Background High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in HIV co-infection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity. Methods In this phase II open-label trial, Ugandan adults with suspected TBM were randomised to standard-of-care control (PO-10, rifampicin 10mg/kg/day), intravenous rifampicin (IV-20, 20mg/kg/day), or high-dose oral rifampicin (PO-35, 35mg/kg/day). We performed PK sampling on day 2 and 14. The primary outcomes were total exposure (AUC0-24), maximum concentration (Cmax), CSF concentration and grade 3-5 adverse events. Results We enrolled 61 adults, 92% were HIV-positive, median CD4 count was 50cells/µL (IQR 46–56). On day 2, geometric mean plasma AUC0-24hr was 42.9h.mg/L with standard-of-care 10mg/kg dosing, 249h.mg/L for IV-20 and 327h.mg/L for PO-35 (P<0.001). In CSF, standard-of-care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC0-24hr 0.27mg/L, compared with 1.74mg/L (95%CI 1.2–2.5) for IV-20 and 2.17mg/L (1.6–2.9) for PO-35 regimens (p<0.001). Achieving CSF concentrations above rifampicin minimal inhibitory concentration (MIC) occurred in 11% (2/18) of standard-of-care, 93% (14/15) of IV-20, and 95% (18/19) of PO-35 participants. Higher serum and CSF levels were sustained at day 14. Adverse events did not differ by dose (p=0.34) Conclusion Current international guidelines result in sub-therapeutic CSF rifampicin concentration for 89% of Ugandan TBM patients. High-dose intravenous and oral rifampicin were safe, and respectively resulted in exposures ~6- and ~8-fold higher than standard-of-care, and CSF levels above the MIC
Early cryptococcal disease can be detected via circulating antigen in blood before fulminant meningitis develops, when early antifungal therapy improves survival. Two semiquantitative cryptococcal antigen (CrAg) lateral flow assays (LFAs) have been developed, but their diagnostic performance has not been defined. Cryopreserved serum samples from HIV-infected Ugandans obtained as part of a prospective CrAg-screening cohort were tested in duplicate for CrAg by the CrAgSQ (IMMY) and CryptoPS (Biosynex) lateral flow assays. Case-controlled diagnostic performance was measured using the FDA-approved CrAg LFA (IMMY) as a reference standard via McNemar’s test. Of 99 serum samples tested, 57 were CrAg positive (CrAg+) by the CrAg LFA reference standard. By CrAgSQ, 57 were read as positive, with 98% sensitivity (56/57; 95% confidence interval [CI], 0.91 to 0.99) and 98% specificity (41/42; 95% CI, 0.88 to 0.99) (McNemar’s, P = 0.99). The sample with a false-negative result by CrAgSQ (n = 1) had a titer of <1:5, while the sample with a false-positive result (n = 1) yielded a 1+ result. By CryptoPS, 52 samples were read as positive, with 88% sensitivity (50/57; 95% CI, 0.76 to 0.95) and 95% specificity (40/42; 95% CI, 0.84 to 0.99) (McNemar’s, P = 0.18). The CryptoPS false-negative results included samples with titers of <1:5 (n = 1), 1:5 (n = 5), and 1:20 (n = 1), while samples with false-positive results by CryptoPS (n = 2) yielded Positive results. The CryptoPS assay missed 35% (7/20) of samples with CrAg LFA titers of ≤1:20. The new semiquantitative CrAg LFAs allow rapid estimation of titer levels in easy-to-perform platforms. The CrAgSQ demonstrated better qualitative sensitivity and specificity than the CryptoPS compared to the reference standard. The exact grading of the CrAgSQ results has some subjectivity, with interreader variability; however, qualitative reads were generally concordant for both assays.
Background Diagnosis of extrapulmonary tuberculosis (TB) remains challenging. We sought to determine the prevalence of disseminated TB by testing urine with TB-lipoarabinomannan (TB-LAM) lateral flow assay and Xpert MTB/RIF Ultra (Ultra) in hospitalized adults. Methods We prospectively enrolled human immunodeficiency virus (HIV)-positive adults with suspected meningitis in Uganda during 2018–2020. Participants underwent standardized urine-based TB screening. Urine (60 mcL) was tested with TB-LAM (Alere), and remaining urine was centrifuged with the cell pellet resuspended in 2 mL of urine for Xpert Ultra testing. Results We enrolled 348 HIV-positive inpatients with median CD4 of 37 cells/mcL (interquartile range, 13–102 cells/mcL). Overall, 26% (90 of 348; 95% confidence interval [CI], 21%–30%) had evidence of disseminated TB by either urine assay. Of 243 participants with both urine TB-LAM and Ultra results, 20% (48 of 243) were TB-LAM-positive, 12% (29 of 243) were Ultra-positive, and 6% (14 of 243) were positive by both assays. In definite and probable TB meningitis, 37% (14 of 38) were TB-LAM-positive and 41% (15 of 37) were Ultra-positive. In cryptococcal meningitis, 22% (40 of 183) were TB-LAM-positive and 4.4% (6 of 135) were Ultra-positive. Mortality trended higher in those with evidence of disseminated TB by either assay (odds ratio = 1.44; 95% CI, 0.83–2.49; P = .19) and was 6-fold higher in those with definite TB meningitis who were urine Ultra-positive (odds ratio = 5.67; 95% CI, 1.13–28.5; P = .04). Conclusions In hospitalized Ugandans with advanced HIV disease and suspected meningitis, systematic screening with urine TB-LAM and Ultra found a high prevalence of urine TB test positivity (26%). In those with TB meningitis, urine tests were positive in over one third. There was little concordance between Ultra and TB-LAM, which warrants further investigation.
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