Mathematical modeling and systems pharmacology of tuberculosis: Isoniazid as a case study

Lalande, Laure; Bourguignon, Laurent; Maire, Pascal; Goutelle, Sylvain

doi:10.1016/j.jtbi.2016.03.038

Cited by 8 publications

(5 citation statements)

References 52 publications

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“…When resistance to antibiotics is driven by point mutations at single positions, natural mutation rates will lead to the repeated presence of naturally occurring, resistant cells. Conservatively, taking values from the more slow-growing and non-recombining M. tuberculosis, a mutation rate of ~8 × 10 -9 mutations per site per month [26] and a typical extracellular population of ~10 9 cells [27] clearly means that, during treatment, a typical within-patient population will repeatedly give rise to cells with the rrl 2058 mutation (for example). Typically, such mutations have fitness costs, so remain at a low frequency, but in the presence of antibiotics, they rapidly achieve dominance.…”

Section: Discussionmentioning

confidence: 99%

Children With Cystic Fibrosis Are Infected With Multiple Subpopulations of Mycobacterium abscessus With Different Antimicrobial Resistance Profiles

Shaw

Doyle

Kavaliūnaitė

et al. 2019

Clinical Infectious Diseases

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BackgroundChildren with cystic fibrosis (CF) can develop life-threatening infections of Mycobacterium abscessus. These present a significant clinical challenge, particularly when the strains involved are resistant to antibiotics. Recent evidence of within-patient subclones of M. abscessus in adults with CF suggests the possibility that within-patient diversity may be relevant for the treatment of pediatric CF patients.MethodsWe performed whole-genome sequencing (WGS) on 32 isolates of M. abscessus that were taken from multiple body sites of 2 patients with CF who were undergoing treatment at Great Ormond Street Hospital, United Kingdom, in 2015.ResultsWe found evidence of extensive diversity within patients over time. A clustering analysis of single nucleotide variants revealed that each patient harbored multiple subpopulations, which were differentially abundant between sputum, lung samples, chest wounds, and pleural fluid. The sputum isolates did not reflect the overall within-patient diversity and did not allow for the detection of subclones with mutations previously associated with macrolide resistance (rrl 2058/2059). Some variants were present at intermediate frequencies before the lung transplants. The time of the transplants coincided with extensive variation, suggesting that this event is particularly disruptive for the microbial community, but the transplants did not clear the M. abscessus infections and both patients died as a result of these infections.ConclusionsIsolates of M. abscessus from sputum do not always reflect the entire diversity present within the patient, which can include subclones with differing antimicrobial resistance profiles. An awareness of this phenotypic variability, with the sampling of multiple body sites in conjunction with WGS, may be necessary to ensure the best treatment for this vulnerable patient group.

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Section: Discussionmentioning

confidence: 99%

Children With Cystic Fibrosis Are Infected With Multiple Subpopulations of Mycobacterium abscessus With Different Antimicrobial Resistance Profiles

Shaw

Doyle

Kavaliūnaitė

et al. 2019

Clinical Infectious Diseases

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“…It may be that the slower INH killing of fast growers leads to a lack of regrowth. INH has also been shown to have an antagonistic effect on the efficacy of PZA in mice (19, 27, 35, 36), providing further support for the removal of INH either entirely or after an appropriate duration of treatment, and it would therefore be interesting to see, using our continuous culture models, whether the removal of INH after 1 to 2 days (with continued exposure to PZA and RIF) reduces the presence of regrowth.…”

Section: Discussionmentioning

confidence: 76%

Regrowth of Mycobacterium tuberculosis Populations Exposed to Antibiotic Combinations Is Due to the Presence of Isoniazid and Not Bacterial Growth Rate

Hendon-Dunn

Pertinez

Marriott

et al. 2019

Antimicrob Agents Chemother

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Modulation of the growth rate in Mycobacterium tuberculosis is key to its survival in the host, particularly with regard to its adaptation during chronic infection, when the growth rate is very slow. The resulting physiological changes influence the way in which this pathogen interacts with the host and responds to antibiotics. Therefore, it is important that we understand how the growth rate impacts antibiotic efficacy, particularly with respect to recovery/relapse.

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“…anti-TB drugs, a PK model was developed to simulate the concentration-time profiles in plasma, epithelial lining fluid (ELF, extracellular concentrations) and alveolar cells (AC, intracellular concentrations). These models have been found to best describe PK data of the respective anti-TB drugs in previous studies (14,(18)(19)(20)(21)(22)(23)(24)(25). Except for INH of which the PK model structure included both ELF and AC compartments (14), ELF-to-plasma and AC-to-plasma concentration ratios were used to extrapolate ELF and AC concentrations from simulated plasma concentrations.…”

Section: Pharmacokinetics and Pharmacodynamics Of Anti-tb Drugs For mentioning

confidence: 97%

“…For a mathematical model to realistically mimic the evolutionary dynamics of Mycobacterium tuberculosis (Mtb) in a human host environment and correctly estimate drug effects, it is essential to combine the immune response into pharmacokinetic (PK) and pharmacodynamic (PD) models of anti-TB drugs (14). This is because of the important role that the immune response plays in the proliferation and clearance of Mtb in the host environment (15), as well as the complex interactions between the immune response and the pathogen that determine pharmacological effects of a drug (14). To the best of our knowledge, there has been no attempt to link PK-PD models to host immune response models to optimise MDR-TB regimens.…”

Section: Introductionmentioning

confidence: 99%

Predicting the Outcomes of New Short-Course Regimens for Multi-Drug Resistant Tuberculosis Using Intrahost and Pharmacokinetic-Pharmacodynamic Modelling

Doan

Cao

Emeto

et al. 2018

Preprint

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Short-course regimens for multi-drug resistant tuberculosis (MDR-TB) are urgently needed.Limited data suggest that the new drug, bedaquiline (BDQ), may have the potential to shorten MDR-TB treatment to less than six months when used in conjunction with standard anti-TB drugs.However, the feasibility of BDQ in shortening MDR-TB treatment duration remains to be established. Mathematical modelling provides a platform to investigate different treatment regimens and predict their efficacy. We developed a mathematical model to capture the immune response to TB inside a human host environment. This model was then combined with a pharmacokinetic-pharmacodynamic model to simulate various short-course BDQ-containing regimens. Our modelling suggests that BDQ could reduce MDR-TB treatment duration to just 18 weeks (four months) while still maintaining a very high treatment success rate (100% for daily BDQ for two weeks, or 95% for daily BDQ for one week during the intensive phase). The estimated time to bacterial clearance of these regimens ranges from 27 to 33 days. Our findings provide the justification for empirical evaluation of short-course BDQ-containing regimens. If short-course BDQ-containing regimens are found to improve outcomes then we anticipate clear cost-savings and a subsequent improvement in the efficiency of national TB programs.

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Mathematical modeling and systems pharmacology of tuberculosis: Isoniazid as a case study

Cited by 8 publications

References 52 publications

Children With Cystic Fibrosis Are Infected With Multiple Subpopulations of Mycobacterium abscessus With Different Antimicrobial Resistance Profiles

Children With Cystic Fibrosis Are Infected With Multiple Subpopulations of Mycobacterium abscessus With Different Antimicrobial Resistance Profiles

Regrowth of Mycobacterium tuberculosis Populations Exposed to Antibiotic Combinations Is Due to the Presence of Isoniazid and Not Bacterial Growth Rate

Predicting the Outcomes of New Short-Course Regimens for Multi-Drug Resistant Tuberculosis Using Intrahost and Pharmacokinetic-Pharmacodynamic Modelling

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