Thermoresponsive in situ forming and self-healing double-network hydrogels as injectable dressings for silymarin/levofloxacin delivery for treatment of third-degree burn wounds.

Our study aimed to introduce a novel double-cross-linked and thermoresponsive hydrogel with remarkable potential for accelerating third-degree burn wound healing. Burn injuries are recognized as challenging, critical wounds. Especially in third-degree burns, treatment is demanding due to extended wounds, irregular shapes, significant exudation, and intense pain during dressing changes. In this work, hydrogels made of zwitterionic chitosan and dialdehyde starch (ZCS and ZDAS) were created to deliver silymarine (SM) and levofloxacin (LEV). The hydrogels were effortlessly produced using dynamic Schiff base linkages and ionic interactions between ZCS and ZDAS at appropriate times. The pore uniformity, gel fraction, and commendable swelling properties can imply a suitable degree of Schiff base cross-link. The hydrogel demonstrated outstanding shape retention, and significant self-healing and flexibility abilities, enabling it to uphold its form even during bodily movements. After injecting biocompatible hydrogel on the wound, a notable acceleration in wound closure was observed on day 21 (98.1 ± 1.10 %) compared to the control group (75.1 ± 6.13 %), and histopathological analysis revealed a reduction of inflammation that can be linked to remarkable antioxidant and antibiotic properties. The results demonstrate the hydrogel's efficacy in promoting burn wound healing, making it a promising candidate for medical applications.

Treatment Outcome of Severe Respiratory Type B Tularemia Using Fluoroquinolones.

BACKGROUND: Fluoroquinolones lack approval for treatment of tularemia but have been used extensively for milder illness. Here, we evaluated fluoroquinolones for severe illness. METHODS: In an observational study, we identified case-patients with respiratory tularemia from July to November 2010 in Jämtland County, Sweden. We defined severe tularemia by hospitalization for >24 hours and severe bacteremic tularemia by Francisella tularensis subsp. holarctica growth in blood or pleural fluid. Clinical data and drug dosing were retrieved from electronic medical records. Chest images were reexamined. We used Kaplan-Meier curves to evaluate time to defervescence and hospital discharge. RESULTS: Among 67 case-patients (median age, 66 years; 81% males) 30-day mortality was 1.5% (1 of 67). Among 33 hospitalized persons (median age, 71 years; 82% males), 23 had nonbacteremic and 10 had bacteremic severe tularemia. Subpleural round consolidations, mediastinal lymphadenopathy, and unilateral pleural fluid were common on chest computed tomography. Among 29 hospitalized persons with complete outcome data, ciprofloxacin/levofloxacin (n = 12), ciprofloxacin/levofloxacin combinations with doxycycline and/or gentamicin (n = 11), or doxycycline as the single drug (n = 6) was used for treatment. One disease relapse occurred with doxycycline treatment. Treatment responses were rapid, with median fever duration 41.0 hours in nonbacteremic and 115.0 hours in bacteremic tularemia. Increased age-adjusted Charlson comorbidity index predicted severe bacteremic tularemia (odds ratio, 2.7 per score-point; 95% confidence interval, 1.35-5.41). A 78-year-old male with comorbidities and delayed ciprofloxacin/gentamicin treatment died. CONCLUSIONS: Fluoroquinolone treatment is effective for severe tularemia. Subpleural round consolidations and mediastinal lymphadenopathy were typical findings on computed tomography among case-patients in this study.

Primary antibiotic resistance of Helicobacter pylori in the Asia-Pacific region between 1990 and 2022: an updated systematic review and meta-analysis.

