Publications by authors named "Andreas H Diacon"

127 Publications

Comparing rates of mycobacterial clearance in sputum smear-negative and smear-positive adults living with HIV.

BMC Infect Dis 2021 May 22;21(1):466. Epub 2021 May 22.

Department of Science and Technology/National Research Foundation Centre of Excellence for Biomedical TB Research (CBTBR), University of the Witwatersrand, National Health Laboratory Service, Johannesburg, South Africa.

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 prospective case cohort study, 118 HIV-seropositive TB patients were assessed prior to initiation of standard four-drug TB therapy and at several time points through 35 days. Sputum bacillary load, as a marker of treatment response, was determined serially by: smear microscopy, Xpert MTB/RIF, liquid culture, and colony counts on agar medium.

Results: By all four measures, patients who were baseline smear-positive had higher bacterial loads than those presenting as smear-negative, until day 35. However, most smear-negative PLH had significant bacillary load at enrolment and their mycobacteria were cleared more rapidly than smear-positive patients. Smear-negative patients' decline in bacillary load, determined by colony counts, was linear to day 7 suggesting measurable bactericidal activity. Moreover, the decrease in bacterial counts was comparable to smear-positive individuals. Increasing cycle threshold values (Ct) on the Xpert assay in smear-positive patients to day 14 implied decreasing bacterial load.

Conclusion: Our data suggest that smear-negative PLH can be included in clinical trials of novel treatment regimens as they contain sufficient viable bacteria, but allowances for late exclusions would have to be made in sample size estimations. We also show that increases in Ct in smear-positive patients to day 14 reflect treatment responses and the Xpert MTB/RIF assay could be used as biomarker for early treatment response.
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http://dx.doi.org/10.1186/s12879-021-06133-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141145PMC
May 2021

Anaerobe-enriched gut microbiota predicts pro-inflammatory responses in pulmonary tuberculosis.

EBioMedicine 2021 May 8;67:103374. Epub 2021 May 8.

DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, and SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa. Electronic address:

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 controls (SCs)] and whole blood transcriptome were done in pre-treatment presumptive pulmonary TB patients. This was a cross-sectional study. Microbiota were also characterised in close contacts of cases (CCCs, n = 73) and close contacts of SCs (CCSCs, n = 82) without active TB.

Findings: Cases and SCs each had similar α- and β-diversities in oral washes and sputum, however, β-diversity differed in stool (PERMANOVA p = 0•035). Cases were enriched with anaerobes in oral washes, sputum (Paludibacter, Lautropia in both) and stool (Erysipelotrichaceae, Blautia, Anaerostipes) and their stools enriched in microbial genes annotated as amino acid and carbohydrate metabolic pathways. In pairwise comparisons with their CCCs, cases had Megasphaera-enriched oral and sputum microbiota and Bifidobacterium-, Roseburia-, and Dorea-depleted stools. Compared to their CCSCs, SCs had reduced α-diversities and many differential taxa per specimen type. Cases differed transcriptionally from SCs in peripheral blood (PERMANOVA p = 0•001). A co-occurrence network analysis showed stool taxa, Erysipelotrichaceae and Blautia, to negatively co-correlate with enriched "death receptor" and "EIF2 signalling" pathways whereas Anaerostipes positively correlated with enriched "interferon signalling", "Nur77 signalling" and "inflammasome" pathways; all of which are host pathways associated with disease severity. In contrast, none of the taxa enriched in SCs correlated with host pathways.

Interpretation: TB-specific microbial relationships were identified in oral washes, induced sputum, and stool from cases before the confounding effects of antibiotics. Specific anaerobes in cases' stool predict upregulation of pro-inflammatory immunological pathways, supporting the gut microbiota's role in TB.

Funding: European & Developing Countries Clinical Trials Partnership, South African-Medical Research Council, National Institute of Allergy and Infectious Diseases.
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http://dx.doi.org/10.1016/j.ebiom.2021.103374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122180PMC
May 2021

Effect of Clofazimine Concentration on QT Prolongation in Patients Treated for Tuberculosis.

Antimicrob Agents Chemother 2021 Jun 17;65(7):e0268720. Epub 2021 Jun 17.

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.

Clofazimine is classified as a WHO group B drug for the treatment of rifampin-resistant tuberculosis. QT prolongation, which is associated with fatal cardiac arrhythmias, is caused by several antitubercular drugs, including clofazimine, but there are no data quantifying the effect of clofazimine concentration on QT prolongation. Our objective was to describe the effect of clofazimine exposure on QT prolongation. Fifteen adults drug-susceptible tuberculosis patients received clofazimine monotherapy as 300 mg daily for 3 days, followed by 100 mg daily in one arm of a 2-week, multiarm early bactericidal activity trial in South Africa. Pretreatment Fridericia-corrected QT (QTcF) (105 patients, 524 electrocardiograms [ECGs]) and QTcFs from the clofazimine monotherapy arm matched with clofazimine plasma concentrations (199 ECGs) were interpreted with a nonlinear mixed-effects model. Clofazimine was associated with significant QT prolongation described by a maximum effect () function. We predicted clofazimine exposures using 100-mg daily doses and 2 weeks of loading with 200 and 300 mg daily, respectively. The expected proportions of patients with QTcF change from baseline above 30 ms (ΔQTcF > 30) were 2.52%, 11.6%, and 23.0% for 100-, 200-, and 300-mg daily doses, respectively. At steady state, the expected proportion with ΔQTcF of >30 ms was 23.7% and with absolute QTcF of >450 ms was 3.42% for all simulated regimens. The use of loading doses of 200 and 300 mg is not predicted to expose patients to an increased risk of QT prolongation, compared with the current standard treatment, and is, therefore, an alternative option for more quickly achieving therapeutic concentrations.
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http://dx.doi.org/10.1128/AAC.02687-20DOI Listing
June 2021

QT effects of bedaquiline, delamanid, or both in patients with rifampicin-resistant tuberculosis: a phase 2, open-label, randomised, controlled trial.

