Statin adjunctive therapy shortens the duration of TB treatment in mice

Noton K. Dutta, Natalie Bruiners, Michael L. Pinn, Matthew D. Zimmerman, Brendan Prideaux, Véronique Dartois, Maria L. Gennaro, Petros C. Karakousis

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Background: The repurposing of existing agents mayaccelerate TB drug development. Recently,we reported that the lipid-lowering drug simvastatin, when added to the first-line antitubercular regimen, reduces the lung bacillary burden in chronically infected mice. Objectives: We investigated whether the addition of simvastatin to the first-line regimen (isoniazid/rifampicin/ pyrazinamide) shortens the duration of curative TB treatment in mice. Methods: Mycobacterium tuberculosis-infected THP-1 cells were exposed to simvastatin to determine the effect of statins on the activity of first-line anti-TB drug activity and intracellular rifampicin concentration. Single-dose and steady-state pharmacokinetic studies guided optimized simvastatin dosing in vivo. BALB/c mice were aerosol- infected with M. tuberculosis H37Rv and drug treatment was initiated 6 weeks post-infection. Separate groups of mice received standard TB treatment with or without simvastatin. Relapse rates were assessed 3 months after discontinuation of each treatment regimen. MALDI-MS imaging was used to image the cholesterol content of mouse lung lesions. Results: Simvastatin significantly enhanced the bactericidal activity of first-line drugs against intracellular M. tuberculosis without altering intracellular rifampicin concentrations. Adjunctive treatment with 60 mg/kg simvastatin shortened the time required to achieve culture-negative lungs from 4.5 to 3.5 months. Following 2.5, 3.5 and 4.5 months of treatment, relapse rates were 100%, 50% and 0%, respectively, in the control group and 50% (P=0.03), 20% and 0%, respectively, in the statin group. Simvastatin did not alter plasma or lung lesion cholesterol levels. Conclusions: Statins are attractive candidates for host-directed, adjunctive TB therapy. Further preclinical studies are needed to define the optimal statin and dosing.

Original languageEnglish (US)
Pages (from-to)1570-1577
Number of pages8
JournalJournal of Antimicrobial Chemotherapy
Volume71
Issue number6
DOIs
StatePublished - Jun 13 2016
Externally publishedYes

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Simvastatin
Rifampin
Mycobacterium tuberculosis
Lung
Pharmaceutical Preparations
Therapeutics
Cholesterol
Pyrazinamide
Recurrence
Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry
Isoniazid
Aerosols
Pharmacokinetics
Lipids
Control Groups

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Dutta, N. K., Bruiners, N., Pinn, M. L., Zimmerman, M. D., Prideaux, B., Dartois, V., ... Karakousis, P. C. (2016). Statin adjunctive therapy shortens the duration of TB treatment in mice. Journal of Antimicrobial Chemotherapy, 71(6), 1570-1577. https://doi.org/10.1093/jac/dkw014

Statin adjunctive therapy shortens the duration of TB treatment in mice. / Dutta, Noton K.; Bruiners, Natalie; Pinn, Michael L.; Zimmerman, Matthew D.; Prideaux, Brendan; Dartois, Véronique; Gennaro, Maria L.; Karakousis, Petros C.

In: Journal of Antimicrobial Chemotherapy, Vol. 71, No. 6, 13.06.2016, p. 1570-1577.

Research output: Contribution to journalArticle

Dutta, NK, Bruiners, N, Pinn, ML, Zimmerman, MD, Prideaux, B, Dartois, V, Gennaro, ML & Karakousis, PC 2016, 'Statin adjunctive therapy shortens the duration of TB treatment in mice', Journal of Antimicrobial Chemotherapy, vol. 71, no. 6, pp. 1570-1577. https://doi.org/10.1093/jac/dkw014
Dutta, Noton K. ; Bruiners, Natalie ; Pinn, Michael L. ; Zimmerman, Matthew D. ; Prideaux, Brendan ; Dartois, Véronique ; Gennaro, Maria L. ; Karakousis, Petros C. / Statin adjunctive therapy shortens the duration of TB treatment in mice. In: Journal of Antimicrobial Chemotherapy. 2016 ; Vol. 71, No. 6. pp. 1570-1577.
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abstract = "Background: The repurposing of existing agents mayaccelerate TB drug development. Recently,we reported that the lipid-lowering drug simvastatin, when added to the first-line antitubercular regimen, reduces the lung bacillary burden in chronically infected mice. Objectives: We investigated whether the addition of simvastatin to the first-line regimen (isoniazid/rifampicin/ pyrazinamide) shortens the duration of curative TB treatment in mice. Methods: Mycobacterium tuberculosis-infected THP-1 cells were exposed to simvastatin to determine the effect of statins on the activity of first-line anti-TB drug activity and intracellular rifampicin concentration. Single-dose and steady-state pharmacokinetic studies guided optimized simvastatin dosing in vivo. BALB/c mice were aerosol- infected with M. tuberculosis H37Rv and drug treatment was initiated 6 weeks post-infection. Separate groups of mice received standard TB treatment with or without simvastatin. Relapse rates were assessed 3 months after discontinuation of each treatment regimen. MALDI-MS imaging was used to image the cholesterol content of mouse lung lesions. Results: Simvastatin significantly enhanced the bactericidal activity of first-line drugs against intracellular M. tuberculosis without altering intracellular rifampicin concentrations. Adjunctive treatment with 60 mg/kg simvastatin shortened the time required to achieve culture-negative lungs from 4.5 to 3.5 months. Following 2.5, 3.5 and 4.5 months of treatment, relapse rates were 100{\%}, 50{\%} and 0{\%}, respectively, in the control group and 50{\%} (P=0.03), 20{\%} and 0{\%}, respectively, in the statin group. Simvastatin did not alter plasma or lung lesion cholesterol levels. Conclusions: Statins are attractive candidates for host-directed, adjunctive TB therapy. Further preclinical studies are needed to define the optimal statin and dosing.",
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T1 - Statin adjunctive therapy shortens the duration of TB treatment in mice

