Transformation Morphisms and Time-to-Extinction Analysis That Map Therapy Duration From Preclinical Models to Patients With Tuberculosis: Translating From Apples to Oranges

Magombedze, Gesham; Pasipanodya, Jotam G.; Srivastava, Shashikant; Deshpande, Devyani; Visser, Marianne E; Cosson, E.; McIlleron, Helen; Gumbo, Tawanda

doi:10.1093/cid/ciy623

Cited by 26 publications

(73 citation statements)

References 41 publications

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“…When coupled with complex and caseous granuloma structure with impaired vascular supply, this can lead to longer sterilization times using standard HRZE TB therapy (Figure 7). Other models using various experimental data, including hollow fiber experiments, show that low drug exposure can lead to decreased rates in bacterial killing (Srivastava and Gumbo, 2011), and have used variability in PK to predict variability in required treatment durations (Magombedze et al, 2018). The model we present builds on these findings by providing the ability to simulate sterilization in a granuloma, while accounting for human-based PK variability and granuloma structure.…”

Section: Cicchese Et Almentioning

confidence: 99%

Both Pharmacokinetic Variability and Granuloma Heterogeneity Impact the Ability of the First-Line Antibiotics to Sterilize Tuberculosis Granulomas

et al. 2020

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Tuberculosis (TB) remains as one of the world's deadliest infectious diseases despite the use of standardized antibiotic therapies. Recommended therapy for drug-susceptible TB is up to 6 months of antibiotics. Factors that contribute to lengthy regimens include antibiotic underexposure in lesions due to poor pharmacokinetics (PK) and complex granuloma compositions, but it is difficult to quantify how individual antibiotics are affected by these factors and to what extent these impact treatments. We use our next-generation multi-scale computational model to simulate granuloma formation and function together with antibiotic pharmacokinetics and pharmacodynamics, allowing us to predict conditions leading to granuloma sterilization. In this work, we focus on how PK variability, determined from human PK data, and granuloma heterogeneity each quantitatively impact granuloma sterilization. We focus on treatment with the standard regimen for TB of four first-line antibiotics: isoniazid, rifampin, ethambutol, and pyrazinamide. We find that low levels of antibiotic concentration due to naturally occurring PK variability and complex granulomas leads to longer granuloma sterilization times. Additionally, the ability of antibiotics to distribute in granulomas and kill different subpopulations of bacteria contributes to their specialization in the more efficacious combination therapy. These results can inform strategies to improve antibiotic therapy for TB.

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Section: Cicchese Et Almentioning

confidence: 99%

Both Pharmacokinetic Variability and Granuloma Heterogeneity Impact the Ability of the First-Line Antibiotics to Sterilize Tuberculosis Granulomas

et al. 2020

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“…Of the 2 penultimate articles, the first provides the derivation of an approach that could be used to predict optimal clinical therapy duration, starting in the HFS-TB, while the second applied the approach to high-dose group D drugs plus moxifloxacin HFS-TB findings to determine whether therapy duration could be shortened to <6 months [58,59]. The final article is an editorial on the supplement, which summarizes how the results could be used to advance dosing in the clinical setting [60].…”

Section: Organization Of the Special Supplement: Tinker Tailor Soldmentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic Background and Methods and Scientific Evidence Base for Dosing of Second-line Tuberculosis Drugs

Gumbo

Alffenaar

2018

Clinical Infectious Diseases

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A World Health Organization workshop systematically examined the evidence base for dosing second-line tuberculosis drugs, identifying knowledge gaps. To fill these in, pharmacokinetics/pharmacodynamics, Monte Carlo experiments, and artificial intelligence algorithms were used in hollow-fiber model studies and clinical data analyses. Keywords. WHO second-line drugs; pharmacokinetics/pharmacodynamics; systematic analyses; hollow-fiber system model of tuberculosis; optimal dosing. What has been will be again, what has been done will be done again; there is nothing new under the sun. Is there anything of which one can say, "Look! This is something new"? It was here already, long ago; it was here before our time.

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“…However, on inspection the kill rate clearly plateaued off and could be broken into two curves, one with an exponential decline rate constant of 1.85 per day (half-life, 0.37 days), which is similar to the overall decline rate constant presented above, and a second terminal exponential decline rate constant of 0.06 per day (half-life, 12.76 days) with an r 2 value of Ͼ0.99. With the latter rates, it would take 284 days (about 9.3 months) for the bacterial population to decline to 10 Ϫ2 CFU/ml starting at this bacterial burden, which we have declined to bacterial population extinction elsewhere (37). If the starting bacterial burdens were increased 2.0 log 10 CFU/ml, then this would take about 369 days, or just over 1 year.…”

Section: Resultsmentioning

confidence: 86%

Clofazimine for the Treatment of Mycobacterium kansasii

Srivastava

Gumbo

2018

Antimicrob Agents Chemother

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pulmonary infection is a global problem. Standard combination therapy consists of isoniazid at 300 mg/day, rifampin at 600 mg/day, and ethambutol at 15 mg/kg of body weight/day for 18 months. Coincubation of with different clofazimine concentrations over 7 days in test tubes resulted in a maximal kill (maximum effect []) of 2.03 log CFU/ml below the day 0 bacterial burden. The concentration associated with was 110 times the MIC. Next, the effects of human-like concentration-time profiles of clofazimine human-equivalent doses ranging from 0 to 200 mg daily for 21 days were examined in the hollow-fiber model of intracellular (HFS-). On day 14, when the clofazimine microbial effect was maximal, the was 2.57 log CFU/ml, while the dose associated with was 100 mg/day. However, no dose killed to levels below the day 0 bacterial burden. Thus, the antimicrobial effect of clofazimine monotherapy in the HFS- was modest. Human-equivalent concentration-time profiles of standard combination therapy and doses were used as comparators in the HFS- On day 14, standard therapy killed to a level 2.32 log CFU/ml below the day 0 bacterial burden. The effect of standard therapy was consistent with a biexponential decline, with kill rate constants of 1.85 per day (half-life = 0.37 days) and 0.06 per day (half-life = 12.76 days) ( > 0.99). This means that standard therapy would take 9.3 to 12 months to completely eliminate in the model, which is consistent with clinical observations. This observation for standard therapy means that the modest to poor effect of clofazimine on identified here is likely to be the same in the clinic.

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Transformation Morphisms and Time-to-Extinction Analysis That Map Therapy Duration From Preclinical Models to Patients With Tuberculosis: Translating From Apples to Oranges

Cited by 26 publications

References 41 publications

Both Pharmacokinetic Variability and Granuloma Heterogeneity Impact the Ability of the First-Line Antibiotics to Sterilize Tuberculosis Granulomas

Both Pharmacokinetic Variability and Granuloma Heterogeneity Impact the Ability of the First-Line Antibiotics to Sterilize Tuberculosis Granulomas

Pharmacokinetic/Pharmacodynamic Background and Methods and Scientific Evidence Base for Dosing of Second-line Tuberculosis Drugs

Clofazimine for the Treatment of Mycobacterium kansasii

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