Mycobacterium abscessus is a nontuberculous mycobacterium (NTM) of particular concern in individu... more Mycobacterium abscessus is a nontuberculous mycobacterium (NTM) of particular concern in individuals with obstructive lung diseases such as cystic fibrosis (CF). Treatment requires multiple drugs and is characterised by high rates of relapse; thus, new strategies to limit infection are urgently required. This study sought to determine how Bacille Calmette-Guérin (BCG) vaccination may impact NTM infection, using a murine model of Mycobacterium abscessus infection and observational data from a non-BCG vaccinated CF cohort in Sydney, Australia and a BCG-vaccinated CF cohort in Cape Town, South Africa. In mice, BCG vaccination induced multifunctional antigen-specific CD4+ T cells circulating in the blood and was protective against dissemination of bacteria to the spleen. Prior infection with M. abscessus afforded the highest level of protection against M. abscessus challenge in the lung, and immunity was characterised by a greater frequency of pulmonary cytokine-secreting CD4+ T cells c...
Tuberculosis (TB) is the leading infectious cause of human mortality and is responsible for nearl... more Tuberculosis (TB) is the leading infectious cause of human mortality and is responsible for nearly 2 million deaths every year. It is often regarded as a ‘silent killer’ because it predominantly affects the poor and marginalized, and disease outbreaks occur in ‘slow motion’ compared to Ebola or coronavirus 2 (COVID-19). In low incidence countries, TB is predominantly an imported disease and TB control in migrants is pivotal for countries to progress towards TB elimination in accordance with the World Health Organisations (WHO’s) End TB strategy. This review provides a brief overview of the different screening approaches and surveillance processes that are in place in low TB incidence countries. It also includes a detailed discussion of the ethical issues related to TB screening of migrants in these settings and the different interests that need to be balanced. Given recognition that a holistic approach that recognizes and respects basic human rights is required to end TB, the review...
Treatment of latent tuberculosis infection (LTBI) is an important component of strategies to achi... more Treatment of latent tuberculosis infection (LTBI) is an important component of strategies to achieve global tuberculosis (TB) elimination, but implementation is rarely monitored. This is a retrospective review of TB contact tracing outcomes at one of the busiest TB clinics in Australia, measured against the Centre for Disease Control and Prevention performance indicators. In total, 45 of 53 (85%) pulmonary TB cases had 171 close contacts, of whom 139 (81%) were evaluated with a tuberculin skin test (TST); 58 of 139 (42%) were positive at baseline. Among 57 close contacts of 16 sputum smear-positive TB cases, the elicitation, evaluation, initiation of LTBI treatment and completion rates were 93%, 86%, 14% and 100%, and among 114 close contacts of 37 sputum smear-negative pulmonary TB cases 81%, 83%, 16% and 89%, respectively. Of 79 contacts with an initial negative TST, 19 of 47 (40%) demonstrated TST conversion when retested; 5 of 19 (26%) were offered LTBI treatment. Four secondary...
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2017
Multidrug-resistant tuberculosis (MDR-TB) is a threat to tuberculosis (TB) control. To guide TB c... more Multidrug-resistant tuberculosis (MDR-TB) is a threat to tuberculosis (TB) control. To guide TB control, it is essential to understand the extent to which and the circumstances in which MDR-TB will replace drug-susceptible TB (DS-TB) as the dominant phenotype. The issue was examined by assessing evidence from genomics, pharmacokinetics, and epidemiology studies. This evidence was then synthesized into a mathematical model. This model considers two TB strains, one with and one without an MDR phenotype. It was considered that intrinsic transmissibility may be different between the two strains, as may the control response including the detection, treatment failure, and default rates. The outcomes were explored in terms of the incidence of MDR-TB and time until MDR-TB surpasses DS-TB as the dominant strain. The ability of MDR-TB to dominate DS-TB was highly sensitive to the relative transmissibility of the resistant strain; however, MDR-TB could dominate even when its transmissibility w...
