ABSTRACT
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.
Subject(s)
Amikacin , Anti-Bacterial Agents , Clofazimine , Disease Models, Animal , Drug Therapy, Combination , Imipenem , Linezolid , Mycobacterium Infections, Nontuberculous , Mycobacterium abscessus , Tetracyclines , Animals , Clofazimine/administration & dosage , Clofazimine/therapeutic use , Linezolid/administration & dosage , Linezolid/therapeutic use , Mice , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/therapeutic use , Amikacin/administration & dosage , Amikacin/therapeutic use , Tetracyclines/administration & dosage , Tetracyclines/therapeutic use , Tetracyclines/pharmacology , Mycobacterium abscessus/drug effects , Imipenem/administration & dosage , Imipenem/therapeutic use , Imipenem/pharmacology , Mycobacterium Infections, Nontuberculous/drug therapy , Mycobacterium Infections, Nontuberculous/microbiology , Female , Treatment Outcome , Microbial Sensitivity Tests , Lung Diseases/drug therapy , Lung Diseases/microbiology , Administration, Oral , Lung/microbiologyABSTRACT
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. CONCLUSION: CFZ-induced pigmentation and QT interval prolongation are associated with serum CFZ concentrations. CFZ dosage may be optimized by monitoring serum CFZ concentration.
Subject(s)
Clofazimine , Mycobacterium Infections, Nontuberculous , Mycobacterium abscessus , Humans , Clofazimine/administration & dosage , Clofazimine/therapeutic use , Female , Male , Prospective Studies , Aged , Mycobacterium Infections, Nontuberculous/drug therapy , Middle Aged , Mycobacterium abscessus/drug effects , Mycobacterium avium-intracellulare Infection/drug therapy , Mycobacterium avium Complex/drug effects , Treatment Outcome , Lung Diseases/drug therapy , Lung Diseases/microbiology , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacokineticsABSTRACT
BACKGROUND: Leprosy is a neglected dermato-neurologic, infectious disease caused by Mycobacterium leprae or M. lepromatosis. Leprosy is treatable and curable by multidrug therapy/MDT, consisting of 12 months rifampicin, dapsone and clofazimine for multibacillary/MB patients and for 6 months for paucibacillary/PB patients. The relapse rate is considered a crucial treatment outcome. A randomized Controlled Clinical Trial (U-MDT/CT-BR) conducted from 2007â2012 compared clinical outcomes in MB patients after 12 months regular MDT/R-MDT and 6 months uniform MDT/U-MDT in two highly endemic Brazilian areas. OBJECTIVES: To estimate the 10 years relapse rate of MB patients treated with 6 months U-MDT. METHODS: The statistical analyses treated the data as a case-control study, sampled from the cohort generated for the randomized trial. Analyses estimated univariate odds ratio and applied logistic regression for multivariate analysis, controlling the confounding variables. RESULTS: The overall relapse rate was 4.08 %: 4.95 % (16 out of 323) in the U-MDT group and 3.10 % (9 out of 290) in the regular/R-MDT group. The difference in relapse proportion between U-MDT and R-MDT groups was 1.85 %, not statistically significant (Odds Ratio = 1.63, 95 % CI 0.71 to 3.74). However, misdiagnosis of relapses, may have introduced bias, underestimating the force of the association represented by the odds ratio. CONCLUSIONS: The relapse estimate of 10 years follow-up study of the first randomized, controlled study on U-MDT/CT-BR was similar to the R-MDT group, supporting strong evidence that 6 months U-MDT for MB patients is an acceptable option to be adopted by leprosy endemic countries worldwide. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00669643.