Lancet Infect Dis 2021 Feb 12. Epub 2021 Feb 12.

Division of Clinical Pharmacology, Department of Medicine, Cape Town, South Africa.

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 characterise the effects of bedaquiline, delamanid, or both on the QTc interval, longitudinally over 6 months of multidrug treatment, among patients with multidrug-resistant or rifampicin-resistant tuberculosis taking multidrug background therapy.

Methods: ACTG A5343 is a phase 2, open-label, randomised, controlled trial in which adults with multidrug-resistant or rifampicin-resistant tuberculosis receiving multidrug background treatment were randomly assigned 1:1:1 by centrally, computer-generated randomisation, by means of permuted blocks to receive bedaquiline, delamanid, or both for 24 weeks. Participants were enrolled at TASK in Cape Town and the South African Tuberculosis Vaccine Initiative in Worcester, both in South Africa, and Hospital Maria Auxiliadora in Peru. Individuals with QTc greater than 450 ms were excluded. HIV-positive participants received dolutegravir-based antiretroviral therapy. Clofazimine was disallowed, and levofloxacin replaced moxifloxacin. ECG in triplicate and sputum cultures were done fortnightly. The primary endpoint was mean QTcF change from baseline (averaged over weeks 8-24); cumulative culture conversation at week 8-24 was an exploratory endpoint. Analyses included all participants who initiated study tuberculosis treatment (modified intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT02583048 and is ongoing.

Findings: Between Aug 26, 2016 and July 13, 2018, of 174 screened, 84 participants (28 in each treatment group, and 31 in total with HIV) were enrolled. Two participants did not initiate study treatment (one in the delamanid group withdrew consent and one in the bedaquiline plus delamanid group) did not meet the eligibility criterion). Mean change in QTc from baseline was 12·3 ms (95% CI 7·8-16·7; bedaquiline), 8·6 ms (4·0-13·1; delamanid), and 20·7 ms (16·1-25·3) (bedaquiline plus delamanid). There were no grade 3 or 4 adverse QTc prolongation events and no deaths during study treatment. Cumulative culture conversion by week 8 was 21 (88%) of 24 (95% CI 71-97; bedaquiline), 20 (83%) of 24 (65-95; delamanid), and 19 (95%) of 20 (79-100; bedaquiline plus delamanid) and was 92% (77-99) for bedaquiline, 91% (76-99), for delamanid, and 95% (79-100) for bedaquiline plus delamanid at 24 weeks.

Interpretation: Combining bedaquiline and delamanid has a modest, no more than additive, effect on the QTc interval, and initial microbiology data are encouraging. This study provides supportive evidence for use of these agents together in patients with multidrug-resistant or rifampicin-resistant tuberculosis with normal baseline QTc values.

Funding: Division of AIDS, National Institutes of Health.
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http://dx.doi.org/10.1016/S1473-3099(20)30770-2DOI Listing
February 2021

Increased bactericidal activity but dose-limiting intolerability at 50 mg·kg rifampicin.

Eur Respir J 2021 Feb 4. Epub 2021 Feb 4.

Department of Lung Diseases, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands.

Accumulating data have indicated that higher rifampicin doses are more effective and shorten tuberculosis 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 HIGHRIF1, a dose-escalation study in treatment-naive adult smear-positive patients with tuberculosis. Patients received, in consecutive cohorts, 40 or 50 mg·kg rifampicin once daily in monotherapy (day 1-7), supplemented with standard dose isoniazid, pyrazinamide and ethambutol between day 8-14. In the 40 mg·kg cohort (n=15), 13 patients experienced a total of 36 adverse events (AEs) during monotherapy, resulting in one treatment discontinuation. In the 50 mg·kg group (n=17), all patients experienced AEs during monotherapy, 93 in total; 11 patients withdrew or stopped study medication. AEs were mostly mild/moderate and tolerability- rather than safety-related, gastrointestinal disorders, pruritis, hyperbilirubinemia and jaundice. There was a more than proportional increase in the rifampicin geometric mean AUCh for 50 mg·kg compared to 40 mg·kg; 571 mg·L*h (range 320-995) 387 mg·L*h (201-847), while peak exposures saw proportional increases. Protein-unbound exposure after 50 mg·kg (11%, 8-17%) was comparable with lower rifampicin doses. Rifampicin exposures and bilirubin concentrations were correlated (day-3 Spearman's rho 0.670, p<0.001). EBA increased considerably with dose, with the highest seen after 50 mg·kg; 14-day EBA -0.427 logCFU·mL·day (95%CI -0.500, -0.355). In conclusion, although associated with an increased bactericidal effect, the 50 mg·kg dose was not well tolerated. Rifampicin at 40 mg·kg was well tolerated and therefore selected for evaluation in a phase IIC treatment shortening trial.
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http://dx.doi.org/10.1183/13993003.00955-2020DOI Listing
February 2021

Fourteen-day PET/CT imaging to monitor drug combination activity in treated individuals with tuberculosis.

Sci Transl Med 2021 Feb;13(579)

Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892, USA.