AU - Dutta, Noton K.

AU - Bruiners, Natalie

AU - Pinn, Michael L.

AU - Zimmerman, Matthew D.

AU - Prideaux, Brendan

AU - Dartois, Véronique

AU - Gennaro, Maria L.

AU - Karakousis, Petros C.

PY - 2016/6/13

Y1 - 2016/6/13

N2 - Background: The repurposing of existing agents mayaccelerate TB drug development. Recently,we reported that the lipid-lowering drug simvastatin, when added to the first-line antitubercular regimen, reduces the lung bacillary burden in chronically infected mice. Objectives: We investigated whether the addition of simvastatin to the first-line regimen (isoniazid/rifampicin/ pyrazinamide) shortens the duration of curative TB treatment in mice. Methods: Mycobacterium tuberculosis-infected THP-1 cells were exposed to simvastatin to determine the effect of statins on the activity of first-line anti-TB drug activity and intracellular rifampicin concentration. Single-dose and steady-state pharmacokinetic studies guided optimized simvastatin dosing in vivo. BALB/c mice were aerosol- infected with M. tuberculosis H37Rv and drug treatment was initiated 6 weeks post-infection. Separate groups of mice received standard TB treatment with or without simvastatin. Relapse rates were assessed 3 months after discontinuation of each treatment regimen. MALDI-MS imaging was used to image the cholesterol content of mouse lung lesions. Results: Simvastatin significantly enhanced the bactericidal activity of first-line drugs against intracellular M. tuberculosis without altering intracellular rifampicin concentrations. Adjunctive treatment with 60 mg/kg simvastatin shortened the time required to achieve culture-negative lungs from 4.5 to 3.5 months. Following 2.5, 3.5 and 4.5 months of treatment, relapse rates were 100%, 50% and 0%, respectively, in the control group and 50% (P=0.03), 20% and 0%, respectively, in the statin group. Simvastatin did not alter plasma or lung lesion cholesterol levels. Conclusions: Statins are attractive candidates for host-directed, adjunctive TB therapy. Further preclinical studies are needed to define the optimal statin and dosing.

AB - Background: The repurposing of existing agents mayaccelerate TB drug development. Recently,we reported that the lipid-lowering drug simvastatin, when added to the first-line antitubercular regimen, reduces the lung bacillary burden in chronically infected mice. Objectives: We investigated whether the addition of simvastatin to the first-line regimen (isoniazid/rifampicin/ pyrazinamide) shortens the duration of curative TB treatment in mice. Methods: Mycobacterium tuberculosis-infected THP-1 cells were exposed to simvastatin to determine the effect of statins on the activity of first-line anti-TB drug activity and intracellular rifampicin concentration. Single-dose and steady-state pharmacokinetic studies guided optimized simvastatin dosing in vivo. BALB/c mice were aerosol- infected with M. tuberculosis H37Rv and drug treatment was initiated 6 weeks post-infection. Separate groups of mice received standard TB treatment with or without simvastatin. Relapse rates were assessed 3 months after discontinuation of each treatment regimen. MALDI-MS imaging was used to image the cholesterol content of mouse lung lesions. Results: Simvastatin significantly enhanced the bactericidal activity of first-line drugs against intracellular M. tuberculosis without altering intracellular rifampicin concentrations. Adjunctive treatment with 60 mg/kg simvastatin shortened the time required to achieve culture-negative lungs from 4.5 to 3.5 months. Following 2.5, 3.5 and 4.5 months of treatment, relapse rates were 100%, 50% and 0%, respectively, in the control group and 50% (P=0.03), 20% and 0%, respectively, in the statin group. Simvastatin did not alter plasma or lung lesion cholesterol levels. Conclusions: Statins are attractive candidates for host-directed, adjunctive TB therapy. Further preclinical studies are needed to define the optimal statin and dosing.

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