Subject(s)
Clofazimine , Dapsone , Drug Therapy, Combination , Leprostatic Agents , Recurrence , Rifampin , Adolescent , Adult , Female , Humans , Male , Middle Aged , Young Adult , Brazil , Case-Control Studies , Clofazimine/therapeutic use , Clofazimine/administration & dosage , Dapsone/therapeutic use , Dapsone/administration & dosage , Leprostatic Agents/therapeutic use , Leprostatic Agents/administration & dosage , Leprosy/drug therapy , Leprosy, Multibacillary/drug therapy , Rifampin/therapeutic use , Rifampin/administration & dosage , Time Factors , Treatment OutcomeSubject(s)
Clofazimine , Rifampin , Tuberculosis, Multidrug-Resistant , Humans , Child , Rifampin/administration & dosage , Clofazimine/administration & dosage , Clofazimine/therapeutic use , Adolescent , Tuberculosis, Multidrug-Resistant/drug therapy , Male , Female , Capsules , Antitubercular Agents/administration & dosageABSTRACT
Inhalation therapy treating severe infectious disease is among the more complex and emerging topics in controlled drug release. Micron-sized carriers are needed to deposit drugs into the lower airways, while nano-sized carriers are of preference for cell targeting. Here, we present a novel and versatile strategy using micron-sized spherical particles with an excellent aerodynamic profile that dissolve in the lung fluid to ultimately generate nanoparticles enabling to enhance both extra- and intra-cellular drug delivery (i.e., dual micro-nano inhalation strategy). The spherical particles are synthesised through the condensation of nano-sized amorphous silicon dioxide resulting in high surface area, disordered mesoporous silica particles (MSPs) with monodispersed size of 2.43 µm. Clofazimine (CLZ), a drug shown to be effective against multidrug-resistant tuberculosis, was encapsulated in the MSPs obtaining a dry powder formulation with high respirable fraction (F.P.F. <5 µm of 50%) without the need of additional excipients. DSC, XRPD, and Nitrogen adsorption-desorption indicate that the drug was fully amorphous when confined in the nano-sized pores (9-10 nm) of the MSPs (shelf-life of 20 months at 4 °C). Once deposited in the lung, the CLZ-MSPs exhibited a dual action. Firstly, the nanoconfinement within the MSPs enabled a drastic dissolution enhancement of CLZ in simulated lung fluid (i.e., 16-fold higher than the free drug), increasing mycobacterial killing than CLZ alone (p = 0.0262) and reaching concentrations above the minimum bactericidal concentration (MBC) against biofilms of M. tuberculosis (i.e., targeting extracellular bacteria). The released CLZ permeated but was highly retained in a Calu-3 respiratory epithelium model, suggesting a high local drug concentration within the lung tissue minimizing risk for systemic side effects. Secondly, the micron-sized drug carriers spontaneously dissolve in simulated lung fluid into nano-sized drug carriers (shown by Nano-FTIR), delivering high CLZ cargo inside macrophages and drastically decreasing the mycobacterial burden inside macrophages (i.e., targeting intracellular bacteria). Safety studies showed neither measurable toxicity on macrophages nor Calu-3 cells, nor impaired epithelial integrity. The dissolved MSPs also did not show haemolytic effect on human erythrocytes. In a nutshell, this study presents a low-cost, stable and non-invasive dried powder formulation based on a dual micro-nano carrier to efficiently deliver drug to the lungs overcoming technological and practical challenges for global healthcare.
Subject(s)
Antitubercular Agents , Clofazimine , Drug Carriers , Lung , Nanoparticles , Administration, Inhalation , Porosity , Antitubercular Agents/administration & dosage , Antitubercular Agents/pharmacokinetics , Antitubercular Agents/pharmacology , Antitubercular Agents/chemistry , Antitubercular Agents/therapeutic use , Drug Carriers/chemistry , Nanoparticles/chemistry , Nanoparticles/administration & dosage , Humans , Lung/metabolism , Clofazimine/administration & dosage , Clofazimine/pharmacokinetics , Clofazimine/therapeutic use , Silicon Dioxide/chemistry , Silicon Dioxide/administration & dosage , Drug Delivery Systems , Animals , Drug Liberation , Particle Size , Tuberculosis/drug therapy , Mycobacterium tuberculosis/drug effects , MiceABSTRACT
BACKGROUND: Clofazimine (CFZ) is routinely used worldwide for the treatment of leprosy and TB. However, no liquid or dispersible tablet formulations of CFZ are currently available commercially for patients with challenges ingesting soft gelatin capsules or solid formulations. The aim of this research was to develop stable extemporaneous liquid formulations of CFZ that can be stored at room temperature for several weeks to enable practical dosing in the field. METHODS: Two formulations were prepared in syrup and sugar-free vehicles with CFZ tablets using a simple method that can be used in a routine pharmacy. Suspensions were stored at room temperature and at 30°C for 30 days. Formulation aliquots were tested on Days 0, 15 and 30 for appearance, pH, potency and microbial counts. RESULTS: Appearance remained unchanged during storage. The pH of both formulations was between 4.0 and 6.0. Potency was between 90% and 110% for 30 days in the syrup formulation and for 15 days in the sugar-free formulation. Microbial counts met United States Pharmacopeia 1111 limits for oral aqueous liquids and specific organisms were absent. CONCLUSIONS: A simple field-friendly method was successfully developed for the preparation of CFZ liquid formulations using commonly available ingredients. This will permit practical dosing and titration for children and other patients with swallowing challenges.