The management of childhood tuberculosis (TB) is hampered by the low sensitivity and limited acce... more The management of childhood tuberculosis (TB) is hampered by the low sensitivity and limited accessibility of microbiological testing. Optimizing clinical approaches is therefore critical to close the persistent gaps in TB case detection and prevention necessary to realize the child mortality targets of the End TB Strategy. In this review, we provide practical guidance summarizing the evidence and guidelines describing the use of symptoms and signs in decision making for children being evaluated for either TB preventive treatment (TPT) or TB disease treatment in high-TB incidence settings. Among at-risk children being evaluated for TPT, a symptom screen may be used to differentiate children who require further investigation for TB disease before receiving TPT. For symptomatic children being investigated for TB disease, an algorithmic approach can inform which children should receive TB treatment, even in the absence of imaging or microbiological confirmation. Though clinical approac...
ABSTRACTBackgroundMany children with pulmonary tuberculosis remain undiagnosed and untreated with... more ABSTRACTBackgroundMany children with pulmonary tuberculosis remain undiagnosed and untreated with related high morbidity and mortality. Diagnostic challenges in children include low bacterial burden, challenges around specimen collection, and limited access to diagnostic expertise. Algorithms that guide decisions to initiate tuberculosis treatment in resource-limited settings could help to close the persistent childhood tuberculosis treatment gap. Recent advances in childhood tuberculosis algorithm development have incorporated prediction modelling, but studies conducted to date have been small and localised, with limited generalizability.MethodsWe collated individual participant data including clinical, bacteriological, and radiologic information from prospective diagnostic studies in high-tuberculosis incidence settings enrolling children <10 years with presumptive pulmonary tuberculosis. Using this dataset, we first retrospectively evaluated the performance of several existing...
IntroductionTreatment of latent tuberculosis infection (LTBI) plays a substantial role in the pre... more IntroductionTreatment of latent tuberculosis infection (LTBI) plays a substantial role in the prevention of drug-susceptible tuberculosis (TB). However, clinical trials to evaluate the efficacy of preventive therapy for presumed multidrug-resistant (MDR) LTBI are lacking. This trial aims to evaluate the efficacy of the antibiotic levofloxacin in preventing the development of active TB among latently infected contacts of index patients with MDR-TB.Methods and analysisA double-blind placebo-controlled parallel group randomised controlled trial will be conducted in 10 provinces of Vietnam. Household contacts living with patients with bacteriologically confirmed rifampicin-resistant or MDR-TB will be eligible for recruitment if they have a positive tuberculin skin test or are known to be immunosuppressed, and do not have active TB. Participants will be randomised to receive either levofloxacin or placebo tablets once per day for 6 months. Screening for incident TB will be performed at 6...
The World Health Organization estimates that 10 million new cases of tuberculosis (TB) occurred w... more The World Health Organization estimates that 10 million new cases of tuberculosis (TB) occurred worldwide in 2017, of which 600,000 were rifampicin or multidrug-resistant (RR/MDR) TB. Modelling estimates suggest that 32,000 new cases of MDR-TB occur in children annually, but only a fraction of these are correctly diagnosed and treated. Accurately diagnosing TB in children, who usually have paucibacillary disease, and implementing effective TB prevention and treatment programmes in resource-limited settings remain major challenges. In light of the underappreciated RR/MDR-TB burden in children, and the lack of paediatric data on newer drugs for TB prevention and treatment, we present an overview of new and repurposed TB drugs, describing the available evidence for safety and efficacy in children to assist clinical care and decision-making.
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2017
The study review guidelines on isolation of patients with tuberculosis, TB, from the World Health... more The study review guidelines on isolation of patients with tuberculosis, TB, from the World Health Organization, WHO, Centers for Disease Control and Prevention, CDC, and the European Center for Disease Control, ECDC. The review found that unequivocal guidelines for removing patients out of negative-pressure isolation and de-isolation patients from either single rooms or isolation at home is needed. Studies show that the time of effective treatment is the key parameter to follow to determine if patients are contagious to others or not. This means that standard treatment of multi-drug resistant, MDR, TB will not result in the patient being non-infectious. Thus it is important right from the time of diagnosis to know if the patient is infected with MDR TB or not. Thus the early use of molecular techniques to reveal drug susceptibility is important. Clear guidelines stating if patient with microscopy negative sputum no matter infected with fully susceptible or MDR TB, no matter HIV posi...
