Clofazimine (CLF) is a riminophenazine derivative and a new therapeutic option with high efficacy for patients with rifampicin-resistant tuberculosis (TB). The blood levels of CLF are low and suboptimal, so therapeutic drug monitoring is required. Prior to this study, there were no molecular imprinting-based solid phase extraction (SPE) sorbents that could be used to determine the blood CLF levels. Hence, we prepared a magnetic molecularly imprinted polymer (MMIPs) to capture CLF. We employed computational selection of a functional monomer and crosslinker and confirmed these selections based on the association constant (K a) and a Job plot. We synthesised MMIPs with two surface modifiers and characterized the polymers. Our computational analysis based on the bond energy revealed that methyl methacrylate (MMA) was the most suitable functional monomer at a CLF-to-MMA molar ratio of 1:4. Based on the bond energy, the most suitable crosslinker was trimethylolpropane trimethacrylate (TRIM) at a CLF-to-TRIM molar ratio of 1:1. We determined the K a of MMA and TRIM in different solvents. Isopropanol produced the highest K a. The Job plot showed that a template-to-MMA-to-TRIM molar ratio of 1:4:20 was optimal to synthesize imprinted polymer in isopropanol. We prepared MMIPs using two different modifiers, namely aminopropyltrimethoxysilane (APTES) and oleic acid (OA), using the ratio determined from the Job plot. Physical characteristic tests carried out using FT-IR, SEM-EDS, PSA, BET and VSM, showed that the synthesis was success with a spherical and uniform agglomeration of particles, also a flat surface with many holes with a particle size of MMIP-APTES and MMIP-OA respectively 0.14 μm and 0.28 μm, showed a surface area for MMIP-APTES is 2874.51 m2/g and MMIP-OA 2913.07 m2/g, exhibiting superparamagnetic properties with a saturation magnetization value of MMIP-APTES 21.1 emu/g-1 and MMIP-OA 49.9 emu/g-1. Adsorption capacity result showed that MMIP-OA fits well with the Langmuir model, while MMIP-APTES fits better with the Freundlich. Application of MMIP-SPE (Magnetic Molecular Imprinted Polymer-Solid Phase Extraction) APTES resulted 92.3 ± 6.1 % and MMIP-SPE-OA 51.5 ± 8.1 % for recovering CLF in blood. The result of selectivity test also showed that MMIP-SPE-APTES is better than MMIP-SPE-OA and selectively recover CLF from human blood plasma existed together with other TB-Drugs. The study result shows that MMIPs with APTES modification can be used for CLF determination in human blood plasma.

Clofazimine is an antimycobacterial, anti-inflammatory agent used in the management of leprosy and multidrug-resistant (MDR) tuberculosis. It has high oral bioavailability and poor solubility because of which prolonged administration of the drug results in its accumulation as intracellular biocrystals in tissue macrophages. We describe the case of a female patient in her early 30s who was on therapy for MDR tuberculosis. She presented with streaky haemoptysis of 6 months. Radiographic examination showed no abnormality in pulmonary vasculature and parenchyma. Bronchoscopy showed diffuse red-coloured flecks in tracheal and bronchial mucosa. The retrieved bronchoalveolar lavage (BAL) fluid was reddish-purple in colour. Microscopic examination of BAL fluid showed reddish clofazimine crystal deposition in alveolar macrophages. Serum and BAL clofazimine levels were performed using high performance liquid chromatography which confirmed high drug levels. She developed reddish discolouration of the skin during therapy due to clofazimine deposition. A diagnosis of pulmonary clofazimine crystal deposition syndrome causing pseudohaemoptysis was established.

