minocycline and Tuberculosis

Drug-resistant tuberculosis represents a global emergency, requiring new drugs. We found that minocycline was highly potent in laboratory strains of Mycobacterium tuberculosis and that 30 drug-susceptible and multidrug/extensively drug-resistant clinical strains were susceptible to clinically achievable concentrations. In the hollow fiber system model, lung concentration-time profiles of 7 mg/kg/day human-equivalent minocycline dose achieved bacterial kill rates equivalent to those of first-line antituberculosis agents. Minocycline killed extracellular bacilli directly. Minocycline also killed intracellular bacilli indirectly, via concentration-dependent granzyme A-driven apoptosis. Moreover, minocycline demonstrated dose-dependent antiinflammatory activity and downregulation of extracellular matrix-based remodeling pathways and, thus, could protect patients from tuberculosis immunopathology. In RNA sequencing of repetitive samples from the hollow fiber system and in independent protein abundance experiments, minocycline demonstrated dose-dependent inhibition of sonic hedgehog-patched-gli signaling. These findings have implications for improved lung remodeling and for dual immunomodulation and direct microbial kill-based treatment shortening regimens for drug-susceptible and drug-resistant latent and active M. tuberculosis infection.

Topics: Anti-Inflammatory Agents; Antitubercular Agents; Apoptosis; Granzymes; Hedgehog Proteins; Humans; Microbial Sensitivity Tests; Minocycline; Mycobacterium tuberculosis; Signal Transduction; THP-1 Cells; Tuberculosis; Tuberculosis, Multidrug-Resistant

We determined the in vitro antimycobacterial activity of rifampicin, isoniazid and a third agent in combination using a three-dimensional chequerboard in Middlebrook 7H9 broth microdilutions. Of 28 agents screened, ethambutol, streptomycin, clarithromycin, minocycline, ciprofloxacin, levofloxacin, sparfloxacin, gatifloxacin and sitafloxacin were potentially synergistic. A further three-dimensional chequerboard assay quantitatively looked for synergy against ten clinical isolates of Mycobacterium tuberculosis, including seven multidrug-resistant isolates. Sitafloxacin, gatifloxacin and clarithromycin showed significant synergy, with fractional inhibitory concentration indices ranging from 0.41 to 0.79, 0.39 to 0.90 and 0.48 to 0.95, respectively. It is concluded that three-dimensional chequerboard assay can quantitatively determine antimycobacterial synergy, and that fluoroquinolones and antibacterial agents such as clarithromycin are effective against multidrug-resistant isolates of M. tuberculosis when combined with rifampicin and isoniazid.

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Antitubercular Agents; Ciprofloxacin; Clarithromycin; Drug Synergism; Ethambutol; Fluoroquinolones; Humans; Isoniazid; Levofloxacin; Microbial Sensitivity Tests; Minocycline; Mycobacterium tuberculosis; Ofloxacin; Rifampin; Tuberculosis

The WHO MDT regimens have proved highly successful in preventing relapse of leprosy cases. It has indirectly lad to marked reduction in prevalence of disabilities. For PB leprosy, rifampicin 600 mg monthly and 100 mg dapsone daily for a total of 6 months therapy is required. For MB leprosy clofazimine 300 mg once monthly, supervised and 50 mg daily self administered is added. For single skin lesion the current WHO recommendation is 600 mg rifampicin + 400 mg ofloxacin + 100 mg minocycline given as a single dose for adults. Dose adjustment for children and clinical information have been discussed in a nutshell. A number of trials are going on, some are yet to be completed which do offer the prospect of perhaps simplifying therapy and improving with shorter duration.

Topics: Anti-Bacterial Agents; Clofazimine; Dapsone; Dose-Response Relationship, Drug; Drug Combinations; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; HIV Infections; Humans; Hypersensitivity; India; Leprosy; Minocycline; Nausea; Ofloxacin; Rifampin; Secondary Prevention; Tuberculosis; World Health Organization

A twenty-five-year-old female was admitted with lower right abdominal pain, right coxalgia and an inability to extend her right inferior limb. She had a history of tuberculosis pleurisy two years before. Abdominal ultrasonography, computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated a right retroperitoneal mass which was suspected to be an abscess or tumor. Percutaneous aspiration of the mass was followed by the administration (p.o.) of antituberculosis drugs (pyrazinamide, ethanbutol, isoniazide, refampicin). One month after initial drainage, the tube was removed but intra-cystic fluid collection was still visible a month later using CT and MRI. Therefore, a second percutaneous aspiration was followed by the instillation of streptomycin and minocycline hydrochloride. Six months after employing this therapy, no fluid collection was found.

Topics: Abdominal Abscess; Adult; Anti-Bacterial Agents; Drainage; Female; Humans; Minocycline; Sclerotherapy; Tuberculosis

C57BL/6 mice were pretreated with rifabutin or clarithromycin alone or combined with minocycline 3 days before intravenous challenge (day 0) with Mycobacterium avium. Treatment was continued until sacrifice at days 1, 8, 15, and 21. Rifabutin or clarithromycin decreased the level of infection in both the lungs and the spleen. Rifabutin was as effective as clarithromycin in the lungs but was less [corrected] effective in the spleen. The clarithromycin-minocycline combination was as effective as clarithromycin alone.

Topics: Animals; Anti-Bacterial Agents; Clarithromycin; Disease Models, Animal; Drug Therapy, Combination; Lung; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Minocycline; Mycobacterium avium; Rifabutin; Rodent Diseases; Spleen; Time Factors; Tuberculosis