1: Antimicrob Agents Chemother. 2009 Apr;53(4):1434-42. Epub 2009 Feb 2. Intracellular activity of antibiotics in a model of human THP-1 macrophages infected by a Staphylococcus aureus small-colony variant strain isolated from a cystic fibrosis patient: pharmacodynamic evaluation and comparison with isogenic normal-phenotype and revertant strains. Nguyen HA, Denis O, Vergison A, Theunis A, Tulkens PM, Struelens MJ, Van Bambeke F. Louvain Drug Research Institute, Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, Brussels, Belgium. Small-colony variant (SCV) strains of Staphylococcus aureus show reduced antibiotic susceptibility and intracellular persistence, potentially explaining therapeutic failures. The activities of oxacillin, fusidic acid, clindamycin, gentamicin, rifampin, vancomycin, linezolid, quinupristin-dalfopristin, daptomycin, tigecycline, moxifloxacin, telavancin, and oritavancin have been examined in THP-1 macrophages infected by a stable thymidine-dependent SCV strain in comparison with normal-phenotype and revertant isogenic strains isolated from the same cystic fibrosis patient. The SCV strain grew slowly extracellularly and intracellularly (1- and 0.2-log CFU increase in 24 h, respectively). In confocal and electron microscopy, SCV and the normal-phenotype bacteria remain confined in acid vacuoles. All antibiotics tested, except tigecycline, caused a net reduction in bacterial counts that was both time and concentration dependent. At an extracellular concentration corresponding to the maximum concentration in human serum (total drug), oritavancin caused a 2-log CFU reduction at 24 h; rifampin, moxifloxacin, and quinupristin-dalfopristin caused a similar reduction at 72 h; and all other antibiotics had only a static effect at 24 h and a 1-log CFU reduction at 72 h. In concentration dependence experiments, response to oritavancin was bimodal (two successive plateaus of -0.4 and -3.1 log CFU); tigecycline, moxifloxacin, and rifampin showed maximal effects of -1.1 to -1.7 log CFU; and the other antibiotics produced results of -0.6 log CFU or less. Addition of thymidine restored intracellular growth of the SCV strain but did not modify the activity of antibiotics (except quinupristin-dalfopristin). All drugs (except tigecycline and oritavancin) showed higher intracellular activity against normal or revertant phenotypes than against SCV strains. The data may help rationalizing the design of further studies with intracellular SCV strains. PMCID: PMC2663071 [Available on 2009/10/01] PMID: 19188393 [PubMed - in process] Related Links Intracellular activity of antibiotics in a model of human THP-1 macrophages infected by a Staphylococcus aureus small-colony variant strain isolated from a cystic fibrosis patient: study of antibiotic combinations. [Antimicrob Agents Chemother. 2009] PMID:19188397 Pharmacodynamic evaluation of the intracellular activities of antibiotics against Staphylococcus aureus in a model of THP-1 macrophages. [Antimicrob Agents Chemother. 2006] PMID:16495241 Activities of antistaphylococcal antibiotics towards the extracellular and intraphagocytic forms of Staphylococcus aureus isolates from a patient with persistent bacteraemia and endocarditis. [Clin Microbiol Infect. 2008] PMID:18727801 Evaluation of the extracellular and intracellular activities (human THP-1 macrophages) of telavancin versus vancomycin against methicillin-susceptible, methicillin-resistant, vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus. [J Antimicrob Chemother. 2006] PMID:17062609 Quantitative analysis of gentamicin, azithromycin, telithromycin, ciprofloxacin, moxifloxacin, and oritavancin (LY333328) activities against intracellular Staphylococcus aureus in mouse J774 macrophages. [Antimicrob Agents Chemother. 2003] PMID:12821480