing (pDST) results were used as gold standards. Regarding the limit of detection, the tNGS assay detected 2.9 to 3.8% minority variants in 4% mutant mixtures. The sensitivity and specificity of tNGS were 97.0% (95% confidence interval [CI] = 93.1 to 98.7%) and 99.1% (95% CI = 97.7 to 99.7%), respectively. The concordance of tNGS with pDST was 98.5% (95% CI = 97.2 to 99.2%), which was comparable to that of WGS (98.7%, 95% CI = 97.4 to 99.3%) and better than that of Sanger sequencing (96.9%, 95% CI = 95.3 to 98.0%). The agreement between tNGS and pDST was almost perfect for RIF, INH, EMB, MFX, LFX, AMK, CM, KM, SM, BDQ, and LZD (kappa value = 0.807 to 1.000) and substantial for PZA (kappa value = 0.791). Our customized novel whole-gene-based tNGS panel is highly consistent with pDST and WGS for comprehensive and accurate prediction of drug resistance in a strengthened and streamlined DR-TB laboratory program. IMPORTANCE We developed and validated a tNGS assay that was the first to target 22 whole genes instead of regions of drug resistance genes and comprehensively detected susceptibility to 14 anti-TB drugs, with great flexibility to include new or repurposed drugs. Notably, we demonstrated that our custom-designed Ion AmpliSeq TB research panel platform had high concordance with pDST and could significantly reduce turnaround time (by approximately 70%) to meet a clinically actionable time frame. Our tNGS assay is a promising DST solution for providing needed clinical information for precision medicine-guided therapies for DR-TB and allows the rollout of active pharmacovigilance.

Assessment of nationally recommended antibiotics for treatment of UTI in U.S.-Mexico border emergency departments.

BACKGROUND: Urinary tract infections (UTIs) seen in the emergency department are commonly treated as an outpatient with oral antibiotics. Given that antibiotics are available for over-the-counter purchase in Mexico, there is speculation that potential misuse and overuse of antibiotics in United States-Mexico border areas could lead to antibiotic resistance patterns that would render some empiric treatments for UTIs less effective. The purpose of this study was to examine the effectiveness of Infectious Disease Society of America (IDSA) guideline-recommended antibiotics for treatment of outpatient UTI diagnosed in the emergency department. Data were collected from a county hospital on the U.S.-Mexico border with a metropolitan area of over 2 million people. Secondary analysis included frequency of urine culture isolated, resistance rates of urine pathogens, and prescriber habits. METHODS: This study was a retrospective chart review of adult patients diagnosed and treated for UTI from August 1, 2019, to February 29, 2020. Culture results of included patients were analyzed against in vitro-tested antibiotics. Bacterial isolate frequency, resistance rates, and prescribing habits were collected. RESULTS: A total of 985 patient charts were reviewed, of which 520 patients met inclusion criteria for analysis of prescribing habits. Of these, 329 positive bacterial culture growths were included in the analysis of antibiotic resistance rates. Oral antibiotics with comparatively lower resistance rates were amoxicillin/clavulanate, cefdinir, cefuroxime, and nitrofurantoin. Oral antibiotics with notably high resistance rates included trimethoprim-sulfamethoxazole (TMP-SMX), tetracycline, ciprofloxacin, levofloxacin, and cephalexin. Nitrofurantoin was prescribed most frequently for outpatient treatment of UTI/cystitis (41.6%) while cephalexin was the most commonly prescribed antibiotic for outpatient treatment of pyelonephritis (50%). CONCLUSION: Our findings suggest that, while part of standard IDSA guidelines, fluoroquinolones and TMP-SMX are not ideal empiric antibiotics for treatment of outpatient UTI in the U.S.-Mexico border region studied due to high resistance rates. Although not listed as first line agents per current IDSA recommendations, 2nd and 3rd generation cephalosporins, and amoxicillin/clavulanate would be acceptable options given resistance patterns demonstrated in accordance with IDSA allowance for tailoring selection to local resistance. Nitrofurantoin appears to be consistent with recommendations and demonstrates a favorable resistance profile for treatment of outpatient UTI within this region.

