RESUMEN
BACKGROUND: The value, speed of completion and robustness of the evidence generated by TB treatment trials could be improved by implementing standards for best practice.METHODS: A global panel of experts participated in a Delphi process, using a 7-point Likert scale to score and revise draft standards until consensus was reached.RESULTS: Eleven standards were defined: Standard 1, high quality data on TB regimens are essential to inform clinical and programmatic management; Standard 2, the research questions addressed by TB trials should be relevant to affected communities, who should be included in all trial stages; Standard 3, trials should make every effort to be as inclusive as possible; Standard 4, the most efficient trial designs should be considered to improve the evidence base as quickly and cost effectively as possible, without compromising quality; Standard 5, trial governance should be in line with accepted good clinical practice; Standard 6, trials should investigate and report strategies that promote optimal engagement in care; Standard 7, where possible, TB trials should include pharmacokinetic and pharmacodynamic components; Standard 8, outcomes should include frequency of disease recurrence and post-treatment sequelae; Standard 9, TB trials should aim to harmonise key outcomes and data structures across studies; Standard 10, TB trials should include biobanking; Standard 11, treatment trials should invest in capacity strengthening of local trial and TB programme staff.CONCLUSION: These standards should improve the efficiency and effectiveness of evidence generation, as well as the translation of research into policy and practice.
Asunto(s)
Tuberculosis , Humanos , Bancos de Muestras Biológicas , Tuberculosis/tratamiento farmacológico , Ensayos Clínicos como AsuntoRESUMEN
BACKGROUND: Pretomanid (Pa) is a nitroimidazole-class drug recently approved by the US Food and Drug Administration and other regulatory authorities as part of a regimen for treating highly drug-resistant pulmonary Mycobacterium tuberculosis infections. Studies in rodents identified the testis as a target organ of concern, which led to monitoring of reproductive hormones in >800 male patients enrolled in four clinical trials of Pa-containing regimens and the HRZE (isoniazid+rifampin+pyrazinamide+ethambutol) control regimen.METHODS: Serum hormone levels relevant to male reproductive health - follicle stimulating hormone (FSH), luteinizing hormone (LH), inhibin B (InhB) and total testosterone (T) - from the four clinical trials were summarized numerically and analyzed by repeated-measures modeling.RESULTS: Hormone levels generally behaved similarly in Pa-containing and HRZE arms. Relative to baseline, serum T and InhB levels generally increased at the end of treatment and follow-up. FSH and LH levels were variable, but were generally at or below baseline levels by follow-up. Before treatment, many patients were borderline hypogonadal, with T levels near the lower limits of the normal range.CONCLUSION: Changes in male hormones in four clinical trials studying patients with TB indicate that Pa-containing treatment was not associated with testicular toxicity but rather led to improvement in the underlying hypogonadism.
Asunto(s)
Nitroimidazoles , Tuberculosis Resistente a Múltiples Medicamentos , Hormona Folículo Estimulante , Humanos , Hormona Luteinizante , Masculino , Nitroimidazoles/uso terapéutico , Testosterona , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológicoRESUMEN
BACKGROUND: There are no data comparing the 6-9 month oral three-drug Nix regimen (bedaquiline, pretomanid and linezolid [BPaL]) to conventional regimens containing bedaquiline (B, BDQ) and linezolid (L, LZD).METHODS: Six-month post end-of-treatment outcomes were compared between Nix-TB (n = 109) and 102 prospectively recruited extensively drug-resistant TB patients who received an Ë18-month BDQ-based regimen (median of 8 drugs). A subset of patients received BDQ and LZD (n = 86), and a subgroup of these (n = 75) served as individually matched controls in a pairwise comparison to determine differences in regimen efficacy.RESULTS: Favourable outcomes (%) were significantly better with BPaL than with the B-L-based combination regimen (98/109, 89.9% vs. 56/86, 65.1%; adjusted relative risk ratio [aRRR] 1.35; P < 0.001) and in the matched pairwise analysis (67/75, 89.3% vs. 48/75, 64.0%; aRRR 1.39; P = 0.001), despite significantly higher baseline bacterial load and prior second-line drug exposure in the BPaL cohort. Time to culture conversion (P < 0.001), time to unfavourable outcome (P < 0.01) and time to death (P < 0.03) were significantly better or lower with BPaL than the B-L-based combinations.CONCLUSION: The BPaL regimen (and hence substitution of multiple other drugs by pretomanid and/or higher starting-dose LZD) may improve outcomes in drug-resistant TB patients with poor prognostic features. However, prospective controlled studies are required to definitively answer this question.