BACKGROUND: We previously showed rising primary antibiotic resistance of Helicobacter pylori during 1990-2015 in the Asia-Pacific region. However, whether primary antibiotic resistance continues to rise is unknown. Therefore, we aimed to assess the latest prevalence of H pylori antibiotic resistance in this region. METHODS: We did an updated systematic review and meta-analysis of observational studies and randomised controlled trials published in PubMed, Embase, and Cochrane Library between Jan 1, 1990, and July 12, 2023. Studies investigating primary H pylori resistance to clarithromycin, metronidazole, levofloxacin, amoxicillin, or tetracycline in individuals naive to eradication therapy in the Asia-Pacific region (as defined by the UN geoscheme) were eligible for inclusion. There were no language restrictions. Studies that focused on specific subpopulations (eg, children) were excluded. Using a standardised extraction form, two authors independently reviewed and extracted summary data from all eligible articles. The updated prevalence of antibiotic resistance was generated by meta-analysis under a random-effects model and subgroup analyses were done by countries and periods of study. Between-study variability was assessed by use of I2. The study is registered in PROSPERO, CRD42022339956. FINDINGS: A total of 351 studies, including 175 new studies and 176 studies from our previous analysis, were included in this meta-analysis. The overall prevalence of primary antibiotic resistance of H pylori between 1990 and 2022 was 22% (95% CI 20-23; I2=96%) for clarithromycin, 52% (49-55; I2=99%) for metronidazole, 26% (24-29; I2=96%) for levofloxacin, 4% (3-5; I2=95%) for tetracycline, and 4% (3-5; I2=95%) for amoxicillin. Prevalence varied considerably between countries and across study periods. From 1990 to 2022, the prevalence of primary resistance increased for clarithromycin, metronidazole, and levofloxacin but remained stable for amoxicillin and tetracycline. The latest primary resistance prevalences were 30% (95% CI 28-33; I2=93%) for clarithromycin, 61% (55-66; I2=99%) for metronidazole, 35% (31-39; I2=95%) for levofloxacin, 4% (2-6; I2=96%) for tetracycline, and 6% (4-8; I2=96%) for amoxicillin in the Asia-Pacific region. INTERPRETATION: Treatment guidelines should be adapted in response to the rising primary resistance of key antibiotics for H pylori eradication. A global policy to control and monitor the antibiotic resistance of H pylori is urgently needed. FUNDING: Ministry of Health and Welfare of Taiwan, National Science and Technology Council of Taiwan, and National Taiwan University. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Nephroprotective effect of vitamin D Against Levofloxacin-induced renal injury: an observational study.

The pathogenesis of kidney damage involves complicated interactions between vascular endothelial and tubular cell destruction. Evidence has shown that vitamin D may have anti-inflammatory effects in several models of kidney damage. In this study, we evaluated the effects of synthetic vitamin D on levofloxacin-induced renal injury in rats. Forty-two white Albino rats were divided into six groups, with each group comprising seven rats. Group I served as the control (negative control) and received intraperitoneal injections of normal saline (0.5 ml) once daily for twenty-one days. Group II and Group III were treated with a single intraperitoneal dose of Levofloxacin (50 mg/kg/day) and (100 mg/kg/day), respectively, for 14 days (positive control groups). Group IV served as an additional negative control and received oral administration of vitamin D3 (500 IU/rat/day) for twenty-one days. In Group V, rats were orally administered vitamin D3 (500 IU/rat/day) for twenty-one days, and intraperitoneal injections of Levofloxacin (50 mg/kg/day) were administered on day 8 for 14 days. Group VI received oral vitamin D3 supplementation (500 IU/rat/day) for twenty-one days, followed by intraperitoneal injections of Levofloxacin (100 mg/kg/day) on day 8 for fourteen days. Blood samples were collected to measure creatinine, urea, malondialdehyde, glutathione reductase, and superoxide dismutase levels. Compared to the positive control group, vitamin D supplementation lowered creatinine, urea, and malondialdehyde levels, while increasing glutathione reductase and superoxide dismutase levels. Urea, creatinine, and malondialdehyde levels were significantly (p<0.05) higher in rats administered LFX 50mg and 100mg compared to rats given (LFX + vitamin D). The main findings of this study show that vitamin D reduces renal dysfunction, suggesting that vitamin D has antioxidant properties and may be used to prevent renal injury.

Comparing the Therapeutic Potency of Camel Milk and Whey Protein Against Toxicity-Induced by Levofloxacin in Male Albino Rats.

<b>Background and Objective:</b> Levofloxacin (LFX) is a wide-spectrum antibiotic that is used to treat many types of infections. Camel milk (CM) and camel whey protein (CWP) are natural antioxidants that work as dietary supplements that enhance immune defenses. The goal of this study was to estimate the therapeutic efficacy of camel whey protein and camel milk, in addition to the toxic effects of the antibiotic levofloxacin. <b>Materials and Methods:</b> As 42 male albino rats were divided as follows: G1: Control, G2: CM orally for 15 days, G3: CWP orally for 15 days, G4: LFX orally for 10 days, G5: LFX for 10 days and followed with CM daily for 15 days and G6: LFX for 10 days followed by CWP orally for 15 days. At the end of the study blood sera from all groups were collected for estimation of serum total protein, albumin, globulins and glucose. Sections of the liver and kidney were separated for estimation of GSH, CAT, GSH-PX. All data were statistically analyzed using analysis of variance. <b>Results:</b> The LFX treatment induced a decrease in serum levels of proteinogram, glucose, hepatic and renal values of oxidative stress and raising values of serum kidney and liver functions, hepatic and renal MDA. The treatment of LFX-treated rats with CWP led to a more increase in serum proteinogram, glucose, hepatic and renal (GSH, CAT, GSH-PX) a decline in serum values of (urea, ALAT, ASAT, ALP, BIL, T.P, D. BIL, Ind. BIL creatinine), hepatic and renal MDA than the treatment with CWP did. <b>Conclusion:</b> The use of CWP after LFX-treatment showed greater therapeutic potency than the use of CM.

