title: Discrepancy between uptake and intracellular activity of moxifloxacin in a Staphylococcus aureus-human THP-1 monocytic cell model.
abstract: The correlation between uptake of moxifloxacin by THP-1, a continuous line of monocytic cells devoid of intrinsic bactericidal properties, and its activity against Staphylococcus aureus ATCC 25923, a susceptible reference strain (MIC and minimal bactericidal concentration of moxifloxacin, 0.1 mg/liter), was studied in a 5-h assay. The uptake of the drug, added to the culture medium at 0.2 to 32 mg/liter, was evaluated by high-performance liquid chromatography. The ratio of the cellular to extracellular concentration of moxifloxacin reached, at equilibrium, 4.36 +/- 0.39 in uninfected cells and 6.25 +/- 0.41 in infected cells. The intracellular activity of moxifloxacin, introduced into the extracellular fluid at 0.06 to 8 mg/liter, was determined by the enumeration of viable bacteria. At concentrations < or =0.2 mg/liter, the drug inhibited only the intracellular bacterial growth, while at concentrations > or =0.5 mg/liter, it decreased the bacterial inoculum by less than 1 log(10) unit, with a maximum effect at 3 to 4 h, followed by regrowth of surviving bacteria to 80 to 120% of the original level at 5 h. In contrast, when killing curves were determined by using Mueller-Hinton broth with a similar inoculum (10(7) CFU/ml), moxifloxacin at concentrations > or =0.2 mg/liter reduced the inoculum by at least 3 log(10) units at 3 to 4 h, leaving < or =0.1% survival at 24 h. Persisters exhibited a fluoroquinolone susceptibility identical to that of S. aureus ATCC 25923. Our data indicate that moxifloxacin at therapeutic extracellular concentrations accumulates approximately sixfold in infected THP-1 cells and remains active intracellularly, but significantly less active than under in vitro conditions.
authors.affiliation: Laboratoire de Pharmacocinétique, Faculté de Pharmacie, Université de Bordeaux 2, Bordeaux, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Paillard
authors.forename: Jean
authors.initials: J
authors.lastname: Grellet
authors.forename: Véronique
authors.initials: V
authors.lastname: Dubois
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Saux
authors.forename: Claudine
authors.initials: C
authors.lastname: Quentin
mesh_terms: D000890:Anti-Infective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001372:Aza Compounds; D002478:Cells, Cultured; D024841:Fluoroquinolones; D006801:Humans; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism / Q000382:microbiology*; D000077266:Moxifloxacin; D011804:Quinolines; D013211:Staphylococcus aureus / Q000187:drug effects*; D013997:Time Factors
chemical_list: D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D000077266:Moxifloxacin