Asunto(s)
Tuberculosis Extensivamente Resistente a Drogas , Tuberculosis Resistente a Múltiples Medicamentos , Antituberculosos/uso terapéutico , Diarilquinolinas/uso terapéutico , Tuberculosis Extensivamente Resistente a Drogas/tratamiento farmacológico , Humanos , Linezolid/uso terapéutico , Nitroimidazoles , Estudios Prospectivos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológicoRESUMEN
BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI -2.2% to 15.4%) difference per protocol and 9.9% (95%CI -4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.
Asunto(s)
Antituberculosos , Pirazinamida , Tuberculosis , Humanos , Antituberculosos/uso terapéutico , Quimioterapia Combinada , Moxifloxacino , Nitroimidazoles , Resultado del Tratamiento , Tuberculosis/tratamiento farmacológicoRESUMEN
BACKGROUND: In the REMoxTB study of 4-month treatment-shortening regimens containing moxifloxacin compared to the standard 6-month regimen for tuberculosis, the proportion of unfavourable outcomes for women was similar in all study arms, but men had more frequent unfavourable outcomes (bacteriologically or clinically defined failure or relapse within 18 months after randomisation) on the shortened moxifloxacin-containing regimens. The reason for this gender disparity in treatment outcome is poorly understood. METHODS: The gender differences in baseline variables were calculated, as was time to smear and culture conversion and Kaplan-Meier plots were constructed. In post hoc exploratory analyses, multivariable logistic regression modelling and an observed case analysis were used to explore factors associated with both gender and unfavourable treatment outcome. RESULTS: The per-protocol population included 472/1548 (30%) women. Women were younger and had lower rates of cavitation, smoking and weight (all p < 0.05) and higher prevalence of HIV (10% vs 6%, p = 0.001). They received higher doses (mg/kg) than men of rifampicin, isoniazid, pyrazinamide and moxifloxacin (p ≤ 0.005). There was no difference in baseline smear grading or mycobacterial growth indicator tube (MGIT) time to positivity. Women converted to negative cultures more quickly than men on Lowenstein-Jensen (HR 1.14, p = 0.008) and MGIT media (HR 1.19, p < 0.001). In men, the presence of cavitation, positive HIV status, higher age, lower BMI and 'ever smoked' were independently associated with unfavourable treatment outcome. In women, only 'ever smoked' was independently associated with unfavourable treatment outcome. Only for cavitation was there a gender difference in treatment outcomes by regimen; their outcome in the 4-month arms was significantly poorer compared to the 6-month treatment arm (p < 0.001). Women, with or without cavities, and men without cavities had a similar outcome on all treatment arms (p = 0.218, 0.224 and 0.689 respectively). For all other covariate subgroups, there were no differences in treatment effects for men or women. CONCLUSIONS: Gender differences in TB treatment responses for the shorter regimens in the REMoxTB study may be explained by poor outcomes in men with cavitation on the moxifloxacin-containing regimens. We observed that women with cavities, or without, on the 4-month moxifloxacin regimens had similar outcomes to all patients on the standard 6-month treatment. The biological reasons for this difference are poorly understood and require further exploration.
