RESUMEN
INTRODUCTION: The lack of safe, effective, and simple short-course regimens (SCRs) for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment has significantly impeded TB control efforts in China. METHODS: This phase 4, randomized, open-label, controlled, non-inferiority trial aims to assess the efficacy and safety of a 9-month all-oral SCR containing bedaquiline (BDQ) versus an all-oral SCR without BDQ for adult MDR-TB patients (18-65 years) in China. The trial design mainly mirrors that of the "Evaluation of a Standardized Treatment Regimen of Anti-Tuberculosis Drugs for Patients with MDR-TB" (STREAM) stage 2 study, while also incorporating programmatic data from South Africa and the 2019 consensus recommendations of Chinese MDR/RR-TB treatment experts. Experimental arm participants will receive a modified STREAM regimen C that replaces three group C drugs, ethambutol (EMB), pyrazinamide (PZA), and prothionamide (PTO), with two group B drugs, linezolid (LZD) and cycloserine (CS), while omitting high-dose isoniazid (INH) for confirmed INH-resistant cases. BDQ duration will be extended from 6 to 9 months for participants with Mycobacterium tuberculosis-positive sputum cultures at week 16. The control arm will receive a modified STREAM regimen B without high-dose INH and injectable kanamycin (KM) that incorporates experimental arm LZD and CS dosages, treatment durations, and administration methods. LZD (600 mg) will be given daily for ≥ 24 weeks as guided by observed benefits and harm. The primary outcome measures the proportion of participants with favorable treatment outcomes at treatment completion (week 40), while the same measurement taken at 48 weeks post-treatment completion is the secondary outcome. Assuming an α = 0.025 significance level (one-sided test), 80% power, 15% non-inferiority margin, and 10% lost to follow-up rate, each arm requires 106 participants (212 total) to demonstrate non-inferiority. DISCUSSION: PROSPECT aims to assess the safety and efficacy of a BDQ-containing SCR MDR-TB treatment at seventeen sites across China, while also providing high-quality data to guide SCRs administration under the direction of the China National Tuberculosis Program for MDR-TB. Additionally, PROSPECT will explore the potential benefits of extending the administration of the 9-month BDQ-containing SCR for participants without sputum conversion by week 16. TRIAL REGISTRATION: ClinicalTrials.gov NCT05306223. Prospectively registered on 16 March 2022 at https://clinicaltrials.gov/ct2/show/NCT05306223?term=NCT05306223&draw=1&rank=1 {2}.
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Tuberculosis Resistente a Múltiples Medicamentos , Tuberculosis , Adulto , Humanos , Antituberculosos , Ensayos Clínicos Fase IV como Asunto , Diarilquinolinas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Tuberculosis/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/diagnóstico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/microbiologíaRESUMEN
BACKGROUND: Bedaquiline (BDQ), by targeting the electron transport chain and having a long half-life, is a good candidate to simplify leprosy treatment. Our objectives were to (i) determine the minimal effective dose (MED) of BDQ administered orally, (ii) evaluate the benefit of combining two inhibitors of the respiratory chain, BDQ administered orally and clofazimine (CFZ)) and (iii) evaluate the benefit of an intramuscular injectable long-acting formulation of BDQ (intramuscular BDQ, BDQ-LA IM), in a murine model of leprosy. METHODOLOGY/PRINCIPAL FINDINGS: To determine the MED of BDQ administered orally and the benefit of adding CFZ, 100 four-week-old female nude mice were inoculated in the footpads with 5x103 bacilli of M. leprae strain THAI53. Mice were randomly allocated into: 1 untreated group, 5 groups treated with BDQ administered orally (0.10 to 25 mg/kg), 3 groups treated with CFZ 20 mg/kg alone or combined with BDQ administered orally 0.10 or 0.33 mg/kg, and 1 group treated with rifampicin (RIF) 10 mg/kg. Mice were treated 5 days a week during 24 weeks. To evaluate the benefit of the BDQ-LA IM, 340 four-week-old female swiss mice were inoculated in the footpads with 5x103 to 5x101 bacilli (or 5x100 for the untreated control group) of M. leprae strain THAI53. Mice were randomly allocated into the following 11 groups treated with a single dose (SD) or 3 doses (3D) 24h after the inoculation: 1 untreated group, 2 treated with RIF 10 mg/kg SD or 3D, 8 treated with BDQ administered orally or BDQ-LA IM 2 or 20 mg/kg, SD or 3D. Twelve months later, mice were sacrificed and M. leprae bacilli enumerated in the footpad. All the footpads became negative with BDQ at 3.3 mg/kg. The MED of BDQ administered orally against M. leprae in this model is therefore 3.3 mg/kg. The combination of CFZ and BDQ 10-fold lower than this MED did not significantly increase the bactericidal activity of CFZ. The BDQ-LA IM displayed similar or lower bactericidal activity than the BDQ administered orally. CONCLUSION: We demonstrated that the MED of BDQ administered orally against M. leprae was 3.3 mg/kg in mice and BDQ did not add significantly to the efficacy of CFZ at the doses tested. BDQ-LA IM was similar or less active than BDQ administered orally at equivalent dosing and frequency but should be tested at higher dosing in order to reach equivalent exposure in further experiments.
