Metformin Adjunctive Therapy Does Not Improve the Sterilizing Activity of the First-Line Antitubercular Regimen in Mice

Abstract

Preliminary preclinical and observational studies suggest the potential utility of metformin as an adjunctive, host-directed agent for treatment of tuberculosis (TB). In this study, we sought to investigate the bactericidal and sterilizing activities of human-like exposures of metformin when given in combination with the firstline regimen against chronic tuberculosis in BALB/c mice. Mice receiving metformin adjunctive therapy had similar lung bacillary burdens with control mice during treatment, and the proportion of mice with microbiological relapse was similar between the two groups.KEYWORDS Mycobacterium tuberculosis, metformin, standard first-line regimen, BALB/c, bactericidal, sterilizing, host-directed therapy, relapse, cure, Denver regimen H ost-directed therapy (HDT) may offer expanded therapeutic options for improving tuberculosis (TB) treatment (1-5). Metformin (MetF), an AMP-activated protein kinase (AMPK)-activating drug for type 2 diabetes (DM), was reported to inhibit intracellular growth of mycobacteria by inducing reactive oxygen species and to enhance the efficacy of conventional anti-TB drugs in mouse models of acute and chronic TB; its use was associated with decreased TB severity and improved clinical outcomes in a retrospective analysis of 220 patients with DM and TB (6). In another retrospective study, Srujitha et al. showed that MetF use was associated with a 3.9-fold reduction in TB incidence among patients with DM (7). Based on these findings, we hypothesized that MetF adjunctive therapy would enhance the bactericidal and sterilizing activities of the standard first-line treatment (8, 9) against chronic TB infection in mice and shorten the duration of curative treatment as assessed by microbiological relapse.All animal-related procedures were approved by the Johns Hopkins University (JHU) School of Medicine Animal Care and Use Committee. A total of 170 female BALB/c mice aged 4 to 6 weeks (Charles River Labs, Wilmington, MA) were aerosol infected with Mycobacterium tuberculosis H37Rv (JHU) using the inhalation exposure system (GlasCol, Terre Haute, IN) calibrated to deliver ϳ10 2 CFU per mouse lung in two consecutive runs. After aerosol infection, the mice were randomized into the two treatment groups. Six weeks postinfection, the mice were treated daily (5 days/week) via esophageal cannulation with human-equivalent doses of rifampin (10 mg/kg), isoniazid (10 mg/kg), pyrazinamide (150 mg/kg), and ethambutol (100 mg/kg) (RHZE) with or without MetF (250 mg/kg) for up to 6 months (2, 10, 11). For the first 2 months of treatment, the mice received RHZE and, for the remaining 4 months, only rifampin and isoniazid (RH) to mirror the first-line regimen in humans. The rifampin dose preceded that of the other drugs by at least 1 h to prevent pharmacokinetic antagonism (12, 13). The dose of MetF (6) and is estimated (14) to be equivalent to 25 mg/kg in humans (15), which is well tolerated (15, 16). Groups of 5 mice were sacrificed on the day after infection, on the day of treatment initi...

Metformin enhances protection in guinea pigs chronically infected with Mycobacterium tuberculosis

“…In contrast to decreased lung lesion burden, there were no significant differences in the extrapulmonary lesion or bacterial burden in metformin treated animals, which likely explains the lack of improved survival. In addition, these studies did not assess the use of metformin as a therapy for pre-existing infection or as adjunctive therapy in combination with antimicrobial drug treatment of TB 49 . These are critical questions that will be evaluated in our future work and must be taken into consideration before metformin is evaluated as a practical host-directed therapy in humans.…”

Metformin use is associated with a low risk of tuberculosis among newly diagnosed diabetes mellitus patients with normal renal function: A nationwide cohort study with validated diagnostic criteria

“…In line with previous studies [ 29 – 31 ], it also demonstrates that statin (HR 0.29 [0.18–0.48]), aspirin (HR 0.68 [0.50–0.91]) and CCBs (HR 0.65 [0.51–0.82]) may reduce the risk of active TB. The finding that metformin and statin has a negative interaction in TB protection is surprising, but may partially explain the discrepant findings in different studies on metformin as a HDT for TB [ 10 , 32 – 34 ]. Though the current study is not designed to explore the pathophysiology underlying this phenomenon, we speculate that this may probably because metformin and statin both target on facilitation of phagosome–lysosome fusion [ 10 ], and therefore counteract each other.…”

Metformin Decreases Risk of Tuberculosis Infection in Type 2 Diabetes Patients

“…The potential role of metformin as an adjunctive therapy to TB infection is currently under investigation [ 16 ]. Although Singhal et al showed that metformin might enhance the efficacy of conventional anti-TB drugs in mice [ 5 ], another recent animal study did not find any improvement in the sterilizing activity of first-line anti-TB treatment [ 17 ]. It is believed that the prevention of clinical onset of TB infection by metformin might be more effective than the use of metformin to treat a full-blown clinical disease.…”