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Extended-spectrum beta-lactamases (ESBLs) are enzymes that inactivate and confer resistance to most beta-lactam antibiotics, including penicillins, cephalosporins, and the monobactam aztreonam. They are found exclusively in gram-negative organisms, primarily Klebsiella pneumoniae, Klebsiella oxytoca, and Escherichia coli. Many different varieties of ESBL exist. They differ in their activity against particular beta-lactam substrates and in their geographical distribution. Most ESBLs do not break down cephamycins or carbapenems and are susceptible to beta-lactamase inhibitors.
Laboratory detection of an ESBL in an organism is based on resistance to particular cephalosporins and the ability of a beta-lactamase inhibitor to block this resistance. However, the heterogeneity of the ESBL varieties can make identification difficult. Thus, the Clinical and Laboratory Standards Institute has adjusted susceptibility breakpoint recommendations for gram-negative bacilli. As a result, many organisms that previously would have been categorized as susceptible using the former breakpoints may now be considered intermediate or resistant. This often precludes the need to identify the ESBL in order to make treatment decisions.
ESBL-producing gram-negative bacilli have been reported worldwide. They are most often isolated from hospitalized patients but are an increasing cause of community-acquired infections. Risk factors
for infection include prior administration of an antibiotic, presence of urinary or vascular catheters, and longer hospital or ICU
The best therapeutic option for severe infections caused by ESBL-producing organisms is a carbapenem (imipenem, meropenem, doripenem, and ertapenem). We use meropenem or imipenem for most ESBL infections. Ertapenem is an acceptable option in the absence of resistance or severe sepsis and can be particularly useful in the outpatient setting.
may be effective against ESBL-producing organisms that test susceptible if administered in high doses (ie
, 2 g every eight hours). Use of other cephalosporins
has been associated with treatment failures. Ceftolozane-tazobactam and ceftazidime-avibactam
combinations appear promising, but further clinical data are needed to establish their efficacy relative to carbapenems. There is little clinical evidence for cephamycin
use, which has been associated with development of resistance. Resistance to aminoglycosides
is also common in these organisms.
Infections with ESBL-producing organisms are associated with higher mortality rates, longer hospital stays, greater hospital expenses, and reduced rates of clinical and microbiologic response compared with similar infections with gram-negative bacteria that do not produce ESBL.
The spread of ESBL-producing organisms within institutions can be slowed by the use of barrier protection and restriction of later generation cephalosporins.
Studies evaluating clinical outcomes in patients with extended-spectrum beta-lactamase (ESBL) infections have shown a trend toward higher mortality, longer hospital stay, greater hospital expenses, and reduced rates of clinical and microbiologic response.
In a meta-analysis of 32 studies of bacteremia with Enterobacteriaceae, infection with ESBL-producing organisms was associated with higher mortality than non-ESBL-producing organisms, (OR 2.35, 95% CI 1.90-2.91).
Evaluation of the studies that performed adjusted analyses suggested that much of the increased mortality may be due to ineffective empiric therapy. As mentioned above, mortality rates of 3.7 percent have been described with carbapenems, with much higher mortality rates with antibiotics not active against these organisms (7 of 11 [64%]) and with cephalosporin monotherapy or a beta-lactam/beta-lactamase inhibitor combination such as piperacillin-tazobactam (4 of 9 [44%]).
Some individuals infected or colonized by ESBL-producing organisms continue to shed bacteria for prolonged periods. Among 42 patients with infection due to ESBL-producing E. coli, persistent colonization was observed after a median of 58 months among five patients. It is unclear whether systemic antibiotic therapy affects colonization status.
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Carbapenem therapy is associated with improved survival compared with piperacillin-tazobactam for patients with extended-spectrumβ-lactamase bacteremia.