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Diarilquinolinas , Lepra , Femenino , Animales , Ratones , Modelos Animales de Enfermedad , Ratones Desnudos , Diarilquinolinas/farmacología , Diarilquinolinas/uso terapéutico , Rifampin/uso terapéutico , Rifampin/farmacología , Clofazimina/uso terapéutico , Lepra/tratamiento farmacológico , Mycobacterium leprae , AntituberculososRESUMEN
BACKGROUND: The World Health Organization recommends supervising the treatment of tuberculosis. Intermittent regimens have the potential to simplify the supervision and improve compliance. Our objective was to analyse the sterilising activity of once-weekly regimens based on drugs with a long half-life, bedaquiline and rifapentine, in a murine model of tuberculosis. METHODS: 300 Swiss mice were infected intravenously infected with ×10-6â CFU Mycobacterium tuberculosis H37Rv. Mice were treated once weekly with regimens containing: 1) bedaquiline, rifapentine and pyrazinamide (BPZ); 2) BPZ plus moxifloxacin (BPZM); 3) BPZM plus clofazimine (BPZMC); 4) the standard daily regimen of tuberculosis. All regimens were given for 4 or 6â months. Bactericidal and sterilising activity were assessed. RESULTS: After 2â months of treatment, the mean count in lungs was 0.76±0.60â log10 CFU in mice treated with the daily control regimen and negative in all mice treated with once-weekly regimens (p<0.05 compared to the daily control). All mice had negative lung cultures on completion of either 4 or 6â months of treatment, whereas 3â months after 4 and 6â months of treatment, respectively, the relapse rate was 64% and 13% in the standard daily regimen, 5% and 0% in BPZ, 0% and 0% in BPMZ and 0% and 5% in BPMZC (p<0.05 for all once-weekly regimens versus 4-month daily control; p>0.05 for all once-weekly regimens versus 6-month daily control). CONCLUSIONS: BPZ-based once-weekly regimens have higher sterilising activity than the standard daily regimen and could greatly simplify treatment administration and possibly shorten the duration of tuberculosis treatment.
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Mycobacterium tuberculosis , Tuberculosis , Animales , Antituberculosos/uso terapéutico , Esquema de Medicación , Quimioterapia Combinada , Isoniazida/uso terapéutico , Ratones , Pirazinamida/uso terapéutico , Tuberculosis/tratamiento farmacológicoRESUMEN
Bedaquiline (BDQ) is a recently approved antibiotic for the treatment of multidrug-resistant tuberculosis, but its potential against slow-growing mycobacteria (SGM) is still unknown. The objective of this study was to determine the in vitro activity of BDQ on SGM by assessing their MIC and minimal bactericidal concentration (MBC). The MIC of BDQ against 17 clinical isolates including Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium chimaera, Mycobacterium kansasii and Mycobacterium simiae species was determined by the resazurin microtitre assay and the MBC by the c.f.u. determination on 7H10 agar plates. BDQ has a bacteriostatic activity on all SGM tested with a MIC range from 0.03 to 0.007 µg ml-1 and surprisingly a good bactericidal activity on the majority of the isolates tested with an MBC of 1-2 µg ml-1 . Based on these preliminary results BDQ seems to be very promising for treatment of diseases caused by SGM.