Punica granatum peel extract modulates levofloxacin-induced oxidative stress and testicular damage in rats.

Levofloxacin (LEV) is one of the Fluoroquinolones antibiotic groups, which are utilized in the therapy of numerous diseases, particularly in reproductive organs. Punica granatum peel is a waste byproduct rich in phytochemicals that are known for their different biological activities. The current research was designed to assess the capability of pomegranate peel extract (PGPE) in counteracting LEV-induced oxidative stress and testicular injury in rats. Rats groups were divided as follows: control, PGPE (500 mg/kg BW), LEV (300 mg/kg BW), and PGPE plus LEV. Rats were treated orally for two weeks daily. The chemical and nutritional content of Punica granatum peel (PGP) were investigated. GC/MS analysis showed the major phytochemical constituents in PGPE as gallic acid, ellagic acid, 4H-Pyran-4-one, 2,3-dihydro-3,5-dihydroxy-6-methyl, and caffeic acid with DPPH, ABTS, and NO radical scavenging activity, as well as Fe3+- reducing antioxidant activity. Results revealed that LEV increased TBARS and H2O2 concentrations and LDH activity in rat testes significantly. While the activities of antioxidant enzymes, phosphatases, aminotransferases, and reduced glutathione content as well as protein levels, were significantly reduced. Worthy changes in testosterone, luteinizing, and follicle-stimulating hormone levels, as well as sperm characteristics, were also discovered. LEV was also found to trigger apoptosis, as evidenced by elevated p53 and caspase-3 levels and decreased Bcl2 levels. Furthermore, alterations in histological and immunohistochemical PCNA expression were observed in rat testes, confirming the biochemical findings. Furthermore, PGPE pretreatment of LEV-treated rats restored the majority of the tested parameters when compared to the LEV-treated group. In conclusion, pomegranate peel extract had a powerful modulating role against the adverse effects of levofloxacin in rat testes and represents a perspective of the utilization of food waste by-products.

Fluoroquinolone resistance mutations among Mycobacterium tuberculosis and their interconnection with treatment outcome.

Background: Fluoroquinolone (FQ) antibiotics are among the most potent second-line antitubercular drugs these days. The aim of the study was to analyze the frequency and pattern of genetic mutation in preextensive (pre-XDR) and extensively drug-resistant Mycobacterium tuberculosis using second-line line probe assay (LPA) and to compare drug-resistant mutations with different treatment outcomes. Methods: Sputum, lymph node aspirate, and cold accesses from patients with rifampicin-resistant Tuberculosis (TB) were subjected to first-line and second-line LPA (Genotype MTBDRsl by Hain Life Science, Germany) to assess additional drug resistance to fluoroquinolones (levofloxacin and moxifloxacin). Final treatment outcomes as per the National TB Elimination Program were assessed and compared with the mutation profile. Results: One hundred and fifty subjects were observed to have mutations associated with resistance to FQs and constituted the final study population. The most frequent mutation observed among GyrA drug resistance mutation was D94G (Gyr A MUT3C, 44/150, 66%) corresponding to high-level resistance to levofloxacin and moxifloxacin. The same mutation was associated with poor treatment outcome as died or treatment failure (odds ratio 2.50, relative risk 1.67, P = 0.043). The most common hetero-resistance mutation pattern observed in GyrA gene was wild type plus Asp94Gly mutation in 24.6% of isolates. Conclusions: GyrA MUT3C hybridization corresponding to single-point mutation of aspartic acid to glycine at codon 94 constitutes the most common mutation in GyrA gene locus in M. tuberculosis with significant association with treatment outcome as died compared to those with treatment outcome as cured.

Study effect and mechanism of ofloxacin and levofloxacin on development of Rana nigromaculata tadpoles based on the hypothalamus-pituitary-thyroid axis.

Excessive antibiotics transferred into the aquatic environment may affect the development of amphibians. Previous studies on the aquatic ecological risk of ofloxacin generally ignored its enantiomers. The purpose of this study was to compare the effects and mechanisms of ofloxacin (OFL) and levofloxacin (LEV) on the early development of Rana nigromaculata. After 28-day exposure at environmental levels, we found that LEV exerted more severe inhibitory effects on the development of tadpoles than OFL. According to the enrichment results of differentially expressed genes in the LEV and OFL treatments, LEV and OFL had different effects on the thyroid development of tadpoles. dio2 and trh were affected by the regulation of dexofloxacin instead of LEV. At the protein level, LEV was the main component that affected thyroid development-related protein, while dexofloxacin in OFL had little effect on thyroid development. Furthermore, molecular docking results further confirmed that LEV was a major component affecting thyroid development-related proteins, including DIO and TSH. In summary, OFL and LEV regulated the thyroid axis by differential binding to DIO and TSH proteins, thereby exerting differential effects on the thyroid development of tadpoles. Our research is of great significance for comprehensive assessment of chiral antibiotics aquatic ecological risk.

