About
235
Publications
25,166
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
11,053
Citations
Citations since 2017
Publications
Publications (235)
A milestone in the development of novel anti-tuberculosis drugs is demonstrating early bactericidal activity (EBA) in a phase IIa clinical trial. The significant variability in measurements of bacterial load complicates the data analysis in these trials. We performed a systematic review and evaluation of methods for determination of EBA in pulmonar...
Biomarkers are quantifiable characteristics of biological processes. In Mycobacterium tuberculosis, common biomarkers used in clinical drug development are colony forming unit (CFU) and time-to-positivity (TTP) from sputum samples. This analysis aimed to develop a combined quantitative tuberculosis biomarker model for CFU and TTP biomarkers for ass...
Aim:
Delamanid is a novel drug to treat of drug-resistant tuberculosis, manufactured as 50 mg solid and 25 mg dispersible tablets. We evaluated the effects of dispersing the 50 mg tablet, focusing on the relative bioavailability.
Methods:
Delamanid 50 mg tablets administered dispersed versus swallowed whole, was investigated in a phase I, four-p...
Introduction
The Pan-African Consortium for the Evaluation of Anti-Tuberculosis Antibiotics (PanACEA) was designed to build tuberculosis (TB) trial capacity whilst conducting clinical trials on novel and existing agents to shorten and simplify TB treatment. PanACEA has now established a dynamic network of 11 sub-Saharan clinical trial sites and fou...
There has been an increased interest in pharmacokinetics and pharmacodynamics (PKPD) of anti-tuberculosis drugs. A better understanding of the relationship between drug exposure, antimicrobial kill and acquired drug resistance is essential not only to optimize current treatment regimens but also to design appropriately dosed regimens with new anti-...
We present an automatic non-invasive way of detecting cough events based on both accelerometer and audio signals. The acceleration signals are captured by a smartphone firmly attached to the patient's bed, using its integrated accelerometer. The audio signals are captured simultaneously by the same smartphone using an external microphone. We have c...
Background
The WHO-endorsed shorter-course regimen for MDR-TB includes high-dose isoniazid. The pharmacokinetics of high-dose isoniazid within MDR-TB regimens has not been well described.
Objectives
To characterize isoniazid pharmacokinetics at 5–15 mg/kg as monotherapy or as part of the MDR-TB treatment regimen.
Methods
We used non-linear mixed-...
Background and objective:
Delamanid is a nitroimidazole, a novel class of drug for treating tuberculosis, and is primarily metabolized by albumin into the metabolite DM-6705. The aims of this analysis were to develop a population pharmacokinetic (PK) model to characterize the concentration-time course of delamanid and DM-6705 in adults with drug-r...
Background
Antibiotic treatments are often associated with a late slowdown in bacterial killing. This separates the killing of bacteria into at least two distinct phases: a quick phase followed by a slower phase, the latter of which is linked to treatment success. Current mechanistic explanations for the in vitro slowdown are either antibiotic pers...
Background
BCG vaccination prevents severe childhood tuberculosis (TB) and was introduced in South Africa in the 1950s. It is hypothesised that BCG trains the innate immune system by inducing epigenetic and functional reprogramming, thus providing non-specific protection from respiratory tract infections. We evaluated BCG for reduction of morbidity...
Delamanid and bedaquiline are two drugs approved to treat drug‐resistant tuberculosis, and each have been associated with QTc prolongation. We aimed to investigate the relationships between the drugs’ plasma concentrations and observed QTcF prolongation and to evaluate their combined effects on QTcF, using a model‐based population approach. Further...
We present a deep learning based automatic cough classifier which can discriminate tuberculosis (TB) coughs from COVID-19 coughs and healthy coughs. Both TB and COVID-19 are respiratory disease, have cough as a predominant symptom and claim thousands of lives each year. The cough audio recordings were collected at both indoor and outdoor settings a...
Background
Despite the high global disease burden of tuberculosis (TB), the disease caused by Mycobacterium tuberculosis ( Mtb ) infection, novel treatments remain an urgent medical need. Development efforts continue to be hampered by the reliance on culture-based methods, which often take weeks to obtain due to the slow growth rate of Mtb . The av...
Background
With current treatment options most patients with CNS TB develop severe disability or die. Drug-resistant tuberculous meningitis is nearly uniformly fatal. Novel treatment strategies are needed. Bedaquiline, a potent anti-TB drug, has been reported to be absent from CSF in a single report.
