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Extracellular and intracellular activities of quinupristin-dalfopristin (Synercid) against Staphylococcus aureus, with different resistant phenotypes (MSSA, MRSA, VISA)

Abstract number: 1733_1554

Baudoux P., Glupczynski Y., Tulkens P., Van Bambeke F.

Objectives:S. aureus survives and thrives in mild acidic pH environments, such as found intracellularly in phagolysosomes. Synercid, a semi-synthetic streptogramin antibiotic composed of quinupristin and dalfopristin (30:70 w/w ratio), displays a synergistic antibacterial activity against S. aureus and other Gram-positive bacteria in vitro. Synercid also displays activity against S. aureus phagocytised by murine J774 macrophages (JAC, 1992; 30 Suppl A:107–15), but this has been examined after short term incubation (2 h) and at a single fixed concentration (10×MIC) only. Our objective was to assess the activity of Synercid in a newly developed model of S. aureus-infected human THP1 macrophages that allows longer exposure periods and a detailed analysis of dose-responses for extracellular and intracellular activities (AAC 2006; 50:841–851), and using strains of S. aureus with resistance phenotypes of clinical significance.

Methods: We used an erythromycin-susceptible MSSA strain (ATCC 25923) and two erythromycin-resistant (MLSB) MRSA (ATCC 33591) and VISA (NRS 126) strains. MICs were determined by arithmetic dilution in MH Broth adjusted to pH 7.4 and 5.4. Change in CFU, compared to controls, were examined for bacteria incubated in MH broth (extracelllar activity) or phagocytised by THP-1 macrophages (intracellular activity) after 24 h exposure to concentrations from 0.01 to 100× the MIC. Key microbiological and pharmacological parameters (static concentration [Cs]; concentration yielding 50% of the maximal effect [EC50]; and maximal effect for drug concentration at infinity [Emax]) were determined by non-linear regression (Hill equation; slope factor = 1).

Results: Results are shown in the Table.

StrainMIC at pHExtracellular activityaIntracellular activitya
7.45.4EC50CsEmaxEC50CsEmax 
MSSA0.450.400.580.68-2.963.950.43-3.45
MRSA (MLSB)0.400.400.400.49-2.940.710.16-1.40
VISA (MLSB)0.300.300.310.43-2.360.220.27-1.19
aEC50 and Cs in mg/L; Emax is change in CFU (log10) from the original inoculum (~106 cfu per mL [extracell.] or per mg cell protein [intracell.]).

Conclusion: Synercid (a) shows no increase in MIC at acid pH; (b) shows comparable activities against extracellular erythromycin-susceptible MSSA and erythromycin-resistant MRSA and erythromycin-resistant VISA; (c) shows also activity against their intracellular forms (but a bactericidal effect [>3 log] is only observed with the erythromycin-susceptible MSSA).

Session Details

Date: 31/03/2007
Time: 00:00-00:00
Session name: European Society of Clinical Microbiology and Infectious Diseases
Subject:
Location: ICC, Munich, Germany
Presentation type:
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