Tuberculosis vaccine: A journey from BCG to present
Authors: Fatima, Samreen; Kumari, Anjna; Das, Gobardhan; Dwivedi, Ved Prakash
Tuberculosis (TB) is the leading cause of death worldwide due to an infectious disease, causing around 1.6 million deaths each year. This situation has become more complicated by the emergence of drug-resistant Mycobacterium tuberculosis (M.tb) and HIV-TB co-infection, which has significantly worsened TB prognosis and treatment. Despite years of intensive research, Bacille Calmette-Guerin (BCG) remains the only licensed vaccine and has variable efficacy. It provides protection against childhood TB but is not effective in adult pulmonary TB. As a result of intense research in understanding TB vaccinology, there are many new vaccine candidates in clinical development and many more in pre-clinical trials which aim either to replace or boost BCG vaccine. This review discusses the history of BCG vaccine development and summarizes limitations of the current vaccine strategy and recent advances in improving BCG immunization along with other new vaccines in clinical trials which are promising candidates for the future tuberculosis vaccinology program.
Evaluation of Ceftriaxone Plus Avibactam in an Intracellular Hollow Fiber Model of Tuberculosis: Implications for the Treatment of Disseminated and Meningeal Tuberculosis in Children
PEDIATRIC INFECTIOUS DISEASE JOURNAL
Authors: Srivastava, Shashikant; van Zyl, Johanna; Cirrincione, Kayle; Martin, Katherine; Thomas, Tania; Deshpande, Devyani; Alffenaar, Jan-William; Seddon, James A.; Gumbo, Tawanda
Background: Ceftazidime-avibactam is an effective agent for the treatment of tuberculosis (TB) but requires frequent administration because of a short half-life. Due to a longer half-life, ceftriaxone could allow intermittent dosing. Methods: First, we identified the MIC of ceftriaxone with 15 mg/L avibactam in 30 clinical Mycobacterium tuberculosis isolates. Next, 2 ceftriaxone exposure-effect studies in the intracellular hollow fiber model of TB (HFS-TB) that mimics disseminated disease in young children, were performed. Ceftriaxone was administered once or twice daily for 28 days to explore percentage of time that the concentration persisted above MIC (%T-MIC) ranging from 0 to 100%. In a third HFS-TB experiment, the "double cephalosporin" regimen of ceftazidime-ceftriaxone-avibactam was examined and analyzed using Bliss Independence. Conclusion: The MIC99 of the clinical strains was 32 mg/L, in the presence of 15 mg/L avibactam. Ceftriaxone %T-MIC <42 had no microbial effect in the HFS-TB, %T-MIC >54% demonstrated a 4.1 log(10) colony-forming units per milliliter M. tuberculosis kill, while %T-MIC mediating E-max was 68%. The "double cephalosporin" combination was highly synergistic. Monte Carlo experiments of 10,000 subjects identified the optimal ceftriaxone dose as 100 mg/kg twice a day. Conclusion: The combination of ceftriaxone-avibactam at 100 mg/kg could achieve E-max in >90% of children. The ceftriaxone potent activity M. tuberculosis could potentially shorten therapy in children with disseminated TB.