Asunto(s)
Tuberculosis/tratamiento farmacológico , Femenino , Identidad de Género , Humanos , Masculino , Resultado del Tratamiento , Tuberculosis/patologíaRESUMEN
BACKGROUND: Drug-induced liver injury (DILI) is a common complication of tuberculosis treatment. We utilised data from the REMoxTB clinical trial to describe the incidence of predisposing factors and the natural history in patients with liver enzyme levels elevated in response to tuberculosis treatment. METHODS: Patients received either standard tuberculosis treatment (2EHRZ/4HR), or a 4-month regimen in which moxifloxacin replaced either ethambutol (isoniazid arm, 2MHRZ/2MHR) or isoniazid (ethambutol arm, 2EMRZ/2MR). Hepatic enzymes were measured at 0, 2, 4, 8, 12 and 17 weeks and as clinically indicated during reported adverse events. Patients included were those receiving at least one dose of drug and with two or more hepatic enzyme measurements. RESULTS: A total of 1928 patients were included (639 2EHRZ/4HR, 654 2MHRZ/2MHR and 635 2EMRZ/2MR). DILI was defined as peak alanine aminotransferase (ALT) ≥ 5 times the upper limit of normal (5 × ULN) or ALT ≥ 3 × ULN with total bilirubin > 2 × ULN. DILI was identified in 58 of the 1928 (3.0%) patients at a median time of 28 days (interquartile range IQR 14-56). Of 639 (6.4%) patients taking standard tuberculosis therapy, 41 experienced clinically significant enzyme elevations (peak ALT ≥ 3 × ULN). On standard therapy, 21.1% of patients aged >55 years developed a peak ALT/aspartate aminotransferase (AST) ≥ 3 × ULN (p = 0.01) and 15% of HIV-positive patients experienced a peak ALT/AST ≥ 3 × ULN compared to 9% of HIV-negative patients (p = 0.160). The median peak ALT/AST was higher in isoniazid-containing regimens vs no-isoniazid regimens (p < 0.05), and lower in moxifloxacin-containing arms vs no-moxifloxacin arms (p < 0.05). Patients receiving isoniazid reached a peak ALT ≥ 3 × ULN 9.5 days earlier than those on the ethambutol arm (median time of 28 days vs 18.5 days). Of the 67 Asian patients with a peak ALT/AST ≥ 3 × ULN, 57 (85.1%) were on an isoniazid-containing regimen (p = 0.008). CONCLUSIONS: Our results provide evidence of the risk of DILI in tuberculosis patients on standard treatment. Older patients on standard therapy, HIV-positive patients, Asian patients and those receiving isoniazid were at higher risk of elevated enzyme levels. Monitoring hepatic enzymes during the first 2 months of standard therapy detected approximately 75% of patients with a peak enzyme elevation ≥3 × ULN, suggesting this should be a standard of care. These results provide evidence for the potential of moxifloxacin in hepatic sparing.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Tuberculosis/complicaciones , Adolescente , Adulto , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Tuberculosis/tratamiento farmacológico , Adulto JovenRESUMEN
The recent approval of new tuberculosis (TB) drugs raises hope for new and more effective anti-tuberculosis treatment regimens. The Global Alliance for TB Drug Development (TB Alliance) is committed to ensuring that new anti-tuberculosis drugs fulfill the needs of patients, their families and the local health services that serve the communities. Here we present highlights of the TB Alliance's pipeline of regimen development, with novel regimens for patients with drug-susceptible, multidrug-resistant and extensively drug-resistant TB. The ongoing clinical trials (STAND, NC-005, Nix-TB and LIN-CL001) are outlined and their rationale and goals presented.
Asunto(s)
Antituberculosos/uso terapéutico , Tuberculosis Extensivamente Resistente a Drogas/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Protocolos Clínicos , Diarilquinolinas/uso terapéutico , Relación Dosis-Respuesta a Droga , Etambutol/uso terapéutico , Fluoroquinolonas/uso terapéutico , Humanos , Isoniazida/uso terapéutico , Linezolid/uso terapéutico , Moxifloxacino , Nitroimidazoles/uso terapéutico , Pirazinamida/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Rifampin/uso terapéuticoRESUMEN
Tuberculosis has affected Europe for millennia and continues to be a burden upon modern society. It is estimated that one-third of the world's population is infected with Mycobacterium tuberculosis, the causative agent of this condition. Despite the introduction of control strategies, the disease continues to be one of the most common causes of death globally. Within the framework of the Lithuanian Mummy Project, seven spontaneously mummified human bodies from a church crypt in Vilnius, dating from the 18th and 19th century, were CT-scanned to assess the presence of tuberculosis or other lung diseases. We encountered pulmonary lesions suggestive of cases of pulmonary tuberculosis. In addition, one case might have been affected by extra-pulmonary tuberculosis. This report replicates the image findings from previous studies on ancient mummies that provided evidence of tuberculosis in soft tissues, thus helping reconstruct the history of this disease over time.
