TY - JOUR AB - BACKGROUND: Linezolid is a key component globally in first-line therapy for drug-resistant tuberculosis but has considerable toxicity. New and safer alternative oxazolidinones are needed. Sutezolid is one such promising alternative. We aimed to evaluate preliminary efficacy and safety of sutezolid and to identify an optimal dose. METHODS: PanACEA-SUDOCU-01 was a prospective, open-label, randomised, phase 2b dose-finding study in four tuberculosis trial sites in Tanzania and South Africa. Adults aged 18-65 years with newly diagnosed, drug-sensitive, smear-positive tuberculosis were enrolled and randomly assigned (1:1:1:1:1) by a probabilistic minimisation algorithm using a web-based interface, stratified by site, sex, and HIV status, to receive no sutezolid (U0), sutezolid 600 mg once daily (U600), sutezolid 1200 mg once daily (U1200), sutezolid 600 mg twice daily (U600BD), or sutezolid 800 mg twice daily (U800BD), all administered orally for 12 weeks followed by standard therapy for 6 months. All participants received oral bedaquiline (400 mg once daily for 14 days followed by 200 mg thrice weekly), oral delamanid (100 mg twice daily), and oral moxifloxacin (400 mg once daily). For the primary endpoint, measured in the modified intention-to-treat population, sputum samples were taken weekly to measure the change in bacterial load measured by time to positivity using the mycobacterial growth indicator tube system. Safety was assessed through weekly electrocardiography, safety blood tests, vision testing, and physical and neurological examinations. Intensive pharmacokinetic measurements were done on day 14 to determine exposure to sutezolid, bedaquiline, delamanid, and moxifloxacin. This trial is registered with ClinicalTrials.gov (NCT03959566). FINDINGS: Between May 20, 2021, and Feb 17, 2022, 186 individuals were screened for eligibility, 75 of whom were enrolled and randomly assigned to U0 (n=16), U600 (n=15), U1200 (n=14), U600BD (n=15), or U800BD (n=15). 56 (75%) participants were male and 19 (25%) were female. The final pharmacokinetic-pharmacodynamic model showed a benefit of sutezolid, with an increase in time to positivity slope steepness of 16·7% (95% CI 0·7-35·0) at the maximum concentration typical for the 1200 mg dose, compared with no sutezolid exposure. A maximum effect of sutezolid exposure was not observed within the investigated dose range. Six (8%) participants (one in the U600 group, two in the U600BD group, one in the U800BD group, and two retrospectively identified in the U600 group) had an increase in a QT interval using Fridericia correction greater than 60 ms from baseline. Two (3%) participants in the U600BD group had grade 4 adverse events, one each of neutropenia and hepatotoxicity, but they were not deemed associated with the use of sutezolid by the investigators. No neuropathy was reported. INTERPRETATION: Sutezolid, combined with bedaquiline, delamanid, and moxifloxacin, was shown to be efficacious and added activity to the background drug combination, although we cannot make a final dose recommendation yet. This study provides valuable information for the selection of sutezolid doses for future studies, and described no oxazolidinone class toxicities at the doses used. FUNDING: EDCTP2 programme funded by the EU; German Ministry for Education and Research; German Center for Infection Research; and Nederlandse Organisatie voor Wetenschappelijk Onderzoek. AU - Heinrich, N.* AU - Manyama, C.* AU - Koele, S.E.* AU - Mpagama, S.* AU - Mhimbira, F.* AU - Sebe, M.* AU - Wallis, R.S.* AU - Ntinginya, N.E.* AU - Liyoyo, A.* AU - Huglin, B.* AU - Minja, L.T.* AU - Wagnerberger, L.* AU - Stoycheva, K.