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    • First line anti TB drugs exert

    2018-10-23

    First-line anti-TB drugs exert their effect by binding directly to the bacterial targets inside the Mycobacterium tuberculosis (Mtb) cells. Only non-protein bound drug concentrations enter bacteria. Therefore, in TB pericarditis each antibiotic must penetrate several layers of tissue to achieve adequate free-drug concentrations in the pericardial space. The antibacterial effect of rifampicin, isoniazid, ethambutol and pyrazinamide is closely linked to specific peak concentration, 0–24h area under the concentration–time curve (AUC0–24), and minimum inhibitory concentration (MIC) (Gumbo et al., 2007a; Gumbo et al., 2007b; Gumbo et al., 2009; Pasipanodya et al., 2013; Srivastava et al., 2010; Chigutsa et al., 2015). Utilizing standard treatment of pulmonary TB, recommended doses barely achieve these target concentrations (Gumbo et al., 2007a; Gumbo et al., 2007b; Gumbo et al., 2009; Pasipanodya et al., 2013; Srivastava et al., 2010; Chigutsa et al., 2015). Moreover, despite administration of recommended doses, between-patient pharmacokinetic variability leads substantial proportions of patients to metabolize some of the drugs more extensively than others, who may end up on effective monotherapy, therapy failure, and acquired drug resistance (Pasipanodya et al., 2013; Srivastava et al., 2011a; Pasipanodya et al., 2012). It is unknown to what extent these drugs penetrate into pericardial space, or the variability thereof. We performed two sets of sub-studies during the ongoing IMPI registry (Mayosi et al., 2006; Mayosi et al., 2008), a pilot study to identify the rifampicin concentrations in paired retinoic acid and pericardial fluid samples, followed by a second more intensive pericardial fluid pharmacokinetic sampling study for all four anti-TB drugs. The findings of these studies are reported herein.
    Methods
    Results Sixteen patients were enrolled in the pilot study. The clinical and demographic features of these patients are shown in Table 1. Ten (63%) patients were male. Of the 16 patients, 10 were HIV-infected, with the mean CD4+ count shown in Table 1. All patients, apart from one, received four FDC anti-TB tablets (one patient received loose individual tablets), amounting to rifampicin 600mg a day, isoniazid 300mg a day, pyrazinamide 1600mg a day, and ethambutol 1100mg a day. Blood and pericardial fluid were collected commencing 1h to 24h after the dose, as summarized in Table 1. The paired plasma and pericardial rifampicin concentrations are shown in Fig. 1A. The dramatic difference illustrated in the figure, is summarized by ratio of rifampicin pericardial fluid concentration to plasma concentration of 0.19±0.33 for paired samples. Fig. 1B compares the distribution of all the non-protein bound rifampicin concentrations to rifampicin MICs in Western Cape clinical isolates, and shows that none of the pericardial concentrations, at any sampling time-point, was above the MICs. The median concentration was 0.125mg/L and was lower than the median MIC 0.208mg/L (p=0.001). However, in the pilot study the timing of sampling with respect to the antibiotic dose was varied, which could explain some of the inter-individual variability of the results, and thus a more intensive sampling procedure was planned for prior to dose recommendations. The pilot study results were used to identify the best sampling times to assess rifampicin and companion drugs concentrations over a 24-h period. Eleven patients were enrolled in this more intensive pharmacokinetic sampling study during the IMPI trial. Their clinical and demographic characteristics are shown in Table 2. Five patients were allocated to prednisolone, so that patients were split in the middle between those receiving placebo or immunotherapy, similar to the larger IMPI trial. All eleven patients received four FDC tablets, amounting to rifampin 600mg, isoniazid 300mg, ethambutol 1100mg and pyrazinamide 1600mg each day. One patient was also on antiretroviral therapy. The rifampicin concentrations achieved in patients in both the plasma and pericardium are shown in Fig. 2A. The time to peak concentration in pericardial fluid was a median (range) of 8.18 (6.85–15.40) hours compared to 3.44 (2.76–3.77) hours in blood (p<0.0001). The shape of the concentration time curves in Fig. 2A is characterized by high plasma peak concentrations and very low and flattened peak concentrations in the pericardium. The shape is due to both delay and decrease in penetration from the blood into pericardial fluid, as well as higher rifampicin clearance from pericardial fluid compared to the blood (Fig. 2A–B). As regards to clearance (Fig. 2B), all patients except one had higher clearances in pericardium than in blood, and the median clearances differed significantly (p=0.002). The non-protein bound rifampicin concentrations in pericardial fluid are also shown in Fig. 2A–D, which demonstrates very low effective rifampicin concentrations in pericardial fluid. A comparison of free rifampicin peak concentrations to MICs encountered in isolates is shown in Fig. 2E, which shows that the median rifampicin peak concentrations in pericardial fluid, were lower than the median MIC (p=0.001).