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1.
Clin Infect Dis ; 76(8): 1412-1422, 2023 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-36482216

RESUMO

BACKGROUND: Drug regimens that include intensified antibiotics alongside effective anti-inflammatory therapies may improve outcomes in tuberculous meningitis (TBM). Safety data on their use in combination and in the context of human immunodeficiency virus (HIV) are needed to inform clinical trial design. METHODS: We conducted a phase 2, open-label, parallel-design, randomized, controlled trial to assess the safety of high-dose rifampicin, linezolid, and high-dose aspirin in HIV-associated TBM. Participants were randomized (1.4:1:1) to 3 treatment arms (1, standard of care [SOC]; 2, SOC + additional rifampicin [up to 35 mg/kg/d] + linezolid 1200 mg/d reducing after 28 days to 600 mg/d; 3, as per arm 2 + aspirin 1000 mg/d) for 56 days, when the primary outcome of adverse events of special interest (AESI) or death was assessed. RESULTS: A total of 52 participants with HIV-associated TBM were randomized; 59% had mild disease (British Medical Research Council (MRC) grade 1) vs 39% (grade 2) vs 2% (grade 3). AESI or death occurred in 10 of 16 (63%; arm 3) vs 4 of 14 (29%; arm 2) vs 6 of 20 (30%; arm 1; P = .083). The cumulative proportion of AESI or death (Kaplan-Meier) demonstrated worse outcomes in arm 3 vs arm 1 (P = .04); however, only 1 event in arm 3 was attributable to aspirin and was mild. There was no difference in efficacy (modified Rankin scale) between arms. CONCLUSIONS: High-dose rifampicin and adjunctive linezolid can safely be added to the standard of care in HIV-associated TBM. Larger studies are required to determine whether potential toxicity associated with these interventions, particularly high-dose aspirin, is outweighed by mortality or morbidity benefit. CLINICAL TRIALS REGISTRATION: NCT03927313.


Assuntos
Infecções por HIV , Tuberculose Meníngea , Humanos , Rifampina/efeitos adversos , Antituberculosos/efeitos adversos , Aspirina/efeitos adversos , Tuberculose Meníngea/complicações , Tuberculose Meníngea/tratamento farmacológico , Linezolida/efeitos adversos , HIV , Resultado do Tratamento , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico
3.
Wellcome Open Res ; 6: 136, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34286103

RESUMO

Background: Tuberculous meningitis (TBM) is the most lethal form of tuberculosis with a mortality of ~50% in those co-infected with HIV-1. Current antibiotic regimens are based on those known to be effective in pulmonary TB and do not account for the differing ability of the drugs to penetrate the central nervous system (CNS). The host immune response drives pathology in TBM, yet effective host-directed therapies are scarce. There is sufficient data to suggest that higher doses of rifampicin (RIF), additional linezolid (LZD) and adjunctive aspirin (ASA) will be beneficial in TBM yet rigorous investigation of the safety of these interventions in the context of HIV associated TBM is required. We hypothesise that increased dose RIF, LZD and ASA used in combination and in addition to standard of care for the first 56 days of treatment with be safe and tolerated in HIV-1 infected people with TBM. Methods: In an open-label randomised parallel study, up to 100 participants will receive either; i) standard of care (n=40, control arm), ii) standard of care plus increased dose RIF (35mg/kg) and LZD (1200mg OD for 28 days, 600mg OD for 28 days) (n=30, experimental arm 1), or iii) as per experimental arm 1 plus additional ASA 1000mg OD (n=30, experimental arm 2). After 56 days participants will continue standard treatment as per national guidelines. The primary endpoint is death and the occurrence of solicited treatment-related adverse events at 56 days. In a planned pharmacokinetic (PK) sub-study we aim to assess PK/pharmacodynamic (PD) of oral vs IV rifampicin, describe LZD and RIF PK and cerebrospinal fluid concentrations, explore PK/PD relationships, and investigate drug-drug interactions between LZD and RIF. Safety and pharmacokinetic data from this study will inform a planned phase III study of intensified therapy in TBM. Clinicaltrials.gov registration: NCT03927313 (25/04/2019).

4.
SA J Radiol ; 23(1): 1720, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824739

RESUMO

BACKGROUND: The immediate response to cardiac arrest is regarded as the most time-critical intervention. First responders for cardiac arrests in imaging departments are often radiology staff. The study aim was to determine radiology staff members' confidence in initiating basic life support. OBJECTIVES: The objectives of this study included determining the general confidence levels regarding identifying cardiac arrest and initiation of basic life support (BLS) amongst Radiology staff within the studied sites, as well as to identify potential areas of uncertainty. Another objective included identifying what would contribute to increasing levels of confidence and competence in identifying cardiac arrest and initiating BLS. METHOD: A multi-centre cross-sectional survey was conducted using peer-validated, anonymous questionnaires. Questionnaires were distributed to radiology staff working in public sector hospitals within the Cape Town Metropole West. Due to the limited subject pool, a convenience sample was collected. Data were therefore statistically analysed using only summary statistics (mean, standard deviation, proportions, and so on), and detailed comparisons were not made. RESULTS: We disseminated 200 questionnaires, and 74 were completed (37%). There were no incomplete questionnaires or exclusions from the final sample. Using a 10-point Likert scale, the mean ability to recognise cardiac arrest was 6.45 (SD ± 2.7), securing an airway 4.86 (SD ± 2.9), and providing rescue breaths and initiating cardiac compressions 6.14 (SD ± 2.9). Only two (2.7%) of the participants had completed a basic life support course in the past year; 11 (14.8%) had never completed any basic life support course and 28 (37.8%) had never completed any life support or critical care course. Radiologists, radiology trainees and nurses had the greatest confidence in providing rescue breaths and initiating cardiac compressions from all the groups. CONCLUSION: The study demonstrated a substantial lack of confidence in providing basic life support in the participating hospital imaging departments' staff. The participants indicated that regular training and improved support systems would increase confidence levels and improve skills.

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