暂无摘要。

Managing ocular microbial infections typically requires pharmacotherapy using antibiotic eye drops, such as moxifloxacin hydrochloride (MFX), combined with an antifungal agent like amphotericin B (AB). We carried out and validated an LC-MS/MS assay to quantify these compounds in rabbit tear fluid in order to look into the pharmacokinetics of these two drugs. We employed a protein precipitation technique for the extraction of drugs under examination. A Waters Symmetry C18 column was used to separate the analytes and internal standard. The composition of the mobile phase was like (A) 0.1% v/v formic acid in water and (B) methanol. The detection of MFX and AB was accomplished through the utilization of positive ion electrospray ionization under multiple reaction monitoring mode. The linearity curves for both analytes exhibited an acceptable trendline across a concentration range of 2.34-300 ng/mL for MFX and 7.81-1000 ng/mL for AB in surrogate rabbit tear fluid. The lower limit of quantitation for MFX was 2.34 ng/mL, while for AB, it was 7.81 ng/mL. The approach was strictly validated, encompassing tests of selectivity, linearity (with r2 > 0.99), precision, accuracy, matrix effects, and stability. Consequently, we employed this method to evaluate the pharmacokinetics profiles of MFX and AB in rabbit tear fluid following single topical doses.

BACKGROUND: Despite several incremental improvements in the management of tuberculous meningitis (TBM), the mortality rates remain high. In spite of national and international guidelines, variation in the choice, dose, and duration of drugs exist between countries and clinicians. We propose to evaluate a shorter and more effective regimen containing agents with augmented intracerebral drug exposure and anti-inflammatory approaches to improve disability-free survival among patients with TBM. Our strategy incorporates the various developments in the field of TBM over the last two decades and only few trials have evaluated a composite of these strategies in the overall outcomes of TBM.
METHODS: An open label, parallel arms, randomized controlled superiority trial will be conducted among 372 participants across 6 sites in India. Eligible participants will be randomly allocated in 1:1:1 ratio into one of the three arms. The intervention arm consists of 2 months of high-dose rifampicin (25 mg/kg), moxifloxacin (400 mg), pyrazinamide, isoniazid, aspirin (150 mg), and steroids followed by rifampicin, isoniazid, and pyrazinamide for 4 months. The second intervention arm includes all the drugs as per the first arm except aspirin and the patients in the control arm will receive treatment according to the National TB Elimination Program guidelines. All participants will be followed up for 1 year after the treatment.  DISCUSSION: Current WHO regimens have agents with poor central nervous system drug exposure and is too long. It does not reflect the accumulating evidence in the field. We propose a comprehensive clinical trial incorporating the emerging evidence accrued over the last two decades to shorten the duration and improve the treatment outcomes. This multi-centric trial may generate crucial evidence with policy and practice implications in the treatment of TBM.
BACKGROUND: Clinical Trial Registry India CTRI/2023/05/053314. Registered on 31 May 2023 ( https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=ODYzMzg=&Enc=&userName=CTRI/2023/05/053314 ).
RESULTS: gov NCT05917340. Registered on 6 August 2023 ( https://classic.
RESULTS: gov/ct2/show/NCT05917340 ).
METHODS: Version 1.3 dated 12 July 2023.

OBJECTIVE: The hollow‐fibre system for tuberculosis (HFS‐TB) is a preclinical model qualified by the European Medicines Agency to underpin the anti‐TB drug development process. It can mimic in vivo pharmacokinetic (PK)–pharmacodynamic (PD) attributes of selected antimicrobials, which could feed into in silico models to inform the design of clinical trials. However, historical data and published protocols are insufficient and omit key information to allow experiments to be reproducible. Therefore, in this work, we aim to optimize and standardize various HFS‐TB operational procedures.
METHODS: First, we characterized bacterial growth dynamics with different types of hollow‐fibre cartridges, Mycobacterium tuberculosis strains and media. Second, we mimicked a moxifloxacin PK profile within hollow‐fibre cartridges, in order to check drug–fibres compatibility. Lastly, we mimicked the moxifloxacin total plasma PK profile in human after once daily oral dose of 400 mg to assess PK–PD after different sampling methods, strains, cartridge size and bacterial adaptation periods before drug infusion into the system.
RESULTS: We found that final bacterial load inside the HFS‐TB was contingent on the studied variables. Besides, we demonstrated that drug–fibres compatibility tests are critical preliminary HFS‐TB assays, which need to be properly reported. Lastly, we uncovered that the sampling method and bacterial adaptation period before drug infusion significantly impact actual experimental conclusions.
CONCLUSIONS: Our data contribute to the necessary standardization of HFS‐TB experiments, draw attention to multiple aspects of this preclinical model that should be considered when reporting novel results and warn about critical parameters in the HFS‐TB currently overlooked.