Subject(s)
Clofazimine , Drug Compounding , Pharmaceutical Services , Child , Humans , Clofazimine/administration & dosage , Clofazimine/chemistry , Tuberculosis , LeprosyABSTRACT
A parte de ser un principio activo de la multiterapia (MDT) para la lepra, la clofazimina a mayores dosis se administra para tratar las reacciones de Tipo 2 (ENL) de la lepra. Todavía falta evidencia en los ensayos clínicos sobre las indicaciones, pauta óptima y ratio riesgo/beneficio para apoyar las directrices publicadas sobre su uso como medicamento antileprorreacción. La experiencia clínica indica que, en adultos, la dosis más alta (de 300 mg/ día) es segura durante períodos limitados de tiempo, pero se necesita precaución en individuos de poco peso corporal y en aquellos en tratamiento con otros medicamentos que puedan interaccionar. (AU)
Besides its role in multidrug therapy, clofazimine at higher doses is widely used for relief of Type 2 (ENL) reaction in leprosy. There is a lack of evidence from clinical trials regarding indications, optimum regimen and risk/benefit ratio to support published guidelines on its use as an anti-reaction drug. Clinical experience suggests that in adults it is safe at high doses (up to 300 mg/day) for limited periods of time but caution is needed with patients of low body weight and in those taking other drugs which may interact. (AU)
Subject(s)
Humans , Clofazimine/adverse effects , Clofazimine/administration & dosage , Leprosy , Guidelines as TopicABSTRACT
PURPOSE: This study was undertaken to develop novel mucoadhesive formulations of clofazimine (CFZ), a drug candidate for the treatment of cryptosporidiosis, with the aim of strategic delivery to the small intestine, the main site of the disease parasites. METHODS: CFZ-loaded nanoparticles (nCFZ) coated with non-biodegradable anionic polymer (nCFZ/A) and biodegradable anionic protein complex (nCFZ/dA) were prepared by Flash NanoPrecipitation (FNP) and evaluated for their physicochemical and biopharmaceutical properties. RESULTS: The mean diameters of nCFZ/A and nCFZ/dA were ca. 90 and 240 nm, respectively, and they showed narrow size distributions and negative ζ-potentials. Both formulations showed higher solubility of CFZ in aqueous solution than crystalline CFZ. Despite their improved dispersion behaviors, both formulations exhibited significantly lower diffusiveness than crystalline CFZ in a diffusion test using artificial mucus (AM). Quartz crystal microbalance analysis showed that both formulations clearly interacted with mucin, which appeared to be responsible for their reduced diffusiveness in AM. These results suggest the potent mucoadhesion of nCFZ/A and nCFZ/dA. After the oral administration of CFZ samples (10 mg-CFZ/kg) to rats, nCFZ/dA and nCFZ/A exhibited a prolongation in Tmax by 2 and >9 h, respectively, compared with crystalline CFZ. At 24 h after oral doses of nCFZ/A and nCFZ/dA with mucoadhesion, there were marked increases in the intestinal CFZ concentration (4-7 fold) compared with Lamprene®, a commercial CFZ product, indicating enhanced CFZ exposure in the small intestine. CONCLUSION: The use of FNP may produce mucoadhesive CFZ formulations with improved intestinal exposure, possibly offering enhanced anti-cryptosporidium therapy.