Effective photodegradation of rhodamine B and levofloxacin over CQDs modified BiOCl and BiOBr composite: Mechanism and toxicity assessment.

In this contribution, carbon quantum dots (CQDs) modified 3D-flower like BiOX (X = Cl, Br, I) photocatalyst were successfully prepared via a facile mechanical compounding method. The crystal structure, surface composition, morphologies, optical properties and photocatalytic activities were investigated in detail. The photocatalytic activity of the as-obtained photocatalyst were evaluated by degradation of rhodamine B (RhB) and Levofloxacin (LEV) under near IR-UV-vis light irradiation, the CQDs/BiOX composite displayed enhanced photocatalytic activity as compared with individual BiOX materials. The CQDs/BiOX composite had the outstanding light harvesting and electron transfer ability because of the ordered ultrathin nanosheet structure of the BiOX, the formation of metal Bi under photoinduction, and the synergistic effects between CQDs and pure BiOX. Antibacterial activity and effects on Rye seeds growth of the LEV degradation intermediate were also researched. Reactive-species-trapping experiments exhibited that h+ and O2- were the active reactive species during photodegradation process. This work provided an effective and simple strategy for designing QDs modified Bi-rich oxyhalides in organic pollutant containing wastewater treatment.

The global impact of household contact management for children on multidrug-resistant and rifampicin-resistant tuberculosis cases, deaths, and health-system costs in 2019: a modelling study.

BACKGROUND: Estimates suggest that at least 30 000 children develop multidrug-resistant or rifampicin-resistant tuberculosis each year. Despite household contact management (HCM) being widely recommended, it is rarely done. METHODS: We used mathematical modelling to evaluate the potential country-level and global effects and cost-effectiveness of multidrug-resistant or rifampicin-resistant tuberculosis HCM for children younger than 15 years who are living with a person with newly diagnosed multidrug-resistant or rifampicin-resistant tuberculosis. We compared a baseline of no HCM with several HCM strategies and tuberculosis preventive therapy regimens, calculating the effect on multidrug-resistant or rifampicin-resistant tuberculosis cases, deaths, and health-system costs. All HCM strategies involved the screening of children for prevalent tuberculosis disease but with tuberculosis preventive therapy either not given or targeted dependent on age, HIV status, and result of tuberculin skin test. We evaluated the use of fluoroquinolones (ie, levofloxacin and moxifloxacin), delamanid, and bedaquiline as tuberculosis preventive therapy. FINDINGS: Compared with a baseline without HCM, HCM for all adults diagnosed with multidrug-resistant or rifampicin-resistant tuberculosis in 2019 would have entailed screening 227 000 children (95% uncertainty interval [UI]: 205 000-252 000) younger than 15 years globally, and averted 2350 tuberculosis deaths (1940-2790), costing an additional US$63 million (74-95 million). If all the children within the household who had been in contact with the person with multidrug-resistant or rifampicin-resistant tuberculosis received tuberculosis preventive therapy with levofloxacin, 5620 incident tuberculosis cases (95% UI 4540-6890) and an additional 1240 deaths (970-1540) would have been prevented. Incremental cost-effectiveness ratios were lower than half of per-capita gross domestic product for most interventions in most countries. Targeting only children younger than 5 years and those living with HIV reduced the number of incident cases and deaths averted, but improved cost-effectiveness. Tuberculosis preventive therapy with delamanid increased the effect, in terms of reduced incidence and mortality, compared with levofloxacin. INTERPRETATION: HCM for patients with multidrug-resistant or rifampicin-resistant tuberculosis is cost-effective in most settings and could avert a substantial proportion of multidrug-resistant or rifampicin-resistant tuberculosis cases and deaths in children globally. FUNDING: UK Medical Research Council.

Economic Evaluation of Nemonoxacin, Moxifloxacin and Levofloxacin in the Treatment of Early Community-Acquired Pneumonia with Possible Pulmonary Tuberculosis.

