Factors compromising the activity of moxifloxacin against intracellular Staphylococcus aureus.

OBJECTIVES: The aim of this study was to determine the intracellular activity of moxifloxacin against a reference strain and a clinical strain and to study the factors compromising the intracellular activity of moxifloxacin.
METHODS: The bactericidal activity of moxifloxacin at therapeutic concentrations was studied against extracellular (broth) and intracellular (infected THP-1 monocytes) forms of Staphylococcus aureus and compared with that of levofloxacin. The activity of moxifloxacin was also evaluated in the presence of alkalinizing agents, in intracellular salt medium mimicking the phagolysosomal environment and in cell lysate.
RESULTS: Moxifloxacin, bactericidal against two S. aureus strains (ATCC 25923 and a clinical isolate, Sa2669) in broth, accumulated over 6-fold in monocytes. Against intracellular bacteria, moxifloxacin displayed a markedly reduced activity, not better than levofloxacin, with a maximal reduction of 1 log(10) cfu at 5 h. Cellular accumulation of moxifloxacin was not modified by the addition of efflux pump inhibitors or lysosomal alkalinizing agents. Alkalinization of phagolysosomes significantly enhanced intracellular killing by moxifloxacin. The bactericidal activity of moxifloxacin, abolished in the intracellular salt medium, was partially restored when the pH was raised from 5.0 to 7.4. The binding to intracellular components (35%) did not influence the activity of moxifloxacin. In all cases, surviving bacteria remained fully susceptible to the antibiotic.
CONCLUSIONS: The defeat of intracellular activity of moxifloxacin against S. aureus appeared to be more substantially related to cellular parameters (acidic pH and composition of the phagolysosomes) than to the intrinsic activity of the drug and to pharmacokinetic properties.