Subject(s)
Clofazimine/administration & dosage , Nanoparticle Drug Delivery System/chemistry , Administration, Oral , Animals , Clofazimine/pharmacokinetics , Cryptosporidiosis/drug therapy , Drug Liberation , Humans , Intestinal Absorption , Intestinal Mucosa/metabolism , Intestine, Small/metabolism , Male , Models, Animal , Rats , SolubilityABSTRACT
Clofazimine is classified as a WHO group B drug for the treatment of rifampin-resistant tuberculosis. QT prolongation, which is associated with fatal cardiac arrhythmias, is caused by several antitubercular drugs, including clofazimine, but there are no data quantifying the effect of clofazimine concentration on QT prolongation. Our objective was to describe the effect of clofazimine exposure on QT prolongation. Fifteen adults drug-susceptible tuberculosis patients received clofazimine monotherapy as 300 mg daily for 3 days, followed by 100 mg daily in one arm of a 2-week, multiarm early bactericidal activity trial in South Africa. Pretreatment Fridericia-corrected QT (QTcF) (105 patients, 524 electrocardiograms [ECGs]) and QTcFs from the clofazimine monotherapy arm matched with clofazimine plasma concentrations (199 ECGs) were interpreted with a nonlinear mixed-effects model. Clofazimine was associated with significant QT prolongation described by a maximum effect (Emax) function. We predicted clofazimine exposures using 100-mg daily doses and 2 weeks of loading with 200 and 300 mg daily, respectively. The expected proportions of patients with QTcF change from baseline above 30 ms (ΔQTcF > 30) were 2.52%, 11.6%, and 23.0% for 100-, 200-, and 300-mg daily doses, respectively. At steady state, the expected proportion with ΔQTcF of >30 ms was 23.7% and with absolute QTcF of >450 ms was 3.42% for all simulated regimens. The use of loading doses of 200 and 300 mg is not predicted to expose patients to an increased risk of QT prolongation, compared with the current standard treatment, and is, therefore, an alternative option for more quickly achieving therapeutic concentrations.
Subject(s)
Clofazimine/adverse effects , Long QT Syndrome , Tuberculosis , Adult , Clofazimine/administration & dosage , Electrocardiography , Heart Rate , Humans , Long QT Syndrome/chemically induced , South Africa , Tuberculosis/drug therapy , Young AdultABSTRACT
BACKGROUND: Mycobacterium abscessus pulmonary disease (M abscessus-PD) is challenging to treat because of its resistance to antibiotics. RESEARCH QUESTION: What are the outcomes of treatment-naive patients with M abscessus-PD treated with inhaled amikacin-containing multidrug regimens? STUDY DESIGN AND METHODS: We identified 82 treatment-naive patients with M abscessus-PD from a prospective observational cohort treated with regimens containing inhaled amikacin with or without clofazimine between March 2015 and June 2018 (ClinicalTrials.gov identifier: NCT00970801). During the initial phase, all patients received IV amikacin, imipenem (or cefoxitin), and oral azithromycin. Oral clofazimine was added in cases of (1) M abscessus subspecies abscessus (here M abscessus) or (2) M abscessus subspecies massiliense (here M massiliense) with cavitary lesions. During the continuation phase, amikacin was changed from an injectional to inhalational form. RESULTS: Of 82 patients, 46 (56%) had M massiliense-PD and 36 (44%) had M abscessus-PD. Among 59 patients with nodular bronchiectatic disease (72%), 23 of 59 had a concurrent cavitary lesion. The remaining 23 patients (28%) had fibrocavitary disease. Twelve months after treatment initiation, cure was achieved in 53 patients (65%): 42 of 46 patients (91%) with M massiliense-PD and 11 of 36 patients (31%) with M abscessus-PD (P < .001). Symptomatic and radiologic improvements were observed in 72 patients (88%) and 64 patients (78%), respectively, with significantly greater improvement in patients with M massiliense-PD (symptom improvement, 96% vs 78% [P = .047]; improvement on CT scanning, 93% vs 61% [P = .002]). INTERPRETATION: Inhaled amikacin with or without clofazimine in the regimen provides favorable treatment outcomes in M massiliense-PD. However, more effective treatments are needed for M abscessus-PD.