Objectives
To explore the pharmacokinetics of b...
Rationale:
Carbapenems are recommended for treatment of drug-resistant tuberculosis. Optimal dosing remains uncertain.
Objective:
Evaluate the fourteen-day bactericidal activity of meropenem, at different doses, with or without rifampin,.
Methods:
Individuals with pulmonary tuberculosis were randomized to one of four intravenous meropenem-base...
We present a machine learning based long-term cough monitoring system by detecting patient's bed occupancy from a bed-attached smartphone-inbuilt accelerometer automatically. Previously this system was used to detect cough events successfully and long-term cough monitoring requires bed occupancy detection, as the initial experiments show that patie...
Rates of antimicrobial resistance are increasing globally while the pipeline of new antibiotics is drying up, putting patients with disease caused by drug-resistant bacteria at increased risk of complications and death. The growing costs for diagnosis and management of drug resistance threaten tuberculosis control where the disease is endemic and r...
We present 'wake-cough', an application of wake-word spotting to coughs using Resnet50 and identifying coughers using i-vectors, for the purpose of a long-term, personalised cough monitoring system. Coughs, recorded in a quiet (73$\pm$5 dB) and noisy (34$\pm$17 dB) environment, were used to extract i-vectors, x-vectors and d-vectors, used as featur...
Rationale:
There is accumulating evidence that higher-than-standard doses of isoniazid are effective against low-to-intermediate-level isoniazid-resistant strains of Mycobacterium tuberculosis, but the optimal dose remains unknown.
Objective:
Characterizing the association between isoniazid pharmacokinetics (standard or high-dose) and early bact...
Background
Direct bronchial spread of tuberculosis was extensively described in pre-antibiotic human pathology literature but this description has been overlooked in the post-antibiotic era, in which most pathology data come from animal models that emphasise the granuloma. Modern techniques, such as [¹⁸F]2-fluoro-2-deoxy-D-glucose (FDG) PET-CT scan...
BACKGROUND: There are no data comparing the 6-9 month oral three-drug Nix regimen (bedaquiline, pretomanid and linezolid [BPaL]) to conventional regimens containing bedaquiline (B, BDQ) and linezolid (L, LZD).METHODS: Six-month post end-of-treatment outcomes were compared between Nix-TB (n = 109) and 102 prospectively recruited extensively drug-res...
Background: Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability.
Methods: Patients were randomized to one of four treatment groups: meropenem 2 g...
Background
Pulmonary tuberculosis (TB) in people living with HIV (PLH) frequently presents as sputum smear-negative. However, clinical trials of TB in adults often use smear-positive individuals to ensure measurable bacterial responses following initiation of treatment, thereby excluding HIV-infected patients from trials.
Methods
In this prospecti...
Background
The relationship between tuberculosis (TB), one of the leading infectious causes of death worldwide, and the microbiome, which is critical for health, is poorly understood.
Methods
To identify potential microbiome-host interactions, profiling of the oral, sputum and stool microbiota [n = 58 cases, n = 47 culture-negative symptomatic con...
Rationale
Clofazimine is classified as a WHO group B drug for the treatment of rifampicin-resistant tuberculosis. QT prolongation, which is associated with fatal cardiac arrhythmias, is caused by several anti-tubercular drugs, including clofazimine, but there are no data quantifying the effect of clofazimine concentration on QT prolongation.
Object...
Background
Accumulating data indicate that higher rifampicin doses are more effective and shorten tuberculosis (TB) treatment duration. This study evaluated the safety, tolerability, pharmacokinetics, and 7- and 14-day early bactericidal activity (EBA) of increasing doses of rifampicin. Here we report the results of the final cohorts of PanACEA HIG...
Early bactericidal activity studies monitor daily sputum bacterial counts in individuals with tuberculosis (TB) for 14 days during experimental drug treatment. The rate of change in sputum bacterial load over time provides an informative, but imperfect, estimate of drug activity and is considered a critical step in development of new TB drugs. In t...
Background
Bedaquiline and delamanid are the first drugs of new classes registered for tuberculosis treatment in 40 years. Each can prolong the QTc interval, with maximum effects occurring weeks after drug initiation. The cardiac safety and microbiological activity of these drugs when co-administered are not well-established. Our aim was to charact...
