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The activity of NXL101 against fluoroquinolone-resistant clinical isolates of Staphylococcus aureus

Abstract number: 1732_299

Morrissey I., Lowther J., Soltani M., Northwood J.

Objectives: To evaluate the novel topoisomerase inhibitor NXL101 against fluoroquinolone-resistant (FQR) S. aureus (SA).

Methods: MIC against 39 FQR SA and the control strain ATCC29213 (Cont) was determined for NXL101, levofloxacin (LFX), ciprofloxacin (CFX), moxifloxacin (MFX) and gemifloxacin (GFX) by CLSI broth microdilution. Topoisomerase gene (grlA, grlB, gyrA & gyrB) quinolone resistance determining regions (QRDRs) were amplified and sequenced and the effect of reserpine (RES, 20 mg/L) on MIC (i.e. the role of FQ efflux) was evaluated to determine mechanism(s) of resistance.

Results: MIC, QRDR and efflux data are shown in the table. Most FQR SA possessed combined GrlA (S80F)–GyrA (S84L) changes. Others had additional changes in GrlA, GyrA or GrlB, but none were found in GyrB. The effect of RES on CFX MIC was variable, but this did not affect FQ MIC as much as QRDR changes. Other FQ were less affected by RES than CFX. NXL101 MIC ranged from 0.03 to 1 mg/L (mode 0.06/0.12 mg/L) and was not affected by any QRDR changes. Some RES effect was observed with NXL101, but most FQR SA had similar NXL101 MIC to the Cont strain (for which NXL101 MIC was not affected by RES).

No. of IsolatesAA ChangeEffluxMIC range (mg/L)
Grl AGrIBGyrANXLMFXGFXLFXCFX  
10S80FS84L++0.06–0.2522–88–1632–512
5S80FS84L+++0.06–122–88–16256 
5S80FS84LN0.12–0.252–42–88–1616–256 
3S80FS84L+0.06–0.52–42–88–1632–256 
2S80FD432VS84L++0.25816–3232256
1S80F, P144SE422DS84L++0.12488256
1S80F, P144SE422DS84L+0.124816256
1S80F, P144SS84LN0.06241616
1S80F, E84KS84L+++0.068816256
1S80F, E84KS84L++0.128832256
1S80F, E84KS84L+0.064816128
1S80F, E84KS84LN0.0681632256
1S80F, E84KS84VN0.068416256
1S80F, E84GS84L++0.0683232128
1S80FD132NS84V++0.034216128
1S80FS84L, G106D+0.522816
1S80YD432HS84L+++0.064216256
1S80YD432NS84L++0.124832256
1S80YS84L++0.2522816
ContN0.060.060.0150.250.25
aEfflux: effect of RES on CFX MIC: +++ (4–6 dilutions decreased), ++ (2–3 dilutions decreased), + (1 dilution decreased), N (no effect).

Conclusion: NXL101 retained activity against highly FQR SA exhibiting a range of QRDR mutations and CFX efflux. NXL101 must target topoisomerases in a manner distinct to that of FQs.

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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