Extended-spectrum beta-lactamases

The definition of extended-spectrum beta-lactamases (ESBLs) has 
expanded rapidly, in terms of both the number and the variety of 
enzymes. Bacteria bearing plasmidic ESBLs are spreading widely 
throughout the world. In Canada, the problem has grown less rapidly 
than in other parts of the world; however, ESBLs still present a significant 
impediment to the treatment of serious infections with extendedspectrum 
cephalosporins and penicillins. Although SHV-derived 
enzymes were the primary concern in the late 1980s and early 1990s, 
these enzymes have been rapidly overtaken by the CTX-M family of 
ESBLs. There is no reason to believe that the problem of ESBLs will 
not expand rapidly in the face of intense antimicrobial pressure and 
lapses in infection control practices. Control should focus on early 
detection, accurate characterization, effective treatment and measures 
to prevent further spread.


Extended-spectrum beta-lactamases
Can J Infect Dis Med Microbiol Vol 17 Suppl B May/June 2006 7B E coli.In their study, 70% of strains of beta-lactamases were in the CTX-M family and greater than two-thirds were from patients in the community (10).In their patient population, ciprofloxacin resistance was often associated with ESBL-mediated resistance.
In the United States, ESBL-mediated resistance has increased slightly more rapidly than in Canada.In a SENTRY study (11) of third-generation cephalosporin-resistant Klebsiella species, the prevalence in the United States was higher than that in Canada but less than that in other countries (Latin America [45%], the western Pacific region [25%], Europe [23%], the United States [8%] and Canada [5%]).
Also in Canada, outbreaks of multiresistant E coli in longterm care facilities have been well documented by Muller et al (12).In one long-term care facility, 93 of 149 residents were colonized with an outbreak strain.In another investigation (12) in the Durham region north of Toronto, Ontario, more than 200 individuals were colonized with an ESBL-bearing E coli.A number of risk factors for ESBL infection colonization have been identified.The duration of both hospital and intensive care unit stay, prior use of a third-generation cephalosporin antibiotic and severe illnesses increase patient susceptibility to infection in the acute care setting (13-15) (Table 2).
When hospital outbreaks occur, they may be difficult to control.Lucet et al (16) described their experience in a Paris, France hospital.By flagging colonized patients and by reinforcing handwashing and other infection control measures, they were able to reduce the rate of acquisition of ESBL-producing Enterobacteriaceae from 117 to only 19 cases per year.This corresponded to a nosocomial rate reduction of 0.56 to 0.06 per 100 admissions.Also of interest, in this setting, is that they did not apply any antibiotic restrictions, while at the same time, they achieved a considerable reduction in transmission.
In another study, Rahal et al (17) responded to an ESBLbearing Klebsiella outbreak with a strategy that included restriction of third-generation cephalosporins.They restricted cephalosporin use to certain pediatric infections, single-dose surgical prophylaxis, acute bacterial meningitis and spontaneous bacterial peritonitis.They were able to achieve an 80% reduction in the amount of cephalosporin use and, correspondingly, a 44% reduction in the number of cases of ceftazidime-resistant Klebsiella.Correspondingly, there was a 140% increase in the amount of imipenem used and a 69% increase in the incidence of imipenem-resistant Pseudomonas aeruginosa.Lee et al (18) found that prior exposure to third-generation cephalosporins was an independent risk factor for acquisition of ESBL-producing K pneumoniae, and that reducing the use of this class of antibiotics appeared to lower the acquisition rate (18).For others, formulary intervention did not appear to have a significant effect (19).At this time, the relative importance of tight infection control measures and improved antibiotic stewardship is not known.The optimal strategy presumably involves both measures undertaking the concurrent implementation of both strategies.
There is no doubt that infection with ESBL-bearing bacteria adversely affects patients' outcomes.Paterson et al (20) studied 445 patients with K pneumoniae bacteria; 85 of these infections were due to ESBL-producing strains (20).Eight of 23 patients not receiving antibiotics other than a carbapenem died within 10 days.Only one of 27 patients receiving a carbapenem died in the same period.Kim et al (21) examined the outcomes of children with bacteremia due to E coli and K pneumoniae with and without ESBLs; the case fatality rate for the ESBL group was significantly higher (12 of 45; P=0.001) than that for the non-ESBL group (five of 87).
The antibiotic class of choice for the treatment of ESBLbearing Enterobacteriaceae appears to be a carbapenem (22).Although in vitro susceptibility suggests that cefepime should be active in vivo, there is a clear inoculum effect (ie, a large concentration of organisms can overwhelm the antibacterial affect of this antibiotic) (23)(24)(25).A rat model of P aeruginosa pneumonia responded poorly to cefepime (26).At this point in time, it cannot  be considered a first-line agent.Piperacillin-tazobactam also shows an inoculum effect, and several animal studies have suggested that it is less efficacious than carbapenems (26,27).However, the importance of the inoculum effect has recently been questioned; further studies are required to clarify the degree to which it influences in vivo response to antibiotics, particularly in settings where the bacterial burden is high (28).For many ESBL strains, aminoglycosides, fluoroquinolones and trimethoprim-sulfamethoxazole retain activity.However, several studies have shown high levels of coresistance to these antibiotics in ESBL-bearing strains (29)(30)(31)(32)(33)(34).
While carbapenems are currently considered to be the drug of choice, bacterial strains with porin mutations may infer resistance (35).There is also concern that the spread of carbapenemase enzymes (of which there are two classes) will threaten the usefulness of this class of antibiotics in the future (36)(37).
DISCLOSURES: In the past year, Dr Forward has served on advisory boards for both Wyeth-Ayerst Canada Inc and Merck Frosst Canada Ltd, and has developed educational materials for both.He has also received research funding from sanofi-aventis Canada.

TABLE 1
Molecular and phenotypic classification of more commonly occurring or important beta-lactamases (BLAs)

TABLE 2
ForwardCan J Infect Dis Med Microbiol Vol 17 Suppl B May/June 2006 8B