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Antituberculosos/farmacología , Diarilquinolinas/farmacología , Micobacterias no Tuberculosas/efectos de los fármacos , Humanos , Viabilidad Microbiana/efectos de los fármacos , Infecciones por Mycobacterium no Tuberculosas/microbiología , Micobacterias no Tuberculosas/crecimiento & desarrolloAsunto(s)
Antituberculosos/uso terapéutico , Diarilquinolinas/uso terapéutico , Tuberculosis Extensivamente Resistente a Drogas/tratamiento farmacológico , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Adulto JovenRESUMEN
The emergence of multidrug resistant-tuberculosis (MDR-TB), defined as Mycobacterium tuberculosis strains with in vitro resistance to at least isoniazid and rifampicin, has necessitated evaluation and validation of appropriate surrogate endpoints for treatment response in drug trials for MDR-TB. The trial that has demonstrated efficacy of bedaquiline, a diarylquinoline that inhibits mycobacterial ATP synthase, possesses the requisite features to conduct this evaluation. Approval of bedaquiline for use in MDR-TB was based primarily on the results of the controlled C208 Stage II study (ClinicalTrials.gov number, NCT00449644) including 160 patients randomized 1:1 to receive bedaquiline or placebo for 24 weeks when added to an 18-24-month preferred five-drug background regimen. Since randomization in C208 Stage II was preserved until study end, the trial results allow for the investigation of the complex relationship between sustained durable outcome with either Week 8 or Week 24 culture conversion as putative surrogate endpoints. The relationship between Week 120 outcome with Week 8 or Week 24 culture conversion was investigated using a descriptive analysis and with a recently developed statistical methodology for surrogate endpoint evaluation using methods of causal inference. The results demonstrate that sputum culture conversion at 24 weeks is more reliable than sputum culture conversion at 8 weeks when assessing the outcome of adding one new drug to a MDR-TB regimen.
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Antituberculosos/uso terapéutico , Biomarcadores/análisis , Mycobacterium tuberculosis/efectos de los fármacos , Esputo/microbiología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Adolescente , Adulto , Anciano , Técnicas Bacteriológicas/métodos , Diarilquinolinas/uso terapéutico , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/fisiología , Evaluación de Resultado en la Atención de Salud , Factores de Tiempo , Tuberculosis Resistente a Múltiples Medicamentos/diagnóstico , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Adulto JovenRESUMEN
Background: Respiratory syncytial virus (RSV) disease has no effective treatment. JNJ-53718678 is a fusion inhibitor with selective activity against RSV. Methods: After confirmation of RSV infection or 5 days after inoculation with RSV, participants (n = 69) were randomized to JNJ-53718678 75 mg (n = 15), 200 mg (n = 17), 500 mg (n = 18), or placebo (n = 17) orally once daily for 7 days. Antiviral effects were evaluated by assessing RSV RNA viral load (VL) area under the curve (AUC) from baseline (before the first dose) until discharge, time-to-peak VL, duration of viral shedding, clinical symptoms, and quantity of nasal secretions. Results: Mean VL AUC was lower for individuals treated with different doses of JNJ-53718678 versus placebo (203.8-253.8 vs 432.8 log10 PFUe.hour/mL). Also, mean peak VL, time to peak VL, duration of viral shedding, mean overall symptom score, and nasal secretion weight were lower in each JNJ-53718678-treated group versus placebo. No clear exposure-response relationship was observed. Three participants discontinued due to treatment-emergent adverse events of grade 2 and 1 electrocardiogram change (JNJ-53718678 75 mg and 200 mg, respectively) and grade 2 urticaria (placebo). Conclusions: JNJ-53718678 at all 3 doses substantially reduced VL and clinical disease severity, thus establishing clinical proof of concept and the compound's potential as a novel RSV treatment. Clinical trials registration: ClinicalTrials.gov: NCT02387606; EudraCT number: 2014-005041-41.