Subject(s)
Amikacin/administration & dosage , Anti-Bacterial Agents/administration & dosage , Lung Diseases/drug therapy , Lung Diseases/microbiology , Mycobacterium Infections, Nontuberculous/drug therapy , Mycobacterium Infections, Nontuberculous/microbiology , Mycobacterium abscessus/isolation & purification , Administration, Inhalation , Aged , Azithromycin/administration & dosage , Clofazimine/administration & dosage , Drug Therapy, Combination , Female , Humans , Imipenem/administration & dosage , Male , Middle Aged , Prospective StudiesSubject(s)
Insecticides/administration & dosage , Leprostatic Agents/administration & dosage , Leprosy, Lepromatous/diagnosis , Mycobacterium leprae/drug effects , Sarcoptes scabiei/drug effects , Scabies/diagnosis , Adult , Animals , Clofazimine/administration & dosage , Humans , Ivermectin/administration & dosage , Leprosy, Lepromatous/drug therapy , Leprosy, Lepromatous/microbiology , Leprosy, Lepromatous/pathology , Male , Neglected Diseases , Permethrin/administration & dosage , Rifampin/administration & dosage , Scabies/drug therapy , Scabies/parasitology , Scabies/pathology , Skin/microbiology , Skin/parasitology , Skin/pathology , Tropical MedicineABSTRACT
Multidrug-resistant tuberculosis (MDR-TB) remains a serious public health threat worldwide. To date, the anti-TB activity of TB47 (T), an imidazopyridine amide class of antibiotics targeting QcrB in the electron transport chain, has not been systematically evaluated, especially in a new regimen against MDR-TB. This study employed both macrophage infection and a mouse model to test the activity of T alone or in combination with other antimicrobial agents. Different regimens containing amikacin (A), levofloxacin (L), ethambutol (E), and pyrazinamide (Z) + clofazimine (C)/T were evaluated in the mouse model. The bacterial burdens of mice from different groups were monitored at different time points while relapse was assessed 6 months after treatment cessation. Colonies obtained at relapse underwent drug susceptibility testing. We found that T exhibited highly synergistic bactericidal activity with C in all models. Adding T to ALEZC might shorten the MDR-TB treatment duration from ≥ 9 months to ≤ 5months, as five months of treatment with ALEZCT achieved zero relapse rates in 2 animal experiments. These findings indicate that T exhibits a highly synergistic sterilizing activity when combined with C. All isolates from relapsing mice remained sensitive to each drug, suggesting that the relapse was not due to drug resistance but rather associated with the type of regimen.
Subject(s)
Antitubercular Agents/pharmacology , Clofazimine/pharmacology , Mycobacterium tuberculosis/drug effects , Tuberculosis, Multidrug-Resistant/drug therapy , Animals , Antitubercular Agents/administration & dosage , Antitubercular Agents/chemistry , Clofazimine/administration & dosage , Disease Models, Animal , Drug Synergism , Female , Imidazoles/administration & dosage , Imidazoles/pharmacology , Mice , Mice, Inbred BALB C , Microbial Sensitivity Tests , Mycobacterium tuberculosis/isolation & purification , Pyridines/administration & dosage , Pyridines/pharmacology , Recurrence , Tuberculosis, Multidrug-Resistant/microbiologyABSTRACT
Leprosy is a stigmatizing, chronic infection which degenerates the nervous system and often leads to incapacitation. Multi-drug therapy which consists of dapsone, rifampicin and clofazimine has been effective to combat this disease. In Indonesia, especially in Papua Island, leprosy is still a problem. Furthermore, there had been higher reports of Dapsone Hypersensitivity Syndrome (DHS) which also challenges leprosy elimination in certain aspects. Globally, DHS has a prevalence rate of 1.4% and a fatality rate up to 13%. The aim of this study is to validate HLA-B*13:01, a previously discovered biomarker for DHS in the Chinese population, as a biomarker for DHS in the Papua population.This is a case-control study of 34 leprosy patients who presented themselves with DHS (case subjects) and 52 leprosy patients without DHS (control subjects). Patients were recruited from 2 provinces: Papua and West Papua. DNA was extracted from 3 ml blood specimens. HLA-B alleles were typed using the gold-standard sequence based typing method. Results were then analysed using logistic regression and risk assessment was carried out. The results of HLA-typing showed that HLA-B*13:01 was the most significant allele associated with DHS, with odds ratio = 233.64 and P-value = 7.11×10-9, confirming the strong association of HLA-B*13:01 to DHS in the Papua population. The sensitivity of this biomarker is 91.2% and specificity is 96.2%, with an area under the curve of 0.95. HLA-B*13:01 is validated as a biomarker for DHS in leprosy patients in Papua, Indonesia, and can potentially be a good predictor of DHS to help prevent this condition in the future.