The Chinese community-acquired pneumonia (CAP) Diagnosis and Treatment Guideline 2020 recommends quinolone antibiotics as the initial empirical treatment options for CAP. However, patients with pulmonary tuberculosis (PTB) are often misdiagnosed with CAP because of the similarity of symptoms. Moxifloxacin and levofloxacin have inhibitory effects on mycobacterium tuberculosis as compared with nemonoxacin, resulting in delayed diagnosis of PTB. Hence, the aim of this study is to compare the cost-effectiveness of nemonoxacin, moxifloxacin and levofloxacin in the treatment of CAP and to determine the value of these treatments in the differential diagnosis of PTB. Primary efficacy data were collected from phase II-III randomized, double-blind, multi-center clinical trials comparing nemonoxacin to moxifloxacin (CTR20130195) and nemonoxacin to levofloxacin (CTR20140439) for the treatment of Chinese CAP patients. A decision tree was constructed to compare the cost-utility among three groups under the perspective of healthcare system. The threshold for willingness to pay (WTP) is 1-3 times GDP per capita ($11,174-33,521). Scenarios including efficacy and cost for CAP patients with a total of 6% undifferentiated PTB. Sensitivity and scenario analyses were performed to test the robustness of basic analysis. The costs of nemonoxacin, moxifloxacin, and levofloxacin were $903.72, $1053.59, and $1212.06 and the outcomes were 188.7, 188.8, and 188.5 quality-adjusted life days (QALD), respectively. Nemonoxacin and moxifloxacin were dominant compared with levofloxacin, and the ICER of moxifloxacin compared with nemonoxacin was $551,643, which was much greater than WTP; therefore, nemonoxacin was the most cost-effective option. Regarding patients with PTB who were misdiagnosed with CAP, taking nemonoxacin could save $290.76 and $205.51 when compared with moxifloxacin and levofloxacin and resulted in a gain of 2.83 QALDs. Our findings demonstrate that nemonoxacin is the more economical compared with moxifloxacin and levofloxacin, and non-fluoroquinolone antibiotics are cost-saving and utility-increasing compared to fluoroquinolones in the differential diagnosis of PTB, which can help healthcare system in making optimal policies and help clinicians in the medication of patients.

Probability of target attainment of oral antimicrobials for Escherichia coli and Klebsiella pneumoniae based on Monte Carlo simulations.

Although early transition from intravenous to oral antimicrobials can reduce hospitalization duration, susceptibility breakpoints have not been established for many oral antimicrobials against Escherichia coli and Klebsiella pneumoniae bacteremia. Thus, we used population pharmacokinetic models, pharmacokinetic/pharmacodynamic indices, and Monte Carlo simulations to evaluate the probability of target attainment (PTA) for common oral antimicrobial dosages against E. coli and K. pneumoniae. The oral antimicrobial agents evaluated included cephalexin, cefaclor, cefditoren, amoxicillin/clavulanic acid, faropenem, and levofloxacin. For E. coli, the percentage of isolates with minimum inhibitory concentrations for which a PTA >90% was achieved was 53% and less than 20% for levofloxacin and the ß-lactams, respectively. For K. pneumoniae, the percentages of isolates for which a PTA >90% was achieved were comparatively higher (cephalexin, 73%; amoxicillin/clavulanic acid, 83%; levofloxacin, 96%). Our results suggest clinicians should check if pharmacokinetic/pharmacodynamic indices are achieved in individual patients before transitioning to oral antimicrobial therapy.

Oral levofloxacin: population pharmacokinetics model and pharmacodynamics study in bone and joint infections.