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Antivirales/administración & dosificación , Imidazolidinas/administración & dosificación , Indoles/administración & dosificación , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Virus Sincitial Respiratorio Humano/efectos de los fármacos , Administración Oral , Adolescente , Adulto , Antivirales/farmacología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Voluntarios Sanos , Humanos , Imidazolidinas/farmacología , Indoles/farmacología , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Infecciones por Virus Sincitial Respiratorio/patología , Infecciones por Virus Sincitial Respiratorio/prevención & control , Virus Sincitial Respiratorio Humano/aislamiento & purificación , Resultado del Tratamiento , Carga Viral , Esparcimiento de Virus , Adulto JovenAsunto(s)
Antituberculosos/uso terapéutico , Resistencia a Múltiples Medicamentos , Mycobacterium tuberculosis/efectos de los fármacos , Esputo/microbiología , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Objectives: Resistance-associated variants (RAVs) in Rv0678 , a regulator of the MmpS5-MmpL5 efflux pump, have been shown to lead to increased MICs of bedaquiline (2- to 8- fold) and clofazimine (2- to 4-fold). The prevalence of these Rv0678 RAVs in clinical isolates and their impact on treatment outcomes are important factors to take into account in bedaquiline treatment guidelines. Methods: Baseline isolates from two bedaquiline MDR-TB clinical trials were sequenced for Rv0678 RAVs and corresponding bedaquiline MICs were determined on 7H11 agar. Rv0678 RAVs were also investigated in non-MDR-TB sequences of a population-based cohort. Results: Rv0678 RAVs were identified in 23/347 (6.3%) of MDR-TB baseline isolates. Surprisingly, bedaquiline MICs for these isolates were high (> 0.24â mg/L, n = 8), normal (0.03-0.24 mg/L, n = 11) or low (< 0.03â mg/L, n = 4). A variant at position -11 in the intergenic region mmpS5 - Rv0678 was identified in 39 isolates (11.3%) and appeared to increase the susceptibility to bedaquiline. In non-MDR-TB isolates, the frequency of Rv0678 RAVs was lower (6/852 or 0.7%). Competition experiments suggested that rifampicin was not the drug selecting for Rv0678 RAVs. Conclusions: RAVs in Rv0678 occur more frequently in MDR-TB patients than previously anticipated, are not associated with prior use of bedaquiline or clofazimine, and in the majority of cases do not lead to bedaquiline MICs above the provisional breakpoint (0.24â mg/L). Their origin remains unknown. Given the variety of RAVs in Rv0678 and their variable effects on the MIC, only phenotypic drug-susceptibility methods can currently be used to assess bedaquiline susceptibility.
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Antituberculosos/farmacología , Clofazimina/farmacología , Diarilquinolinas/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Antiinflamatorios/farmacología , Antibióticos Antituberculosos/uso terapéutico , Antituberculosos/uso terapéutico , Ensayos Clínicos como Asunto , Clofazimina/uso terapéutico , Diarilquinolinas/uso terapéutico , Humanos , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/genética , Prevalencia , Rifampin/uso terapéutico , Análisis de Secuencia de ADN , Tuberculosis Resistente a Múltiples Medicamentos/epidemiologíaRESUMEN
Our objective was to establish reference MIC quality control (QC) ranges for drug susceptibility testing of antimycobacterials, including first-line agents, second-line injectables, fluoroquinolones, and World Health Organization category 5 drugs for multidrug-resistant tuberculosis using a 7H9 broth microdilution MIC method. A tier-2 reproducibility study was conducted in eight participating laboratories using Clinical Laboratory and Standards Institute (CLSI) guidelines. Three lots of custom-made frozen 96-well polystyrene microtiter plates were used and prepared with 2× prediluted drugs in 7H9 broth-oleic acid albumin dextrose catalase. The QC reference strain was Mycobacterium tuberculosis H37Rv. MIC frequency, mode, and geometric mean were calculated for each drug. QC ranges were derived based on predefined, strict CLSI criteria. Any data lying outside CLSI criteria resulted in exclusion of the entire laboratory data set. Data from one laboratory were excluded due to higher MIC values than other laboratories. QC ranges were established for 11 drugs: isoniazid (0.03 to 0.12 µg/ml), rifampin (0.03 to 0.25 µg/ml), ethambutol (0.25 to 2 µg/ml), levofloxacin (0.12 to 1 µg/ml), moxifloxacin (0.06 to 0.5 µg/ml), ofloxacin (0.25 to 2 µg/ml), amikacin (0.25 to 2 µg/ml), kanamycin (0.25 to 2 µg/ml), capreomycin (0.5 to 4 µg/ml), linezolid (0.25 to 2 µg/ml), and clofazimine (0.03 to 0.25 µg/ml). QC ranges could not be established for nicotinamide (pyrazinamide surrogate), prothionamide, or ethionamide, which were assay nonperformers. Using strict CLSI criteria, QC ranges against the M. tuberculosis H37Rv reference strain were established for the majority of commonly used antituberculosis drugs, with a convenient 7H9 broth microdilution MIC method suitable for use in resource-limited settings.
