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Antimicrobial activity of ceftaroline combined with NXL104 tested against a collection of organisms expressing multiple lactamases

Abstract number: P1270

Sader H., Williams G., Moet G., Castanheira M., Critchley I., Jones R.

Objective: To evaluate the activity of ceftaroline combined with NXL104 (fixed 4 mg/L; CPT104) against Enterobacteriaceae (ENT) with various types of b-lactamases (BL), with most strains carrying multiple BLs. Ceftaroline is a novel, parenteral cephalosporin with broad-spectrum activity against Gram-positive (including MRSA and MDRSP) and -negative organisms. Ceftaroline has limited activity against extended-spectrum b-lactamase (ESBL)- and AmpC-producing strains. NXL104 is a novel non-b-lactam BL inhibitor that inhibits Ambler class A, C, and D enzymes (eg, ESBL, KPC, and AmpC).

Methods: CPT104 and comparators were tested for susceptibility (S) by CLSI broth microdilution methods against 148 clinical strains of ENT producing KPC + AmpC (26 strains), ESBL + AmpC (27), KPC + ESBL (7), multiple ESBLs (38 strains), SME or NMC-A carbapenemases (7), KPC (12), CTX-M (8), plasmidic AmpC (15), and metallo-BL (MBL; 8). Isolates were collected from 1999–2008 from global surveillance programs.

Results: CPT104 exhibited potent inhibitory effects against all BL types except MBLs. All isolates were inhibited at CPT104 MIC leqslant R: less-than-or-eq, slant4 mg/L except the MBL-producing strains (Table). CPT104 was highly active against ENT producing KPC (MIC90, 0.5 mg/L), KPC + AmpC (MIC90, 2 mg/L), and KPC + ESBL (MIC100, 1 mg/L). CPT104 was more active than meropenem (MIC90, >8 mg/L) against these 3 groups. ENT-producing CTX-M (highest CPT104 MIC, 0.5 mg/L) and those producing more than one ESBL type (including CTX-M, SHV, TEM, OXA and OXY; MIC90, 1 mg/L) were also very S to CPT104. The highest CPT104 MIC observed among plasmidic AmpC was 0.5 mg/L. All strains producing SME or NMC-A were also inhibited at leqslant R: less-than-or-eq, slant0.5 mg/L of CPT104. CPT104 (MIC, >32 mg/L) and all b-lactam compounds tested showed limited activity against MBL-producing ENT.

Conclusions: Results of this study clearly demonstrated that NXL104, when combined with ceftaroline, effectively lowers ceftaroline MIC for ENT that produce the most clinically significant BLs, except MBLs. CPT104 was highly active against ENT that produce KPC, various ESBL types, and AmpC (chromosomally derepressed or plasmid mediated), as well as those producing more than one of these BL types (Table). CPT104 represents a promising therapeutic option for treatment of infections caused by multidrug-resistant ENT.

BL type (no. tested)Cumulative % inhibited at CPT104 MIC (mg/L):
 leqslant R: less-than-or-eq, slant0.060.120.250.5124>4
KPC + AmpC (26)3.83.88.630.873.196.2100.0-
ESBL + AmpC (27)0.014.837.055.674.096.3100.0-
KPC + ESBL (7)0.00.014.357.1100.0---
Multiple ESBLs (38)2.660.586.889.597.4100.0--
SME/NMC-A (7)0.014.342.9100.0----
KPC (12)0.00.016.791.7100.0---
CTX-M (8)12.575.087.5100.0----
Plasmidic AmpC (15)13.360.086.7100.0----
MBL (8)0.00.00.00.00.00.00.0100.0

Session Details

Date: 10/04/2010
Time: 00:00-00:00
Session name: Abstracts 20th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Vienna, Austria, 10 - 13 April 2010
Presentation type:
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