Mecillinam/clavulanate combination: a possible option for the treatment of community-acquired uncomplicated urinary tract infections caused by extended-spectrum -lactamase-producing Escherichia coli

Extended-spectrum -lactamases (ESBLs) have emerged as an important mechanism of -lactam resistance among community uropathogens. We characterized the ESBLs of a collection of Escherichia coli isolates recovered from outpatients with urinary tract infection during nationwide surveillance conducted from 2005 to 2006 in Greece, and evaluated the in vitro activity of mecillinam and mecillinam/clavulanate against them. ESBLs were characterized with PCR and sequencing. In vitro interactions were evaluated with agar dilution with and without clavulanate (4 mg/L) using an inoculum of 10(4) or 10(6) cfu/spot as well as with timekill methodology. Among 48 ESBL producers, 47 (97.9) were susceptible to mecillinam. CTX-M-type enzymes were produced by 87.2, with CTX-M-3 being the most prevalent. SHV enzymes were found in 10.6, VEB enzymes in 2.1, TEM enzymes in 19.2 and OXA-type enzymes in 12.8. Synergy with clavulanate was detected in 60.4 using the agar dilution method and in 43.8 using the timekill methodology. An inoculum effect was detected in 64.6 of isolates, but this phenomenon was inverted and synergy was evidenced for 85.4 with clavulanate. When a high inoculum was used, 60.4 (29/48) were resistant to mecillinam, but 97.9 (47/48) were susceptible in the presence of clavulanate. CTX-M-type enzymes were the most prevalent among ESBL-producing E. coli uropathogens in Greece. Mecillinam may be useful in uncomplicated cystitis caused by ESBL producers with low MICs. The addition of the inhibitor could improve and extend the activity of mecillinam, even in the setting of infection with a high bacterial inoculum, and merits clinical evaluation.