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Antituberculosos/farmacología , Clofazimina/farmacología , Fluoroquinolonas/farmacología , Linezolid/farmacología , Pruebas de Sensibilidad Microbiana/métodos , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Humanos , Control de Calidad , Tuberculosis Resistente a Múltiples Medicamentos/microbiologíaRESUMEN
The aim of this study was to establish standardized drug susceptibility testing (DST) methodologies and reference MIC quality control (QC) ranges for bedaquiline, a diarylquinoline antimycobacterial, used in the treatment of adults with multidrug-resistant tuberculosis. Two tier-2 QC reproducibility studies of bedaquiline DST were conducted in eight laboratories using Clinical Laboratory and Standards Institute (CLSI) guidelines. Agar dilution and broth microdilution methods were evaluated. Mycobacterium tuberculosis H37Rv was used as the QC reference strain. Bedaquiline MIC frequency, mode, and geometric mean were calculated. When resulting data occurred outside predefined CLSI criteria, the entire laboratory data set was excluded. For the agar dilution MIC, a 4-dilution QC range (0.015 to 0.12 µg/ml) centered around the geometric mean included 95.8% (7H10 agar dilution; 204/213 observations with one data set excluded) or 95.9% (7H11 agar dilution; 232/242) of bedaquiline MICs. For the 7H9 broth microdilution MIC, a 3-dilution QC range (0.015 to 0.06 µg/ml) centered around the mode included 98.1% (207/211, with one data set excluded) of bedaquiline MICs. Microbiological equivalence was demonstrated for bedaquiline MICs determined using 7H10 agar and 7H11 agar but not for bedaquiline MICs determined using 7H9 broth and 7H10 agar or 7H9 broth and 7H11 agar. Bedaquiline DST methodologies and MIC QC ranges against the H37Rv M. tuberculosis reference strain have been established: 0.015 to 0.12 µg/ml for the 7H10 and 7H11 agar dilution MICs and 0.015 to 0.06 µg/ml for the 7H9 broth microdilution MIC. These methodologies and QC ranges will be submitted to CLSI and EUCAST to inform future research and provide guidance for routine clinical bedaquiline DST in laboratories worldwide.
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Antituberculosos/farmacología , Diarilquinolinas/farmacología , Pruebas de Sensibilidad Microbiana/métodos , Pruebas de Sensibilidad Microbiana/normas , Mycobacterium tuberculosis/efectos de los fármacos , Control de Calidad , Humanos , Reproducibilidad de los ResultadosRESUMEN
Bedaquiline, a diarylquinoline, improved cure rates when added to a multidrug-resistant tuberculosis (MDR-TB) treatment regimen in a previous placebo-controlled, phase 2 trial (TMC207-C208; NCT00449644). The current phase 2, multicenter, open-label, single-arm trial (TMC207-C209; NCT00910871) reported here was conducted to confirm the safety and efficacy of bedaquiline.Newly diagnosed or previously treated patients with MDR-TB (including pre-extensively drug-resistant (pre-XDR)-TB or extensively drug-resistant (XDR)-TB) received bedaquiline for 24â weeks with a background regimen of anti-TB drugs continued according to National TB Programme treatment guidelines. Patients were assessed during and up to 120â weeks after starting bedaquiline.Of 233 enrolled patients, 63.5% had MDR-TB, 18.9% had pre-XDR-TB and 16.3% had XDR-TB, with 87.1% having taken second-line drugs prior to enrolment. 16 patients (6.9%) died. 20 patients (8.6%) discontinued before week 24, most commonly due to adverse events or MDR-TB-related events. Adverse events were generally those commonly associated with MDR-TB treatment. In the efficacy population (n=205), culture conversion (missing outcome classified as failure) was 72.2% at 120â weeks, and 73.1%, 70.5% and 62.2% in MDR-TB, pre-XDR-TB and XDR-TB patients, respectively.Addition of bedaquiline to a background regimen was well tolerated and led to good outcomes in this clinically relevant patient cohort with MDR-TB.
