title: Simvastatin increases the in vivo activity of the first-line tuberculosis regimen.
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.
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Ciaran
authors.initials: C
authors.lastname: Skerry
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Pinn
authors.affiliation: Public Health Research Institute, Rutgers New Jersey Medical School, Newark, NJ, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Bruiners
authors.affiliation: Public Health Research Institute, Rutgers New Jersey Medical School, Newark, NJ, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Pine
authors.affiliation: Public Health Research Institute, Rutgers New Jersey Medical School, Newark, NJ, USA.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Gennaro
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA petros@jhmi.edu.
authors.forename: Petros C
authors.initials: PC
authors.lastname: Karakousis
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D058491:Bacterial Load; D002460:Cell Line; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D007538:Isoniazid / Q000494:pharmacology / Q000627:therapeutic use; D008168:Lung / Q000382:microbiology; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D008807:Mice, Inbred BALB C; D011718:Pyrazinamide / Q000494:pharmacology / Q000627:therapeutic use; D012293:Rifampin / Q000494:pharmacology / Q000627:therapeutic use; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D019821:Simvastatin; D007538:Isoniazid; D012293:Rifampin
keywords: TB; lipids; mice; statins