暂无摘要。

Treatment outcomes for Mycobacteroides abscessus (Mab, also known as Mycobacterium abscessus) disease are still unsatisfactory, mainly due to issues with drug toxicity, tolerability, and efficacy. Treating Mab disease is challenging due to its high baseline antibiotic resistance, initial requirement for intravenous therapy, and poor medication tolerance. Omadacycline, a new tetracycline, is active against Mab. Since any new antibiotic effective against Mab is expected to be used in combination with other antibiotics, we evaluated the efficacy of two triple-drug combinations comprising omadacycline, omadacycline + amikacin + imipenem, and omadacycline + clofazimine + linezolid against two contemporary Mab clinical isolates in a mouse model of Mab lung disease. Antibiotic administration was initiated 1-week post-infection and was given daily, with Mab burden in the lungs at treatment completion serving as the endpoint. Omadacycline alone moderately reduced Mab levels and maintained better health in mice compared to untreated ones, which typically suffered from the infection. The omadacycline + clofazimine + linezolid combination showed immediate bactericidal activity and enhanced efficacy over 6 weeks, particularly against the more resistant strain (M9507). However, the clofazimine + linezolid combination lacked early bactericidal activity. When combined with amikacin and imipenem, omadacycline did not improve the regimen\'s effectiveness over 4 weeks of treatment. Our study showed that omadacycline + clofazimine + linezolid exhibited significant bactericidal activity over an extended treatment duration. However, adding omadacycline to amikacin and imipenem did not improve regimen effectiveness against the evaluated clinical isolates within 4 weeks. Further research in Mab disease patients is needed to determine the most effective omadacycline-containing regimen.IMPORTANCEMycobacteroides abscessus is a common environmental bacterium that causes infections in people with compromised lung function, including those with bronchiectasis, cystic fibrosis, chronic obstructive pulmonary disease, and weakened immune systems, especially among older individuals. Treating M. abscessus disease is challenging due to the limited effectiveness and toxicity of current antibiotics, which often require prolonged use. Omadacycline, a new antibiotic, shows promise against M. abscessus. Using a mouse model that mimics M. abscessus disease in humans, we studied the effectiveness of including omadacycline with recommended antibiotics. Adding omadacycline to clofazimine and linezolid significantly improved treatment outcomes, rapidly clearing the bacteria from the lungs and maintaining effectiveness throughout. This oral combination is convenient for patients. However, adding omadacycline to amikacin and imipenem did not improve treatment effectiveness within 4 weeks. Further study with M. abscessus patients is necessary to optimize omadacycline-based treatment strategies for this disease.

暂无摘要。

暂无摘要。

Tuberculosis (TB) is an airborne bacterial infection caused by Mycobacterium tuberculosis (M. tb), resulting in approximately 1.3 million deaths in 2022 worldwide. Oral therapy with anti-TB drugs often fails to achieve therapeutic concentrations at the primary infection site (lungs). In this study, we developed a dry powder inhalable formulation (DPI) of clofazimine (CFZ) to provide localized drug delivery and minimize systemic adverse effects. Poly (lactic acid-co-glycolic acid) (PLGA) microparticles (MPs) containing CFZ were developed through a single emulsion solvent evaporation technique. Clofazimine microparticles (CFZ MPs) displayed entrapment efficiency and drug loading of 66.40 ± 2.22 %w/w and 33.06 ± 1.45 µg/mg, respectively. To facilitate pulmonary administration, MPs suspension was spray-dried to yield a dry powder formulation (CFZ SD MPs). Spray drying had no influence on particle size (~1 µm), zeta potential (-31.42 mV), and entrapment efficiency. Solid state analysis (PXRD and DSC) of CFZ SD MPs studies demonstrated encapsulation of the drug in the polymer. The drug release studies showed a sustained drug release. The optimized formulation exhibited excellent aerosolization properties, suggesting effective deposition in the deeper lung region. The in vitro antibacterial studies against H37Ra revealed improved (eight-fold) efficacy of spray-dried formulation in comparison to free drug. Hence, clofazimine dry powder formulation presents immense potential for the treatment of tuberculosis with localized pulmonary delivery and improved patient compliance.