OBJECTIVE: Staphylococcus epidermidis bone and joint infections (BJIs) on material are often difficult to treat. The activity of delafloxacin has not yet been studied on S. epidermidis in this context. The aim of this study was to assess its in vitro activity compared with other fluoroquinolones, against a large collection of S. epidermidis clinical strains.
METHODS: We selected 538 S. epidermidis strains isolated between January 2015 and February 2023 from six French teaching hospitals. One hundred and fifty-two strains were ofloxacin susceptible and 386 were ofloxacin resistant. Identifications were performed by MS and MICs were determined using gradient concentration strips for ofloxacin, levofloxacin, moxifloxacin and delafloxacin.
RESULTS: Ofloxacin-susceptible strains were susceptible to all fluoroquinolones. Resistant strains had higher MICs of all fluoroquinolones. Strains resistant to ofloxacin (89.1%) still showed susceptibility to delafloxacin when using the Staphylococcus aureus 2021 CA-SFM/EUCAST threshold of 0.25 mg/L. In contrast, only 3.9% of the ofloxacin-resistant strains remained susceptible to delafloxacin with the 0.016 mg/L S. aureus breakpoint according to CA-SFM/EUCAST guidelines in 2022. The MIC50 was 0.094 mg/L and the MIC90 was 0.38 mg/L.
CONCLUSIONS: We showed low delafloxacin MICs for ofloxacin-susceptible S. epidermidis strains and a double population for ofloxacin-resistant strains. Despite the absence of breakpoints for S. epidermidis, delafloxacin may be an option for the treatment of complex BJI, including strains with MICs of ≤0.094 mg/L, leading to 64% susceptibility. This study underlines the importance for determining specific S. epidermidis delafloxacin breakpoints for the management of BJI on material.

UNASSIGNED: Shorter regimens for drug-resistant tuberculosis (DR-TB) have non-inferior efficacy compared with longer regimens, but QT prolongation is a concern. T-wave morphology abnormalities may be a predictor of QT prolongation.
UNASSIGNED: STREAM Stage 1 was a randomized controlled trial in rifampicin-resistant TB, comparing short and long regimens. All participants had regular ECGs. QT/QTcF prolongation (≥500 ms or increase in ≥60 ms from baseline) was more common on the short regimen which contained high-dose moxifloxacin and clofazimine. Blinded ECGs were selected from the baseline, early (weeks 1-4), and late (weeks 12-36) time points. T-wave morphology was categorized as normal or abnormal (notched, asymmetric, flat-wave, flat peak, or broad). Differences between groups were assessed using Chi-Square tests (paired/unpaired, as appropriate).
UNASSIGNED: Two-hundred participants with available ECGs at relevant times were analyzed (QT prolongation group n = 82; non-prolongation group n = 118). At baseline, 23% (45/200) of participants displayed abnormal T-waves, increasing to 45% (90/200, p < 0.001) at the late time point. Abnormalities were more common in participants allocated the Short regimen (75/117, 64%) than the Long (14/38, 36.8%, p = 0.003); these occurred prior to QT/QTcF ≥500 ms in 53% of the participants (Long 2/5; Short 14/25).
UNASSIGNED: T-wave abnormalities may help identify patients at risk of QT prolongation on DR-TB treatment.
UNASSIGNED: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02409290). Current Controlled Trial number, ISRCTN78372190.

Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator used as an oral treatment option for immune-mediated inflammatory disorders. This randomized, double-blind, placebo- and positive-controlled, parallel-group, healthy adult study investigated etrasimod\'s effect on the QT interval and other electrocardiogram parameters. All participants received etrasimod-matched placebo on day 1. Group A received once-daily, multiple ascending doses of etrasimod (2-4 mg) on days 1-14 and moxifloxacin-matched placebo on days 1 and 15. Group B received etrasimod-matched placebo on days 1-14 and either moxifloxacin 400 mg or moxifloxacin-matched placebo on days 1 and 15. The primary analysis was a concentration-QTc analysis using a corrected QT interval by Fridericia (QTcF). The etrasimod concentration-QTc analysis predicted placebo-corrected change from baseline QTcF (ΔΔQTcF) values and associated 90% confidence intervals remained <10 milliseconds over the observed etrasimod plasma concentration range (≤279 ng/mL). Etrasimod was associated with mild, transient, asymptomatic heart rate slowing that was most pronounced on day 1 (2 mg, first dose). The largest-by-time point mean placebo-corrected changes in heart rate from time-matched day -1 baseline (∆∆HR) on days 1, 7 (2 mg, last dose), and 14 (4 mg, last dose) were -15.1, -8.5, and -6.0 bpm, respectively. Etrasimod\'s effects on PR interval were small, with the largest least squares mean placebo-corrected change from baseline in PR interval (∆∆PR) being 6.6 milliseconds. No episodes of atrioventricular block were observed. Thus, multiple ascending doses of etrasimod were not associated with clinically relevant QT/QTc effects in healthy adults and only had a mild, transient, and asymptomatic impact on heart rate.

A single-center, phase I, partially double-blind (double-blind regarding doses of rimegepant and placebo, and open label with respect to moxifloxacin), randomized, 12-sequence, four-period crossover study of therapeutic (75 mg) and supratherapeutic (300 mg) doses of rimegepant with placebo and moxifloxacin (400 mg) controls was designed to evaluate drug effect on the Fridericia corrected QT (QTcF) interval in healthy fasted adults. A total of 38 participants were randomized and dosed in the study. Electrocardiogram (ECG) data were available from 37 participants in the rimegepant 75-mg group, 38 participants in the rimegepant 300-mg group, and 36 participants in the moxifloxacin and placebo groups. Both the 75- and 300-mg doses of rimegepant had no clinically relevant effect on ECG parameters, including QTcF, heart rate, PR and QRS interval, T-wave morphology, and U-wave presence. All upper 90% confidence intervals for the QTcF effect with rimegepant were less than or equal to 4.69 ms, well below the 10-ms threshold for potential clinical significance. Assay sensitivity was demonstrated by the QT effect of moxifloxacin. Using both by-timepoint and concentration-QTc analysis, a placebo-corrected change-from-baseline QTcF greater than 10 ms could be excluded for rimegepant plasma concentrations up to ~10,000 ng/mL, representing concentrations at least 10.8-fold the maximum observed concentration of the 75-mg therapeutic dose of rimegepant.

