Anti-Mycobacterium avium complex activity of clarithromycin, rifampin, rifabutin, and ethambutol in combination with adenosine 5'-triphosphate.

We previously reported that adenosine 5'-triphosphate (ATP) inhibited the growth of various bacteria, including mycobacteria, Staphylococcus, and Pseudomonas, without damaging bacterial surface structures. Notably, ATP's antibacterial activity was found to be attributable to its iron-chelating ability. ATP exhibited combined effects with some antimicrobials against Mycobacterium intracellulare and methicillin-resistant S. aureus, suggesting its usefulness as an adjunctive drug in the chemotherapy against certain intractable infections. In this study, we examined detailed profiles of the anti-Mycobacterium avium complex (MAC) activity of some antimicrobial agents, including clarithromycin (CLA), rifampin (RIF), rifabutin (RBT), and ethambutol (EMB), in combination with ATP. It was found that the anti-MAC activity of CLA+RIF, CLA+RBT, and CLA+EMB was markedly potentiated in a strain-dependent manner. In this case, the onset of the regrowth of antimicrobial agent-treated mycobacteria during cultivation was significantly delayed in the presence of ATP, indicating the usefulness of ATP as an adjunctive drug in chemotherapy against MAC infections.

Comparative in vitro and in vivo antimicrobial activities of sitafloxacin, gatifloxacin and moxifloxacin against Mycobacterium avium.

Moxifloxacin exhibits therapeutic activity against Mycobacterium avium infection in mice. Since not only moxifloxacin but also another 8-methoxy quinolone, gatifloxacin, and a C-8-chloro quinolone, sitafloxacin, show favourable antimycobacterial activity in vitro, their anti-M. avium activities were compared in vivo. Minimum inhibitory concentrations (MICs), minimum bactericidal concentrations (MBCs) and mutant prevention concentrations (MPCs) of the test quinolones for M. avium were determined by microdilution in 7HSF broth. Antimicrobial activity against intracellular bacteria was measured using Mono Mac 6 human macrophages. Therapeutic efficacy of the quinolones when administered subcutaneously with or without clarithromycin plus ethambutol was assessed using mice intravenously infected with M. avium in terms of changes in bacterial loads in the lungs and spleen following infection. Based on the MICs, MBCs and MPCs, the in vitro activities of sitafloxacin and moxifloxacin were greater than that of gatifloxacin. Moxifloxacin exhibited the strongest activity against intramacrophage M. avium. When each test quinolone was administered alone to infected mice, sitafloxacin and gatifloxacin exhibited greater therapeutic efficacy than moxifloxacin based on intrapulmonary bacterial elimination. However, moxifloxacin exerted greater activity in killing bacteria in the spleen. Moxifloxacin and sitafloxacin exhibited combined effects on intrapulmonary bacterial elimination when administered to mice in combination with clarithromycin plus ethambutol. Sitafloxacin exerted the most marked combined effects in bacterial killing in the spleen. Levofloxacin displayed the lowest in vitro and in vivo activities amongst the tested quinolones. Taken together, these findings indicate that sitafloxacin and moxifloxacin exhibit favourable activities against M. avium in vitro and in vivo.

Antimicrobial activity of picolinic acid against extracellular and intracellular Mycobacterium avium complex and its combined activity with clarithromycin, rifampicin and fluoroquinolones.

OBJECTIVES: A natural metal ion chelator, picolinic acid (PA), is known to potentiate macrophage antimycobacterial activity. Here, we studied the antimicrobial activity of PA against extracellular and intramacrophage Mycobacterium avium complex (MAC) organisms. METHODS: MAC organisms, MAC-infected macrophages or MAC-infected type II pneumocytes were cultured in the presence or absence of PA with or without antimycobacterial drugs, and residual bacterial cfu of extracellular or intracellular MAC were counted on 7H11 agar plates. RESULTS: First, PA exhibited antimicrobial activity against extracellular and intramacrophage MAC. The effect of PA was mimicked by other metal ion-chelating agents, such as ethylenediamine tetraacetic acid and O,O'-bis (2-aminophenyl) ethyleneglycol-N,N,N',N'-tetraacetic acid. Second, PA potentiated antimicrobial effects of a two-drug combination of clarithromycin/rifampicin and some fluoroquinolones (levofloxacin, sitafloxacin and gatifloxacin) against extracellular and intramacrophage MAC. Similar combined effects of PA with clarithromycin/rifampicin were also seen in the case of MAC residing within type II alveolar epithelial cells. CONCLUSIONS: PA exerted an appreciable anti-MAC activity, when used singly or in combination with some antimycobacterial drugs (clarithromycin/rifampicin and fluoroquinolones), suggesting the usefulness of PA as an adjunct for clinical antimicrobial chemotherapy of MAC infections.