A BONE-MARROW-DERIVED MURINE MACROPHAGE MODEL FOR EVALUATING EFFICACY OF ANTIMYCOBACTERIAL DRUGS UNDER RELEVANT PHYSIOLOGICAL CONDITIONS

Even though the macrophage is the host cell for the intracellular bacterial parasite Mycobacterium avium, macrophages have undergone only limited evaluation as models for determining the capacities of antimycobacterial drugs to inhibit the growth of M. avium within this relevant intracellular environment. In the present study, we demonstrated that a panel of M. avium isolates could actively infect homogeneous monolayers of murine bone marrow-derived macrophages. A number of established and experimental antimycobacterial drugs were then added to these cultures at a range of concentrations, and their effects on the numbers of surviving bacilli were determined 8 days later. By plotting such numbers versus drug concentrations it was then possible to clearly distinguish between compounds with bactericidal activity (such as rifabutin and PD 125354) and those with bacteriostatic effects (such as clarithromycin), even though several of these compounds had very similar MICs. In addition, an estimate of the potential therapeutic efficiency of each drug could be made by determining the concentration needed to destroy an arbitrary percentage of the inoculum (in this case, the bactericidal concentration destroying 99% of the inoculum). Such values were considerably in excess of the MICs and may more realistically reflect the concentrations in serum required to effectively reduce the bacterial burden in vivo.