Simvastatin increases the in vivo activity of the first-line tuberculosis regimen

J Antimicrob Chemother. 2014 Sep;69(9):2453-7. doi: 10.1093/jac/dku166. Epub 2014 May 22.

Abstract

Background: The need to develop new, improved treatments for tuberculosis (TB) remains urgent, and the repurposing of existing drugs represents a possible shortcut to market. Recently, there has been significant interest in host-directed adjuvant therapy to enhance bacillary killing. HMG-CoA reductase inhibitors (statins), which are among the most commonly prescribed drugs, have immunomodulatory properties and improve the clinical outcomes of bacterial infections.

Methods: We studied the tuberculocidal activity of simvastatin alone and in combination with first-line anti-TB drugs in J774 macrophages and during chronic TB infection.

Results: Exposure to 5 μM simvastatin significantly increased the tuberculocidal activity of isoniazid in J774 macrophages at Day 3 after infection versus isoniazid alone (P=0.02). Similarly, relative to the standard oral regimen of rifampicin (10 mg/kg), isoniazid (10 mg/kg) and pyrazinamide (150 mg/kg) given five times weekly, the addition of 25 mg/kg simvastatin enhanced bacillary killing, reducing the number of lung cfu by an additional 1 log10 at Day 28 (P<0.01) and by a further 1.25 log10 at Day 56 (P<0.01).

Conclusions: The potential additive activity of simvastatin to first-line TB treatment holds promise. However, further studies to identify the optimal statin and dosing are required. In addition the ability of combination treatment with statins to accelerate the time required to achieve a stable cure remains to be explored.

Keywords: TB; lipids; mice; statins.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antitubercular Agents / pharmacology
  • Antitubercular Agents / therapeutic use*
  • Bacterial Load
  • Cell Line
  • Colony Count, Microbial
  • Disease Models, Animal
  • Drug Synergism*
  • Drug Therapy, Combination / methods
  • Female
  • Isoniazid / pharmacology
  • Isoniazid / therapeutic use
  • Lung / microbiology
  • Macrophages / drug effects
  • Macrophages / microbiology
  • Mice, Inbred BALB C
  • Pyrazinamide / pharmacology
  • Pyrazinamide / therapeutic use
  • Rifampin / pharmacology
  • Rifampin / therapeutic use
  • Simvastatin / pharmacology
  • Simvastatin / therapeutic use*
  • Treatment Outcome
  • Tuberculosis / drug therapy*

Substances

  • Antitubercular Agents
  • Pyrazinamide
  • Simvastatin
  • Isoniazid
  • Rifampin