Asunto(s)
Momias/diagnóstico por imagen , Tuberculosis Pulmonar/historia , Femenino , Historia del Siglo XVIII , Historia del Siglo XIX , Humanos , Lituania , Pulmón/diagnóstico por imagen , Masculino , Tomografía Computarizada por Rayos X , Tuberculosis Pulmonar/diagnóstico por imagenRESUMEN
In the face of a growing global burden of resistance to existing antibiotics, a combination of scientific and economic challenges has posed significant barriers to the development of novel antibacterials over the past few decades. Yet the bottlenecks at each stage of the pharmaceutical value chain-from discovery to post-marketing-present opportunities to reengineer an innovation pipeline that has fallen short. The upstream hurdles to lead identification and optimization may be eased with greater multi-sectoral collaboration, a growing array of alternatives to high-throughput screening, and the application of open source approaches. Product development partnerships and South-South innovation platforms have shown promise in bolstering the R&D efforts to tackle neglected diseases. Strategies that delink product sales from the firms' return on investment can help ensure that the twin goals of innovation and access are met. To effect these changes, both public and private sector stakeholders must show greater commitment to an R&D agenda that will address this problem, not only for industrialized countries but also globally.
Asunto(s)
Antibacterianos/uso terapéutico , Industria Farmacéutica/economía , Farmacorresistencia Bacteriana , Pandemias/prevención & control , Asociación entre el Sector Público-Privado/economía , Antibacterianos/síntesis química , Bacterias/patogenicidad , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/microbiología , Descubrimiento de Drogas , Industria Farmacéutica/organización & administración , Ensayos Analíticos de Alto Rendimiento , Humanos , Internacionalidad , Inversiones en Salud/economía , Enfermedades Desatendidas/tratamiento farmacológicoRESUMEN
Current tuberculosis (TB) treatment is based on a combination of drugs that were developed mostly in the central decades of the last century. Cure rates are high for drug sensitive strains of Mycobacterium tuberculosis (M. tb) when the recommended complex and lengthy treatment protocols are adhered to. However the difficulty in correctly prescribing and adhering to these protocols, the emergence of M tb strains resistant to multiple drugs, and drug-drug interactions that interfere with optimal treatment of HIV and TB coinfected patients have generated a pressing need for improved TB therapies. Together with the ominous global burden of TB, these shortcomings of current treatment have contributed to a renewed interest in the development of improved drugs and protocols for the treatment of tuberculosis. This article highlights hurdles related to the optimized use of existing drugs and challenges related to the development of novel, improved products, focusing in particular on aspects inherent in TB drug clinical development. Concluding comments propose processes for more efficient development of new TB therapies.
Asunto(s)
Antituberculosos/uso terapéutico , Tuberculosis/tratamiento farmacológico , Antituberculosos/farmacología , Ensayos Clínicos como Asunto , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Malato Sintasa/antagonistas & inhibidoresAsunto(s)
Histiocitosis de Células de Langerhans/historia , Tuberculosis Pulmonar/historia , Causas de Muerte , Preescolar , Femenino , Histiocitosis de Células de Langerhans/complicaciones , Histiocitosis de Células de Langerhans/patología , Historia del Siglo XVIII , Humanos , Hungría , Lactante , Masculino , Tuberculosis Pulmonar/complicaciones , Tuberculosis Pulmonar/patologíaRESUMEN
The recent debate over MRSA in our community is really getting to the state of the ridiculous. There is no question that this bacterium, which has been around for at least 40 years, is becoming a bigger and bigger menace in hospitals. Prior to the election, the shadow health secretary, Andrew Lansley, claimed that hospitals are being told to push more patients through beds rather than concentrating on hygiene and this is the cause of the epidemic. He calls for a search and destroy strategy to clean up wards. The health secretary, Dr John Reid, blames the increased use of contract cleaners under the last Tory government for the rise in the rates of infection. This is supported by the Public Sector Trades Union. They believe that it is the high input of patients that prevents MRSA and other hospital-acquired infections being tackled effectively. The answer, they feel, is strict hospital hygiene and frequent hand washing, with a higher proportion of single rooms.Now, we are told that matrons should take charge of cleanliness in hospitals. Despite all the hand wringing and washing, the morbidity and mortality are both in an upward spiral.