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 this clinical study, 160 participants with TB received isoniazid, pyrazinamide, or rifampicin, components of first-line chemotherapy, and moxifloxacin individually and in combination. In addition to standard bacterial enumeration in sputum, participants underwent 2-deoxy-2-[F]fluoro-d-glucose positron emission tomography and computerized tomography ([F]FDG-PET/CT) at the beginning and end of the 14-day drug treatment. Quantitating radiological responses to drug treatment provided comparative single and combination drug activity measures across lung lesion types that correlated more closely with established clinical outcomes when combined with sputum enumeration compared to sputum enumeration alone. Rifampicin and rifampicin-containing drug combinations were most effective in reducing both lung lesion volume measured by CT imaging and lesion-associated inflammation measured by PET imaging. Moxifloxacin was not superior to rifampicin in any measure by PET/CT imaging, consistent with its performance in recent phase 3 clinical trials. PET/CT imaging revealed synergy between isoniazid and pyrazinamide and demonstrated that the activity of pyrazinamide was limited to lung lesion, showing the highest FDG uptake during the first 2 weeks of drug treatment. [F]FDG-PET/CT imaging may be useful for measuring the activity of single drugs and drug combinations during evaluation of potential new TB drug regimens before phase 3 trials.
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http://dx.doi.org/10.1126/scitranslmed.abd7618DOI Listing
February 2021

Face masks in the post-COVID-19 era: a silver lining for the damaged tuberculosis public health response?

Lancet Respir Med 2021 04 22;9(4):340-342. Epub 2021 Jan 22.

DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research and SA/MRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town 7550, South Africa. Electronic address:

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http://dx.doi.org/10.1016/S2213-2600(21)00020-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826055PMC
April 2021

The Utility of Pleural Fluid Lactate Dehydrogenase to Adenosine Deaminase Ratio in Pleural Tuberculosis.

Respiration 2021;100(1):59-63. Epub 2020 Dec 17.

Division of Pulmonology, Department of Medicine, Stellenbosch University & Tygerberg Academic Hospital, Cape Town, South Africa,

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 pleural effusions and that the LDH/ADA ratio may be useful in differentiating pleural TB from other pleural exudates. We compared the pleural LDH/ADA ratios, ADA levels, and lymphocyte predominance of a prospectively collected cohort of patients with proven pleural TB (n = 160) to those with a definitive alternative diagnosis (n = 68). The mean pleural fluid LDH/ADA ratio was lower in patients with pleural TB than alternative diagnoses (6.2 vs. 34.3, p < 0.001). The area under the receiver operating characteristic curve was 0.92 (p < 0.001) for LDH/ADA ratio and 0.88 (p < 0.001) for an ADA ≥40 U/L alone. A ratio of ≤12.5 had the best overall diagnostic efficiency, while a ratio of ≤10 had a specificity of 90% and a positive predictive value of 95%, with a sensitivity of 78%, making it a clinically useful "rule in" value for pleural TB in high incidence settings. When comparing the LDH/ADA ratio to an ADA level ≥40 U/L in the presence of a lymphocyte predominant effusion, the latter performed better. When lymphocyte values are unavailable, our data suggest that the LDH/ADA ratio is valuable in distinguishing TB effusions from other pleural exudates.
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http://dx.doi.org/10.1159/000509555DOI Listing
December 2020

Anton Ghon and His Colleagues and Their Studies of the Primary Focus and Complex of Tuberculosis Infection and Their Relevance for the Twenty-First Century.

Respiration 2020 Dec 15:1-11. Epub 2020 Dec 15.

Department of Pediatrics, Division of Pneumonology and Immunology with Intensive Medicine, Charité Universitätsmedizin, Berlin, Germany.

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 quoted, but precise details of his monograph are neglected, his results often misquoted, and his later publications virtually unknown. This review highlights aspects of Ghon's anatomical pathology studies in children and adults not necessarily dying of tuberculosis but with signs of tuberculosis infection. Ghon found a single primary tuberculosis focus in approximately 80% of tuberculosis-infected children situated close to the pleura in two-thirds of cases. Cavitation of the focus was common, and lymphatic spread involved lymph nodes in the abdomen and neck in many children. Studies amongst adults and children frequently found the healed primary tuberculosis focus to be completely calcified without histological signs of tuberculosis activity; however, particularly in the presence of pulmonary tuberculosis, histological signs of tuberculosis activity were often found in the lymph nodes of the angulus venosus, despite apparent healing with extensive calcification. Both earlier studies and more recent investigations, with molecular biological tools, unavailable to Ghon and earlier researchers, have confirmed the presence of viable mycobacteria in apparently normal or healed thoracic nodes and also found molecular biological indications of viable mycobacteria in these nodes. As suggested by Ghon, lympho-haematogenous spread of tuberculosis may be more common than is usually appreciated.
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http://dx.doi.org/10.1159/000509522DOI Listing
December 2020

Xpert MTB/RIF-detected Rifampicin Resistance is a Sub-Optimal Surrogate for Multidrug Resistant Tuberculosis in Eastern Democratic Republic of the Congo: Diagnostic and Clinical Implications.

Clin Infect Dis 2020 Jun 26. Epub 2020 Jun 26.

Laboratoire de Recherche Biomédicale Professeur André Lurhuma, Université Catholique de Bukavu (UCB), Bukavu, DRC.

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 conducted a cross-sectional study involving data from new or retreatment pulmonary adult TB cases evaluated between July 2013 and December 2016. Separate, paired sputa for smear microscopy and MTBDRplus were collected. Xpert testing was performed subject to the availability of Xpert cartridges on sample remnants after microscopy.