* AU - Zumba, T.* AU - Noreña, I.* AU - Peter, D.D.* AU - Makkan, H.* AU - Sloan, D.J.* AU - Brake, L.T.* AU - Schildkraut, J.A.* AU - Aarnoutse, R.E.* AU - McHugh, T.D.* AU - Wildner, L.* AU - Boeree, M.J.* AU - Aldana, B.H.* AU - Phillips, P.P.J.* AU - Hoelscher, M. AU - Svensson, E.M.* C1 - 75129 C2 - 57833 TI - Sutezolid in combination with bedaquiline, delamanid, and moxifloxacin for pulmonary tuberculosis (PanACEA-SUDOCU-01): A prospective, open-label, randomised, phase 2b dose-finding trial. JO - Lancet Infect. Dis. PY - 2025 SN - 1473-3099 ER - TY - JOUR AB - BACKGROUND: Linezolid plays a crucial role in the first-line treatment of drug-resistant tuberculosis globally. Its prolonged use can lead to neurological and haematological toxicity, highlighting the need for safer oxazolidinones. Delpazolid, a novel oxazolidinone, might be safer. We aimed to evaluate the safety and efficacy of delpazolid and identify an optimal dose. METHODS: PanACEA-DECODE-01 was a prospective, randomised, open-label, phase 2b, multicentre, dose-finding trial done in five tuberculosis trial sites in Tanzania and South Africa. Adults aged 18-65 years, who weighed 40-90 kg, and had newly diagnosed, smear positive pulmonary tuberculosis were randomly assigned (1:1:1:1:1) through centralised allocation, using a probabilistic minimisation algorithm to receive no delpazolid (D0), delpazolid 400 mg once daily (D400), delpazolid 800 mg once daily (D800), delpazolid 1200 mg once daily (D1200), or delpazolid 800 mg twice daily (D800BD), all administered orally for 16 weeks with follow-up to week 52. All participants received bedaquiline (400 mg orally once daily for the first 14 days, then 200 mg orally thrice weekly), delamanid (100 mg orally twice daily), and moxifloxacin (400 mg orally once daily). Randomisation was stratified based on bacterial load in sputum as measured by GeneXpert cycle threshold (<16 vs ≥16), site, and HIV status. The primary efficacy objective was to establish an exposure-response model with the primary endpoint, measured in the modified intention-to-treat population, of change in mycobacterial load measured by time to positivity using the liquid culture mycobacterial growth indicator tube system. A secondary outcome was the time on treatment to sustained conversion to negative sputum culture in liquid media. The primary safety outcome was the occurrence of oxazolidinone class toxicities defined as peripheral or optical neuropathy, incident leukopenia, anaemia or thrombocytopenia, or adverse events in line with tyramine pressor response, all of grade 2 or higher, possibly, probably or definitely related to delpazolid. This study was registered with ClinicalTrials.gov, NCT04550832. FINDINGS: Between Oct 28, 2021, and Aug 31, 2022, 156 individuals were screened for eligibility, 76 of whom were enrolled and randomly assigned to D0 (n=15), D400 (n=15), D800 (n=15), D1200 (n=16), or D800BD (n=15). 60 (79%) of 76 participants were male and 16 (21%) were female. Population pharmacokinetic-pharmacodynamic modelling suggests maximal microbiological activity at a daily total exposure of delpazolid (area under the concentration curve from 0 h to 24 h [AUC0-24]) of 50 mg/L per h; close to the median exposure observed after a 1200 mg dose. This maximal effect was estimated at a 38% (95% CI 4-83; p=0·025) faster decline in bacterial load compared with no delpazolid. In the secondary time-to-event analysis, there was no significant difference in time to culture conversion between treatment arms or exposure tertile. When all delpazolid-containing groups were combined, the hazard ratio for the time to sustained culture conversion to negative, comparing all