Extended-spectrum plasmid-mediated beta-lactamases

Extended-spectrum beta-lactamases (ESBLs) are mutant enzymes which derive from TEM or SHV (class A) enzymes. They confer variable levels of resistance to cefotaxime, ceftazidime and other broad-spectrum cephalosporins and to monobactams such as aztreonam but have no detectable activity against cephamycins and carbapenems. Recently, new plasmid-mediated ESBLs, not derived from TEM or SHV enzymes but related to cephalosporinases of Enterobacteriaceae (class C enzymes), that confer resistance to all cephalosporins including cephamycins, have been reported. However, to date there have been no reported outbreaks due to strains producing transferable cephalosporinases. Klebsiella pneumoniae is the species in which the ESBL enzymes have been most commonly reported around the world. Most of the clinical isolates that produce TEM- or SHV-derived ESBL, come from hospitalised patients and have frequently caused nosocomial outbreaks. Care should be taken in the selection of a beta-lactam for the treatment of infections because the presence of an ESBL does not prevent other mechanisms of resistance, such as decreased permeability, from emerging. Broad-spectrum cephalosporins including cefepime and cefpirome are hydrolysed by ESBL. However, low level resistance to cefotaxime, ceftriaxone, cefepime and aztreonam does occur in some strains producing certain TEM-derived ESBL. It remains to be seen, therefore, whether such isolates are clinically susceptible to these drugs. The combination of a third-generation cephalosporin and a beta-lactamase inhibitor such as sulbactam could be of interest against some strains producing certain ESBLs. Among the 7-alpha-methoxy cephalosporins, cefotetan and latamoxef are the most active. However, cephamycins should be used with caution to treat infections caused by ESBL-producing K. pneumoniae because of the relative ease with which clinical strains decrease the expression of outer membrane proteins. The most active beta-lactams are the carbapenems, imipenem and meropenem, which are highly resistant to hydrolysis by TEM and SHV related beta-lactamases. Meropenem is intrinsically the more active agent, with MICs (0.03-0.12 mg/L) generally lower than those of imipenem (0.06-0.5 mg/L) and appears stable to all the beta-lactamases belonging to class A or C, including those with an extended-spectrum against third-generation cephalosporins.