In high-burden settings, the diagnosis of pleural tuberculosis (TB) is frequently inferred in patients who present with lymphocyte predominant exudative effusions and high adenosine deaminase (ADA) levels. Two recent small retrospective studies suggested that the lactate dehydrogenase (LDH)/ADA ratio is significantly lower in TB than in non-TB pleu...
Anton Ghon is well known in the field of childhood tuberculosis, and the tuberculosis primary focus and complex are frequently called the Ghon focus and complex; this is largely the result of the wide publication of the English translation of his monograph “ Der primäre Lungenherd bei der Tuberkulose der Kinder.” Ghon’s studies are frequently quote...
PurposePara-aminosalicylic acid (PAS) is currently one of the add-on group C medicines recommended by the World Health Organization for multidrug-resistant tuberculosis treatment. At the recommended doses (8–12 g per day in two to three divided doses) of the widely available slow-release PAS formulation, studies suggest PAS exposures are lower than...
Background. An outbreak of a novel coronavirus in China in late 2019 has resulted in a global pandemic. The virus (SARS-CoV-2) causes a
severe acute respiratory syndrome and had been responsible for >14 000 deaths in South Africa (SA) at the time of writing, 30 August 2020.
Autopsies in our setting have not been prioritised owing to the infective r...
Background:
Rifampicin (RIF) resistance is highly correlated with isoniazid (INH) resistance and used as proxy for multidrugresistant tuberculosis (MDR-TB). Using MTBDRplus as a comparator, we evaluated the predictive value of Xpert® MTB/RIF (Xpert)detected RIF resistance for MDR-TB in eastern Democratic Republic of the Congo (DRC).
Methods:
We...
We thank Kim and colleagues for their interest in our study.…
Following its introduction as an antituberculosis agent close to 75 years ago, the use of para‐aminosalicylic acid (PAS) has been limited by gastro‐intestinal intolerance and multiple formulations were produced in attempts to reduce its occurrence. More recently, an enteric‐coated, granular, slow‐release PAS formulation (PASER) was introduced and i...
Telacebec (Q203) is a novel drug that targets Mycobacterium tuberculosis cellular energy production through inhibition of the mycobacterial cytochrome bc1 complex. This proof-of-concept study evaluated the bactericidal activity of telacebec over a period of 14 days in patients with newly diagnosed, drug-susceptible pulmonary tuberculosis.
Background:
Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes.
Methods:
In an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that hav...
Tuberculosis (TB) drug development is dependent on informative trials to secure development of new antibiotics and combination regimens. Clofazimine (CLO) and pyrazinamid (PZA) are important components of recommended standard multi-drug treatments of TB. Paradoxically, in a Phase IIa trial aiming to define the early bactericidal activity (EBA) of C...
Summary
Background Xpert MTB/RIF Ultra (Ultra) is a new test for tuberculosis undergoing global roll-out. We assessed the
performance of Ultra compared with Xpert MTB/RIF (Xpert) in an HIV-endemic setting where previous tuberculosis
is frequent and current test performance is suboptimal.
Methods In this two-cohort diagnostic accuracy study, we used...
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 trea...
Rationale:
High-dose isoniazid is recommended in short-course regimens for multidrug-resistant TB (MDR-TB). The optimal dose of isoniazid and its individual contribution to efficacy against TB strains with inhA or katG mutations are unknown.
Objective:
Define the optimal dose of isoniazid for patients with isoniazid-resistant TB mediated by inhA...
Background New anti-tuberculosis regimens that are shorter, simpler, and less toxic than those that are currently available are needed as part of the global effort to address the tuberculosis epidemic. We aimed to investigate the bactericidal activity and safety profile of combinations of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide in t...
Introduction:
This study explores uses of microcalorimetry to detect Mycobacterium tuberculosis (TB) in sputum. Microcalorimetry measures metabolic heat evolution during cellular proliferation of TB and is considered as a possible alternative to conventional diagnostic tools.
Objectives:
To compare the time to detection (TTD) from the BACTEC™ MG...
Para‐aminosalicylic acid (PAS), often the last drug remaining for treatment of drug‐resistant tuberculosis, is notorious for causing gastrointestinal intolerance; however, the cause of PAS intolerance is uncertain. The objective of this study was to assess relationships between peak concentrations of PAS administered as a granular slow‐release ente...
Background:
New anti-tuberculosis regimens that are shorter, simpler, and less toxic than those that are currently available are needed as part of the global effort to address the tuberculosis epidemic. We aimed to investigate the bactericidal activity and safety profile of combinations of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide in...