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Antituberculosos/uso terapéutico , Diarilquinolinas/uso terapéutico , Tuberculosis Extensivamente Resistente a Drogas/tratamiento farmacológico , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Adulto JovenRESUMEN
OBJECTIVES: The objective of this study was to evaluate the performance of the BACTEC MGIT960 system to test the susceptibility to bedaquiline for Mycobacterium tuberculosis complex. METHODS: We determined the quality control (QC) range of bedaquiline using the M. tuberculosis H37Rv reference strain and the epidemiological cut-off (ECOFF) in MGIT960 and on Middlebrook 7H11 agar (M7H11) using 47 strains from bedaquiline treatment-naive patients. The accuracy of MGIT960 was evaluated versus M7H11 using 74 'probably susceptible to bedaquiline' and 18 'probably resistant to bedaquiline' strains. Repeatability and reproducibility of MGIT960 were assessed using five strains showing different resistance levels. RESULTS: The QC range for the H37Rv strain was between 0.125 and 0.50 mg/L. The WT MIC distribution ranged from ≤0.03 to 1.00 mg/L in MGIT960 and from ≤0.008 to 0.25 mg/L on M7H11 with suggested ECOFFs of 1.00 and 0.25 mg/L, respectively. Applying these ECOFFs, the probably susceptible and probably resistant strains were distinguishable by both methods, albeit with only a 2-fold increased MIC for one of the resistant strains compared with the ECOFF. Intermethod agreement to classify the isolates was excellent (100%). All replicates in the repeatability and reproducibility experiments fell within the normal range. CONCLUSIONS: The MGIT960 system proved to be highly stable, reproducible and accurate relative to the M7H11 agar method for determining the bedaquiline MIC. The small margin between the suggested ECOFF and the lowest MIC for the mutant strains risks making both methods prone to discordant results. Further validation in clinical settings linked to treatment outcome data is needed.
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Antituberculosos/farmacología , Diarilquinolinas/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Automatización de Laboratorios/métodos , Medios de Cultivo/química , Humanos , Pruebas de Sensibilidad Microbiana/métodos , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Bedaquiline (Sirturo, TMC207), a diarylquinoline that inhibits mycobacterial ATP synthase, has been associated with accelerated sputum-culture conversion in patients with multidrug-resistant tuberculosis, when added to a preferred background regimen for 8 weeks. METHODS: In this phase 2b trial, we randomly assigned 160 patients with newly diagnosed, smear-positive, multidrug-resistant tuberculosis to receive either 400 mg of bedaquiline once daily for 2 weeks, followed by 200 mg three times a week for 22 weeks, or placebo, both in combination with a preferred background regimen. The primary efficacy end point was the time to sputum-culture conversion in liquid broth. Patients were followed for 120 weeks from baseline. RESULTS: Bedaquiline reduced the median time to culture conversion, as compared with placebo, from 125 days to 83 days (hazard ratio in the bedaquiline group, 2.44; 95% confidence interval, 1.57 to 3.80; P<0.001 by Cox regression analysis) and increased the rate of culture conversion at 24 weeks (79% vs. 58%, P=0.008) and at 120 weeks (62% vs. 44%, P=0.04). On the basis of World Health Organization outcome definitions for multidrug-resistant tuberculosis, cure rates at 120 weeks were 58% in the bedaquiline group and 32% in the placebo group (P=0.003). The overall incidence of adverse events was similar in the two groups. There were 10 deaths in the bedaquiline group and 2 in the placebo group, with no causal pattern evident. CONCLUSIONS: The addition of bedaquiline to a preferred background regimen for 24 weeks resulted in faster culture conversion and significantly more culture conversions at 120 weeks, as compared with placebo. There were more deaths in the bedaquiline group than in the placebo group. (Funded by Janssen Pharmaceuticals; TMC207-C208 ClinicalTrials.gov number, NCT00449644.).
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Antituberculosos/uso terapéutico , Diarilquinolinas/uso terapéutico , Mycobacterium tuberculosis/aislamiento & purificación , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Adolescente , Adulto , Antituberculosos/farmacología , Diarilquinolinas/farmacología , Esquema de Medicación , Quimioterapia Combinada , Femenino , Humanos , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/efectos de los fármacos , Esputo/microbiología , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Tuberculosis Resistente a Múltiples Medicamentos/mortalidad , Adulto JovenRESUMEN
Bedaquiline (BDQ), an ATP synthase inhibitor, is the first drug to be approved for treatment of multi-drug resistant tuberculosis in decades. In vitro resistance to BDQ was previously shown to be due to target-based mutations. Here we report that non-target based resistance to BDQ, and cross-resistance to clofazimine (CFZ), is due to mutations in Rv0678, a transcriptional repressor of the genes encoding the MmpS5-MmpL5 efflux pump. Efflux-based resistance was identified in paired isolates from patients treated with BDQ, as well as in mice, in which it was confirmed to decrease bactericidal efficacy. The efflux inhibitors verapamil and reserpine decreased the minimum inhibitory concentrations of BDQ and CFZ in vitro, but verapamil failed to increase the bactericidal effect of BDQ in mice and was unable to reverse efflux-based resistance in vivo. Cross-resistance between BDQ and CFZ may have important clinical implications.
