Phenotypic resistance in mycobacteria: is it because I am old or fat that I resist you?

Hammond, Robert; Baron, Vincent O.; Oravcova, Katarina; Lipworth, Samuel; Gillespie, Stephen H.

doi:10.1093/jac/dkv178

Cited by 44 publications

(60 citation statements)

References 20 publications

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“…These can often be characterised by the presence of lipid bodies within the bacteria [55]. The importance of lipid-positive bacteria has been emphasised by a recently published in vitro study demonstrating that lipid-body-positive cells can be found in all mycobacterial cultures tested and when purified lipid-rich cells are tested they are phenotypically resistant to antibiotics irrespective of whether they are derived from "old" or "young" cultures, indicating that the presence of a lipid body is associated with phenotypic antibiotic resistance [56]. Lipid-body-positive cells are known to be more resistant to drugs and the concentration of drug required to clear all bacteria (the minimum bactericidal concentration) increases significantly [56].…”

Section: Observations On the Outcome Of Phase III Treatment-shorteninmentioning

confidence: 99%

“…The importance of lipid-positive bacteria has been emphasised by a recently published in vitro study demonstrating that lipid-body-positive cells can be found in all mycobacterial cultures tested and when purified lipid-rich cells are tested they are phenotypically resistant to antibiotics irrespective of whether they are derived from "old" or "young" cultures, indicating that the presence of a lipid body is associated with phenotypic antibiotic resistance [56]. Lipid-body-positive cells are known to be more resistant to drugs and the concentration of drug required to clear all bacteria (the minimum bactericidal concentration) increases significantly [56]. In sequential sputum samples obtained from patients on HRZE between day 21 and 28 the change in the odds ratio of an unfavourable outcome for each percentage point rise in percentage lipid-body-positive and the acid fast bacilli count was 1.21 (95% CI 0.97-1.50; p=0.088).…”

Section: Observations On the Outcome Of Phase III Treatment-shorteninmentioning

confidence: 99%

“…Thus, it appears that patients with a greater percentage of lipid-body-positive mycobacterial cells detected in their sputum smear at later time points are more likely to have an unfavourable outcome [57]. Could this be due to phenotypic resistance to the components of anti-TB therapy [56]? This might suggest that we need a different approach to treatment shortening.…”

Section: Observations On the Outcome Of Phase III Treatment-shorteninmentioning

confidence: 99%

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The role of moxifloxacin in tuberculosis therapy

Gillespie

2016

Eur Respir Rev

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Tuberculosis (TB) remains a global threat with more than 9 million new infections. Treatment remains difficult and there has been no change in the duration of the standard regimen since the early 1980s. Moreover, many patients are unable to tolerate this treatment and discontinue therapy, increasing the risk of resistance. There is a growing tide of multidrug resistance and few effective antibiotics to tackle the problem. Since the turn of the millennium there has been a surge in interest in developing new therapies for TB and a number of new drugs have been developed. In this review the repurposing of moxifloxacin, an 8-methoxy-fluoroquinolone, for TB treatment is discussed. The evidence that underpins the development of this agent is reviewed. The results of the recently completed phase III trials are summarised and the reasons for the unexpected outcome are explored. Finally, the design of new trials that incorporate moxifloxacin, and that address both susceptible disease and multidrug resistance, is described. @ERSpublications A review of the role of moxifloxacin in tuberculosis therapy http://ow.ly/WaAyC

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Section: Observations On the Outcome Of Phase III Treatment-shorteninmentioning

confidence: 99%

Section: Observations On the Outcome Of Phase III Treatment-shorteninmentioning

confidence: 99%

Section: Observations On the Outcome Of Phase III Treatment-shorteninmentioning

confidence: 99%

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The role of moxifloxacin in tuberculosis therapy

Gillespie

2016

Eur Respir Rev

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“…Bacteria that are present in or on the tissue surface are 'extracellular'. M. tuberculosis has been shown to exhibit 'dormancy', associated with the accumulation of lipid bodies, whereby it reduces its replication rate but becomes more resistant to antibiotics [20,21]. In order to incorporate this, we allow bacteria to switch between a 'replicating' (B ER ) and a 'dormant' (B ED ) state when extracellular.…”

Section: Environmentmentioning

confidence: 99%

Modelling the effects of environmental heterogeneity within the lung on the tuberculosis life-cycle

Pitcher

Bowness

Dobson

et al. 2019

Preprint

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Progress in shortening the duration of tuberculosis (TB) treatment is hampered by the lack of a predictive model that accurately reflects the diverse environment within the lung. This is important as TB has been shown to produce distinct localisations to different areas of the lung during different disease stages, with the environmental heterogeneity within the lung of factors such as air ventilation, blood perfusion and oxygen tension believed to contribute to the apical localisation witnessed during the post-primary form of the disease.Building upon our previous model of environmental lung heterogeneity, we present a networked metapopulation model that simulates TB across the whole lung, incorporating these notions of environmental heterogeneity across the whole TB lifecycle to show how different stages of the disease are influenced by different environmental and immunological factors. The alveolar tissue in the lung is divided into distinct patches, with each patch representing a portion of the total tissue and containing environmental attributes that reflect the internal conditions at that location. We include populations of bacteria and immune cells in various states, and events are included which determine how the members of the model interact with each other and the environment. By allowing some of these events to be dependent on environmental attributes, we create a set of heterogeneous dynamics, whereby the location of the tissue within the lung determines the disease pathological events that occur there.Our results show that the environmental heterogeneity within the lung is a plausible driving force behind the apical localisation during post-primary disease. After initial infection, bacterial levels will grow in the initial infection location at the base of the lung until an adaptive immune response is initiated. During this period, bacteria are able to disseminate and create new lesions throughout the lung. During the latent stage, the lesions that are situated towards the apex are the largest in size, and once a post-primary immune-suppressing event occurs, it is the uppermost lesions that reach the highest levels of bacterial proliferation. Our sensitivity analysis also shows that it is the differential in blood perfusion, causing reduced immune activity towards the apex, which has the biggest influence of disease outputs.

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“…In vitro and animal models are becoming more sophisticated and have enabled us to generate more insight regarding the immunopathology of the disease and the interaction between various Mycobacterium tuberculosis (Mtb) subpopulations [22]. However, given the major differences in TB susceptibility and histopathology that currently exist between animal models, it is unlikely that a single experimental system will become available that could fully mimic the infection process in humans.…”

Section: Evidence Generation and Synthesis At Candidate Selectionmentioning

confidence: 99%

The implications of model-informed drug discovery and development for tuberculosis

Muliaditan¹,

Davies

Simonsson

et al. 2017

Drug Discovery Today

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Phenotypic resistance in mycobacteria: is it because I am old or fat that I resist you?

Abstract: We have shown that phenotypic antibiotic resistance is associated with the presence of lipid bodies irrespective of cell age. These data have important implications for our understanding of relapse in mycobacterial infections.

Cited by 44 publications

References 20 publications

The role of moxifloxacin in tuberculosis therapy

The role of moxifloxacin in tuberculosis therapy

Modelling the effects of environmental heterogeneity within the lung on the tuberculosis life-cycle

The implications of model-informed drug discovery and development for tuberculosis

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