OBJECTIVES: This study aimed at characterizing the pharmacokinetics (PK) of oral levofloxacin in adult patients in order to optimize dosing scheme and explore the PK/pharmacodynamics (PD) of levofloxacin in bone and joint infections (BJIs). METHODS: From November 2015 to December 2019, all patients hospitalized in Cochin Hospital, treated with levofloxacin and who had at least one dosage for therapeutic drug monitoring were included. PK was described using non-linear mixed-effect modelling. In a subgroup of patients with BJIs, the association between PK, MIC for the isolated pathogen and clinical outcome was investigated. Monte Carlo simulations investigated dosing regimens to achieve the PK/PD target (AUC/MIC ratio >100). RESULTS: One hundred and two patients were included (199 measurements), including 32 treated for BJI. A one-compartment model with first-order absorption and elimination best described the data. Effects of estimated creatinine clearance (eCLCR) and age were significant on levofloxacin clearance. In BJI patients, no significant association was found between levofloxacin PK/microbiological parameters and either clinical outcome or adverse events. Based on our model, we proposed optimized oral levofloxacin dosing regimens according to renal function, to reach the PK/PD target AUC/MIC ratio >100 for three frequent causative pathogens (Staphylococcus aureus, Enterobacterales and Pseudomonas aeruginosa). CONCLUSIONS: Our results reinforce the need of determining the MIC and using therapeutic drug monitoring in complex infections caused by P. aeruginosa.

Assessment the efficacy of some various treatment methods, in vitro and in vivo, against Aeromonas hydrophila infection in fish with regard to side effects and residues.

Aeromonas hydrophila is an opportunistic bacteria with an overwhelming impact on fish farming industry especially with upraising of drug resistant mutants. This study aimed to evaluate and compare the therapeutic and side effects of levofloxacin (LEV), chitosan-nanoparticles (CNPs), and fructooligosaccharides (FOS) in control of this infection in tilapia. A total of 160 Nile-tilapia divided into 8-groups; G1: negative-control, G2: infected-control, G3: non-infected-(levofloxacin (LEV) 10 mg/kg bwt), G4: non-infected-(chitosan-nanoparticles (CNPs) 1 g/kg ration), G5: non-infected-(fructooligosaccharides (FOS) 20 g/kg ration), G6: infected-LEV, G7: infected-CNPs and G8: infected-FOS for 7 days. MICs were (0.125 µg/ml and 1.25 mg/ml) for LEV and CNPs respectively. No mortalities or significant adverse effects were recorded in non-infected treated-groups while infected were (20%) LEV, (30%) CNPs, (40%) FOS and (70%) G2. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) decreased by LEV and CNPs than FOS while all increased total protein (TP) and albumin than G2. Malondialdehyde (MDA) significantly decreased and superoxide dismutase (SOD) and reduced glutathione (GSH) increased in all infected-treated groups than G2 in various degrees. Urea and creatinine descending order were FOS, LEV then CNPs decreased significantly than G2. LEV musculature residues, using HPLC, decreased gradually till the 5th day; 621.00 ± 0.66, 270.00 ± 0.48 then 64.00 ± 0.40, and 471.00 ± 0.79, 175.00 ± 0.52 ppb then not detected at 1st, 3rd, and 5th days of withdrawal in non-infected and infected groups respectively. Finally, LEV and CNPs were superior as bactericidal, decreasing mortalities and enzyme activities while CNPs and FOS increased performance, non-specific immunity, and antioxidant biomarkers.

Development of a dosing-adjustment tool for fluoroquinolones in osteoarticular infections: The Fluo-pop study.

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 (R2 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.

Population pharmacokinetics of oral levofloxacin in healthy volunteers and dosing optimization for multidrug-resistant tuberculosis therapy.

Levofloxacin is considered a key component of a multidrug-resistant tuberculosis (MDR-TB) regimen. However, there is considerable concern regarding the subtherapeutic concentrations of the currently used doses and the development of drug resistance. Therefore, this study aimed to describe the population pharmacokinetics (PPK) of oral levofloxacin in healthy volunteers and to evaluate the probability of target attainment (PTA) in an attempt to optimize the dosing regimens for MDR-TB therapy. Data of levofloxacin in healthy volunteers from a previous study were used to construct a PPK model. Monte Carlo simulations were performed to derive the PTAs of various regimens. A two-compartment model with linear elimination and transit absorption compartments best described the pharmacokinetics (PK) of levofloxacin. The estimated PK parameters (interindividual variability, %) were: apparent clearance 8.32 L h-1 (22.6%), apparent central volume of distribution 35.8 L (45.2%), apparent peripheral volume of distribution 39.7 L, intercompartmental clearance 40.6 L h-1 (43.8%), absorption rate constant 7.45 h-1 (150%), mean absorption transit time 0.355 h (52.4%), and total number of transit compartments 6.01 (131.9%). Monte Carlo simulations using levofloxacin 750-1000 mg yielded a probability of achieving a target free area under the concentration-time curve/minimum inhibitory concentration (MIC) of 100 at greater than 90% for Mycobacterium tuberculosis with an MIC < 0.5 mg L-1 , while a dose of 1500 mg was required for strains with an MIC of 1 mg L-1 . A higher dose of levofloxacin might be needed to treat tuberculosis. However, further studies on the efficacy and safety of this dose are needed to confirm our findings.

