TY - JOUR
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.
N1 - Funding Information:
This work was supported by BMGF grant OPP 1066499 to V. D., R01 HL106788 to M. L. G. and ACTG grant 110007, CFAR supplement P30AI094189, R01 HL106786 and UH2AI122309 to P. C. K.
Publisher Copyright:
© The Author 2016.
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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U2 - 10.1093/jac/dkw014
DO - 10.1093/jac/dkw014
M3 - Article
C2 - 26903278
AN - SCOPUS:84973332908
SN - 0305-7453
VL - 71
SP - 1570
EP - 1577
JO - Journal of Antimicrobial Chemotherapy
JF - Journal of Antimicrobial Chemotherapy
IS - 6
ER -