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    • Secondly the pyrazinamide concentrations were

    2018-11-07

    Secondly, the pyrazinamide concentrations were approximately similar to those in plasma. However, this is substantially lower than the concentrations associated with effective microbial kill at the site of infection. In pulmonary epithelial lining fluid, pyrazinamide is concentrated 17–22-fold, compared to plasma, which allows the pyrazinamide to achieve the peak concentrations and AUC-to-MIC ratios associated with optimal sterilizing effect in cavitary TB (Gumbo et al., 2009; Pasipanodya et al., 2013; Conte et al., 1999). Indeed, optimal efficacy is achieved at a pyrazinamide AUC-to-MIC ratio of ~210 at site of infection based on hollow fiber system model of TB, which has a quantitative predictive accuracy of 94% of clinical therapeutic values (Gumbo et al., 2009; Pasipanodya et al., 2013; Gumbo et al., 2015b; Gumbo et al., 2015c). Median AUC-to-MIC ratios were ≤1 after adjusting for pH. Similarly, the median peak concentration to MIC ratio is unlikely to produce much microbial kill even under optimal topotecan Supplier conditions (Pasipanodya and Gumbo, 2011; Gumbo et al., 2009). These are all the more concerning given that pyrazinamide has no antimicrobial effect at physiological pH and only works at a pH below 6.0 (Gumbo et al., 2009; McDermott and Tompsett, 1954; Zhang et al., 2002; Zhang and Mitchison, 2003). Direct measurement of pericardial fluid pH in the patients revealed that in fact the pH was slightly alkaline and similar to physiologic pH. At this pH, we expect little to no pyrazinamide effect on Mtb in pericardial fluid. Since rifampicin concentrations are also low, and the sterilizing effect of the current regimen is driven by the synergistic effect of these two drugs, this suggests that there may be little to no sterilizing effect during treatment of pericardial TB (Pasipanodya et al., 2013; Chigutsa et al., 2015). Given the foregoing it means the current rifampicin, isoniazid, ethambutol, and pyrazinamide combination regimen is a “one trick pony”. Only isoniazid seems to penetrate into pericardial fluid to adequate concentrations. However, we have shown elsewhere that at low rifampicin concentrations such as those in pericardial fluid, isoniazid antagonizes rifampicin efficacy in a concentration-dependent fashion (Chigutsa et al., 2015; Conte et al., 1999; Srivastava et al., 2011b). Thus one consequence of a low rifampicin concentration but adequate isoniazid concentration could be drug antagonism, further compromising the regimen. We likely have an anti-TB drug regimen that is of limited utility in TB pericarditis, based on the poor penetration of the key sterilizing effect drugs. Indeed, in the IMPI trial, and IMPI registry studies, there were high rates of mortality from TB pericarditis and disseminated TB, encountered while patients are on therapy. Given that we have now shown that proven TB pericarditis is a high bacillary burden disease, with about 106 colony forming units per milliliter, and that TB pericarditis mortality is higher at CD4+ counts below 200 cells/mL (Pasipanodya et al., nd), it means that we are unlikely to derive benefit from the immune system to sterilize the pericardial space of this large bacterial burden. Thus antibiotics with high efficacy are needed. For drugs such as rifampicin and pyrazinamide, the gap could be too wide to be achieved by further dose optimization. Nevertheless, attempts at dose optimization for these drugs should still be made. We propose that a new regimen specific to TB pericarditis that is developed using the PK/PD aspects specific to TB pericarditis, is needed. Indeed, there is need for drugs that are rapidly bactericidal and can sterilize the Mtb encountered in TB pericarditis within weeks rather than months. Our study has several limitations. First is the small sample size. It is possible that with larger studies different results could be obtained. However, given the need to leave a pigtail catheter for the intensive pharmacokinetic sampling, it was important to limit the number of patients exposed to this procedure. Thus, our results should be interpreted with caution. However, given the dramatic nature of the results, and that rifampicin was actually studied in a total of 27 patients and showed the same results, it is very likely that the same results will be obtained in larger studies. Second, we did not measure the MICs directly from the patients in the study. However, given the numbers of patients, the number of Mtb isolates would have been too small to identify a good enough distribution, and we would still have had to rely on MICs from larger studies. Third, use of steroids could have altered the ability of antibiotics to penetrate into pericardium. However, there were no apparent differences in antibiotic concentrations between patients who received steroids and those who did not.