Simultaneous staining of sputum smears for acid-fast and lipid-containing Myobacterium tuberculosis can enhance the clinical evaluation of antituberculosis treatments

Kayigire, Xavier A.; Friedrich, Sven O.; Merwe, Lize van der; Donald, Peter R.; Diacon, Andreas H.

doi:10.1016/j.tube.2015.08.001

Cited by 24 publications

(28 citation statements)

References 42 publications

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“…Incomplete killing of such bacilli is one of the proposed reasons for relapse after treatment completion 25 as is poor penetration to the site of infection 26 . Higher doses of rifampicin seem to more effectively kill this subpopulation in experimental models4, 24 and in human beings 27, 28. Since liquid media, unlike solid media, detect such bacilli, 29 we believe that the higher efficacy of RIF 35 HZE seen in liquid media represents increased activity of this regimen on this bacterial phenotype.…”

Section: Discussionmentioning

confidence: 99%

High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial

Boeree

Heinrich

Aarnoutse

et al. 2017

The Lancet Infectious Diseases

321

285

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SummaryBackgroundTuberculosis is the world's leading infectious disease killer. We aimed to identify shorter, safer drug regimens for the treatment of tuberculosis.MethodsWe did a randomised controlled, open-label trial with a multi-arm, multi-stage design. The trial was done in seven sites in South Africa and Tanzania, including hospitals, health centres, and clinical trial centres. Patients with newly diagnosed, rifampicin-sensitive, previously untreated pulmonary tuberculosis were randomly assigned in a 1:1:1:1:2 ratio to receive (all orally) either 35 mg/kg rifampicin per day with 15–20 mg/kg ethambutol, 20 mg/kg rifampicin per day with 400 mg moxifloxacin, 20 mg/kg rifampicin per day with 300 mg SQ109, 10 mg/kg rifampicin per day with 300 mg SQ109, or a daily standard control regimen (10 mg/kg rifampicin, 5 mg/kg isoniazid, 25 mg/kg pyrazinamide, and 15–20 mg/kg ethambutol). Experimental treatments were given with oral 5 mg/kg isoniazid and 25 mg/kg pyrazinamide per day for 12 weeks, followed by 14 weeks of 5 mg/kg isoniazid and 10 mg/kg rifampicin per day. Because of the orange discoloration of body fluids with higher doses of rifampicin it was not possible to mask patients and clinicians to treatment allocation. The primary endpoint was time to culture conversion in liquid media within 12 weeks. Patients without evidence of rifampicin resistance on phenotypic test who took at least one dose of study treatment and had one positive culture on liquid or solid media before or within the first 2 weeks of treatment were included in the primary analysis (modified intention to treat). Time-to-event data were analysed using a Cox proportional-hazards regression model and adjusted for minimisation variables. The proportional hazard assumption was tested using Schoelfeld residuals, with threshold p<0·05 for non-proportionality. The trial is registered with ClinicalTrials.gov (NCT01785186).FindingsBetween May 7, 2013, and March 25, 2014, we enrolled and randomly assigned 365 patients to different treatment arms (63 to rifampicin 35 mg/kg, isoniazid, pyrazinamide, and ethambutol; 59 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, SQ109; 57 to rifampicin 20 mg/kg, isoniazid, pyrazinamide, and SQ109; 63 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, and moxifloxacin; and 123 to the control arm). Recruitment was stopped early in the arms containing SQ109 since prespecified efficacy thresholds were not met at the planned interim analysis. Time to stable culture conversion in liquid media was faster in the 35 mg/kg rifampicin group than in the control group (median 48 days vs 62 days, adjusted hazard ratio 1·78; 95% CI 1·22–2·58, p=0·003), but not in other experimental arms. There was no difference in any of the groups in time to culture conversion on solid media. 11 patients had treatment failure or recurrent disease during post-treatment follow-up: one in the 35 mg/kg rifampicin arm and none in the moxifloxacin arm. 45 (12%) of 365 patients reported grade 3–5 adverse events, with similar proportions in each arm.Interpr...

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Section: Discussionmentioning

confidence: 99%

High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial

Boeree

Heinrich

Aarnoutse

et al. 2017

The Lancet Infectious Diseases

321

285

View full text Add to dashboard Cite

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“…These lipid bodies can be detected in sputum via staining with auramine-labelled Nile-Red stain both pre- and during treatment. Change in detectable lipid bodies during the first 2 weeks of treatment, is hypothesized to reflect an increase in viable but non-culturable persisters, and significantly varies with different drugs [39]. In a preliminary study, Sloan et al showed that at week 3-4 of treatment, there was 21% increased odds of unfavourable outcome (failure/relapse) for each percentage rise in % lipid body positive acid-fast bacilli (AFB).…”

Section: Pathogen Based Models and Biomarkersmentioning

confidence: 99%

Assessment of treatment response in tuberculosis

Rockwood

Bruyn

Morris

et al. 2016

Expert Review of Respiratory Medicine

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Antibiotic treatment of tuberculosis has a duration of several months. There is significant variability of the host immune response and the pharmacokineticpharmacodynamic properties of Mycobacterium tuberculosis sub-populations at the site of disease. A limitation of sputum-based measures of treatment response may be sub-optimal detection and monitoring of Mycobacterium tuberculosis sub-populations. Potential biomarkers and surrogate endpoints should be benchmarked against hard clinical outcomes (failure/relapse/death) and may need tailoring to specific patient populations. Here, we assess the evidence supporting currently utilized and future potential host and pathogen-based models and biomarkers for monitoring treatment response in active and latent tuberculosis. Biomarkers for monitoring treatment response in extrapulmonary, pediatric and drug resistant tuberculosis are research priorities.

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“…In line with that, TB treatment enriched the lipid droplet-positive population in the sputum of patients [323]. When we tested if antibiotic treatment enriched the acid-fast or lipid droplet-positive bacterial phenotype inside macrophages, we did not observe any changes (data not shown).…”

Section: Intracellular Mtb Phenotype Intracellular Mtb Phenotype Intrsupporting

confidence: 74%

“…Furthermore, time to positivity of sputum samples correlated with the proportion of lipid droplet-positive bacteria [319], indicating that this subpopulation requires more time to resume growth upon inoculation into broth. Combination of acid-fast and lipid staining has been suggested to enhance the clinical evaluation of TB treatment, since treatment increases the proportion of lipid dropletcontaining cells and reduced the acid-fast population [323]. This enrichment of 'fat and lazy' bacilli is in agreement with the concept of mainly growing bacilli being targeted by TB antibiotics.…”

Section: Mtb Mtb Mtbmentioning

confidence: 64%

Interplay of human macrophages and Mycobacterium tuberculosis phenotypes

Raffetseder¹

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Simultaneous staining of sputum smears for acid-fast and lipid-containing Myobacterium tuberculosis can enhance the clinical evaluation of antituberculosis treatments

Cited by 24 publications

References 42 publications

High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial

High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial

Assessment of treatment response in tuberculosis

Interplay of human macrophages and Mycobacterium tuberculosis phenotypes

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