Tuberculosis is the leading infectious cause of death worldwide, with 9·6 million cases and 1·5 m... more Tuberculosis is the leading infectious cause of death worldwide, with 9·6 million cases and 1·5 million deaths reported in 2014. WHO estimates 480 000 cases of these were multidrug resistant (MDR). Less than half of patients who entered into treatment for MDR tuberculosis successfully completed that treatment, mainly due to high mortality and loss to follow-up. These in turn illustrate weaknesses in current treatment regimens and national tuberculosis programmes, coupled with operational treatment challenges. In this Review we provide an update on recent developments in the tuberculosis drug-development pipeline (including new and repurposed antimicrobials and host-directed drugs) as they are applied to new regimens to shorten and improve outcomes of tuberculosis treatment. Several new or repurposed antimicrobial drugs are in advanced trial stages for MDR tuberculosis, and two new antimicrobial drug candidates are in early-stage trials. Several trials to reduce the duration of thera...
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Jan 15, 2015
Consensus case definitions for childhood tuberculosis have been proposed by an international expe... more Consensus case definitions for childhood tuberculosis have been proposed by an international expert panel, aiming to standardize the reporting of cases in research focusing on the diagnosis of intrathoracic tuberculosis in children. These definitions are intended for tuberculosis diagnostic evaluation studies of symptomatic children with clinical suspicion of intrathoracic tuberculosis, and were not intended to predefine inclusion criteria into such studies. Feedback from researchers suggested that further clarification was required and that these case definitions could be further improved. Particular concerns were the perceived complexity and overlap of some case definitions, as well as the potential exclusion of children with acute onset of symptoms or less severe disease. The updated case definitions proposed here incorporate a number of key changes that aim to reduce complexity and improve research performance, while maintaining the original focus on symptomatic children suspect...
Mycobacterium abscessus is a nontuberculous mycobacterium (NTM) of particular concern in individu... more Mycobacterium abscessus is a nontuberculous mycobacterium (NTM) of particular concern in individuals with obstructive lung diseases such as cystic fibrosis (CF). Treatment requires multiple drugs and is characterised by high rates of relapse; thus, new strategies to limit infection are urgently required. This study sought to determine how Bacille Calmette-Guérin (BCG) vaccination may impact NTM infection, using a murine model of Mycobacterium abscessus infection and observational data from a non-BCG vaccinated CF cohort in Sydney, Australia and a BCG-vaccinated CF cohort in Cape Town, South Africa. In mice, BCG vaccination induced multifunctional antigen-specific CD4+ T cells circulating in the blood and was protective against dissemination of bacteria to the spleen. Prior infection with M. abscessus afforded the highest level of protection against M. abscessus challenge in the lung, and immunity was characterised by a greater frequency of pulmonary cytokine-secreting CD4+ T cells c...
Tuberculosis (TB) is the leading infectious cause of human mortality and is responsible for nearl... more Tuberculosis (TB) is the leading infectious cause of human mortality and is responsible for nearly 2 million deaths every year. It is often regarded as a ‘silent killer’ because it predominantly affects the poor and marginalized, and disease outbreaks occur in ‘slow motion’ compared to Ebola or coronavirus 2 (COVID-19). In low incidence countries, TB is predominantly an imported disease and TB control in migrants is pivotal for countries to progress towards TB elimination in accordance with the World Health Organisations (WHO’s) End TB strategy. This review provides a brief overview of the different screening approaches and surveillance processes that are in place in low TB incidence countries. It also includes a detailed discussion of the ethical issues related to TB screening of migrants in these settings and the different interests that need to be balanced. Given recognition that a holistic approach that recognizes and respects basic human rights is required to end TB, the review...