delpazolid-containing groups with the group without delpazolid was 1·53 (95% CI 0·84-2·76). Two drug-related serious adverse events (one gastritis and one anaemia) occurred in the D800BD group, with high individual AUC0-24. Apart from the anaemia and one event of brief, moderate neutropenia observed at only one visit in the D800 group not in line with the characteristics of oxazolidinone class toxicity, no oxazolidinone class toxicities occurred. INTERPRETATION: The pharmacokinetic-pharmacodynamic modelling results suggest that delpazolid adds efficacy on top of bedaquiline, delamanid, and moxifloxacin; and that a dose of 1200 mg once daily would result in exposures with maximum efficacy. That dose was shown to be safe, raising hope that linezolid toxicities could be averted in long-term treatment. Delpazolid is a promising drug for future tuberculosis treatment regimens and could be widely usable if safety and efficacy are confirmed in larger trials. FUNDING: LigaChem Biosciences, EDCTP2 programme supported by the EU; German Ministry for Education and Research; German Center for Infection Research; Swiss State Secretariat for Education, Research and Innovation; and Nederlandse Organisatie voor Wetenschappelijk Onderzoek. AU - Minja, L.T.* AU - van der Feltz, I.* AU - Manyama, C.* AU - Mpagama, S.* AU - Mhimbira, F.* AU - Noreña, I.* AU - Sebe, M.* AU - Rassool, M.* AU - Wallis, R.S.* AU - Ntinginya, N.E.* AU - Liyoyo, A.* AU - Mbeya, B.* AU - Wagnerberger, L.* AU - Zumba, T.* AU - Peter, D.D.* AU - Makkan, H.* AU - Sloan, D.J.* AU - Brake, L.T.* AU - Schildkraut, J.A.* AU - Aarnoutse, R.E.* AU - McHugh, T.D.* AU - Wildner, L.* AU - Boeree, M.J.* AU - Geiter, L.* AU - Cho, Y.L.* AU - Aldana, B.H.* AU - Phillips, P.P.J.* AU - Hoelscher, M. AU - Svensson, E.M.* AU - Heinrich, N.* C1 - 75128 C2 - 57827 TI - Delpazolid in combination with bedaquiline, delamanid, and moxifloxacin for pulmonary tuberculosis (PanACEA-DECODE-01): A prospective, randomised, open-label, phase 2b, dose-finding trial. JO - Lancet Infect. Dis. PY - 2025 SN - 1473-3099 ER - TY - JOUR AU - Kocher, K.* AU - Moosmann, C.* AU - Drost, F. AU - Schülein, C.* AU - Irrgang, P.* AU - Steininger, P.* AU - Zhong, J.* AU - Träger, J.* AU - Spriewald, B.* AU - Bock, C.* AU - Busch, D.H.* AU - Bogdan, C.* AU - Schubert, B. AU - Winkler, T.H.* AU - Tenbusch, M.* AU - Schuster, E.M.* AU - Schober, K.* C1 - 70175 C2 - 55440 CY - 125 London Wall, London, England SP - e272-e274 TI - Adaptive immune responses are larger and functionally preserved in a hypervaccinated individual. JO - Lancet Infect. Dis. VL - 24 IS - 5 PB - Elsevier Sci Ltd PY - 2024 SN - 1473-3099 ER - TY - JOUR AB - BACKGROUND: Despite causing high mortality worldwide, paediatric tuberculosis is often undiagnosed. We aimed to investigate optimal testing strategies for microbiological confirmation of tuberculosis in children younger than 15 years, including the yield in high-risk subgroups (eg, children younger than 5 years, with HIV, or with severe acute malnutrition [SAM]). METHODS: For this secondary analysis, we used data from RaPaed-TB, a multicentre diagnostic accuracy study evaluating novel diagnostic assays and testing approaches for tuberculosis in children recruited from five health-care centres in Malawi, Mozambique, South Africa, Tanzania, and India conducted between Jan 21, 2019, and June 30, 2021. Children were included if they were younger than 15 years and had signs or symptoms of pulmonary or extrapulmonary tuberculosis; they were excluded if they weighed less than 2 kg, had received three or more doses of anti-tuberculosis medication at time of enrolment, were in a condition deemed critical by the local investigator, or