Factors compromising the activity of moxifloxacin against intracellular Staphylococcus aureus.
OBJECTIVE
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.
Nguyen
Hoang Anh
HA
EA 525, Laboratoire de Pharmacocinétique et de Pharmacie Clinique, Faculté de Pharmacie, Université Victor Ségalen Bordeaux 2, Bordeaux, France.
Grellet
Jean
J
Dubois
Véronique
V
Saux
Marie-Claude
MC
Quentin
Claudine
C
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001372:Aza Compounds / Q000494:pharmacology*; D002460:Cell Line; D005110:Extracellular Space / Q000187:drug effects; D024841:Fluoroquinolones; D006801:Humans; D006863:Hydrogen-Ion Concentration; D064704:Levofloxacin; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism / Q000382:microbiology; D000077266:Moxifloxacin; D015242:Ofloxacin / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D064704:Levofloxacin; D015242:Ofloxacin; D000077266:Moxifloxacin