Treatment of latent tuberculosis infection (LTBI) is an important component of strategies to achi... more Treatment of latent tuberculosis infection (LTBI) is an important component of strategies to achieve global tuberculosis (TB) elimination, but implementation is rarely monitored. This is a retrospective review of TB contact tracing outcomes at one of the busiest TB clinics in Australia, measured against the Centre for Disease Control and Prevention performance indicators. In total, 45 of 53 (85%) pulmonary TB cases had 171 close contacts, of whom 139 (81%) were evaluated with a tuberculin skin test (TST); 58 of 139 (42%) were positive at baseline. Among 57 close contacts of 16 sputum smear-positive TB cases, the elicitation, evaluation, initiation of LTBI treatment and completion rates were 93%, 86%, 14% and 100%, and among 114 close contacts of 37 sputum smear-negative pulmonary TB cases 81%, 83%, 16% and 89%, respectively. Of 79 contacts with an initial negative TST, 19 of 47 (40%) demonstrated TST conversion when retested; 5 of 19 (26%) were offered LTBI treatment. Four secondary...
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2017
Multidrug-resistant tuberculosis (MDR-TB) is a threat to tuberculosis (TB) control. To guide TB c... more Multidrug-resistant tuberculosis (MDR-TB) is a threat to tuberculosis (TB) control. To guide TB control, it is essential to understand the extent to which and the circumstances in which MDR-TB will replace drug-susceptible TB (DS-TB) as the dominant phenotype. The issue was examined by assessing evidence from genomics, pharmacokinetics, and epidemiology studies. This evidence was then synthesized into a mathematical model. This model considers two TB strains, one with and one without an MDR phenotype. It was considered that intrinsic transmissibility may be different between the two strains, as may the control response including the detection, treatment failure, and default rates. The outcomes were explored in terms of the incidence of MDR-TB and time until MDR-TB surpasses DS-TB as the dominant strain. The ability of MDR-TB to dominate DS-TB was highly sensitive to the relative transmissibility of the resistant strain; however, MDR-TB could dominate even when its transmissibility w...
The management of childhood tuberculosis (TB) is hampered by the low sensitivity and limited acce... more The management of childhood tuberculosis (TB) is hampered by the low sensitivity and limited accessibility of microbiological testing. Optimizing clinical approaches is therefore critical to close the persistent gaps in TB case detection and prevention necessary to realize the child mortality targets of the End TB Strategy. In this review, we provide practical guidance summarizing the evidence and guidelines describing the use of symptoms and signs in decision making for children being evaluated for either TB preventive treatment (TPT) or TB disease treatment in high-TB incidence settings. Among at-risk children being evaluated for TPT, a symptom screen may be used to differentiate children who require further investigation for TB disease before receiving TPT. For symptomatic children being investigated for TB disease, an algorithmic approach can inform which children should receive TB treatment, even in the absence of imaging or microbiological confirmation. Though clinical approac...
ABSTRACTBackgroundMany children with pulmonary tuberculosis remain undiagnosed and untreated with... more ABSTRACTBackgroundMany children with pulmonary tuberculosis remain undiagnosed and untreated with related high morbidity and mortality. Diagnostic challenges in children include low bacterial burden, challenges around specimen collection, and limited access to diagnostic expertise. Algorithms that guide decisions to initiate tuberculosis treatment in resource-limited settings could help to close the persistent childhood tuberculosis treatment gap. Recent advances in childhood tuberculosis algorithm development have incorporated prediction modelling, but studies conducted to date have been small and localised, with limited generalizability.MethodsWe collated individual participant data including clinical, bacteriological, and radiologic information from prospective diagnostic studies in high-tuberculosis incidence settings enrolling children <10 years with presumptive pulmonary tuberculosis. Using this dataset, we first retrospectively evaluated the performance of several existing...
