JAC Advance Access originally published online on March 13, 2006
Journal of Antimicrobial Chemotherapy 2006 57(5):883-890; doi:10.1093/jac/dkl079
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Factors influencing the intracellular activity of fluoroquinolones: a study using levofloxacin in a Staphylococcus aureus THP-1 monocyte model
1 EA 525, Laboratoire de Pharmacocinétique et de Pharmacie clinique, Faculté de Pharmacie, Université Victor Ségalen Bordeaux 2, 146 rue Léo-Saignat, 33076 Bordeaux cedex, France; 2 EA 525, Laboratoire de Microbiologie, Faculté de Pharmacie, Université Victor Ségalen Bordeaux 2, Bordeaux, France
Received 26 September 2005; returned 23 December 2005; revised 2 February 2006; accepted 17 February 2006
* Corresponding author. Tel: +33-5-567955-03; Fax: +33-5-5679-5674; E-mail: jean.grellet{at}chu-bordeaux.fr
Objectives: Recent studies have raised the question of whether the intracellular activity of quinolones is optimal with respect to their cellular accumulation. The aim of this study was to compare the intracellular and extracellular activities of a commonly used quinolone, levofloxacin, and to examine the causes of the possible inconsistency between intracellular and extracellular effects.
Methods: The bactericidal activity of levofloxacin at therapeutic levels, alone or in combination with various efflux-pump inhibitors or alkalinizing agents, was studied against Staphylococcus aureus ATCC 25923 in Mueller–Hinton (MH) broth and in a THP-1 monocytic cell model, using intracellular salt medium (ISM) mimicking the phagolysosomal environment, and in cell lysate.
Results: Levofloxacin accumulation was 2-fold higher in uninfected than in infected cells. Intracellular activity was significantly lower than extracellular activity (decrease in the inoculum of 
1 log10 cfu/mL at 4 or 8 mg/L versus 
2 log10 units at 1 mg/L in MH broth over 5 h). Persisters remained fully susceptible to the drug. The efflux pump inhibitors verapamil and gemfibrozil did not affect killing of intracellular bacteria, although gemfibrozil increased cellular accumulation of levofloxacin 1.7-fold. The lysosomotropic alkalinizing agents chloroquine and ammonium chloride significantly enhanced intracellular killing by levofloxacin. The bactericidal activity of levofloxacin, abolished in ISM, was partially restored when the pH was neutralized from 5.0 to 7.4. Binding to intracellular components (20%) substantially decreased the efficiency of levofloxacin.
Conclusions: Levofloxacin exhibited substantially lower intracellular activity than extracellular activity. Cellular compartmentalization of the drug, phagolysosomal environment and antibiotic binding to cellular components most likely contribute to this failure.
Keywords: intracellular infections , cellular pharmacokinetics , intracellular pharmacodynamics
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