JAC Advance Access originally published online on May 12, 2006
Journal of Antimicrobial Chemotherapy 2006 58(1):223-224; doi:10.1093/jac/dkl198
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Correspondence |
Activity of mecillinam against AmpC ß-lactamase-producing Escherichia coli
Department of Microbiology, City Hospital Dudley Road, Birmingham B18 7QH, UK
*Corresponding author. Tel: +44-121-507-4228; Fax: +44-121-507-5521; E-mail: nigel.brenwald{at}swbh.nhs.uk
Keywords: MICs , inoculum effects , benzo(b)thiophene-2-boronic acid
Sir,
We read with interest the recently published correspondence of Thomas et al.1 which looked at the activity of mecillinam against extended spectrum ß-lactamase (ESBL)-producing Escherichia coli and Klebsiella spp. The authors demonstrated significantly raised mecillinam MICs for ESBL producers when tested at higher inocula (106 cfu/spot). In addition to ESBLs, other enzymes, such as AmpC ß-lactamases, are also emerging as important resistance mechanisms in Klebsiella pneumoniae and E. coli. Mecillinam may act as an inhibitor of AmpC ß-lactamases and often shows good in vitro activity against AmpC ß-lactamase producers using standard inoculum densities.2 However, there are few data on the effects of higher inocula on the susceptibility of these types of organisms to mecillinam.
We therefore undertook a study investigating the effects of higher inocula on the in vitro activity of mecillinam against AmpC ß-lactamase-producing E. coli. We also looked at the activity of mecillinam in the presence of clavulanic acid and benzo(b)thiophene-2-boronic acid (BZBTH2B), an AmpC ß-lactamase inhibitor. A total of 22 AmpC ß-lactamase-producing E. coli were tested including 13 isolates producing plasmid-mediated AmpC ß-lactamases. All isolates had previously been characterized as AmpC ß-lactamase producers.3 The MIC of mecillinam was determined following the BSAC standardized agar dilution method with inocula of 104 and 106 cfu per spot.4 Potential synergic effects of clavulanic acid and BZBTH2B were detected by comparing the MIC of mecillinam alone with that determined in the presence of clavulanic acid (fixed concentration 4 mg/L), BZBTH2B (fixed concentration 16 mg/L) or a combination of clavulanic acid plus BZBTH2B (fixed concentrations of 4 and 16 mg/L, respectively). The MIC of cefpodoxime was determined in the presence and absence of BZBTH2B (fixed concentration 16 mg/L) to control for the activity of the inhibitor.
The MIC results of the study are shown in Table 1. Most of the clinical isolates examined would have been considered susceptible to mecillinam using the standard inoculum of 104 cfu/spot; 21 out of 22 isolates had a mecillinam MIC of 
8 mg/L (BSAC breakpoint 8 mg/L). However, the MIC of mecillinam for most isolates increased markedly (
8-fold) when tested at the higher inoculum of 106 cfu/spot. A similar inoculum effect was seen with mecillinam and BZBTH2B. In contrast, when the MIC of mecillinam was determined in the presence of clavulanic acid no inoculum effect was seen and the MICs were significantly reduced compared with that for mecillinam alone. Similarly, the MIC of mecillinam determined with BZBTH2B and clavulanic acid showed no inoculum effect and the MIC values were nearly identical to those for mecillinam plus clavulanic acid. These findings suggest that the observed inoculum effects were due to the presence of clavulanic acid inhibitable ß-lactamases and not the AmpC ß-lactamases. AmpC ß-lactamases should be inhibited by BZBTH2B, but are little affected by clavulanic acid. The lack of activity of BZBTH2B was not due to inactivation of the inhibitor. BZBTH2B reduced the MIC of cefpodoxime (control) for most of the isolates 8-fold compared with cefpodoxime alone, showing that the inhibitor was active. It is likely that our clinical isolates were producing other ß-lactamases in addition to the AmpC ß-lactamase and it was these non-AmpC ß-lactamases which were responsible for the inoculum effects with mecillinam. Two of the isolates had previously been shown to be producing an ESBL and AmpC ß-lactamase.3
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The susceptibility to mecillinam appears little affected by AmpC ß-lactamases, with no appreciable inoculum effect attributable to this type of ß-lactamase. Initially, this suggests that mecillinam may be an effective therapy, although there are few clinical response data for mecillinam against AmpC ß-lactamase producers. However, the demonstration of a significant inoculum effect, most likely caused by the production of ß-lactamases in addition to the AmpC ß-lactamases, suggests that mecillinam may not be effective for treating serious infections. Thomas et al.1 suggested that the co-administration of a ß-lactamase inhibitor, such as co-amoxiclav, together with mecillinam might prove promising for the treatment of uncomplicated community urinary infections caused by ESBL producers. This approach could also be applicable to similar infections caused by AmpC ß-lactamase-producing E. coli in order to overcome potential mecillinam resistance caused by concomitant production of non-AmpC ß-lactamases.
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References
1
Thomas K, Weinbren MJ, Warner M, et al. (2006) Activity of mecillinam against ESBL producers in vitro. J Antimicrob Chemother 57:367–8.
2
Sougakoff W and Jarlier V. (2000) Comparative potency of mecillinam and other ß-lactam antibiotics against Escherichia coli strains producing different ß-lactamases. J Antimicrob Chemother 46:Suppl 1, 9–14.
3
Brenwald NP, Jevons G, Andrews J, et al. (2005) Disc methods for detecting AmpC ß-lactamase-producing clinical isolates of Escherichia coli and Klebsiella pneumoniae. J Antimicrob Chemother 56:600–1.
4 Andrews JM. (2001) Determination of minimum inhibitory concentrations. J Antimicrob Chemother 48:Suppl S1, 5–16.[Abstract]
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