Subject(s)
Dapsone/adverse effects , Drug Hypersensitivity/prevention & control , HLA-B13 Antigen/genetics , Leprostatic Agents/adverse effects , Leprosy/drug therapy , Adolescent , Adult , Alleles , Biomarkers , Case-Control Studies , Clofazimine/administration & dosage , Dapsone/administration & dosage , Drug Hypersensitivity/epidemiology , Drug Therapy, Combination , Female , Humans , Indonesia , Leprostatic Agents/administration & dosage , Logistic Models , Male , Rifampin/administration & dosage , Risk Assessment , Syndrome , Young AdultABSTRACT
BACKGROUND: Persistent and relapsing babesiosis caused by Babesia microti often occurs in immunocompromised patients, and has been associated with resistance to antimicrobial agents such as atovaquone. Given the rising incidence of babesiosis in the United States, novel drugs are urgently needed. In the current study, we tested whether clofazimine (CFZ), an antibiotic used to treat leprosy and drug-resistant tuberculosis, is effective against B. microti. METHODS: Mice with severe combined immunodeficiency were infected with 107B. microti-infected erythrocytes. Parasites were detected by means of microscopic examination of Giemsa-stained blood smears or nested polymerase chain reaction. CFZ was administered orally. RESULTS: Uninterrupted monotherapy with CFZ curtailed the rise of parasitemia and achieved radical cure. B. microti parasites and B. microti DNA were cleared by days 10 and 50 of therapy, respectively. A 7-day administration of CFZ delayed the rise of parasitemia by 22 days. This rise was caused by B. microti isolates that did not carry mutations in the cytochrome b gene. Accordingly, a 14-day administration of CFZ was sufficient to resolve high-grade parasitemia caused by atovaquone-resistant B. microti parasites. CONCLUSIONS: Clofazimine is effective against B. microti infection in the immunocompromised host. Additional preclinical studies are required to identify the minimal dose and dosage of CFZ for babesiosis.
Subject(s)
Babesia microti/drug effects , Babesiosis/drug therapy , Babesiosis/parasitology , Clofazimine/therapeutic use , Immunocompromised Host , Leprostatic Agents/therapeutic use , Amino Acid Sequence , Animals , Babesia microti/genetics , Babesia microti/immunology , Babesiosis/immunology , Clofazimine/administration & dosage , Clofazimine/adverse effects , Cytochromes b/chemistry , Cytochromes b/genetics , DNA, Protozoan , Disease Models, Animal , Drug Evaluation, Preclinical , Drug Resistance , Erythrocytes/parasitology , Leprostatic Agents/administration & dosage , Leprostatic Agents/adverse effects , Mice , Parasitemia/parasitology , Treatment OutcomeABSTRACT
BACKGROUND: Optimal drug levels and minimal toxicity are critical factors in improving treatment outcomes for patients' prescribed new and repurposed medicine for drug-resistant (DR) tuberculosis (TB). The optimal dose of clofazimine (CFZ), a repurposed medicine for DR-TB, that is safe and effective in the South African (SA) population is unknown. OBJECTIVES: To report on dose-related final treatment outcomes in patients receiving CFZ plus a background regimen for DR-TB. METHODS: In a retrospective review of patient folders from 2012 to 2014, treatment outcomes documented for patients receiving high- (≥200 mg) and low-dose (100 mg) CFZ in a centralised DR-TB hospital in KwaZulu-Natal Province, SA, were investigated for an association between dose-weight interactions and outcomes. RESULTS: A total of 600 patients were included, of whom 169 (28.2%) received 100 mg. Of these, 87 (51.5%) weighed <50 kg and 82 (48.5%) ≥50 kg. Four hundred and thirty-one (71.8%) received ≥200 mg, of whom 41 (9.5%) were <50 kg and 390 (90.5%) ≥50 kg. Overall 77.2% were HIV-positive, with 93.95% on antiretroviral medicine. The majority of patients presented with extremely drug-resistant TB (55.3%). Forty-seven and a half percent of patients received a standardised background regimen, and 52.5% received an individualised regimen containing a new or repurposed medicine including CFZ. On multivariate analysis, adjusting for age, gender, HIV status and concomitant antiretrovirals, previous TB history, type of TB and background regimen, patients ≥50 kg prescribed 100 mg CFZ were 60% less likely to have a successful outcome (adjusted odds ratio (OR) 0.4; 95% confidence interval (CI) 0.2 - 0.8; p=0.009) compared with patients <50 kg receiving 100 mg CFZ. Patients <50 kg who received ≥200 mg were 40% less likely to have a successful treatment outcome (adjusted OR 0.6, p=0.3), and were found to have a higher risk of adverse events than patients <50 kg receiving 100 mg CFZ (82.9% v. 65.5%). CONCLUSIONS: Dose-weight interaction plays a role in the odds of a successful outcome. There is an association between dose-weight interactions, outcomes and adverse events. Weight-based dosing in patients <50 kg and ≥50 kg must be considered to achieve optimal treatment outcomes and reduce adverse events. Active drug safety monitoring must be implemented as a package of care for patients receiving CFZ as part of a DR-TB treatment regimen.