Study of the effect of administration of narasin or antibiotics on in vivo selection of a narasin- and multidrug-resistant Enterococcus cecorum strain.

Enterococcus cecorum is a member of the normal poultry gut microbiota and an emerging poultry pathogen. Some strains are resistant to key antibiotics and coccidiostats. We evaluated the impact on chicken excretion and persistence of a multidrug-resistant E. cecorum of administering narasin or antibiotics. E. cecorum CIRMBP-1294 (Ec1294) is non-wild-type to many antimicrobials, including narasin, levofloxacin, oxytetracycline and glycopeptides, it has a low susceptibility to amoxicillin, and carries a chromosomal vanA operon. Six groups of 15 chicks each were orally inoculated with Ec1294 and two groups were left untreated. Amoxicillin, oxytetracycline or narasin were administered orally to one group each, either at the recommended dose for five days (amoxicillin, oxytetracycline) or continuously (narasin). Faecal samples were collected weekly and caecal samples were obtained from sacrificed birds on day 28. Ec1294 titres were evaluated by culture on vancomycin- and levofloxacin-supplemented media in 5 % CO2. For inoculated birds given narasin, oxytetracycline or no antimicrobials, vancomycin-resistant enterococci were searched by culture on vancomycin-supplemented media incubated in air, and a PCR was used to detect the vanA gene. Ec1294 persisted in inoculated chicks up to day 28. Compared to the control group, the Ec1294 titre was significantly lower in the amoxicillin- and narasin-receiving groups on days 21 and 28, but was unexpectedly higher in the oxytetracycline-receiving group before and after oxytetracycline administration, preventing a conclusion for this group. No transfer of the vanA gene to other enterococci was detected. Other trials in various experimental conditions should now be conducted to confirm this apparent absence of co-selection of the multi-drug-resistant E. cecorum by narasin or amoxicillin administration.

Seasonal distribution and dynamic evolution of antibiotics and evaluation of their resistance selection potential and ecotoxicological risk at a wastewater treatment plant in Jinan, China.

The seasonal distribution and dynamic evolution of antibiotics in wastewater from main treatment areas and in sludge and their resistance selection potential and ecotoxicological risk were studied at a municipal wastewater treatment plant in Jinan, East China. Ten antibiotics were selected, and all were detected in wastewater and sludge samples, with fluoroquinolones showing the highest detection concentrations and frequencies. Seasonal fluctuations in the antibiotic concentrations in the influent, effluent, and sludge were observed, with the highest values in winter in most cases. The dynamic evolution of antibiotics during the treatment process differed among the seasons. The antibiotic removal efficiencies were incomplete, ranging from - 40.47 to 100%. Mass balance analysis showed that sulfonamides, roxithromycin, and metronidazole were mainly removed through biological processing, whereas fluoroquinolones, doxycycline, and chloramphenicol were removed through sludge adsorption. Levofloxacin, as well as a mixture of the 10 antibiotics from the effluent, could pose a low ecotoxicological risk to Daphnia in the receiving waters. Additionally, levofloxacin and ciprofloxacin in the effluent and ciprofloxacin and metronidazole in the sludge may facilitate the selection of antibiotic-resistant bacteria in the environment.

Plant-based green fabrication of CuO-CdO-bentonite S-scheme heterojunction with enhanced photocatalytic performance for the degradation of levofloxacin.