Results: Among 353 patients, 193 (54.7%) were previously treated and 224 (63.5%) were MTBDRplus TB-positive. Of the 224, 43 (19.2%) were RIFmono-resistant, 11 (4.9%) were INHmono-resistant, 53 (23.7%) had MDR-TB, and 117 (52.2%) were RIF- and INH-susceptible. Overall, among the 96 samples detected by MTBDRplus as RIF-resistant, 53 (55.2%) had MDR-TB. Xpert testing was performed in 179 (50.7%) specimens, and amongst these, 163 (91.1%) were TB-positive and 73 (44.8%) RIF-resistant. Only 45/73 (61.6%) Xpertidentified RIF-resistant isolates had concomitant MTBDRplus-detected INH resistance. Xpert had a sensitivity of 100.0% (95% CI; 92.1-100.0) for detecting RIFresistance but a positive predictive value of only 61.6% (95% CI; 49.5-72.8) for MDR-TB. The most frequent mutations associated with RIF and INH resistance were S531L and S315T1, respectively.

Conclusions: In this high-risk MDR-TB study population, Xpert had low positive predictive value for the presence of MDR-TB. Comprehensive resistance testing for both INH and RIF should be performed in this setting.
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http://dx.doi.org/10.1093/cid/ciaa873DOI Listing
June 2020

Probability of mycobactericidal activity of para-aminosalicylic acid with novel dosing regimens.

Eur J Clin Pharmacol 2020 Nov 25;76(11):1557-1565. Epub 2020 Jun 25.

Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.

Purpose: Para-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 those reached with older PAS salt formulations and do not generate bactericidal activity. Understanding the PASER dose-exposure-response relationship is crucial for dose optimization. The objective of our study was to establish a representative population pharmacokinetics model for PASER and evaluate the probability of bactericidal and bacteriostatic target attainment with different dosing regimens.

Methods: To this end, we validated and optimized a previously published population pharmacokinetic model on an extended dataset. The probability of target attainment was evaluated for once-daily doses of 12 g, 14 g, 16 g and 20 g PASER.

Results: The final optimized model included the addition of variability in bioavailability and allometric scaling with body weight on disposition parameters. Peak PAS concentrations over minimum inhibitory concentration of 100, which is required for bactericidal activity are achieved in 53%, 65%, 72% and 84% of patients administered 12, 14, 16 and 20 g once-daily PASER, respectively, when MIC is 1 mg/L. For the typical individual, the exposure remained above 1 mg/L for ≥ 98% of the dosing interval in all the evaluated PASER regimens.

Conclusion: The pharmacokinetic/pharmacodynamic parameters linked to bactericidal activity should be determined for 14 g, 16 g and 20 g once-daily doses of PASER.
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http://dx.doi.org/10.1007/s00228-020-02943-8DOI Listing
November 2020

The pharmacokinetics of para-aminosalicylic acid and its relationship to efficacy and intolerance.

Br J Clin Pharmacol 2020 11 21;86(11):2123-2132. Epub 2020 Jun 21.

Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Following its introduction as an antituberculosis agent close to 75 years ago, the use of para-aminosalicylic acid (PAS) has been limited by gastrointestinal 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 is now in wide-spread use for the treatment of drug-resistant tuberculosis. The current PASER dosing regimen is based on recommendations derived from older studies using a variety of different PAS formulations and relegate PAS to a role as an exclusively bacteriostatic agent. However, there is ample evidence that if sufficiently high serum concentrations are reached, PAS can be bactericidal and that intolerance following once daily dosing, that aids the achievement of such concentrations, is no worse than that following intermittent daily dosing. In particular, prevention of resistance to companion drugs appears to be dependent on the size of the single dose, and hence the peak concentrations, and not on maintaining serum levels consistently above minimum inhibitory concentration. We present a narrative review of the development of PAS formulations, dosing practices, and published data regarding pharmacokinetics and pharmacodynamics and the relationship of PAS dosage to intolerance and efficacy. Our conclusions suggests that we are at present not using PAS to its maximum ability to contribute to regimen efficacy and protect companion drugs.
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http://dx.doi.org/10.1111/bcp.14395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576629PMC
November 2020

Treatment of Highly Drug-Resistant Pulmonary Tuberculosis.

N Engl J Med 2020 03;382(10):893-902

From the Clinical HIV Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg (F.C., N.N., P.H.), Sizwe Tropical Disease Hospital, Sandringham (F.C., P.H.), Task Applied Science and Stellenbosch University, Cape Town (A.H.D.), King DiniZulu Hospital Complex, Durban (N.N.), and the TB Alliance, Pretoria (C.V.N., M.O.) - all in South Africa; the TB Alliance, New York (D.E., C.M.M., E.E., J.M., J.T., M.L., M.S.); and the MRC Clinical Trials Unit at UCL (A.M.C., G.H.W.) and the UCL Centre for Clinical Microbiology (T.D.M., A.B., R.H.), University College London, London.

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 have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated.

Results: A total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid.

Conclusions: The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.).
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http://dx.doi.org/10.1056/NEJMoa1901814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955640PMC
March 2020

Drug Effect of Clofazimine on Persisters Explains an Unexpected Increase in Bacterial Load in Patients.

Antimicrob Agents Chemother 2020 04 21;64(5). Epub 2020 Apr 21.

Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden

Antituberculosis (anti-TB) drug development is dependent on informative trials to secure the development of new antibiotics and combination regimens. Clofazimine (CLO) and pyrazinamide (PZA) are important components of recommended standard multidrug treatments of TB. Paradoxically, in a phase IIa trial aiming to define the early bactericidal activity (EBA) of CLO and PZA monotherapy over the first 14 days of treatment, no significant drug effect was demonstrated for the two drugs using traditional statistical analysis. Using a model-based analysis, we characterized the statistically significant exposure-response relationships for both drugs that could explain the original findings of an increase in the numbers of CFU with CLO treatment and no effect with PZA. Sensitive analyses are crucial for exploring drug effects in early clinical trials to make the right decisions for advancement to further development. We propose that this quantitative semimechanistic approach provides a rational framework for analyzing phase IIa EBA studies and can accelerate anti-TB drug development.
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http://dx.doi.org/10.1128/AAC.01905-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179644PMC
April 2020

Xpert MTB/RIF Ultra and Xpert MTB/RIF for diagnosis of tuberculosis in an HIV-endemic setting with a high burden of previous tuberculosis: a two-cohort diagnostic accuracy study.

Lancet Respir Med 2020 04 14;8(4):368-382. Epub 2020 Feb 14.

NRF-DST Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa. Electronic address:

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 sputum samples from patients in South Africa to evaluate the accuracy of Ultra and Xpert against a single culture reference standard. For the first cohort (cohort A), we recruited adults (aged ≥18 years) with symptoms of presumptive tuberculosis at Scottsdene clinic in Cape Town, South Africa. We collected three sputum samples from each patient in cohort A, two at the first visit of which one was tested using Xpert and the other was tested using culture, and one sample the next morning which was tested using Ultra. In a separate cohort of patients with presumptive tuberculosis and recent previous tuberculosis (≤2 years) who had submitted sputum samples to the National Health Laboratory Services (cohort B), decontaminated sediments were, after processing, randomly allocated (1:1) for testing with Ultra or Xpert. For both cohorts we calculated the sensitivity and specificity of Ultra and Xpert and evaluated the effects of different methods of interpreting Ultra trace results.

Findings: Between Feb 6, 2016, and Feb 2, 2018, we recruited 302 people into cohort A, all of whom provided sputum samples and 239 were included in the head-to-head analyses of Ultra and Xpert. For cohort B, we collected sputum samples from eligible patients who had submitted samples between Dec 6, 2016, and Dec 21, 2017, to give a cohort of 831 samples, of which 352 were eligible for inclusion in analyses and randomly assigned to Ultra (n=173) or Xpert (n=179). In cohort A, Ultra gave more non-actionable results (not positive or negative) than did Xpert (28 [10%] 275 vs 14 [5%] 301; p=0·011). In the head-to-head analysis, in smear-negative patients, sensitivity of Ultra was 80% (95% CI 64-90) and of Xpert was 73% (57-85; p=0·45). Overall, specificity of Ultra was lower than that of Xpert (90% [84-94] vs 99% [95-100]; p=0·001). In cohort B, overall sensitivity was 92% (81-98) for Xpert versus 86% (73-95; p=0·36) for Ultra and overall specificity was 69% (60-77) for Ultra versus 84% (78-91; p=0·005) for Xpert. Ultra specificity estimates improved after reclassification of results with the lowest Ultra-positive semiquantitation category (trace) to negative (15% [8-22]). In cohort A, the positive predictive value (PPV) for Ultra was 78% (67-87) and for Xpert was 96% (87-99; p=0·004); in cohort B, the PPV for Ultra was 50% (43-57) and for Xpert was 70% (61-78; p=0·014). Ultra PPV estimates in previously treated patients were low: at 15% tuberculosis prevalence, half of Ultra-positive patients with presumptive tuberculosis would be culture negative, increasing to approximately 70% in patients with recent previous tuberculosis. In cohort B, 21 (28%) of 76 samples that were Ultra positive were rifampicin indeterminate (all trace) and, like cohort A, most were culture negative (19 [90%] of 21).

Interpretation: In a setting with a high burden of previous tuberculosis, Ultra generated more non-actionable results and had diminished specificity compared with Xpert. In patients with recent previous tuberculosis, a quarter of Ultra-positive samples were indeterminate for rifampicin resistance and culture negative, suggesting that additional drug-resistance testing will probably be unsuccessful. Our data have implications for the handling of Ultra-positive results in patients with previous tuberculosis in high burden settings.

Funding: South African Medical Research Council, the EDCTP2 program, and the Faculty of Medicine and Health Sciences, Stellenbosch University.
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http://dx.doi.org/10.1016/S2213-2600(19)30370-4DOI Listing
April 2020

Fourteen-Day Bactericidal Activity, Safety, and Pharmacokinetics of Linezolid in Adults with Drug-Sensitive Pulmonary Tuberculosis.

Antimicrob Agents Chemother 2020 03 24;64(4). Epub 2020 Mar 24.

TB Alliance, New York, New York, USA.

Linezolid is increasingly used for the treatment of tuberculosis resistant to first-line agents, but the most effective dosing strategy is yet unknown. From November 2014 to November 2016, we randomized 114 drug-sensitive treatment-naive pulmonary tuberculosis patients from Cape Town, South Africa, to one of six 14-day treatment arms containing linezolid at 300 mg once daily (QD), 300 mg twice daily (BD), 600 mg QD, 600 mg BD, 1,200 mg QD, 1,200 mg three times per week (TIW), or a combination of isoniazid, rifampin, pyrazinamide, and ethambutol. Sixteen-hour sputum samples were collected overnight, and bactericidal activity was characterized by the daily percentage change in time to positivity (TTP) and the daily rate of change in log(CFU). We also assessed the safety and pharmacokinetics of the study treatments. We found that bactericidal activity increased with increasing doses of linezolid. Based on the daily percentage change in TTP, activity was highest for 1,200 mg QD (4.5%; 95% Bayesian confidence interval [BCI], 3.3 to 5.6), followed by 600 mg BD (4.1%; BCI, 2.5 to 5.7), 600 mg QD (4.1%; BCI, 2.9 to 5.3), 300 mg BD (3.3%; BCI, 1.9 to 4.7), 300 mg QD (2.3%; BCI, 1.1 to 3.5), and 1,200 mg TIW (2.2%; BCI, 1.1 to 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 MIC. There were no unexpected adverse events. 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 1,200 mg given three times weekly, showed the least activity. (This study has been registered at ClinicalTrials.gov under identifier NCT02279875.).
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http://dx.doi.org/10.1128/AAC.02012-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179319PMC
March 2020

