Browsing by Author "Diacon, Andreas"

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    C-Tb skin test to diagnose Mycobacterium tuberculosis infection in children and HIV infected adults : a phase 3 trial
    (Public Library of Science, 2018) Aggerbeck, Henrik; Ruhwald, Morten; Hoff, Soren T.; Borregaard, Bettine; Hellstrom, Elizabeth; Malahleha, Mookho; Siebert, Mirna; Gani, Mashra; Seopela, Vincent; Diacon, Andreas; Lourens, Madeleine; Andersen, Peter; Dheda, Keertan
    Background C-Tb, an ESAT-6/CFP-10-based skin test, has similar sensitivity for active TB compared to tuberculin skin test (TST) and QuantiFERON-TB-Gold-In-Tube (QFT). However, data are limited in children and HIV-infected persons. Methods Asymptomatic South African contacts <5 years (n = 87; HIV-uninfected), or symptomatic individuals of all ages presenting to clinics with suspected TB (n = 1003; 30% HIV-infected) were recruited from eight South African centres. C-Tb and TST were allocated to either forearm double blinded. Samples for QFT were collected in parallel, and test-positivity rates were compared. Results In participants with microbiologically confirmed TB (n = 75; 45% HIV-infected) sensitivity of C-Tb, TST and QFT were similar (72% versus 75% versus 73%; p>0.5). All 3 tests had similar positivity rates in HIV-infected participants with active TB, however, positivity rates were reduced when CD4 counts were <100 cells/μL. In participants where active TB was excluded (n = 920), C-Tb (41%), TST (43%), and QFT (44%) also had similar test-positivity rates. Among asymptomatic contacts aged below five, 32% (28/87) tested positive with C-Tb and 32% (28/87) with TST (concordance 89%). Overall, C-Tb and TST showed a similar safety profile. Conclusion C-Tb was safe and showed similar test-positivity rates, compared to TST and QFT, in children and HIV-infected persons with active or latent M. tuberculosis infection. These data inform the utility of C-Tb in clinical practice.
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    Fourteen-Day Bactericidal Activity, Safety, and Pharmacokinetics of Linezolid in Adults with Drug-Sensitive Pulmonary Tuberculosis
    (2020-01) Diacon, Andreas; De Jager, Veronique R; Dawson, Rodney
    Background: Linezolid is increasingly used for the treatment of tuberculosis resistant to first-line agents, but the most effective dosing strategy is yet unknown. Methods: Between November 2014 and November 2016, we randomised 114 drug-sensitive treatment-naïve pulmonary tuberculosis patients from Cape Town, South Africa, to one of six 14-day treatment arms containing linezolid 300 mg once daily (qd), 300 mg twice daily (bd), 600 mg qd, 600 mg bd, 1200 mg qd, 1200 mg three times per week (tiw) or a combination of isoniazid, rifampicin, pyrazinamide and ethambutol. Sixteen-hour sputum samples were collected overnight, and bactericidal activity characterized by the daily percentage change in time to positivity (TTP) and colony forming units (CFU). We also assessed the safety and pharmacokinetics of the study treatments. Results: Bactericidal activity increased with increasing doses of linezolid. Based on the daily percentage change in TTP, activity was highest for 1200 mg qd (4.5; 95% Bayesian confidence interval [BCI]: 3.3-5.6), followed by 600 mg bd (4.1; BCI: 2.5-5.7), 600 mg qd (4.1; BCI: 2.9-5.3), 300 mg bd (3.3; BCI: 1.9-4.7), 300 mg qd (2.3; BCI: 1.1-3.5) and 1200 mg tiw (2.2; BCI: 1.1-3.3). Similar results were seen with bactericidal activity characterized by the daily rate of change in CFU count. Antimycobacterial activity correlated positively with plasma drug exposure and percentage time over minimum inhibitory concentration. There were no unexpected adverse events. Conclusion: All linezolid doses showed bactericidal activity. For the same total daily dose, once daily dosing proved to be at least as effective as a divided twice daily dose. An intermittent dosing regimen, with 1200 mg given three times weekly, showed the least activity.
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    Phase 2b controlled trial of M72/AS01E vaccine to prevent tuberculosis
    (Massachusetts Medical Society, 2018-10-25) Van der Meeren, Olivier; Hatherill, Mark; Nduba, Videlis; Wilkinson, Robert J.; Muyoyeta, Monde; Van Brakel, Elana; Ayles, Helen M.; Henostroza, German; Thienemann, Friedrich; Scriba, Thomas J.; Diacon, Andreas; Blatner, Gretta L.; Demoitie, Marie-Ange; Tameris, Michele; Malahleha, Mookho; Innes, James C.; Hellstrom, Elizabeth; Martinson, Neil; Singh, Tina; Akite, Elaine J.; Khatoon Azam, Aisha; Bollaerts, Anne; Ginsberg, Ann M.; Evans, Thomas G.; Gillard, Paul; Tait, Dereck R.