Subject(s)
Antitubercular Agents/administration & dosage , Clofazimine/administration & dosage , Extensively Drug-Resistant Tuberculosis/drug therapy , Tuberculosis, Multidrug-Resistant/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Antitubercular Agents/adverse effects , Body Weight , Clofazimine/adverse effects , Cohort Studies , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Retrospective Studies , South Africa , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Optimal drug levels and minimal toxicity are critical factors in improving treatment outcomes for patients prescribed new and repurposed medicine for drug-resistant (DR) tuberculosis (TB). The optimal dose and dose-related safety of clofazimine (CFZ), a repurposed medicine for DR TB, in the South African (SA) population are unknown. OBJECTIVES: To report on dose-related adverse events in patients receiving CFZ plus a background regimen for DR TB. METHODS: In a retrospective review of patient folders from 2012 to 2014, adverse events documented for patients receiving high- (≥200 mg) and low-dose (100 mg) CFZ in a centralised DR TB hospital in KwaZulu-Natal Province, SA, were investigated for an association between dose-weight interactions and adverse events. RESULTS: Of 600 patients included, 78.7% (n=472) weighed ≥50 kg. Of these, 17.4% (n=82) received 100 mg CFZ and 82.6% (n=390) received >200 mg. Of 128 patients (21.3%) who weighed <50 kg, 68.0% (n=87) received 100 mg CFZ and 32.0% (n=41) received ≥200 mg. Of 463 patients (77.2%) who were HIV-positive, 94.0% were on antiretrovirals. There was no difference between the dose-weight cohorts in the background regimen given in addition to high- or low-dose CFZ. The frequency and types of adverse events observed were similar to the published literature. When analysed per dose-weight cohort, patients weighing <50 kg and receiving high-dose CFZ (≥200 mg) had a 2.6 times higher risk of any adverse event (adjusted odds ratio (aOR) 2.57; 95% confidence interval (CI) 1.02 - 6.05; p=0.05: reference category <50 kg and 100 mg). Patients weighing <50 kg and receiving high-dose CFZ had a 3.3 times higher risk of gastrointestinal adverse events than patients weighing <50 kg and receiving 100 mg CFZ (aOR 3.30; 95% CI 1.51 - 7.19; p=0.003). A high risk of chest pain was observed in patients receiving high- and low-dose CFZ, irrespective of weight. Patients weighing <50 kg receiving high-dose CFZ had a slightly higher risk of adverse events related to the skin (aOR 1.2; 95% CI 0.55 - 2.62; p=0.7) There were no documented reports of the CFZ dose being reduced or the drug being stopped due to adverse events in the sample population. CONCLUSIONS: There is an association between dose-weight interaction and adverse events. The odds of any adverse event occurring were higher when low-weight patients (<50 kg) received high-dose CFZ (≥200 mg). Gastrointestinal and skin-related adverse events were more common when high-dose CFZ was used in patients weighing <50 kg. Chest pain was reported in patients receiving high- and low-dose CFZ, irrespective of weight, and may be a symptom of cardiac toxicity. Plasma concentrations of CFZ may be affected by drug-drug interactions, so active drug safety monitoring including electrocardiograms is recommended routinely when CFZ is part of the regimen.
Subject(s)
Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/adverse effects , Clofazimine/administration & dosage , Clofazimine/adverse effects , Tuberculosis, Multidrug-Resistant/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Anti-Inflammatory Agents/therapeutic use , Antitubercular Agents/therapeutic use , Clofazimine/therapeutic use , Dose-Response Relationship, Drug , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , Retrospective Studies , South Africa , Young AdultABSTRACT
Mycobacterium abscessus is an extensively drug-resistant opportunistic pathogen that can cause chronic otomastoiditis. There are no evidence-based treatment regimens for this severe infection. We treated four children with M. abscessus otomastoiditis with a structured regimen of topical imipenem and tigecycline, intravenous imipenem and tigecycline, and oral clofazimine and azithromycin and adjunctive surgery. This structured approach led to cure, with 1 year of follow-up after treatment. Adverse events were frequent, mostly caused by tigecycline.