Asunto(s)
Control de Infecciones/normas , Resistencia a la Meticilina , Infecciones Estafilocócicas/prevención & control , Infección Hospitalaria/prevención & control , Humanos , Staphylococcus aureus/aislamiento & purificaciónRESUMEN
In order to assess the presence of tuberculosis in Pleistocene bison and the origin of tuberculosis in North America, 2 separate DNA extractions were performed by 2 separate laboratories on samples from the metacarpal of an extinct long-horned bison that was radiocarbon dated at 17,870+/-230 years before present and that had pathological changes suggestive of tuberculosis. Polymerase chain reaction amplification isolated fragments of tuberculosis DNA, which were sequenced, and on which spoligotyping was also performed to help determine its relationship to the various members of the Mycobacterium tuberculosis complex. Extensive precautions against contamination with modern M. tuberculosis complex DNA were employed, including analysis of paleontologic and modern specimens in 2 geographically separate laboratories.
Asunto(s)
Bison/microbiología , ADN Bacteriano/análisis , Mycobacterium tuberculosis/genética , Tuberculosis/historia , Animales , ADN Bacteriano/historia , Historia Antigua , Paleontología , Tuberculosis/veterinaria , WyomingRESUMEN
There are several specific PCR-based methods to detect Mycobacterium leprae DNA, but the amplicons are quite large. For example, primers that target the 36-kDa antigen gene and are in common diagnostic use yield a 530-bp product. This may be a disadvantage when examining samples in which the DNA is likely to be damaged and fragmented. Therefore, two sets of M. leprae-specific nested primers were designed, based on existing primer pairs which have been shown to be specific for M. leprae. Primers that targeted the 18-kDa antigen gene gave an outer product of 136 bp and inner product of 110 bp. The primers based on the RLEP repetitive sequence yielded a 129-bp outer product and 99-bp nested product. With dilutions of a standard M. leprae killed whole-cell preparation as the source of DNA, both single-stage and nested PCR were performed after optimisation of the experimental conditions. Compared with the 36-kDa antigen gene primers, the 18-kDa antigen gene outer primers were 100-fold more sensitive and the RLEP outer primers were 1000-fold more sensitive. As an illustration of two possible applications of these new primers, positive results were obtained from three skin slit samples from treated lepromatous leprosy patients and three archaeological samples from human remains showing typical leprosy palaeopathology. It was concluded that these new primers are a useful means of detecting M. leprae DNA which is damaged or present at a very low level.
Asunto(s)
Cartilla de ADN , ADN Bacteriano/análisis , Lepra/diagnóstico , Mycobacterium leprae/aislamiento & purificación , Reacción en Cadena de la Polimerasa/métodos , ADN Bacteriano/historia , Historia Medieval , Humanos , Lepra/historia , Lepra/microbiología , Mycobacterium leprae/genética , Paleopatología/métodos , Polonia , Sensibilidad y EspecificidadAsunto(s)
ADN , Lepra/diagnóstico , Lepra/historia , Lepra/microbiología , Historia Medieval , Mycobacterium leprae/genética , Mycobacterium leprae/aislamiento & purificación , Paleopatología/métodos , Polonia , Cartilla de ADN , Reacción en Cadena de la Polimerasa/métodos , Sensibilidad y EspecificidadRESUMEN
To examine the potential for DNA recovery from spirit-preserved medical material, a set of specimens from the Hunterian Collection of the Royal College of Surgeons was investigated. Using a range of DNA extraction techniques and the PCR, no replicable positive amplifications were made from this material of either human or Helicobacter DNA. Experiments with modern stomach biopsies of H. pylori-positive patients suggest that the bacterial DNA is typically present in a much lower concentration (10(3)-fold) than that of the host. The potential for recovery of this organism from spirit specimens is therefore low. The absence of DNA in this material is probably due to several factors, chiefly the incomplete fixation of the specimen by the ethanol storage fluid. Studies such as this demonstrate the need for a good understanding of specimen history when working with archival material.