In this research, for the first time, CuO and CdO nanoparticles (NPs) were synthesized using Ferula persica and anchored on layered bentonite as a novel S-scheme nano-heterojunction (denoted as CuO-CdO-BT). Ferula persica acted as a naturally-sourced reducing agent and stabilizer for the synthesis of NPs. The performance of CuO-CdO-BT was evaluated for the degradation of levofloxacin from an aqueous solution under sunlight. The characterization results clarified that the bentonite as a support not only reduced the agglomeration of CuO and CdO NPs but also decreased the size of biosynthesized NPs, which increased the active surface of NPs and the photodegardation efficiency. The effect of operational reaction system variables was examined to optimize the photocatalytic capability of CuO-CdO-BT. Under optimum conditions (catalyst dosage = 0.4 g/L, LVF concentration = 10 mg/L and pH = 8), 96.11% of levofloxacin was degraded using CuO-CdO-BT after 30 min with degradation kinetic of 0.108 min-1, which was about 2.4 and 4.2 times higher than those of bare CuO and CdO NPs, respectively. The improvement of the photocatalytic degradation efficiency of CuO-CdO-BT compared to CuO and CdO NPs was due to preventing the recombination of charge carriers in the S-scheme system. The radical quenching experiments ascertained the generation of [Formula: see text]·OH, and [Formula: see text] species in the CuO-CdO-BT system, indicating that ·OH radicals have a more prominent role than [Formula: see text] and [Formula: see text] in the photocatalytic reaction. The six possible levofloxacin pathways of LVF degradation were suggested based on HPLC-MS analysis. Over 88.5% LVF was removed using CuO-CdO-BT after three catalyst reuse cycles, indicating a cost-effectiveness potential of the biosynthesized photocatalyst reusability. Almost complete mineralization of LVF was obtained by the CuO-CdO-BT photocatalyst after 180 min of reaction. Based on findings, the S-scheme mechanism of photo-generated electron-hole pairs transfer in the CuO-CdO-BT system was found. The unique structural features of the new generation of S-scheme heterojunction and green synthesis of NPs using plants provide promising photocatalysts to improve wastewater treatment.

Effects of Catheter Tracking Management on Urinary Tract Function and Infection Rates in Patients With Spinal Cord Injury.

Context: Patients with bone-marrow injuries, such as spinal cord injuries (SCIs), usually have urinary dysfunction, changes to the urethra's anatomical structure, and pathophysiological changes of the urinary system, which can lead to urodynamic changes. If a patient receives improper treatment, repeated infections of the urinary system can easily occur, causing hydronephrosis and damage to renal function. Objective: The study intended to explore the effects of catheter follow-up management for patients with SCIs on the function of the bladder and the urinary tract and on urinary tract infections (UTIs), selecting antibiotics reasonably according to a bacterial culture and drug sensitivity test. Design: The research team designed a randomized controlled trial. Setting: The study took place at the Hebei Cangzhou Hospital of Integrated Traditional Chinese Medicine (TCM)-Western Medicine (WM) in Cangzhou City, Hebei Province, People's Republic of China. Participants: Participants were 92 patients with SCIs who were treated at the hospital between January 2020 and December 2021. Intervention: The research team randomly divided participants into an intervention group (n = 45) and a control group (n = 47). The control group received routine treatment, while the intervention group received catheter follow-up management. Outcome Measures: At baseline and postintervention after six weeks of treatment, the research team: (1) examined participants' bladder function, (2) examine urodynamic indexes including measurement of the maximum bladder volume, maximum urethral closure pressure, maximum urinary flow rate, and maximum detrusor pressure, and (3) assessed participants' QoL using the World Health Organization Quality of Life Questionnaire Abbreviated (WHOQOL-BREF). Results: Improvements in bladder function, urodynamic indexes, QoL, and UTIs occurred in both groups. The intervention group's: (1) total effective rate for bladder function was 91.11%, which was significantly higher than that of the control group (P = .022); (2) maximal bladder volume, urethral closure pressure, and urinary flow rate were 365.59 ± 54.43 ml, 81.19 ± 8.8 cmH2O, and 18.60 ± 2. 43 ml/s, respectively, and were significantly higher than those of the control group (all P = .000); (3) maximal detrusor pressure was 47.48 ± 5.64 cmH2O, which was significantly lower than that of the control group (p=0.000); (4) scores on the WHOQOL-BREF's subdimensions and total score were significantly higher than those in the control group: psychological, 17.92 ± 1.55; physiological, 30.30 ± 1.82; independence, 22.43 ± 1.40; social relations, 16.82 ± 1.32; environment, 21.19 ± 1.85; and total score, 110.02 ±16.64 (all P = .000); (5) incidence of urinary tract infection was 17.78 which was significantly lower than that of the control group (P = .003). The distribution of bacterial species in the UTIs of the intervention and control groups wasn't significantly different (P = .869). The two bacterial groups were Escherichia coli and Enterococcus. Drug sensitivity tests showed that the Escherichia coli were less susceptible to gentamicin, levofloxacin, and piperacillin than to ciprofloxacin, and the Enterococcus were less susceptible to gentamicin, ciprofloxacin, and levofloxacin than to piperacillin. Conclusions: For patients with SCIs, catheter follow-up management can be helpful in restoring the function of the bladder and urinary tract, can improve patients' QoL, and reduce their rate of UTIs. Clinically, medical practitioners should select antibiotics reasonably according to a bacterial culture and drug-sensitivity test.

Antimicrobial Resistance of Helicobacter Pylori Among Low-resource Chinese Minorities.

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.

UHPLC-MS/MS method for simultaneous quantification of doripenem, meropenem, ciprofloxacin, levofloxacin, pazufloxacin, linezolid, and tedizolid in filtrate during continuous renal replacement therapy.