BACKGROUND: The management of multidrug-resistant tuberculosis (MDR-TB) remains challenging. Treatment outcome is influenced by multiple factors; the specific roles of diabetes and glycemic control remain uncertain. This study aims to assess the impact of glycemic control on drug exposure, to investigate the association between drug exposure and treatment outcomes, and to identify clinically significant thresholds predictive of treatment outcome, among patients with diabetes.
METHODS: This multicenter prospective cohort study involved patients with confirmed MDR-TB and diabetes. Drug exposure level was estimated by noncompartmental analysis. The minimum inhibitory concentrations (MICs) were determined for the individual Mycobacterium tuberculosis isolates. The influence of poor glycemic control (glycated hemoglobin ≥7%) on drug exposure and the associations between drug exposure and treatment outcome were evaluated by univariate and multivariate analysis. Classification and regression tree analysis was used to identify the drug exposure/susceptibility thresholds.
RESULTS: Among the 131 diabetic participants, 43 (32.8%) exhibited poor glycemic control. Poor glycemic control was independently associated with decreased exposure to moxifloxacin, linezolid, bedaquiline, and cycloserine, but not clofazimine. Additionally, a higher ratio of drug exposure to susceptibility was found to be associated with a favorable MDR-TB treatment outcome. Thresholds predictive of 6-month culture conversion and favorable outcome were bedaquiline area under the concentration-time curve (AUC)/MIC ≥245 and moxifloxacin AUC/MIC ≥67, demonstrating predictive accuracy in patients, regardless of their glycemic control status.
CONCLUSIONS: Glycemic control and optimal TB drug exposure are associated with improved treatment outcomes. This dual management strategy should be further validated in randomized controlled trials of patients with MDR-TB and diabetes.

BACKGROUND: Clofazimine (CFZ) has shown promising effects against Mycobacterium avium-intracellulare complex pulmonary disease (MAC-PD) and Mycobacterium abscessus species pulmonary disease (MABS-PD). However, the optimal CFZ dose remains unknown. We aimed to explore the relationship between steady-state CFZ concentration and its safety and efficacy in MAC-PD and MABS-PD.
METHODS: This prospective observational study focused on patients with MAC-PD and MABS-PD treated with CFZ (UMIN 000041053). To understand the safety and efficacy profile of CFZ and elucidate its optimal concentration, we analyzed CFZ-induced pigmentation grade, QTc interval, and culture conversion outcomes in relation to serum CFZ concentration using Student\'s t-test, a concentration-QTc model, and multivariable logistic regression analysis, respectively. In total, 64 patients (34 with MAC-PD; 30 with MABS-PD) were included.
RESULTS: The steady-state concentration of CFZ was higher in the moderate-to-severe pigmentation group than in the none-to-light pigmentation group (P < 0.001). At a CFZ concentration of 1 mg/L, the QTc interval was prolonged by 17.3 ms (95 % confidence interval [CI], 3.9-25.4) from baseline. Culture conversion was achieved in 33 (51.6 %) patients. The only significant predictor of culture conversion was surgery (adjusted odds ratio, 5.4; 95 % CI, 1.3-38.0). CFZ concentration and MIC of CFZ less than 0.25 mg/L were not associated with culture conversion in this study.
CONCLUSIONS: CFZ-induced pigmentation and QT interval prolongation are associated with serum CFZ concentrations. CFZ dosage may be optimized by monitoring serum CFZ concentration.

Although clofazimine is currently one of the standard regimens for Mycobacterium abscessus, it frequently causes skin discoloration, posing esthetic concerns for patients. We studied thirteen Asian patients with pulmonary nontuberculous mycobacterial disease treated with clofazimine at the NHO Kinki Chuo Chest Medical Center. In three patients (two women and one man) whose dosing regimens were altered owing to skin discoloration, we continuously measured luminance (L*), red-green (a*), and yellow-blue (b*) values (using a colorimeter) in both sun-exposed and sun-unexposed skin areas at each visit. Compared to baseline L* and a* values, the ΔL* values were negative (decreased brightness) and Δa* values were positive (increased redness) while patients received daily clofazimine. After switching to intermittent or reduced dosing, these changes gradually diminished. If such a dose reduction does not affect the therapeutic outcome, an even lower clofazimine dose may be attempted to minimize skin adverse effects.