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In vitro activity of mecillinam in combination with aminopenicillin/b-lactamase-inhibitor – Combinations against ESBL-producing Enterobacteriaceae

Abstract number: R2326

Herbich K., Zeitlberger E., Stadler M., Janata O., Asboth F., Apfalter P.

Objective: Due to raised MICs at high inocula it has been suggested that the amidinopenicillin Mecillinam (MEC) is not stable to ESBLs and should not be used in severe infections. The same is true for amoxicillin/clavulanic acid (AMC) and piperacillin/tazobactam (PTZ), since their activity largely depends on species, type of b-lactamase and inoculum. MEC preferentially binds to PBP2 and amoxicillin as well as piperacillin to PBP3. The aim of this study was to test (i) if MEC combined with AMC or PTZ would result in synergistic in vitro activity, and (ii) whether the effect would be stable in the presence of a high inoculum.

Material and Methods: Forty-two consecutive ESBL-producers (thereof E. coli, n = 36) isolated in 2007 from urine samples were studied. ESBL production was detected by CLSI methods and an extended double disk diffusion synergy test. Clonal relationship was investigated by means of RAPD and ERIC-PCR. MICs and synergy testing [MEC/AMC; MEC/PTZ] was done by Etest® and fractional inhibitory concentration (FIC) indices were calculated (FIC = MICAB/MICA + MICBA/MICB). In a preliminary study inocula were adjusted to comprise 104 CFU/ml and 108 CFU/ml.

Results: Preliminary experiments: MICs for MEC were 1–64 mg/L at an inoculum of 104 CFU/mL, rising to 2–256 mg/L at 108 CFU/mL. For AMC, PTZ, and the combinations MEC/AMC and MEC/PTZ MICs were not inoculum-dependent. Resistant colonies within the MEC ellipse could be observed in some cases. If these colonies were retested, they proved highly MEC resistant, what did not affect FIC indices. Synergy testing was thus done with the higher inoculum. For MEC, AMC and PTZ alone MICs50 were 1.5 mg/L, 8 mg/L, and 8 mg/L. According to CLSI, 76%, 57%, and 67% strains were susceptible. Synergy testing: the MIC90A/B for MEC/AMC and MEC/PTZ was 1 mg/L each, and the MIC90B/A was 0.7 mg/L and 0.3 mg/L, respectively. A synergistic, additive and indifferent effect for MEC/AMC [MEC/PTZ] was found for 66.6% [92.8%], 28.5% [2.3%], and 5% [5%] strains, respectively.

Polyclonality was shown for 34/42 E. coli (>80%) and 3/5 K. pneumoniae isolates.

Conclusion: MEC has a good, but inoculum dependent, in vitro activity against ESBL-producing enterobacteriaceae. The susceptibility of AMC and PTZ cannot reliably be predicted. When administered combined, both combinations resulted in a significant MIC reduction due to a highly synergistic, inoculum independent effect.

Session Details

Date: 19/04/2008
Time: 00:00-00:00
Session name: 18th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Barcelona, Spain
Presentation type:
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