A Comparative Study of Features for Acoustic Cough Detection Using Deep Architectures

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:2601-2605

Automatic cough detection is key to tracking the condition of patients suffering from tuberculosis. We evaluate various acoustic features for performing cough detection using deep architectures. As most previous studies have adopted features designed for speech recognition, we assess the suitability of these techniques as well as their respective extraction parameters. Short-time Fourier transform (STFT), mel-frequency cepstral coefficients (MFCC) and mel-scaled filter banks (MFB) were evaluated using deep neural networks, convolutional neural networks and long-short term models. We find experimentally that, by regarding each cough sound as a single input feature instead of multiple shorter features, better performance can be achieved. Longer analysis windows also provide enhancement in contrast to the classic 25 ms frame. Although MFCC performance is improved by sinusoidal liftering, STFT and MFB lead to better results. Using MFB and the optimum segment and frame lengths, an improvement exceeding 7% in the area under the receiver operating characteristic curve across all classifiers is achieved.
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http://dx.doi.org/10.1109/EMBC.2019.8856412DOI Listing
July 2019

Early Bactericidal Activity of Different Isoniazid Doses for Drug Resistant TB (INHindsight): A Randomized Open-label Clinical Trial.

Am J Respir Crit Care Med 2020 Jan 16. Epub 2020 Jan 16.

University of Stellenbosch, Internal Medicine, Tygerberg, South Africa.

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 mutations.

Methods: AIDS Clinical Trials Group A5312 is a Phase 2A, open-label trial in which individuals with smear-positive pulmonary TB with isoniazid resistance mediated by an inhA mutation were randomized to receive isoniazid 5, 10 or 15 mg/kg daily for 7 days (inhA group), and controls with drug-sensitive TB received standard dose (5 mg/kg/day). Overnight sputum cultures were collected daily. The 7-day early bactericidal activity of isoniazid was estimated as the average daily change in log10 colony forming units on solid media (EBACFU0-7) or as time to positivity in liquid media in hours (EBATTP0-7) using nonlinear mixed effects models.

Measurements And Main Results: Fifty-nine participants, 88% with cavitary disease, 20% HIV-positive, 16 with isoniazid-sensitive and 41 with isoniazid mono-resistant or MDR TB, were enrolled at one site in South Africa. Mean EBACFU0-7 at doses of 5, 10 and 15 mg/kg in the inhA group was 0.07, 0.17 and 0.22 log10CFU/mL/day, respectively, and 0.16 log10CFU/mL/day in controls. EBATTP0-7 patterns were similar. There were no drug-related Grade >3 adverse events.

Conclusions: Isoniazid 10-15 mg/kg daily had similar activity against TB strains with inhA mutations as 5 mg/kg against drug-sensitive strains. The activity of high-dose isoniazid against strains with katG mutations will be explored next. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT01936831.
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http://dx.doi.org/10.1164/rccm.201910-1960OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7258626PMC
January 2020

Bedaquiline, moxifloxacin, pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b trial.

Lancet Respir Med 2019 12 12;7(12):1048-1058. Epub 2019 Nov 12.

Global Alliance for TB Drug Development, New York, NY, USA.

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 the first 8 weeks of treatment of pulmonary tuberculosis.

Methods: In this multicentre, open-label, partially randomised, phase 2b trial, we prospectively recruited patients with drug-susceptible or rifampicin-resistant pulmonary tuberculosis from seven sites in South Africa, two in Tanzania, and one in Uganda. Patients aged 18 years or older with sputum smear grade 1+ or higher were eligible for enrolment, and a molecular assay (GeneXpert or MTBDRplus) was used to confirm the diagnosis of tuberculosis and to distinguish between drug-susceptible and rifampicin-resistant tuberculosis. Patients who were HIV positive with a baseline CD4 cell count of less than 100 cells per uL were excluded. Patients with drug-susceptible tuberculosis were randomly assigned (1:1:1) using numbered treatment packs with sequential allocation by the pharmacist to receive 56 days of treatment with standard tuberculosis therapy (oral isoniazid, rifampicin, pyrazinamide, and ethambutol; HRZE), or pretomanid (oral 200 mg daily) and pyrazinamide (oral 1500 mg daily) with either oral bedaquiline 400 mg daily on days 1-14 then 200 mg three times per week (BPaZ) or oral bedaquiline 200 mg daily (BPaZ). Patients with rifampicin-resistant tuberculosis received 56 days of the BPaZ regimen plus moxifloxacin 400 mg daily (BPaMZ). All treatment groups were open label, and randomisation was not stratified. Patients, trial investigators and staff, pharmacists or dispensers, laboratory staff (with the exception of the mycobacteriology laboratory staff), sponsor staff, and applicable contract research organisations were not masked. The primary efficacy outcome was daily percentage change in time to sputum culture positivity (TTP) in liquid medium over days 0-56 in the drug-susceptible tuberculosis population, based on non-linear mixed-effects regression modelling of log (TTP) over time. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov, NCT02193776, and all patients have completed follow-up.

