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  • The third important finding was that the bacillary

    2018-11-07

    The third important finding was that the bacillary load was a significant predictor for both early and late mortality outcomes. This aspect outranked well-known hemodynamic predictors of mortality in TB pericarditis such as hypotension. Moreover, this even outranked type of pericardial syndromes such as constrictive pericarditis versus effusive pericarditis versus effusive–constrictive disease. Thus, in prioritizing decisions to decrease the high mortality, a priority should be to find rapidly bactericidal drugs, or even exploration of the notion of decreasing the large bacterial burden via drainage (i.e., draining the cold abscesses). It is a well-known principle of antimicrobial PK/PD science, and indeed of standard microbiology, that the higher the bacterial burden, the greater the chances of treatment failure and development of acquired drug resistance (Gumbo et al., 2015; Jumbe et al., 2003; Gumbo, 2011). Indeed, for some patients, the initial bacillary burden was above the inverse of the mutation frequency of 10 of the only effective antibiotic that penetrates well into pericardial fluid: isoniazid (Shenje et al., 2015). This means that acquired resistance due to effective monotherapy could be a problem at these high pericardial fluid bacterial burdens. Moreover, time to total sterilization of bacteria in higher bacterial burden disease will be longer than with smaller bacterial burdens, given that dose–response curves of order EPZ015666 reveal a ceiling killing rate. Thus, time to cure is longer with high burden disease, especially given the limited number of drugs in the standard regimen that penetrate into pericardium(Shenje et al., 2015).
    Author Contributions J.G. Pasipanodya and T.G. were responsible for data analyses, calculation of CFU/mL of M. tuberculosis, CART models, multivariable regression, interpretation, and, writing manuscript. M. Mubanga, M. Ntsekhe, S. Pandie, F. Gumedze, and L. Myer, were involved in study design, collection of pericardial tuberculosis data, data analysis and interpretation, and writing of manuscript. B.T. Magazi was responsible for collection of sputum tuberculosis data and writing manuscript. B. Mayosi was responsible for study design, collection of data, data analysis and interpretation, and, writing of manuscript.
    Conflicts of Interests
    Role of Funding Source Funding for this study was obtained from the South African Medical Research Council (MRC) for self-initiated research from November 2012 to April 2015, the Lily and Ernst Hausmann Research Trust, and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (R01AI079497). The funding agencies were not involved in the design and conduct of the study; collection, management, analysis, and interpretation of data; and preparation, review, or approval of the manuscript.
    Introduction Tuberculous pericarditis is a common medical condition in many countries in Africa and Asia (Mayosi et al., 2005; Mayosi et al., 2006; Cherian, 2004). Despite treatment, one in every four patients is dead within six months, and close to one in two patients with human immunodeficiency virus (HIV) co-infection are dead within six months (Mayosi et al., 2005). We have recently completed the Investigation of the Management of Pericarditis (IMPI) study, a randomized controlled trial examining the effects of either prednisolone or Mycobacterium indicus pranii or both and the standard regimen (isoniazid, rifampin, ethambutol and pyrazinamide) in 1400 patients (Mayosi et al., 2014). The primary composite outcome (death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis) rate was approximately 15 events per 100patient-years of follow-up; the main causes of death were either the pericarditis or disseminated tuberculosis (TB) in greater than 42% of deaths. These outcomes were encountered despite adherence to treatment in about 90% of patients, and are thus attributable to primary failure of standard therapy. The reasons for therapy failure are unclear, but could include high bacterial burden, concurrent immunodeficiency, or treatment factors that could be summarized as antimicrobial pharmacokinetics/pharmacodynamics (PK/PD) (Gumbo et al., 2015a; Craig, 1998). PK/PD science relates drug concentration of antibiotics at site of infection to microbial kill and resistance emergence; non-protein bound concentrations are central to pharmacodynamics effects (Gumbo et al., 2015a; Craig, 1998; Gumbo, 2011; Ambrose et al., 2007; Pasipanodya and Gumbo, 2011; Zeitlinger et al., 2011).