The relationship between Mycobacterium tuberculosis MGIT time to positivity and cfu in sputum samples demonstrates changing bacterial phenotypes potentially reflecting the impact of chemotherapy on critical sub-populations

Bowness, Ruth; Boeree, Martin J.; Aarnoutse, Rob E.; Dawson, Rodney; Diacon, Andreas H.; Mangu, Chacha; Heinrich, Norbert; Ntinginya, Nyanda Elias; Kohlenberg, Anke; Mtafya, Bariki; Phillips, Patrick P. J.; Rachow, Andrea; Balen, Georgette Plemper van; Gillespie, Stephen H.

doi:10.1093/jac/dku415

Cited by 64 publications

(71 citation statements)

References 19 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

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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

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307

285

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“…Since the TTD and the inoculum concentration are inversely correlated (Diacon et al, 2010; Bowness et al, 2015), this synergistic activity can be highly beneficial during tuberculosis therapy, either in drug susceptible or drug-resistant strains, allowing the antibiotic, combined with the host's immune system, to tackle in the most effective way the infecting strain. This method allowed the monitoring, on a real-time basis, of bacterial growth/survival vs. growth inhibition by the comparison between the TTD of growth of a given strain in the presence and absence of an efflux inhibitor.…”

Section: Discussionmentioning

confidence: 99%

“…The antibiotic resistance levels were quantified as follows: isoniazid low-level resistance when resistant (R) at 0.1 and susceptible (S) at 1 μg/ml; isoniazid high-level resistance when R ≥ 1 μg/ml; rifampicin and amikacin low-level resistance when R at 4 and S at 20 μg/ml; rifampicin and amikacin high-level resistance when R ≥ 20 μg/ml; capreomycin low-level resistance when R at 5 and S at 25 μg/ml; capreomycin high-level resistance when R ≥ 25 μg/ml; ofloxacin low-level resistance when R at 1 and S at 2 μg/ml; ofloxacin high-level resistance when R ≥ 2 μg/ml (Cambau et al, 2015). The evaluation of bacterial growth/survival vs. growth inhibition was done by the comparison between the TTD, defined as the time from the start of incubation to the positivity signal of growth (Diacon et al, 2014; Bowness et al, 2015), of a given strain in the presence and absence of an inhibitor (ΔTTD). To obtain the degree of potentiation of each compound on the antibiotic activity, the ΔTTD was normalized against the control tube with no inhibitor.…”

Section: Methodsmentioning

confidence: 99%

Interplay between Mutations and Efflux in Drug Resistant Clinical Isolates of Mycobacterium tuberculosis

et al. 2017

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Numerous studies show efflux as a universal bacterial mechanism contributing to antibiotic resistance and also that the activity of the antibiotics subject to efflux can be enhanced by the combined use of efflux inhibitors. Nevertheless, the contribution of efflux to the overall drug resistance levels of clinical isolates of Mycobacterium tuberculosis is poorly understood and still is ignored by many. Here, we evaluated the contribution of drug efflux plus target-gene mutations to the drug resistance levels in clinical isolates of M. tuberculosis. A panel of 17 M. tuberculosis clinical strains were characterized for drug resistance associated mutations and antibiotic profiles in the presence and absence of efflux inhibitors. The correlation between the effect of the efflux inhibitors and the resistance levels was assessed by quantitative drug susceptibility testing. The bacterial growth/survival vs. growth inhibition was analyzed through the comparison between the time of growth in the presence and absence of an inhibitor. For the same mutation conferring antibiotic resistance, different MICs were observed and the different resistance levels found could be reduced by efflux inhibitors. Although susceptibility was not restored, the results demonstrate the existence of a broad-spectrum synergistic interaction between antibiotics and efflux inhibitors. The existence of efflux activity was confirmed by real-time fluorometry. Moreover, the efflux pump genes mmr, mmpL7, Rv1258c, p55, and efpA were shown to be overexpressed in the presence of antibiotics, demonstrating the contribution of these efflux pumps to the overall resistance phenotype of the M. tuberculosis clinical isolates studied, independently of the genotype of the strains. These results showed that the drug resistance levels of multi- and extensively-drug resistant M. tuberculosis clinical strains are a combination between drug efflux and the presence of target-gene mutations, a reality that is often disregarded by the tuberculosis specialists in favor of the almost undisputed importance of antibiotic target-gene mutations for the resistance in M. tuberculosis.

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“…There may be loss of viable CFUs cultured if sputum is decontaminated with sodium hydroxide treatment. There is some evidence to suggest type of culture media and growth factors/inhibitors [13] influence growth of different populations of MTB during chemotherapy [14]. …”

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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The relationship between Mycobacterium tuberculosis MGIT time to positivity and cfu in sputum samples demonstrates changing bacterial phenotypes potentially reflecting the impact of chemotherapy on critical sub-populations

Cited by 64 publications

References 19 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

Interplay between Mutations and Efflux in Drug Resistant Clinical Isolates of Mycobacterium tuberculosis

Assessment of treatment response in tuberculosis

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