Findings: Between Oct 24, 2014, and Dec 15, 2015, we enrolled 180 patients with drug-susceptible tuberculosis (59 were randomly assigned to BPaZ, 60 to BPaZ, and 61 to HRZE) and 60 patients with rifampicin-resistant tuberculosis. 57 patients in the BPaZ group, 56 in the BPaZ group, and 59 in the HRZE group were included in the primary analysis. BPaZ produced the highest daily percentage change in TTP (5·17% [95% Bayesian credibility interval 4·61-5·77]), followed by BPaZ (4·87% [4·31-5·47]) and HRZE group (4·04% [3·67-4·42]). The bactericidal activity in BPaZ and BPaZ groups versus that in the HRZE group was significantly different. Higher proportions of patients in the BPaZ (six [10%] of 59) and BPaZ (five [8%] of 60) groups discontinued the study drug than in the HRZE group (two [3%] of 61) because of adverse events. Liver enzyme elevations were the most common grade 3 or 4 adverse events and resulted in the withdrawal of ten patients (five [8%] in the BPaZ group, three [5%] in the BPaZ group, and two [3%] in the HRZE group). Serious treatment-related adverse events affected two (3%) patients in the BPaZ group and one (2%) patient in the HRZE group. Seven (4%) patients with drug-susceptible tuberculosis died and four (7%) patients with rifampicin-resistant tuberculosis died. None of the deaths were considered to be related to treatment.

Interpretation: BPaZ is a promising regimen to treat patients with drug-susceptible tuberculosis. The bactericidal activity of both these regimens suggests that they have the potential to shorten treatment, and the simplified dosing schedule of BPaZ could improve treatment adherence in the field. However, these findings must be investigated further in a phase 3 trial assessing treatment outcomes.

Funding: TB Alliance, UK Department for International Development, Bill & Melinda Gates Foundation, US Agency for International Development, Directorate General for International Cooperation of the Netherlands, Irish Aid, Australia Department of Foreign Affairs and Trade, and the Federal Ministry for Education and Research of Germany.
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http://dx.doi.org/10.1016/S2213-2600(19)30366-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641992PMC
December 2019

Pharmacokinetics of Para-Aminosalicylic Acid and Its 2 Major Metabolites: A Potential Relationship to the Development of Gastrointestinal Intolerance.

J Clin Pharmacol 2020 04 4;60(4):489-494. Epub 2019 Nov 4.

Division of Clinical Pharmacology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.

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 enteric coated formulation, and its metabolites acetyl-PAS and glycine-PAS, and intolerance. PAS and its metabolites were measured in 29 adult patients with drug-resistant tuberculosis at Brooklyn Hospital, Cape Town, randomized to receive granular slow-release enteric-coated PAS 4 g twice daily or 8 g once daily for 1 week, followed by the alternative regimen. Concentrations of PAS and its metabolites were determined by liquid chromatography and tandem mass spectrometry, and a visual analogue scale evaluated intolerance. Spearman's correlation test assessed the relationship between maximum plasma concentrations (C ) and intolerance scores. A large interindividual variability was observed for the PAS C (40.42-68.55 mg/L) following 4 g twice daily; (62.69-102.41 mg/L) for 8 g once daily and a similar wide C range found for the metabolites acetyl-PAS and glycine-PAS. Twenty-six patients reported at least 1 intolerance episode, but most visual analogue scale scores clustered around 0. Significant inverse associations were found between acetyl-PAS C and bloating (rho = -0.448; P = .025) and diarrhea (rho = -0.407; P = .044) for the twice-daily regimen and a similar inverse association found for glycine-PAS and diarrhea (rho = -0.412; P = .041). Plasma concentrations of the metabolites did not correlate with the occurrence of gastrointestinal symptoms, but higher metabolite concentrations correlated with lower intolerance scores; slow metabolism of PAS and its continued presence in the intestinal tract may be the main cause of intolerance.
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http://dx.doi.org/10.1002/jcph.1542DOI Listing
April 2020

Tuberculous pleural effusion.

Respirology 2019 10 16;24(10):962-971. Epub 2019 Aug 16.

Division of Pulmonology, Department of Medicine, Tygerberg Academic Hospital and Stellenbosch University, Cape Town, South Africa.

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 effusive hypersensitivity reaction, compartmentalized within the pleural space. Diagnostic thoracentesis with thorough pleural fluid analysis including biomarkers such as adenosine deaminase and gamma interferon achieves high accuracy in the correct clinical context. Definitive diagnosis may require invasive procedures to demonstrate histological evidence of caseating granulomas or microbiological evidence of the organism on smear or culture. Drug resistance is an emerging problem that requires vigilance and extra effort to acquire a complete drug sensitivity profile for each tuberculous effusion treated. Nucleic acid amplification tests such as Xpert MTB/RIF can be invaluable in this instance; however, the yield is low in pleural fluid. Treatment consists of standard anti-tuberculous therapy or a guideline-based individualized regimen in the case of drug resistance. There is low-quality evidence that suggests possible benefit from corticosteroids; however, they are not currently recommended due to concomitant increased risk of adverse effects. Small studies report some short- and long-term benefit from interventions such as therapeutic thoracentesis, intrapleural fibrinolytics and surgery but many questions remain to be answered.
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http://dx.doi.org/10.1111/resp.13673DOI Listing
October 2019

Toxicity related to standard TB therapy for pulmonary tuberculosis and treatment outcomes in the REMoxTB study according to HIV status.

BMC Pulm Med 2019 Aug 14;19(1):152. Epub 2019 Aug 14.

University of St Andrews Medical School, St Andrews, UK.

