In Vivo Efficacy of ABT-255 against Drug-Sensitive and -Resistant Mycobacterium tuberculosis Strains

Current therapy for pulmonary tuberculosis involves 6 months of treatment with isoniazid, pyrazinamide, rifampin, and ethambutol or streptomycin for reliable treatment efficacy. The long treatment period increases the probability of noncompliance, leading to the generation of multidrug-resistant isolates of Mycobacterium tuberculosis. A treatment option that significantly shortened the course of therapy, or a new class of antibacterial effective against drug-resistant M. tuberculosis would be of value. ABT-255 is a novel 2-pyridone antibacterial agent which demonstrates in vitro potency and in vivo efficacy against drug-susceptible and drug-resistant M. tuberculosis strains. By the Alamar blue reduction technique, the MIC of ABT-255 against susceptible strains of M. tuberculosis ranged from 0.016 to 0.031 μg/ml. The MIC of ABT-255 against rifampin- or ethambutol-resistant M. tuberculosis isolates was 0.031 μg/ml. In a murine model of pulmonary tuberculosis, 4 weeks of oral ABT-255 therapy produced a 2- to 5-log₁₀ reduction in viable drug-susceptible M. tuberculosis counts from lung tissue. Against drug-resistant strains of M. tuberculosis, ABT-255 produced a 2- to 3-log₁₀ reduction in viable bacterial counts from lung tissue. ABT-255 is a promising new antibacterial agent with activity against M. tuberculosis.Length of therapy and patient noncompliance with treatment regimens remain clinical problems in the treatment of Mycobacterium tuberculosis infections. Current therapies reduce the pulmonary bacterial burden, but treatment periods of 6 months for nonimmunosuppressed individuals and at least 9 months for immunosuppressed patients are required for reliable treatment efficacy. The long treatment period increases the probability of noncompliance, leading to the generation of drug-resistant strains of M. tuberculosis (11). A recent survey determined that drug-resistant M. tuberculosis usually arises as a recrudescence of an existing infection, rather than as a primary infection (19). Also, the population in need of therapy often does not comply with the lengthy treatment regimen, causing further potential for treatment failure or an increase in drug resistance. In New York City, only 11% of the patients under care for M. tuberculosis infection reported back to an outpatient clinic to continue therapy (3). Protocols utilizing directly observed therapy have increased compliance, but additional public health resources are required (4, 14, 18).In the United States, M. tuberculosis is most prevalent in immunosuppressed individuals and AIDS patients. Single and combination therapies are used following M. tuberculosis exposure or infection. Current recommended therapy of active infection with drug-susceptible M. tuberculosis is a 6-month regimen of isoniazid, pyrazinamide, rifampin, and ethambutol or streptomycin (5). For treatment of drug-resistant M. tuberculosis, a 24-month regimen of at least three drugs is recommended (7). A treatment option that allowed significant shortening of the course of therapy or represented a new drug class for M. tuberculosis therapy would be a useful advance.The 2-pyridones are a promising class of antibacterial agents that possess broad-spectrum in vitro potency and in vivo efficacy. Like the fluoroquinolones, the 2-pyridones are inhibitors of bacterial DNA gyrase (10). ABT-719, a representative 2-pyridone, was approximately 10-fold more potent in vitro than ciprofloxacin against gram-positive bacterial strains. Against gram-negative bacterial strains, the 2-pyridones were approximately equal in potency to ciprofloxacin (8, 9). In mouse studies, oral efficacy was obtained at dosages that were 6- to 20-fold lower than those of ciprofloxacin against gram-positive bacterial infections and approximately equivalent to those of ciprofloxacin against gram-negative bacterial infections (2). M. tuberculosis isolates are generally susceptible to fluoroquinolones, although resistant isolates have been found (16). However, cross-resistance to fluoroquinolones and isoniazid and rifampin has not been found in M. tuberculosis (1). ABT-719 and structurally similar 2-pyridones produced MICs of ≤0.4 μg/ml against drug-susceptible and drug-resistant M. tuberculosis strains (data not shown). ABT-255 is an analog of ABT-719 with improvements in the therapeutic margin against common gram-positive and -negative bacterial infections (2). The efficacy of ABT-255 was compared to that of the antituberculosis agents isoniazid and rifampin against drug-sensitive and -resistant strains of M. tuberculosis in a murine model of pulmonary tuberculosis.