Intracellular activity of antibiotics in a model of human THP-1 macrophages infected by a Staphylococcus aureus Small Colony Variant isolated from a cystic fibrosis patient : study of antibiotic combinations

Nguyen, Hoang;Denis, Olivier;Vergison, Anne;Tulkens, Paul M.;Van Bambeke, Françoise;et.al.
(2009) Antimicrobial Agents and Chemotherapy — Vol. 53, n° 4, p. 1443-1449 (2009)

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Abstract
In a companion paper (Nguyen et al. Antimicrob. Agents Chemother. 2008; xx:yyy-zzz), we showed that vancomycin, oxacillin, fusidic acid, clindamycin, linezolid, and daptomycin are poorly active against the intracellular form of a thymidine-dependent Small Colony Variant (SCV) isolated from a cystic fibrosis patient, and that the activity of quinupristin/dalfopristin, moxifloxacin, rifampin, and oritavancin remains limited (2-3 log CFU reduction) compared to their extracellular activity. Antibiotic combination is a well-known strategy to improve antibacterial activity, the interest of which was examined here against an intracellular SCV, and using combinations with either rifampin or oritavancin. Time-kill curve analysis using either concentrations that caused static effect for each antibiotic individually or concentrations corresponding to the human Cmax showed largely divergent effects that were favorable when combined with rifampin at low concentrations only and with oritavancin at both low and high concentrations. The nature of the interaction between rifampin, oritavancin, and moxifloxacin was further examined using the Fractional Maximal Effect method, which allows for categorization of the effects of combinations when dose-effects relationships are not linear. Rifampin and oritavancin were synergistic at all concentrations ratios investigated. Oritavancin and moxifloxacin were also synergistic but at high oritavancin concentrations only. Rifampin and moxifloxacin were additive. This approach may help in better assessing and improving the activity of antibiotics against intracellular SCV.
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Nguyen, H., Denis, O., Vergison, A., Tulkens, P. M., Struelens, M. J., & Van Bambeke, F. (2009). Intracellular activity of antibiotics in a model of human THP-1 macrophages infected by a Staphylococcus aureus Small Colony Variant isolated from a cystic fibrosis patient : study of antibiotic combinations. Antimicrobial Agents and Chemotherapy, 53(4), 1443-1449. https://doi.org/10.1128/AAC.01146-08 (Original work published 2009)