A phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for HIV-associated tuberculous meningitis (The LASER-TBM Trial)

Davis, Angharad; Wasserman, Sean; Stek, Cari; Maxebengula, Mpumi; Liang, Chen; Stegmann, Stephani; Koekemoer, Sonya; Jackson, Amanda; Kadenani, Yakub; Bremer, Marise; Daroowala, Remy; Aziz, Saalikha; Goliath, René; Sai, Louise Lai; Sihoyiya, Thandi; Denti, Paolo; Lai, Rachel Pj; Crede, Thomas; Naudé, Jonathan; Szymanski, Patryk; Vallie, Yakoob; Banderker, Ismail Abbas; Moosa, Muhammed Shiraz; Raubenheimer, Peter; Candy, Sally; Offiah, Curtis; Wahl, Gerda; Vorster, Isak; Maartens, Gary; Black, John; Meintjes, Graeme; Wilkinson, Robert J.

doi:10.1101/2022.07.26.22278065

Cited by 3 publications

(2 citation statements)

References 25 publications

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“…We found no statistically significant difference in selfreported or objective measures of treatment adherence between those with and those without low cognitive performance, possibly owing to the small number of participants in whom these data were available (n = 19). Medication nonadherence is the major cause of poor outcome in TBM; hence, this potential Processing speed 36 (15) 43 (9) .10…”

Section: Discussionmentioning

confidence: 99%

Cognitive impairment in tuberculous meningitis

Angharad,

Anna J,

Christine

et al. 2023

Association of British Neurologists: Annual Meeting Abstracts 2023

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Background. Cognitive impairment is reported as a common complication in adult tuberculous meningitis (TBM), yet few studies have systematically assessed the frequency and nature of impairment. Moreover, the impact of impairment on functioning and medication adherence has not been described.Methods. A cognitive test battery (10 measures assessing 7 cognitive domains) was administered to 34 participants with human immunodeficiency virus (HIV)-associated TBM 6 months after diagnosis. Cognitive performance was compared with that a comparator group of 66 people with HIV without a history of tuberculosis. A secondary comparison was made between participants with TBM and 26 participants with HIV 6 months after diagnosis of tuberculosis outside the central nervous system (CNS). Impact on functioning was evaluated, including through assessment of medication adherence.Results. Of 34 participants with TBM, 16 (47%) had low performance on cognitive testing. Cognition was impaired across all domains. Global cognitive performance was significantly lower in participants with TBM than in people with HIV (mean T score, 41 vs 48, respectively; P < .001). These participants also had lower global cognition scores than those with non-CNS tuberculosis (mean global T score, 41 vs 46; P = .02). Functional outcomes were not significantly correlated with cognitive performance in the subgroup of participants in whom this was assessed (n = 19).Conclusions. Low cognitive performance following HIV-associated TBM is common. This effect is independent of, and additional to, effects of HIV and non-CNS tuberculosis disease. Further studies are needed to understand longer-term outcomes, clarify the association with treatment adherence, a key predictor of outcome in TBM, and develop context-specific tools to identify individuals with cognitive difficulties in order to improve outcomes in TBM.

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Section: Discussionmentioning

confidence: 99%

Cognitive impairment in tuberculous meningitis

Angharad,

Anna J,

Christine

et al. 2023

Association of British Neurologists: Annual Meeting Abstracts 2023

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“…This was a sub-study of LASER-TBM [16], a phase IIb, open-label trial that evaluated safety and PK of intensified antibiotic therapy in adults with HIV and TBM [12]. Participants were enrolled from 4 public hospitals in Cape Town and Gqeberha, South Africa, and randomized to study interventions within 5 days of starting antituberculosis treatment.…”

Section: Study Datamentioning

confidence: 99%

Linezolid population pharmacokinetic model in plasma and cerebrospinal fluid among patients with tuberculosis meningitis

Abdelgawad

Wasserman

Abdelwahab

et al. 2023

Preprint

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Background. Linezolid is being evaluated in novel treatment regimens for tuberculous meningitis (TBM). The pharmacokinetics of linezolid have not been characterized in this population, particularly in cerebrospinal fluid (CSF) where exposures may be affected by changes in protein concentration and rifampicin co-administration. Methods. This was a sub-study of a phase 2 clinical trial of intensified antibiotic therapy for adults with HIV-associated TBM. Participants in the intervention groups received high-dose rifampicin (35 mg/kg) plus linezolid 1200 mg daily for 28 days followed by 600 mg daily until day 56. Plasma was intensively sampled, and lumbar CSF was collected at a single timepoint in a randomly allocated sampling window, within 3 days after enrolment. Sparse plasma and CSF samples were also obtained on day 28. Linezolid concentrations were analyzed using non-linear mixed effects modelling. Results. 30 participants contributed 247 plasma and 28 CSF linezolid observations. Plasma PK was best described by a one-compartment model with first-order absorption and saturable elimination. The typical value of maximal clearance was 7.25 L/h. Duration of rifampicin co-treatment (compared on day 3 versus day 28) did not affect linezolid pharmacokinetics. Partitioning between plasma and CSF correlated with CSF total protein concentration up to 1.2 g/L where the partition coefficient reached a maximal value of 37%. The equilibration half-life between plasma and CSF was estimated at ~3.5 hours. Conclusion. Linezolid was readily detected in CSF despite co-administration of the potent inducer rifampicin at high doses. These findings support continued clinical evaluation of linezolid plus high-dose rifampicin for the treatment of TBM in adults.

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Physiologically-Based Pharmacokinetic Modelling to Predict the Pharmacokinetics and Pharmacodynamics of Linezolid in Adults and Children with Tuberculous Meningitis

et al. 2023

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Linezolid is used off-label for treatment of central nervous system infections. However, its pharmacokinetics and target attainment in cranial cerebrospinal fluid (CSF) in tuberculous meningitis patients is unknown. This study aimed to predict linezolid cranial CSF concentrations and assess attainment of pharmacodynamic (PD) thresholds (AUC:MIC of >119) in plasma and cranial CSF of adults and children with tuberculous meningitis. A physiologically based pharmacokinetic (PBPK) model was developed to predict linezolid cranial CSF profiles based on reported plasma concentrations. Simulated steady-state PK curves in plasma and cranial CSF after linezolid doses of 300 mg BID, 600 mg BID, and 1200 mg QD in adults resulted in geometric mean AUC:MIC ratios in plasma of 118, 281, and 262 and mean cranial CSF AUC:MIC ratios of 74, 181, and 166, respectively. In children using ~10 mg/kg BID linezolid, AUC:MIC values at steady-state in plasma and cranial CSF were 202 and 135, respectively. Our model predicts that 1200 mg per day in adults, either 600 mg BID or 1200 mg QD, results in reasonable (87%) target attainment in cranial CSF. Target attainment in our simulated paediatric population was moderate (56% in cranial CSF). Our PBPK model can support linezolid dose optimization efforts by simulating target attainment close to the site of TBM disease.

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A phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for HIV-associated tuberculous meningitis (The LASER-TBM Trial)

Cited by 3 publications

References 25 publications

Cognitive impairment in tuberculous meningitis

Cognitive impairment in tuberculous meningitis

Linezolid population pharmacokinetic model in plasma and cerebrospinal fluid among patients with tuberculosis meningitis

Physiologically-Based Pharmacokinetic Modelling to Predict the Pharmacokinetics and Pharmacodynamics of Linezolid in Adults and Children with Tuberculous Meningitis

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