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

Even though the macrophage is the host cell for the intracellular bact erial parasite Mycobacterium avium, macrophages have undergone only li mited evaluation as models for determining the capacities of antimycob acterial 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 monolay ers of murine bone marrow-derived macrophages. A number of established and experimental antimycobacterial drugs were then added to these cul tures at a range of concentrations, and their effects on the numbers o f surviving bacilli were determined 8 days later. By plotting such num bers versus drug concentrations it was then possible to clearly distin guish between compounds with bactericidal activity (such as rifabutin and PD 125354) and those with bacteriostatic effects (such as clarithr omycin), even though several of these compounds had very similar MICs. In addition, an estimate of the potential therapeutic efficiency of e ach drug could be made by determining the concentration needed to dest roy an arbitrary percentage of the inoculum (in this case, the bacteri cidal 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 bacteri al burden in vivo.