BACKGROUND: Since severe infections frequently cause acute kidney injury (AKI), continuous renal replacement therapy (CRRT) is often initiated for regulation of inflammatory mediators and renal support. Thus, it is necessary to decide the antibiotic dosage considering the CRRT clearance in addition to residual renal function. Some of the hemofilters used in CRRT are known to adsorb antibiotics, and clearance of antibiotics may differ depending on the adsorptive characteristics of hemofilters. Although assay systems for blood and CRRT filtrate concentrations are required, no method for measuring antibiotics concentrations in filtrate has been reported. We developed a UHPLC-MS/MS method for simultaneous quantification of antibiotics commonly used in ICU, comprising carbapenems [doripenem (DRPM) and meropenem (MEPM)], quinolones [ciprofloxacin (CPFX), levofloxacin (LVFX) and pazufloxacin (PZFX)] and anti-MRSA agents [linezolid (LZD), and tedizolid (TZD)] in CRRT filtrate samples. METHODS: Filtrate samples were pretreated by protein precipitation. The analytes were separated with an ACQUITY UHPLC CSH C18 column under a gradient mobile phase consisting of water and acetonitrile containing 0.1% formic acid and 2 mM ammonium formate. RESULTS: The method showed good linearity over wide ranges. Within-batch and batch-to-batch accuracy and precision for each drug fulfilled the criteria of the US Food and Drug Administration guidance. The recovery rate was more than 87.20%. Matrix effect ranged from 99.57% to 115.60%. Recovery rate and matrix effect did not differ remarkably between quality control samples at different concentrations. CONCLUSION: This is the first report of a simultaneous quantification method of multiple antibiotics in filtrate of CRRT circuit.

Levofloxacin loaded clove oil nanoscale emulgel promotes wound healing in Pseudomonas aeruginosa biofilm infected burn wound in mice.

Owing to their tolerance to antibiotics, bacterial biofilms continue to pose a threat to mankind and are leading cause for non-healing of burn wounds. Within the biofilm matrix, antibiotics become functionally inactive due to restricted penetration and enzymatic degradation leading to rise of antimicrobial resistance. The objective of present investigation was to develop and characterize levofloxacin (LFX) loaded clove oil nanoscale emulgel (LFX-NE gel) and evaluate its in vivo therapeutic efficacy in Pseudomonas aeruginosa biofilm infected burn wound in mice. The optimized emulgel was found to possess good texture profile and showed shear thinning behavior. In vitro release study demonstrated complete drug release in 8 h and emulgel was found to be stable for 3 months at 25 °C and 40 °C. In vivo study revealed biofilm dispersal, complete wound closure, re-epithelialization and collagen deposition by LFX-NE gel in comparison to various control groups. LFX-NE gel was able to clear the infection within 7 days of treatment and promote wound healing as well. Therefore, administration of LFX-incorporated NE gel could be a beneficial treatment strategy for P. aeruginosa biofilm-infected burn wounds.

Second-line levofloxacin-based quadruple therapy versus bismuth-based quadruple therapy for Helicobacter pylori eradication and long-term changes to the gut microbiota and antibiotic resistome: a multicentre, open-label, randomised controlled trial.