if they did not have at least one valid microbiological result. We collected tuberculosis-reference specimens via spontaneous sputum, induced sputum, gastric aspirate, and nasopharyngeal aspirates. Microbiological tests were Xpert MTB/RIF Ultra (hereafter referred to as Ultra), liquid culture, and Löwenstein-Jensen solid culture, which were followed by confirmatory testing for positive cultures. The main outcome of this secondary analysis was categorising children as having confirmed tuberculosis if culture or Ultra positive on any sample, unconfirmed tuberculosis if clinically diagnosed, and unlikely tuberculosis if neither of these applied. FINDINGS: Of 5313 children screened, 975 were enrolled, of whom 965 (99%) had at least one valid microbiological result. 444 (46%) of 965 had unlikely tuberculosis, 282 (29%) had unconfirmed tuberculosis, and 239 (25%) had confirmed tuberculosis. Median age was 5·0 years (IQR 1·8-9·0); 467 (48%) of 965 children were female and 498 (52%) were male. 155 (16%) of 965 children had HIV and 110 (11%) children had SAM. 196 (82%) of 239 children with microbiological detection tested positive on Ultra. 110 (46%) of 239 were confirmed by both Ultra and culture, 86 (36%) by Ultra alone, and 43 (18%) by culture alone. 'Trace' was the most common semiquantitative result (93 [40%] of 234). 481 (50%) of 965 children had only one specimen type collected, 99 (21%) of whom had M tuberculosis detected. 484 (50%) of 965 children had multiple specimens collected, 141 (29%) of whom were positive on at least one specimen type. Of the 102 children younger than 5 years with M tuberculosis detected, 80 (78%) tested positive on sputum. 64 (80%) of 80 children who tested positive on sputum were positive on sputum alone; 61 (95%) of 64 were positive on induced sputum, two (3%) of 64 were positive on spontaneous sputum, and one (2%) was positive on both. INTERPRETATION: High rates of microbiological confirmation of tuberculosis in children can be achieved via parallel sampling and concurrent testing procedures. Sample types and choice of test to be used sequentially should be considered when applying to groups such as children younger than 5 years, living with HIV, or with SAM. FUNDING: European and Developing Countries Clinical Trials Partnership programme, supported by the EU, the UK Medical Research Council, Swedish International Development Cooperation Agency, Bundesministerium für Bildung und Forschung, the German Center for Infection Research, and Beckman Coulter. AU - Olbrich, L.* AU - Franckling-Smith, Z.* AU - Larsson, L.* AU - Sabi, I.* AU - Ntinginya, N.E.* AU - Khosa, C.* AU - Banze, D.* AU - Nliwasa, M.* AU - Corbett, E.L.* AU - Semphere, R.* AU - Verghese, V.P.* AU - Michael, J.S.* AU - Ninan, M.M.* AU - Saathoff, E.* AU - McHugh, T.D.* AU - Razid, A.* AU - Graham, S.M.* AU - Song, R.* AU - Nabeta, P.* AU - Trollip, A.* AU - Nicol, M.P.* AU - Hoelscher, M. AU - Geldmacher, C.* AU - Heinrich, N.* AU - Zar, H.J.* C1 - 71809 C2 - 56448 CY - 125 London Wall, London, England SP - 188-197 TI - Sequential and parallel testing for microbiological confirmation of tuberculosis disease in children in five low-income and middle-income countries: A secondary analysis of the RaPaed-TB study. JO - Lancet Infect. Dis. VL - 25 IS - 2 PB - Elsevier Sci Ltd PY - 2024 SN - 1473-3099 ER - TY - JOUR AB - BACKGROUND: Childhood tuberculosis remains a major cause of morbidity and mortality in part due to missed diagnosis. Diagnostic methods with enhanced sensitivity using easy-to-obtain specimens are needed. We aimed to assess the diagnostic accuracy of the Cepheid Mycobacterium tuberculosis Host Response prototype cartridge (MTB-HR), a