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Background Chest radiographs are used for diagnosis and severity assessment in tuberculosis (TB). The extent of disease as determined by smear grade and cavitation as a binary measure can predict 2-month smear results, but little has been done to determine whether radiological severity reflects the bacterial burden at diagnosis. Methods Pre-treatment chest x-rays from 1837 participants with smear-positive pulmonary TB enrolled into the REMoxTB trial (Gillespie et al., N Engl J Med 371:1577–87, 2014) were retrospectively reviewed. Two clinicians blinded to clinical details using the Ralph scoring system performed separate readings. An independent reader reviewed discrepant results for quality assessment and cavity presence. Cavitation presence was plotted against time to positivity (TTP) of sputum liquid cultures (MGIT 960). The Wilcoxon rank sum test was performed to calculate the difference in average TTP for these groups. The average lung field affected was compared to log 10 TTP by linear regression. Baseline markers of disease severity and patient characteristics were added in univariable regression analysis against radiological severity and a multivariable regression model was created to explore their relationship. Results For 1354 participants, the median TTP was 117 h (4.88 days), being 26 h longer (95% CI 16–30, p

This chapter describes the existing vaccines against tuberculosis, the nature of the protective immune response to tuberculosis, and the target populations for a new tuberculosis vaccine. The preclinical animal testing and clinical evaluation of candidate vaccines, the potential approaches to the development of a new tuberculosis vaccine, and the major challenges to tuberculosis vaccine development are reviewed.

This chapter reviews the genetic basis of drug resistance in Mycobacterium tuberculosis and correlates to phenotypic antibiotic susceptibility. It focuses on antituberculous agents (rifampicin, isoniazid, ethionamide, pyrazinamide, ethambutol, fluoroquinolones, para-aminosalicylic acid, aminoglycosides and macrocyclic polypeptide antibiotics) and drug resistance-conferring mutations that are most relevant in the clinical and epidemiological settings.

This chapter discusses the strategies to find new tuberculosis drug scaffolds and the validated drug targets for mycobacterial killing. The rationale, design and synthesis of the thiazole ring scaffold which led to the identification of methyl 2-amino-5-benzylthiazole-4-carboxylate and methyl 2-(2-bromoacetamido)-5-(3-chlorophenyl) thiazole-4-carboxylate are described.

This chapter reviews the use of microscopy, culture, molecular tools (e.g., polymerase chain reaction) and immunological assays in the determination of bacterial to monitor treatment of tuberculosis.

This chapter describes the worldwide burden and methods of diagnosing latent tuberculosis infection. The clinical performance of interferon-gamma release assays (IGRAs) in different populations, including immunocompetent and immunocompromised (HIV, immune-mediated inflammatory diseases) persons, and the predictive value of IGRAs for progression to active tuberculosis are reviewed. The incorporation of IGRAs into international public health guidelines and its use in treatment monitoring and future directions are discussed.

This chapter describes the different types of media for culture and isolation of mycobacteria, and discusses the adaptation of automated liquid culture systems for the qualitative and quantitative drug susceptibility testing of Mycobacterium tuberculosis and non-tuberculous mycobacteria.

This chapter provides the rationale and experimental basis for considering thioridazine (an inexpensive neuroleptic drug used for over 40 years) as a new effective drug for treatment of extensively drug-resistant tuberculosis (XDR-TB). The development of antibiotic resistance in Mycobacterium tuberculosis, the criteria for an effective anti-MDR/XDR-TB, anti-latent M. tuberculosis agent, and the antituberculosis activity of phenothiazines are described.

This chapter discusses the need for molecular-based quantification of bacterial load in Mycobacterium tuberculosis infection and the reasons for a lack of a molecular assay for enumeration of M. tuberculosis in sputum. Measuring gene expression by quantitative polymerase chain reaction (qPCR) to determine bacterial load in sputum samples is described.

This chapter discusses the role of phenotypic methods for drug susceptibility testing of Mycobacterium tuberculosis isolates in timely detection and management of patients with multiple drug resistant (MDR) and extremely drug resistant (XDR) tuberculosis. The different methods and their combinations, as well as their affordability/cost, are described.

This chapter discusses sputum Mycobacterium tuberculosis phenotypes (slow/non-growth, lipid bodies and resuscitation-promoting factor dependency) and their potential as biomarkers for the assessment of patient response to therapy. The relationship between sputum M. tuberculosis phenotypes and antibiotic tolerance is described.

There has been a significant increase in the number of genes associated with antibiotic resistance that have been described. For many antimicrobials all of the principal genes associated with their action have been identified (1). There is increasing interest in the epidemiological distribution of resistance mutations of these genes and research into their origin and routes of transmission. At the more fundamental level, there is interest in the impact of such mutations on the fitness/survivability of the pathogen (2). We have described the strategies for selection of mutants in the mycobacteria (3) and also a polymerase chain reaction-single-stranded conformational polymorphism (PCR-SSCP) approach to investigation of the distribution of such mutants. In this method PCR amplimers are denatured to form single-stranded nucleic acids and then submitted to gel electrophoresis to identify sequence polymorphisms. Sequencing of clones remains relatively expensive and time consuming for investigating a large number of isolates from clinical practice or strains from mutation experiments. This chapter outlines a method for screening large numbers of PCR amplimers, which can then inform rational selection for cloning and sequence analysis, or for identifying novel mutations for detailed sequence. Alternatively, this approach can be used for rapid screening where the SSCP profile relating to each mutation is already known.