BACKGROUND: Levofloxacin-based therapy or bismuth-based quadruple therapy are the recommended second-line regimens for Helicobacter pylori eradication after failure of clarithromycin-based therapy. However, resistance to levofloxacin has increased in the past decade. Furthermore, little is known about the long-term effects of H pylori eradication on the antibiotic resistome. In this study, we compared these second-line eradication therapies for efficacy, tolerability, and short-term and long-term effects on the gut microbiota, antibiotic resistome, and metabolic parameters. METHODS: We did a multicentre, open-label, parallel group, randomised controlled trial at eight hospitals in Taiwan. Adult patients (age ≥20 years) with persistent H pylori infection after first-line clarithromycin-based therapy were randomly assigned (1:1, permuted block sizes of four) to receive levofloxacin-based sequential quadruple therapy for 14 days (EAML14; esomeprazole 40 mg and amoxicillin 1 g for 7 days, followed by esomeprazole 40 mg, metronidazole 500 mg, and levofloxacin 250 mg for 7 days, all twice-daily) or bismuth-based quadruple therapy for 10 days (BQ10; esomeprazole 40 mg twice daily, bismuth tripotassium dicitrate 300 mg four times a day, tetracycline 500 mg four times a day, and metronidazole 500 mg three times a day). All investigators were masked to the randomisation sequence. The primary endpoint was H pylori eradication rate measured by 13C urea breath test 6 weeks after second-line treatment according to both intention-to-treat (ITT) and per-protocol analysis. The microbiota composition and antibiotic resistome of faecal samples collected at baseline (before treatment) and at 2 weeks, 8 weeks, and 1 year after eradication therapy was profiled by shotgun metagenomic sequencing and 16S rRNA gene sequencing. The frequency of adverse effects and changes in the gut microbiota and antibiotic resistome were assessed in all participants with available data. The trial is complete and registered with ClinicalTrails.gov, NCT03148366. FINDINGS: Between Feb 25, 2015, and Dec 11, 2020, 560 patients were randomly assigned to receive EAML14 or BQ10 (n=280 per group; 261 [47%] men and 299 [53%] women). Mean age was 55·9 years (SD 12·7) in the EAML14 group and 54·9 years (12·3) in the BQ10 group. Eradication of H pylori was achieved in 246 (88%) of 280 participants in the EAML14 group and 245 (88%) of 280 in the BQ10 group according to ITT analysis (risk difference -0·4%, 95% CI -5·8 to 5·1; p=0·90). In the per-protocol analysis, 246 (90%) of 273 participants in the EAML14 group and 245 (93%) of 264 participants in the BQ10 group achieved H pylori eradication (risk difference 2·7%, 95% CI -0·2 to 7·4; p=0·27). Transient perturbation of faecal microbiota diversity at week 2 was largely restored to basal state 1 year after EAML14 or BQ10. Diversity recovery was slower with BQ10, and recovery in species abundance was partial after both therapies. On shotgun sequencing, we observed significant increases in total resistome after EAML14 (p=0·0002) and BQ10 (p=4·3 × 10-10) at week 2, which were restored to pretreatment level by week 8. The resistance rates of Escherichia coli and Klebsiella pneumonia to levofloxacin, ciprofloxacin, ampicillin (ampicillin-sulbactam for K pneumonia), and various cephalosporins were significantly increased in the EAML14 group compared with in the BQ10 group at week 2, which were restored to pretreatment levels and showed no significant differences at week 8 and 1 year. The frequency of any adverse effects was significantly higher after BQ10 therapy (211 [77%] of 273 participants) than after EAML14 therapy (134 [48%] of 277; p<0·0001). INTERPRETATION: We found no evidence of superiority between levofloxacin-based quadruple therapy and bismuth-based quadruple therapy in the second-line treatment of H pylori infection. The transient increase in the antibiotic resistome and perturbation of faecal microbiota diversity were largely restored to pretreatment state from 2 months to 1 year after eradication therapy. FUNDING: The Ministry of Science and Technology of Taiwan, the Ministry of Health and Welfare of Taiwan, National Taiwan University Hospital, Taipei Veteran General Hospital, and the Australian Federal Government through the St George and Sutherland Medical Research Foundation. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Transcriptomic and Functional Approaches Unveil the Role of tmRNA in Zinc Acetate Mediated Levofloxacin Sensitivity in Helicobacter pylori.

Rapid increase in resistance of Helicobacter pylori (H. pylori) has hindered antibiotics-based eradication efforts worldwide and raises the need for additional approaches. Here, we investigate the role of zinc-based compounds in inhibiting H. pylori growth and modulating antibiotic sensitivities, interrogate their downstream transcriptomic changes, and highlight the potential mechanism driving the observed effects. We showed that zinc acetate inhibited H. pylori growth and increased H. pylori sensitivity to levofloxacin. Transcriptomic profiling showed distinct gene expression patterns between zinc acetate treated groups versus controls. In particular, we independently replicated the association between zinc acetate treatment and increased ssrA expression. Knockdown of ssrA restored levofloxacin resistance to levels of the control group. In this study, we first demonstrated the role of zinc acetate in H. pylori growth and antibiotic sensitivities. Additionally, we explored the transcriptomic perturbations of zinc acetate followed by functional knockdown follow-up of differentially expressed ssrA, highlighting the role of tmRNA and trans-translation in H. pylori levofloxacin resistance. Our results provide alternative and complementary strategies for H. pylori treatment and shed light on the underlying mechanisms driving these effects. IMPORTANCE Helicobacter pylori (H. pylori) eradication plays an important role in gastric cancer prevention, but the antimicrobial resistance of H. pylori is fast becoming a growing concern. In this study, we investigated the role of zinc acetate in inhibiting H. pylori growth and modulating antibiotic sensitivities in vitro. Additionally, we explored the transcriptomic perturbations of zinc acetate followed by functional knockdown follow-up of differentially expressed ssrA, highlighting the role of tmRNA and trans-translation in H. pylori levofloxacin resistance. Our results open up a new horizon for the treatment of antibiotic-resistant H. pylori.

The treatment effect of Levofloxacin, Moxifloxacin, and Gatifloxacin contained in the conventional therapy regimen for pulmonary tuberculosis: Systematic review and network meta-analysis.