candidate test measuring a three-gene transcriptomic signature from fingerstick blood, in children with presumptive tuberculosis disease. METHODS: RaPaed-TB was a prospective diagnostic accuracy study conducted at four sites in African countries (Malawi, Mozambique, South Africa, and Tanzania) and one site in India. Children younger than 15 years with presumptive pulmonary or extrapulmonary tuberculosis were enrolled between Jan 21, 2019, and June 30, 2021. MTB-HR was performed at baseline and at 1 month in all children and was repeated at 3 months and 6 months in children on tuberculosis treatment. Accuracy was compared with tuberculosis status based on standardised microbiological, radiological, and clinical data. FINDINGS: 5313 potentially eligible children were screened, of whom 975 were eligible. 784 children had MTB-HR test results, of whom 639 had a diagnostic classification and were included in the analysis. MTB-HR differentiated children with culture-confirmed tuberculosis from those with unlikely tuberculosis with a sensitivity of 59·8% (95% CI 50·8-68·4). Using any microbiological confirmation (culture, Xpert MTB/RIF Ultra, or both), sensitivity was 41·6% (34·7-48·7), and using a composite clinical reference standard, sensitivity was 29·6% (25·4-34·2). Specificity for all three reference standards was 90·3% (95% CI 85·5-94·0). Performance was similar in different age groups and by malnutrition status. Among children living with HIV, accuracy against the strict reference standard tended to be lower (sensitivity 50·0%, 15·7-84·3) compared with those without HIV (61·0%, 51·6-69·9), although the difference did not reach statistical significance. Combining baseline MTB-HR result with one Ultra result identified 71·2% of children with microbiologically confirmed tuberculosis. INTERPRETATION: MTB-HR showed promising diagnostic accuracy for culture-confirmed tuberculosis in this large, geographically diverse, paediatric cohort and hard-to-diagnose subgroups. FUNDING: European and Developing Countries Clinical Trials Partnership, UK Medical Research Council, Swedish International Development Cooperation Agency, Bundesministerium für Bildung und Forschung; German Center for Infection Research (DZIF). AU - Olbrich, L.* AU - Verghese, V.P.* AU - Franckling-Smith, Z.* AU - Sabi, I.* AU - Ntinginya, N.E.* AU - Mfinanga, A.* AU - Banze, D.* AU - Viegas, S.* AU - Khosa, C.* AU - Semphere, R.* AU - Nliwasa, M.* AU - McHugh, T.D.* AU - Larsson, L.* AU - Razid, A.* AU - Song, R.* AU - Corbett, E.L.* AU - Nabeta, P.* AU - Trollip, A.* AU - Graham, S.M.* AU - Hoelscher, M. AU - Geldmacher, C.* AU - Zar, H.J.* AU - Michael, J.S.* AU - Heinrich, N.* C1 - 68731 C2 - 54940 CY - 125 London Wall, London, England SP - 140-149 TI - Diagnostic accuracy of a three-gene Mycobacterium tuberculosis host response cartridge using fingerstick blood for childhood tuberculosis: a multicentre prospective study in low-income and middle-income countries. JO - Lancet Infect. Dis. VL - 24 IS - 2 PB - Elsevier Sci Ltd PY - 2023 SN - 1473-3099 ER - TY - JOUR AU - Tenbusch, M.* AU - Schumacher, S.* AU - Vogel, E. AU - Priller, A.* AU - Held, J.* AU - Steininger, P.* AU - Beileke, S.* AU - Irrgang, P.* AU - Brockhoff, R.* AU - Salmanton-García, J.* AU - Tinnefeld, K. AU - Mijočević, H. AU - Schober, K.* AU - Bogdan, C.* AU - Yazici, S.* AU - Knolle, P.* AU - Cornely, O.A.* AU - Überla, K.* AU - Protzer, U. C1 - 62770 C2 - 51008 CY - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England SP - 1212-1213 TI - Heterologous prime-boost vaccination with ChAdOx1 nCoV-19 and BNT162b2. JO - Lancet Infect. Dis. VL - 21 IS - 9 PB - Elsevier Sci Ltd PY - 2021 SN - 1473-3099 ER -