IntroductionTreatment of latent tuberculosis infection (LTBI) plays a substantial role in the pre... more IntroductionTreatment of latent tuberculosis infection (LTBI) plays a substantial role in the prevention of drug-susceptible tuberculosis (TB). However, clinical trials to evaluate the efficacy of preventive therapy for presumed multidrug-resistant (MDR) LTBI are lacking. This trial aims to evaluate the efficacy of the antibiotic levofloxacin in preventing the development of active TB among latently infected contacts of index patients with MDR-TB.Methods and analysisA double-blind placebo-controlled parallel group randomised controlled trial will be conducted in 10 provinces of Vietnam. Household contacts living with patients with bacteriologically confirmed rifampicin-resistant or MDR-TB will be eligible for recruitment if they have a positive tuberculin skin test or are known to be immunosuppressed, and do not have active TB. Participants will be randomised to receive either levofloxacin or placebo tablets once per day for 6 months. Screening for incident TB will be performed at 6...
The World Health Organization estimates that 10 million new cases of tuberculosis (TB) occurred w... more The World Health Organization estimates that 10 million new cases of tuberculosis (TB) occurred worldwide in 2017, of which 600,000 were rifampicin or multidrug-resistant (RR/MDR) TB. Modelling estimates suggest that 32,000 new cases of MDR-TB occur in children annually, but only a fraction of these are correctly diagnosed and treated. Accurately diagnosing TB in children, who usually have paucibacillary disease, and implementing effective TB prevention and treatment programmes in resource-limited settings remain major challenges. In light of the underappreciated RR/MDR-TB burden in children, and the lack of paediatric data on newer drugs for TB prevention and treatment, we present an overview of new and repurposed TB drugs, describing the available evidence for safety and efficacy in children to assist clinical care and decision-making.
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2017
The study review guidelines on isolation of patients with tuberculosis, TB, from the World Health... more The study review guidelines on isolation of patients with tuberculosis, TB, from the World Health Organization, WHO, Centers for Disease Control and Prevention, CDC, and the European Center for Disease Control, ECDC. The review found that unequivocal guidelines for removing patients out of negative-pressure isolation and de-isolation patients from either single rooms or isolation at home is needed. Studies show that the time of effective treatment is the key parameter to follow to determine if patients are contagious to others or not. This means that standard treatment of multi-drug resistant, MDR, TB will not result in the patient being non-infectious. Thus it is important right from the time of diagnosis to know if the patient is infected with MDR TB or not. Thus the early use of molecular techniques to reveal drug susceptibility is important. Clear guidelines stating if patient with microscopy negative sputum no matter infected with fully susceptible or MDR TB, no matter HIV posi...
Tuberculosis is the leading infectious cause of death worldwide, with 9·6 million cases and 1·5 m... more Tuberculosis is the leading infectious cause of death worldwide, with 9·6 million cases and 1·5 million deaths reported in 2014. WHO estimates 480 000 cases of these were multidrug resistant (MDR). Less than half of patients who entered into treatment for MDR tuberculosis successfully completed that treatment, mainly due to high mortality and loss to follow-up. These in turn illustrate weaknesses in current treatment regimens and national tuberculosis programmes, coupled with operational treatment challenges. In this Review we provide an update on recent developments in the tuberculosis drug-development pipeline (including new and repurposed antimicrobials and host-directed drugs) as they are applied to new regimens to shorten and improve outcomes of tuberculosis treatment. Several new or repurposed antimicrobial drugs are in advanced trial stages for MDR tuberculosis, and two new antimicrobial drug candidates are in early-stage trials. Several trials to reduce the duration of thera...
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Jan 15, 2015
Consensus case definitions for childhood tuberculosis have been proposed by an international expe... more Consensus case definitions for childhood tuberculosis have been proposed by an international expert panel, aiming to standardize the reporting of cases in research focusing on the diagnosis of intrathoracic tuberculosis in children. These definitions are intended for tuberculosis diagnostic evaluation studies of symptomatic children with clinical suspicion of intrathoracic tuberculosis, and were not intended to predefine inclusion criteria into such studies. Feedback from researchers suggested that further clarification was required and that these case definitions could be further improved. Particular concerns were the perceived complexity and overlap of some case definitions, as well as the potential exclusion of children with acute onset of symptoms or less severe disease. The updated case definitions proposed here incorporate a number of key changes that aim to reduce complexity and improve research performance, while maintaining the original focus on symptomatic children suspect...
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