    BACKGROUND: A vaccine to interrupt the transmission of tuberculosis is needed. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2b trial of the M72/AS01E tuberculosis vaccine in Kenya, South Africa, and Zambia. Human immunodeficiency virus (HIV)–negative adults 18 to 50 years of age with latent M. tuberculosis infection (by interferon-γ release assay) were randomly assigned (in a 1:1 ratio) to receive two doses of either M72/AS01E or placebo intramuscularly 1 month apart. Most participants had previously received the bacille Calmette–Guérin vaccine. We assessed the safety of M72/AS01E and its efficacy against progression to bacteriologically confirmed active pulmonary tuberculosis disease. Clinical suspicion of tuberculosis was confirmed with sputum by means of a polymerase-chain-reaction test, mycobacterial culture, or both. RESULTS: We report the primary analysis (conducted after a mean of 2.3 years of follow-up) of the ongoing trial. A total of 1786 participants received M72/AS01E and 1787 received placebo, and 1623 and 1660 participants in the respective groups were included in the according-to-protocol efficacy cohort. A total of 10 participants in the M72/AS01E group met the primary case definition (bacteriologically confirmed active pulmonary tuberculosis, with confirmation before treatment), as compared with 22 participants in the placebo group (incidence, 0.3 cases vs. 0.6 cases per 100 person-years). The vaccine efficacy was 54.0% (90% confidence interval [CI], 13.9 to 75.4; 95% CI, 2.9 to 78.2; P=0.04). Results for the total vaccinated efficacy cohort were similar (vaccine efficacy, 57.0%; 90% CI, 19.9 to 76.9; 95% CI, 9.7 to 79.5; P=0.03). There were more unsolicited reports of adverse events in the M72/AS01E group (67.4%) than in the placebo group (45.4%) within 30 days after injection, with the difference attributed mainly to injection-site reactions and influenza-like symptoms. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups. CONCLUSIONS: M72/AS01E provided 54.0% protection for M. tuberculosis–infected adults against active pulmonary tuberculosis disease, without evident safety concerns. (Funded by GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598. opens in new tab.)
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    Population pharmacokinetic/pharmacodynamic analysis of the bactericidal activities of sutezolid (PNU-100480) and its major metabolite against intracellular mycobacterium tuberculosis in ex vivo whole-blood cultures of patients with pulmonary tuberculosis
    (American Society for Microbiology, 2014) Zhu, Tong; Friedrich, Sven O.; Diacon, Andreas; Wallis, Robert S.
    Sutezolid (PNU-100480 [U-480]) is an oxazolidinone antimicrobial being developed for the treatment of tuberculosis. An active sulfoxide metabolite (PNU-101603 [U-603]), which reaches concentrations in plasma several times those of the parent, has been reported to drive the killing of extracellular Mycobacterium tuberculosis by sutezolid in hollow-fiber culture. However, the relative contributions of the parent and metabolite against intracellular M. tuberculosis in vivo are not fully understood. The relationships between the plasma concentrations of U-480 and U-603 and intracellular whole-blood bactericidal activity (WBA) in ex vivo cultures were examined using a direct competitive population pharmacokinetic (PK)/pharmacodynamic 4-parameter sigmoid model. The data set included 690 PK determinations and 345 WBA determinations from 50 tuberculosis patients enrolled in a phase 2a sutezolid trial. The model parameters were solved iteratively. The median U-603/U-480 concentration ratio was 7.1 (range, 1 to 28). The apparent 50% inhibitory concentration of U-603 for intracellular M. tuberculosis was 17-fold greater than that of U-480 (90% confidence interval [CI], 9.9- to 53-fold). Model parameters were used to simulate in vivo activity after oral dosing with sutezolid at 600 mg twice a day (BID) and 1,200 mg once a day (QD). Divided dosing resulted in greater cumulative activity (−0.269 log10 per day; 90% CI, −0.237 to −0.293 log10 per day) than single daily dosing (−0.186 log10 per day; 90% CI, −0.160 to −0.208 log10 per day). U-480 accounted for 84% and 78% of the activity for BID and QD dosing, respectively, despite the higher concentrations of U-603. Killing of intracellular M. tuberculosis by orally administered sutezolid is mainly due to the activity of the parent compound. Taken together with the findings of other studies in the hollow-fiber model, these findings suggest that sutezolid and its metabolite act on different mycobacterial subpopulations.
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    Rapid sequencing of the mycobacterium tuberculosis pncA gene for detection of pyrazinamide susceptibility
    (American Society for Microbiology, 2014) Streicher, Elizabeth M.; Maharaj, Kashmeel; York, Talita; Van Heerden, Carel; Barnard, Marinus; Diacon, Andreas; Mendel, Carl M.; Bosman, Marlein E.; Hepple, Juli A.; Pym, Alexander S.; Warren, Robin M.; Van Helden, Paul D.
    We developed a pyrazinamidase gene DNA-sequencing method to rapidly identify pyrazinamide resistance-causing mutations in GenoLyse-treated, smear-positive sputum specimens. The sensitivity and specificity were 90.9 and 100%, respectively, compared to those of MGIT drug susceptibility testing, after the exclusion of synonymous mutations and nonsynonymous mutations previously associated with susceptibility to pyrazinamide.