BACKGROUND: Tuberculosis (TB) is one of the serious epidemics that highly threaten the global public health. To explore the treatment effect of Levofloxacin, Moxifloxacin, and Gatifloxacin contained in the conventional therapy regimen for pulmonary tuberculosis. METHODS: Medline, PubMed, Embase, and Cochrane Library were searched with the keyword such as "Levofloxacin," "Moxifloxacin," "Gatifloxacin," and "tuberculosis", through June 1992 to 2017. According to the inclusion and exclusion criteria, 2 researchers independently screened the literature, extracted the data, and evaluated the quality of the included studies. The Cochrane system was evaluated by RevMan5.2 and the network meta-analysis was performed by Stata 15. RESULTS: A total of 891 studies were included, with a total of 6565 patients. The results of network meta-analysis showed that Moxifloxacin + conventional therapy (CT) regimen was superior to CT regimen only on the spectrum culture negative. Both Levofloxacin + CT and Moxifloxacin + CT were superior to the CT regimen in treatment success rate. For the adverse events, the Levofloxacin + CT showed much safer results than CT group, while Moxifloxacin + CT had more adverse events than CT group. CONCLUSION: Levofloxacin, Moxifloxacin, and Gatifloxacin have different superiority, comparing to CT regimen in spectrum culture negative, treatment success rate, and adverse events. Hence, combined utilization of these quinolone is important on the clinical treatment for tuberculosis.

Postexposure Prophylaxis and Treatment of Bacillus anthracis Infections: A Systematic Review and Meta-analyses of Animal Models, 1947-2019.

BACKGROUND: Anthrax is endemic to many countries, including the United States. The causative agent, Bacillus anthracis, poses a global bioterrorism threat. Without effective antimicrobial postexposure prophylaxis (PEPAbx) and treatment, the mortality of systemic anthrax is high. To inform clinical guidelines for PEPAbx and treatment of B. anthracis infections in humans, we systematically evaluated animal anthrax treatment model studies. METHODS: We searched for survival outcome data in 9 scientific search engines for articles describing antimicrobial PEPAbx or treatment of anthrax in animals in any language through February 2019. We performed meta-analyses of efficacy of antimicrobial PEPAbx and treatment for each drug or drug combination using random-effects models. Pharmacokinetic/pharmacodynamic relationships were developed for 5 antimicrobials with available pharmacokinetic data. Monte Carlo simulations were used to predict unbound drug exposures in humans. RESULTS: We synthesized data from 34 peer-reviewed studies with 3262 animals. For PEPAbx and treatment of infection by susceptible B. anthracis, effective monotherapy can be accomplished with fluoroquinolones, tetracyclines, ß-lactams (including penicillin, amoxicillin-clavulanate, and imipenem-cilastatin), and lipopeptides or glycopeptides. For naturally occurring strains, unbound drug exposures in humans were predicted to adequately cover the minimal inhibitory concentrations (MICs; those required to inhibit the growth of 50% or 90% of organisms [MIC50 or MIC90]) for ciprofloxacin, levofloxacin, and doxycycline for both the PEPAbx and treatment targets. Dalbavancin covered its MIC50 for PEPAbx. CONCLUSIONS: These animal studies show many reviewed antimicrobials are good choices for PEPAbx or treatment of susceptible B. anthracis strains, and some are also promising options for combating resistant strains. Monte Carlo simulations suggest that oral ciprofloxacin, levofloxacin, and doxycycline are particularly robust choices for PEPAbx or treatment.

The Medium Composition Impacts Staphylococcus aureus Biofilm Formation and Susceptibility to Antibiotics Applied in the Treatment of Bone Infections.

The biofilm-associated infections of bones are life-threatening diseases, requiring application of dedicated antibiotics in order to counteract the tissue damage and spread of microorganisms. The in vitro analyses on biofilm formation and susceptibility to antibiotics are frequently carried out using methods that do not reflect conditions at the site of infection. To evaluate the influence of nutrient accessibility on Staphylococcus aureus biofilm development in vitro, a cohesive set of analyses in three different compositional media was performed. Next, the efficacy of four antibiotics used in bone infection treatment, including gentamycin, ciprofloxacin, levofloxacin, and vancomycin, against staphylococcal biofilm, was also assessed. The results show a significant reduction in the ability of biofilm to grow in a medium containing elements occurring in the serum, which also translated into the diversified changes in the efficacy of used antibiotics, compared to the setting in which conventional media were applied. The differences indicate the need for implementation of adequate in vitro models that closely mimic the infection site. The results of the present research may be considered an essential step toward the development of in vitro analyses aiming to accurately indicate the most suitable antibiotic to be applied against biofilm-related infections of bones.