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 were matched to 220 HIV-negative controls by age, gender, ethnicity, and trial site using coarsened exact matching. Grade 3 and 4 adverse events (AEs) were summarised by MedDRA System Organ Class. Kaplan-Meier curves for time to first grade 3 or 4 AE were constructed according to HIV status with hazard ratios calculated. Patients were considered cured if they were culture negative 18 months after commencing therapy with ≥2 consecutive negative culture results.

Results: Twenty of 42 (47.6%) HIV-positive and 34 of 220 (15.5%) HIV-negative patients experienced ≥1 grade 3 or 4 AE, respectively. The majority of these were hepatobiliary disorders that accounted for 12 of 40 (30.0%) events occurring in 6 of 42 (14.3%) HIV-positive patients and for 15 of 60 (25.0%) events occurring in 9 of 220 (4.1%) HIV-negative patients. The median time to first grade 3 or 4 AE was 54 days (IQR 15.5-59.0) for HIV-positive and 29.5 days (IQR 9.0-119.0) for HIV-negative patients, respectively. The hazard ratio for experiencing a grade 3 or 4 AE among HIV-positive patients was 3.25 (95% CI 1.87-5.66, p < 0.01). Cure rates were similar, with 38 of 42 (90.5%) HIV-positive and 195 of 220 (88.6%) HIV-negative patients (p = 0.73) cured at 18 months.

Conclusions: HIV-positive patients receiving standard TB therapy in the REMoxTB study were at greater risk of adverse events during treatment but cure rates were similar when compared to a matched sample of HIV-negative patients.
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http://dx.doi.org/10.1186/s12890-019-0907-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694514PMC
August 2019

The evaluation of anti-tuberculosis drug effects on phenotypes of Mycobacterium tuberculosis not detected by culture methods.

Tuberculosis (Edinb) 2019 05 5;116:32-34. Epub 2019 Apr 5.

Task Applied Science, Bellville, Cape Town, South Africa; Division of Medical Physiology, MRC Centre for Tuberculosis Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa. Electronic address:

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http://dx.doi.org/10.1016/j.tube.2019.04.001DOI Listing
May 2019

Liquid mycobacterial culture outcomes after different sputum collection techniques before and during treatment.

Tuberculosis (Edinb) 2019 05 28;116:17-21. Epub 2019 Mar 28.

TASK Applied Science, 1 Smal Street, Bellville, 7530, South Africa; Division of Medical Physiology, MRC Centre for Tuberculosis Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa. Electronic address:

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 treatment initiation. The first sputum was collected at home and brought to the clinic, where a second and third sputum were consecutively collected under supervision following mouthwash with bottled water and chlorhexidine solution respectively. All sputa were processed for liquid culture in duplicate.

Results: Out of 556 cultures 430 (77.3%), 91 (16.4%) and 35 (6.3%) were positive, negative or contaminated, respectively. The odds of contamination were higher with home collection and with water rinse than with chlorhexidine rinse (OR: 12.5, p < 0.001 and OR: 6.7, p = 0.015). Chlorhexidine rinse increased the odds of a negative culture compared to water rinse (OR: 3.5, p = 0.002). The odds of a positive culture were greater with water rinse than with home collection (OR: 2.5, p = 0.005). Water rinse significantly reduced time to culture positivity.

Conclusion: Compared to sputum collected at home, chlorhexidine rinse reduces culture contamination and water rinse increases the rate and viable mycobacterial load of positive cultures.
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http://dx.doi.org/10.1016/j.tube.2019.03.008DOI Listing
May 2019

Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human Tuberculosis.

Clin Pharmacokinet 2019 09;58(9):1103-1129

Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town, 8000, South Africa.

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, more toxic, and expensive regimens. Because of cost and fears of toxicity, rifampicin was introduced at an oral daily dose of 600 mg (8-12 mg/kg body weight). At this dose, clinical trials in 1970s found cure rates of ≥ 95% and relapse rates of < 5%. However, recent papers report lower cure rates that might be the consequence of increased emergence of resistance. Several lines of evidence suggest that higher rifampicin doses, if tolerated and safe, could shorten treatment duration even further. We conducted a narrative review of rifampicin pharmacokinetics and pharmacodynamics in adults across a range of doses and highlight variables that influence its pharmacokinetics/pharmacodynamics. Rifampicin exposure has considerable inter- and intra-individual variability that could be reduced by administration during fasting. Several factors including malnutrition, HIV infection, diabetes mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and substandard medicinal products alter rifampicin exposure and/or efficacy. Renal impairment has no influence on rifampicin pharmacokinetics when dosed at 600 mg. Rifampicin maximum (peak) concentration (C) > 8.2 μg/mL is an independent predictor of sterilizing activity and therapeutic drug monitoring at 2, 4, and 6 h post-dose may aid in optimizing dosing to achieve the recommended rifampicin concentration of ≥ 8 µg/mL. A higher rifampicin C is required for severe forms TB such as TB meningitis, with C ≥ 22 μg/mL and area under the concentration-time curve (AUC) from time zero to 6 h (AUC) ≥ 70 μg·h/mL associated with reduced mortality. More studies are needed to confirm whether doses achieving exposures higher than the current standard dosage could translate into faster sputum conversion, higher cure rates, lower relapse rates, and less mortality. It is encouraging that daily rifampicin doses up to 35 mg/kg were found to be safe and well-tolerated over a period of 12 weeks. High-dose rifampicin should thus be considered in future studies when constructing potentially shorter regimens. The studies should be adequately powered to determine treatment outcomes and should include surrogate markers of efficacy such as C/MIC (minimum inhibitory concentration) and AUC/MIC.
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http://dx.doi.org/10.1007/s40262-019-00764-2DOI Listing
September 2019