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Diarilquinolinas/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Animales , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Proteínas Bacterianas/metabolismo , Secuencia de Bases , Clofazimina/farmacología , Diarilquinolinas/uso terapéutico , Genes Bacterianos , Aptitud Genética , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Biológicos , Datos de Secuencia Molecular , Mutación/genética , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/aislamiento & purificación , Reserpina/farmacología , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , Regulación hacia Arriba/efectos de los fármacos , Verapamilo/farmacologíaRESUMEN
Emergence of drug-resistant bacteria represents a high, unmet medical need, and discovery of new antibacterials acting on new bacterial targets is strongly needed. ATP synthase has been validated as an antibacterial target in Mycobacterium tuberculosis, where its activity can be specifically blocked by the diarylquinoline TMC207. However, potency of TMC207 is restricted to mycobacteria with little or no effect on the growth of other Gram-positive or Gram-negative bacteria. Here, we identify diarylquinolines with activity against key Gram-positive pathogens, significantly extending the antibacterial spectrum of the diarylquinoline class of drugs. These compounds inhibited growth of Staphylococcus aureus in planktonic state as well as in metabolically resting bacteria grown in a biofilm culture. Furthermore, time-kill experiments showed that the selected hits are rapidly bactericidal. Drug-resistant mutations were mapped to the ATP synthase enzyme, and biochemical analysis as well as drug-target interaction studies reveal ATP synthase as a target for these compounds. Moreover, knockdown of the ATP synthase expression strongly suppressed growth of S. aureus, revealing a crucial role of this target in bacterial growth and metabolism. Our data represent a proof of principle for using the diarylquinoline class of antibacterials in key Gram-positive pathogens. Our results suggest that broadening the antibacterial spectrum for this chemical class is possible without drifting off from the target. Development of the diarylquinolines class may represent a promising strategy for combating Gram-positive pathogens.
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Complejos de ATP Sintetasa/antagonistas & inhibidores , Antibacterianos/farmacología , Bacterias Grampositivas/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Quinolinas/farmacología , Staphylococcus aureus/efectos de los fármacos , Complejos de ATP Sintetasa/genética , Adenosina Trifosfato/biosíntesis , Secuencia de Aminoácidos , Biopelículas/efectos de los fármacos , Línea Celular Tumoral , Farmacorresistencia Bacteriana/genética , Bacterias Grampositivas/crecimiento & desarrollo , Células HeLa , Humanos , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/crecimiento & desarrollo , Quinolinas/química , Quinolinas/toxicidad , Alineación de Secuencia , Staphylococcus aureus/crecimiento & desarrolloRESUMEN
TMC207 is a first-in-class diarylquinoline with a new mode of action against mycobacteria targeting the ATP synthase. It is metabolized to an active derivative, N-desmethyl TMC207, and both compounds are eliminated with long terminal half-lives (50 to 60 h in mice) reflecting slow release from tissues such as lung and spleen. In vitro, TMC207 is 5-fold more potent against Mycobacterium tuberculosis than N-desmethyl TMC207, and the effects of the two compounds are additive. The pharmacokinetic and pharmacodynamic (PK-PD) response was investigated in the murine model of tuberculosis (TB) infection following oral administration of different doses of TMC207 or N-desmethyl TMC207 at 5 days per week for 4 weeks starting the day after intravenous infection with M. tuberculosis and following administration of different doses of TMC207 at various dosing frequencies for 6 weeks starting 2 weeks after infection. Upon administration of N-desmethyl TMC207, maximum plasma concentration (C(max)), area under the plasma concentration-time curve from time zero to 168 h postdose (AUC(168h)), and minimum plasma concentration (C(min)) were approximately dose proportional between 8 and 64 mg/kg, and the lung CFU counts were strongly correlated with these pharmacokinetic parameters using an inhibitory sigmoid maximum effect (E(max)) model. Administration of the highest dose (64 mg/kg) produced a 4.0-log(10) reduction of the bacillary load at an average exposure (average concentration [C(avg)] or AUC(168h) divided by 168) of 2.7 µg/ml. Upon administration of the highest dose of TMC207 (50 mg/kg) 5 days per week for 4 weeks, the total reduction of the bacillary load was 4.7 log(10). TMC207 was estimated to contribute to a 1.8-log(10) reduction and its corresponding exposure (C(avg)) was 0.5 µg/ml. Optimal bactericidal activity with N-desmethyl TMC207 was reached at a high exposure compared to that achieved in humans, suggesting a minor contribution of the metabolite to the overall bactericidal activity in TB-infected patients treated with TMC207. Following administration of TMC207 at a total weekly dose of 15, 30, or 60 mg/kg fractionated for either 5 days per week, twice weekly, or once weekly, the bactericidal activity was correlated to the total weekly dose and was not influenced by the frequency of administration. Exposures (AUC(168h)) to TMC207 and N-desmethyl TMC207 mirrored this dose response, indicating that the bactericidal activity of TMC207 is concentration dependent and that AUC is the main PK-PD driver on which dose optimization should be based for dosing frequencies up to once weekly. The PK-PD profile supports intermittent administration of TMC207, in agreement with its slow release from tissues.