OBJECTIVE: To investigate the clinical characteristics and prognosis of pneumococcal meningitis (PM), and drug sensitivity of Streptococcus pneumoniae (SP) isolates in Chinese children.
METHODS: A retrospective analysis was conducted on clinical information, laboratory data, and microbiological data of 160 hospitalized children under 15 years old with PM from January 2019 to December 2020 in 33 tertiary hospitals across the country.
RESULTS: Among the 160 children with PM, there were 103 males and 57 females. The age ranged from 15 days to 15 years, with 109 cases (68.1%) aged 3 months to under 3 years. SP strains were isolated from 95 cases (59.4%) in cerebrospinal fluid cultures and from 57 cases (35.6%) in blood cultures. The positive rates of SP detection by cerebrospinal fluid metagenomic next-generation sequencing and cerebrospinal fluid SP antigen testing were 40% (35/87) and 27% (21/78), respectively. Fifty-five cases (34.4%) had one or more risk factors for purulent meningitis, 113 cases (70.6%) had one or more extra-cranial infectious foci, and 18 cases (11.3%) had underlying diseases. The most common clinical symptoms were fever (147 cases, 91.9%), followed by lethargy (98 cases, 61.3%) and vomiting (61 cases, 38.1%). Sixty-nine cases (43.1%) experienced intracranial complications during hospitalization, with subdural effusion and/or empyema being the most common complication [43 cases (26.9%)], followed by hydrocephalus in 24 cases (15.0%), brain abscess in 23 cases (14.4%), and cerebral hemorrhage in 8 cases (5.0%). Subdural effusion and/or empyema and hydrocephalus mainly occurred in children under 1 year old, with rates of 91% (39/43) and 83% (20/24), respectively. SP strains exhibited complete sensitivity to vancomycin (100%, 75/75), linezolid (100%, 56/56), and meropenem (100%, 6/6). High sensitivity rates were also observed for levofloxacin (81%, 22/27), moxifloxacin (82%, 14/17), rifampicin (96%, 25/26), and chloramphenicol (91%, 21/23). However, low sensitivity rates were found for penicillin (16%, 11/68) and clindamycin (6%, 1/17), and SP strains were completely resistant to erythromycin (100%, 31/31). The rates of discharge with cure and improvement were 22.5% (36/160) and 66.2% (106/160), respectively, while 18 cases (11.3%) had adverse outcomes.
CONCLUSIONS: Pediatric PM is more common in children aged 3 months to under 3 years. Intracranial complications are more frequently observed in children under 1 year old. Fever is the most common clinical manifestation of PM, and subdural effusion/emphysema and hydrocephalus are the most frequent complications. Non-culture detection methods for cerebrospinal fluid can improve pathogen detection rates. Adverse outcomes can be noted in more than 10% of PM cases. SP strains are high sensitivity to vancomycin, linezolid, meropenem, levofloxacin, moxifloxacin, rifampicin, and chloramphenicol.
目的: 研究中国儿童肺炎链球菌脑膜炎（pneumococcal meningitis, PM）的临床特征、转归和分离菌株肺炎链球菌（Streptococcus pneumoniae, SP）的药物敏感性。方法: 回顾性分析2019年1月—2020年12月全国33家三级甲等医院160例<15岁的PM住院患儿的临床信息、实验室资料和微生物学资料。结果: 160例PM患儿中，男103例，女57例；年龄15 d至15岁，其中3月龄至<3岁109例（68.1%）。脑脊液培养分离SP菌株95例（59.4%），血培养分离SP菌株57例（35.6%）。脑脊液宏基因组二代测序和脑脊液SP抗原检测阳性率分别为40%（35/87）、27%（21/78）。55例（34.4%）患儿存在1个或多个化脓性脑膜炎高危因素；113例（70.6%）患儿有1个或多个颅外感染病灶；18例（11.3%）有明确基础疾病。临床症状以发热最常见（147例，91.9%），其次是精神萎靡（98例，61.3%）、呕吐（61例，38.1%）等。69例（43.1%）患儿住院期间发生颅内并发症，常见并发症为硬膜下积液和/或积脓（43例，26.9%）、脑积水（24例，15.0%）、脑脓肿（23例，14.4%）、脑出血（8例，5.0%）。硬膜下积液和/或积脓和脑积水主要发生在<1岁患儿，分别为91%（39/43）、83%（20/24）。SP菌株对万古霉素（100%，75/75）、利奈唑胺（100%，56/56）、厄他培南（100%，6/6）完全敏感；对左氧氟沙星（81%，22/27）、莫西沙星（82%，14/17）、利福平（96%，25/26）和氯霉素（91%，21/23）敏感率高；对青霉素（16%，11/68）、克林霉素（6%，1/17）敏感率低；对红霉素完全耐药（100%，31/31）。痊愈和好转出院率分别为22.5%（36/160）、66.2%（106/160）；18例（11.3%）出现不良结局。结论: 儿童PM多见于3月龄至<3岁婴幼儿，颅内并发症多发生在<1岁患儿，发热是PM患儿最常见的临床表现，硬膜下积液和/或积脓、脑积水是最常见的并发症。脑脊液非培养检测方法有助于提高病原菌检出率。超过10% PM患儿出现不良结局。SP菌株对万古霉素、利奈唑胺、厄他培南、左氧氟沙星、莫西沙星、利福平、氯霉素敏感率高。.

OBJECTIVE: To compare the effect of povidone-iodine (PI) 5% and moxifloxacin 0.5% solutions versus PI 5% solution alone on the conjunctival bacterial flora.
METHODS: This is a comparative study in which the study population comprised adult patients scheduled for elective small incision cataract surgery. The eye to be operated (control eye) received topical moxifloxacin 0.5% drops 4 times, 1 day before surgery and 2 applications on the day of surgery. As placebo, the contralateral eye (study eye) received saline 0.90% drops as per the same schedule. Before surgery, on table, PI 5% was instilled in the conjunctival sac in both eyes. Conjunctival swabs were taken before initiation of therapy and 3 min after instillation of PI.
RESULTS: Of the 96 pairs of eyes included in the study, conjunctival cultures before prophylaxis were similar between the two groups (p = 0.31), with 54 samples (56%) of the study group and 49 (51%) of the control group showing growth. With positive cultures reducing to 7 (14%) in the study group and 8 (16%) in the control group, both the prophylaxis methods appeared equally efficacious (p = 0.79). Both the groups showed a significant reduction in positive cultures following prophylaxis (p < 0.0001).
CONCLUSIONS: PI 5% alone as preoperative prophylaxis was as effective as its combination therapy with moxifloxacin 0.5% in the reduction in conjunctival bacterial colonization.