The application of in silico experimental model in the assessment of ciprofloxacin and levofloxacin interaction with main SARS-CoV-2 targets: S-, E- and TMPRSS2 proteins, RNA-dependent RNA polymerase and papain-like protease (PLpro)-preliminary molecular docking analysis.

BACKGROUND: The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified at the end of 2019. Despite growing understanding of SARS-CoV-2 in virology as well as many molecular studies, except remdesivir, no specific anti-SARS-CoV-2 drug has been officially approved. METHODS: In the present study molecular docking technique was applied to test binding affinity of ciprofloxacin and levofloxacin-two commercially available fluoroquinolones, to SARS-CoV-2 S-, E- and TMPRSS2 proteins, RNA-dependent RNA polymerase and papain-like protease (PLPRO). Chloroquine and dexamethasone were used as reference positive controls. RESULTS: When analyzing the molecular docking data it was noticed that ciprofloxacin and levofloxacin possess lower binding energy with S protein as compared to the references. In the case of TMPRSS2 protein and PLPRO protease the best docked ligand was levofloxacin and in the case of E proteins and RNA-dependent RNA polymerase the best docked ligands were levofloxacin and dexamethasone. Moreover, a molecular dynamics study also reveals that ciprofloxacin and levofloxacin form a stable complex with E- and TMPRSS2 proteins, RNA polymerase and papain-like protease (PLPRO). CONCLUSIONS: The revealed data indicate that ciprofloxacin and levofloxacin could interact and potentially inhibit crucial SARS-CoV-2 proteins.

Clinical Benefits and Cost-Effectiveness of Moxifloxacin as Initial Treatment for Community-Acquired Pneumonia: A Meta-Analysis and Economic Evaluation.

PURPOSE: Moxifloxacin and levofloxacin are currently recommended as empirical initial treatment options for community-acquired pneumonia (CAP) in China according to guidelines. Most studies that evaluated the efficacy and safety of moxifloxacin and levofloxacin in treating CAP as initial empirical treatment were single-centered trials assessing different clinical end points. In addition, there is limited research investigating moxifloxacin's clinical benefits in the context of health care resource utilization and reimbursement from the payer's perspective in China. Hence, this study was aimed at comparing the clinical efficacy of moxifloxacin and levofloxacin by conducting a meta-analysis and assessing their economic value from the China payer's perspective through a cost-utility analysis model. METHODS: For the meta-analysis, 6 bibliographic databases were searched for relevant publications from January 2000 to August 2020, and studies were assessed for eligibility under predetermined criteria. Meta-analysis was performed by using a random effects model when analyses included >2 trials. For the economic evaluation, a decision-tree model was constructed to investigate the cost-utility of moxifloxacin versus levofloxacin as initial regimens in the treatment of CAP inpatients. Parameter values were derived from meta-analysis, published literature, and clinician survey. The outcome was reported in the form of an incremental cost-effectiveness ratio. One-way sensitivity analysis and probabilistic sensitivity analysis were undertaken to assess the robustness of the model. FINDINGS: Twenty-seven randomized controlled trials were included in the meta-analysis. Results indicated that the clinical response rate at the test-of-cure visit with initial treatment of moxifloxacin was significantly higher than that of levofloxacin (3441 patients; random effects model; I2 = 49%; odds ratio, 3.35; 95% CI, 2.35-4.77; P < 0.001). In terms of the safety profile, total adverse events were not significantly different between the 2 groups (2770 patients; random effects model; I2 = 40%; odds ratio, 0.77; 95% CI, 0.56-1.06; P = 0.11). Output of the cost-utility model showed that under the willingness-to-pay threshold of one-time China gross domestic product per capita, moxifloxacin is dominant over levofloxacin, being less costly and more efficacious (0.002 quality-adjusted life year gained, CNY 844 [US$131] saved in total cost, negative incremental cost-effectiveness ratio). Sensitivity analyses indicated the robustness of the model as moxifloxacin remained dominant when model parameter values fluctuated. IMPLICATIONS: Moxifloxacin is more efficacious than levofloxacin as the initial empirical treatment for CAP. In addition, treatment of CAP with moxifloxacin instead of levofloxacin is expected to be cost-saving from the perspective of payers in China. However, for the cost-utility analysis, in the absence of a national representative database on costs for hospitalization in China, inputs in the cost-utility model could be underestimated or overestimated due to estimating errors applied to both treatment arms.

