JAC Advance Access originally published online on December 14, 2005
Journal of Antimicrobial Chemotherapy 2006 57(2):367-368; doi:10.1093/jac/dki451
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Correspondence |
Activity of mecillinam against ESBL producers in vitro
1 Department of Microbiology, Coventry and Warwickshire Hospital, University Hospitals of Coventry and Warwickshire, Stoney Stanton Road, Coventry CV1 4FH, UK; 2 Antibiotic Resistance Monitoring and Reference Laboratory, Centre for Infections, Health Protection Agency, 61 Colindale Avenue, London NW9 5HT, UK
* Corresponding author. Tel: +44-24-76844124; Fax: +44-24-76220081; E-mail: michael.weinbren{at}uhcw.nhs.uk
Keywords: CTX-M , TEM , antimicrobial resistance
Sir,
Extended-spectrum ß-lactamases (ESBLs) have emerged as an important mechanism of resistance in Gram-negative bacteria, presenting challenges on several fronts. Until recently most ESBL producers were nosocomial Klebsiella spp. with TEM or SHV enzyme mutants; but this pattern has now changed, with the spread of CTX-M ESBLs in community Escherichia coli as well as nosocomial Klebsiella spp.1 Treatment failures and deaths have occurred when cephalosporins were used against infections caused by ESBL producers that appeared susceptible in vitro, meaning that routine susceptibility tests with individual ß-lactams are unreliable and that direct ESBL detection tests are desirable.2 From a clinical perspective, ESBL-producing organisms frequently possess multiple resistance determinants to non-ß-lactam antibiotics, including aminoglycosides and fluoroquinolones, leaving an extremely limited range of treatment options.1 The management of community urinary tract infections (UTIs) caused by ESBL producers can be particularly difficult, and the paucity of active oral agents (essentially nitrofurantoin and fosfomycin) may necessitate the administration of a parenteral carbapenem.
Mecillinam (amdinocillin), an oral penicillin with good in vitro activity against Enterobacteriaceae, often appears active in vitro against ESBL producers in standard MIC test conditions, but its efficacy against infections caused by producers is uncertain.1 To investigate further, we undertook inoculum effect and synergy studies using 30 ESBL-producing E. coli and Klebsiella spp. These were selected to include representatives of current UK outbreak and non-clonal strains with CTX-M-15 enzymes, along with reference E. coli J62-1 and J53-2 transconjugants with TEM and SHV ESBLs.1 Isolates were confirmed as ESBL producers using cefpodoxime and cefpodoxime plus clavulanic acid discs on Iso-Sensitest agar according to standard Health Protection Agency and BSAC methods.3,4 MICs were determined by agar dilution on Iso-Sensitest agar with or without clavulanate (GlaxoSmithKline, Brentford, UK) at 2 or 4 mg/L. Inocula were adjusted to comprise 104 cfu/spot, as in standard BSAC tests, or 106 cfu/spot. The controls were E. coli NCTC 11954, with a classical TEM-1 ß-lactamase, and E. coli NCTC 12241 (ATCC 25922), fully susceptible to ß-lactams. Plates were incubated and results recorded in-line with standard BSAC protocols.3
The combined results are summarized in Table 1. Mecillinam MICs for CTX-M ESBL-positive E. coli and Klebsiella isolates were 0.125–2 mg/L at an inoculum of 104 cfu/spot, rising to 1–16 mg/L at 106 cfu/spot; MICs for E. coli with TEM-3, -9, -10 and SHV-2, -4 and -5 ESBLs were 4–64 mg/L at the low inoculum, rising to >64 mg/L at the higher inoculum. The ß-lactamase-negative control displayed no significant inoculum effect (MICs of 0.125 mg/L and 0.25 mg/L at 104 and 106 cfu/spot, respectively) whereas an effect was seen with the TEM-1-producing control (MICs of 0.06 and 0.5 mg/L at 104 and 106 cfu/spot, respectively), confirming that even classical penicillinases have activity against mecillinam. The values compared with the BSAC's urinary breakpoints of susceptible, 
1 mg/L; intermediate, 2 to 8 mg/L; and resistant, 
16 mg/L.3 Addition of clavulanate reduced the MICs of mecillinam for ESBL producers, bringing the modal value, as determined with an inoculum of 106 cfu/spot, down from 8–16 mg/L to 0.03–0.06 mg/L, though a few producers remained more resistant, perhaps owing to production of overwhelming amounts of enzyme.
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The raised mecillinam MICs at the higher inoculum and the MIC reductions achieved by clavulanate both suggest that the compound is not stable to ESBLs and should not be used in severe infections caused by producers. It may potentially be useful in uncomplicated lower UTIs caused by ESBL producers with low MICs, because of the high levels of mecillinam achieved in the urine, but clinical investigation is needed. While several recent reviews5,6 of mecillinam's potential in community UTI have appeared, they do not give clear guidance on the agent's relative efficacy in infections caused by ampicillin-susceptible and -resistant E. coli, although its lability to TEM-1 enzyme is well recognized. One Russian study, with only an abstract in English, does note that mecillinam was less efficacious against E. coli with R1 plasmid, which encodes TEM-1 enzyme, than against its plasmid-free counterpart in a murine septicaemia model.7 Although mecillinam can show ß-lactamase-independent synergy with penicillins that bind to penicillin-binding proteins (PBPs) 1 and 3, this seems unlikely to have interfered with the present interaction studies, both because no synergy was seen with the ß-lactamase-negative control and, secondly, because clavulanate, like mecillinam, has primary affinity for PBP-2 of E. coli.8
The simultaneous administration of oral mecillinam with a compound containing a ß-lactamase inhibitor such as co-amoxiclav appears promising, based on the present in vitro data, but cannot be advocated for clinical use without clinical evaluation.
Transparency declarations
We have no conflicts to declare.
References
1.
Livermore DM, Hawkey PM. CTX-M: changing the face of ESBLs in the UK. J Antimicrob Chemother 2005; 56: 451–4.
2.
Paterson DL, Ko WC, Von Gottberg A et al. Outcome of cephalosporin treatment for serious infections due to apparently susceptible organisms producing extended-spectrum ß-lactamases: implications for the clinical microbiology laboratory. J Clin Microbiol 2001; 39: 2206–12.
3.
Andrews JM. BSAC standardized disc susceptibility testing method (version 4). J Antimicrob Chemother 2005; 56: 60–76.
4.
Carter MW, Oakton KJ, Warner M et al. Detection of extended-spectrum ß-lactamases in klebsiellae with the Oxoid combination disk method. J Clin Microbiol 2000; 38: 4228–32.
5.
Nicolle LE. Pivmecillinam in the treatment of urinary tract infections. J Antimicrob Chemother 2000; 46 Suppl 1: 35–9.
6. Graninger W. Pivmecillinam—therapy of choice for lower urinary tract infection. Int J Antimicrob Agents 2003; 22 Suppl 2: 73–8.[Web of Science][Medline]
7. Antipov AV. Chemotherapeutic effectiveness of mecillinam and dioxidine in an experiment using polyresistant Escherichia coli. Antibiot Med Biotekhnol 1987; 32: 683–5.[Web of Science][Medline]
8.
Moosdeen F, Williams JD, Yamabe S. Antibacterial characteristics of YTR 830, a sulfone ß-lactamase inhibitor, compared with those of clavulanic acid and sulbactam. Antimicrob Agents Chemother 1988;32: 925–7.
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