Asunto(s)
Complejos de ATP Sintetasa/antagonistas & inhibidores , Antituberculosos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Pulmón/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Quinolinas/farmacología , Tuberculosis Pulmonar/tratamiento farmacológico , Complejos de ATP Sintetasa/metabolismo , Animales , Antituberculosos/sangre , Antituberculosos/farmacocinética , Área Bajo la Curva , Proteínas Bacterianas/metabolismo , Biotransformación , Recuento de Colonia Microbiana , Diarilquinolinas , Modelos Animales de Enfermedad , Vías de Administración de Medicamentos , Esquema de Medicación , Cálculo de Dosificación de Drogas , Femenino , Semivida , Humanos , Pulmón/microbiología , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/crecimiento & desarrollo , Quinolinas/sangre , Quinolinas/farmacocinética , Tuberculosis Pulmonar/microbiologíaRESUMEN
RATIONALE: The sterilizing activity of the regimen used to treat multidrug resistant tuberculosis (MDR TB) has not been studied in a mouse model. OBJECTIVE AND METHODS: Swiss mice were intravenously inoculated with 6 log10 of Mycobacterium tuberculosis (TB) strain H37Rv, treated with second-line drug combinations with or without the diarylquinoline TMC207, and then followed without treatment for 3 more months to determine relapse rates (modified Cornell model). MEASUREMENTS: Bactericidal efficacy was assessed by quantitative lung colony-forming unit (CFU) counts. Sterilizing efficacy was assessed by measuring bacteriological relapse rates 3 months after the end of treatment. MAIN RESULTS: The relapse rate observed after 12 months treatment with the WHO recommended MDR TB regimen (amikacin, ethionamide, pyrazinamide and moxifloxacin) was equivalent to the relapse rate observed after 6 months treatment with the recommended drug susceptible TB regimen (rifampin, isoniazid and pyrazinamide). When TMC207 was added to this MDR TB regimen, the treatment duration needed to reach the same relapse rate dropped to 6 months. A similar relapse rate was also obtained with a 6-month completely oral regimen including TMC207, moxifloxacin and pyrazinamide but excluding both amikacin and ethionamide. CONCLUSIONS: In this murine model the duration of the WHO MDR TB treatment could be reduced to 12 months instead of the recommended 18-24 months. The inclusion of TMC207 in the WHO MDR TB treatment regimen has the potential to further shorten the treatment duration and at the same time to simplify treatment by eliminating the need to include an injectable aminoglycoside.
Asunto(s)
Antituberculosos/uso terapéutico , Quinolinas/uso terapéutico , Esterilización , Tuberculosis/tratamiento farmacológico , Animales , Antituberculosos/farmacología , Recuento de Colonia Microbiana , Diarilquinolinas , Modelos Animales de Enfermedad , Pulmón/efectos de los fármacos , Pulmón/microbiología , Pulmón/patología , Ratones , Mycobacterium tuberculosis/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Quinolinas/farmacología , Recurrencia , Bazo/patología , Análisis de SupervivenciaRESUMEN
Tuberculosis (TB) is more prevalent in the world today than at any other time in human history. Mycobacterium tuberculosis, the pathogen responsible for TB, uses diverse strategies to survive in a variety of host lesions and to evade immune surveillance. A key question is how robust are our approaches to discovering new TB drugs, and what measures could be taken to reduce the long and protracted clinical development of new drugs. The emergence of multi-drug-resistant strains of M. tuberculosis makes the discovery of new molecular scaffolds a priority, and the current situation even necessitates the re-engineering and repositioning of some old drug families to achieve effective control. Whatever the strategy used, success will depend largely on our proper understanding of the complex interactions between the pathogen and its human host. In this review, we discuss innovations in TB drug discovery and evolving strategies to bring newer agents more quickly to patients.