Assessment of the in vitro activity of azithromycin niosomes alone and in combination with levofloxacin on extensively drug-resistant Klebsiella pneumoniae clinical isolates.

BACKGROUND AND AIM: Extensively drug-resistant (XDR) Klebsiella pneumoniae represent a major threat in intensive care units. The aim of the current study was to formulate a niosomal form of azithromycin (AZM) and to evaluate its in vitro effect on XDR K. pneumoniae as a single agent or in combination with levofloxacin. MATERIAL AND METHODS: Forty XDR K. pneumoniae isolates (23 colistin-sensitive and 17 colistin-resistant) were included in the study. Formulation and characterization of AZM niosomes were performed. The in vitro effect of AZM solution/niosomes alone and in combination (with levofloxacin) was investigated using the checkerboard assay, confirmed with time-kill assay and post-antibiotic effect (PAE). RESULTS: The AZM niosome mean minimal inhibitory concentration (MIC) (187.4 ± 209.1 µg/mL) was significantly lower than that of the AZM solution (342.5 ± 343.4 µg/mL). AZM niosomes/levofloxacin revealed a 40% synergistic effect compared to 20% with AZM solution/levofloxacin. No antagonistic effect was detected. The mean MIC values of both AZM niosomes and AZM solution were lower in the colistin-resistant group than in the colistin-sensitive group. The mean PAE time of AZM niosomes (2.3 ± 1.09 h) was statistically significantly longer than that of the AZM solution (1.37 ± 0.5 h) (p = 0.023). CONCLUSION: AZM niosomes were proved to be more effective than AZM solution against XDR K. pneumoniae, even colistin-resistant isolates.

In Silico Screening and In Vitro Assessment of Natural Products with Anti-Virulence Activity against Helicobacter pylori.

Helicobacter pylori is one of the most frequent human pathogens and a leading etiological agent of various gastric diseases. As stringent response, coordinated by a SpoT protein, seems to be crucial for the survivability of H. pylori, the main goal of this article was to use in silico computational studies to find phytochemical compounds capable of binding to the active site of SpoT from H. pylori and confirm the ability of the most active candidates to interfere with the virulence of this bacterium through in vitro experiments. From 791 natural substances submitted for the virtual screening procedure, 10 were chosen and followed for further in vitro examinations. Among these, dioscin showed the most interesting parameters (the lowest MIC, the highest anti-biofilm activity in static conditions, and a relatively low stimulation of morphological transition into coccoids). Therefore, in the last part, we extended the research with a number of further experiments and observed the ability of dioscin to significantly reduce the formation of H. pylori biofilm under Bioflux-generated flow conditions and its capacity for additive enhancement of the antibacterial activity of all three commonly used antibiotics (clarithromycin, metronidazole, and levofloxacin). Based on these results, we suggest that dioscin may be an interesting candidate for new therapies targeting H. pylori survivability and virulence.