Tuberculous effusion is a common disease entity with a spectrum of presentations from a largely benign effusion, which resolves completely, to a complicated effusion with loculations, pleural thickening and even frank empyema, all of which may have a lasting effect on lung function. The pathogenesis is a combination of true pleural infection and an...
Background:
The phase III REMoxTB study prospectively enrolled HIV-positive (with CD4+ count > 250 cells, not on anti-retroviral therapy) and HIV-negative patients. We investigated the incidence of adverse events and cure rates according to HIV status for patients receiving standard TB therapy in the trial.
Methods:
Forty-two HIV-positive cases...
The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with pulmonary TB to 6 months when combined with pyrazinamide in the first 2 months. Resistance or hypersensitivity to rifampicin effectively condemns a patient to prolonged, less effective, mor...
Objective:
Artificial sputum spiked with Mycobacterium tuberculosis could serve for validation of procedures that determine viable mycobacterial load.
Design:
Artificial sputum specimens prepared in-house were spiked with low, medium or high concentrations of Mycobacterium tuberculosis H37Rv stock solution. In a first series, a single technologi...
Setting:
Mycobacterial sputum culture is a key diagnostic and research tool.
Objective:
To compare mycobacterial culture outcomes of three sputum collection methods.
Design:
We compared culture results within sets of three sputum samples collected from 18 HIV-infected adult tuberculosis patients at regular intervals up to 84 days after treatme...
Background
Current Phase 2a methods in tuberculosis (TB) drug development are severely limited in capturing a drug candidate’s sterilizing activity (ability to prevent TB relapse). We hypothesize that sputum-based measurements of current methods fail to capture drug activity in deep TB lesion compartments, where recalcitrant TB populations are sequ...
Figure S1 (a) Observed bedaquiline concentrations above the limit of quantification presented as average per nominal time‐point. The table below specifies the number of samples contributing to the average value per nominal time point. (b) Observed M2 concentrations above the limit of quantification presented as average per nominal time‐point. The t...
Patients with multidrug-resistant tuberculosis in Peru and South Africa were randomized to weight-banded nominal doses of 11, 14, 17 or 20 mg/kg/day levofloxacin (minimum 750 mg) in combination with other second-line agents. 101 patients were included in noncompartmental pharmacokinetic analyses. Respective median AUC 0-24 were 109.49, 97.86, 145.3...
Abstract Background The incidence and severity of tuberculosis chemotherapy toxicity is poorly characterised. We used data available from patients in the REMoxTB trial to provide an assessment of the risks associated with the standard regimen and two experimental regimens containing moxifloxacin. Methods All grade 3 & 4 adverse events (AEs) and the...
Background:
Tuberculosis remains a huge public health problem and the prolonged treatment duration obstructs effective tuberculosis control. Higher rifampicin doses have been associated with better bactericidal activity, but optimal dosing is uncertain. This analysis aimed to characterize the relationship between rifampicin plasma exposure and tre...
Objectives:
Bedaquiline is an important novel drug for treatment of multidrug-resistant tuberculosis, but no paediatric formulation is yet available. This work aimed to explore the possibility of using the existing tablet formulation in children by evaluating the relative bioavailability, short-term safety, acceptability and palatability of suspen...
According to the World Health Organization (WHO), tuberculosis is the leading cause of death attributed to a single microbial pathogen worldwide. In addition to the large number of patients affected by tuberculosis, the emergence of Mycobacterium tuberculosis drug‐resistance is complicating tuberculosis control in many high‐burden countries. During...
Background:
The current rifampicin dose (10 mg/kg) is sub-optimal for treating tuberculosis. The PanACEA HIGHRIF1 trial evaluated pharmacokinetics and early bactericidal activity with rifampicin doses up to 40 mg/kg. Conventional statistics revealed no significant exposure-response relationship. Our objective was to explore exposure-response for h...
Tuberculosis (TB) is the leading infectious cause of death worldwide, and the commonest cause of death in people living with HIV. Globally, pleural TB remains one of the most frequent causes of pleural exudates, particularly in TB‐endemic areas and in the HIV positive population. Most TB pleural effusions are exudates with high adenosine deaminase...
Background:
Drug-induced liver injury (DILI) is a common complication of tuberculosis treatment. We utilised data from the REMoxTB clinical trial to describe the incidence of predisposing factors and the natural history in patients with liver enzyme levels elevated in response to tuberculosis treatment.
Methods:
Patients received either standard...