Extended-spectrum beta-lactamases (ESBLs)
推せるよ セフェピム ESBLs
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 stays.
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.
Cefepime 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 and piperacillin-tazobactam 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 and fluoroquinolones 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.
The amino acid substitutions responsible for the ESBL phenotype cluster around the active site of the enzyme and change its configuration, allowing access to oxyimino-beta-lactam substrates. Single amino acid substitutions at positions 104, 164, 238, and 240 produce the ESBL phenotype, but ESBLs with the broadest spectrum usually have more than a single amino acid substitution. Based upon different combinations of changes, currently more than 220 TEM-type enzymes have been described. Most are ESBLs, but some are resistant to beta-lactamase inhibitors, and a few are both ESBLs and inhibitor resistant. TEM-10, TEM-12, and TEM-26 are among the most common in the United States.
ESBLs in this family also have amino acid changes around the active site, most commonly at positions 238 or 238 and 240. More than 190 SHV varieties are known, and they are found worldwide. SHV-2, SHV-5, SHV-7, and SHV-12 are among the most common.
These enzymes were named for their greater activity against cefotaxime than other oxyimino-beta-lactam substrates (eg, ceftazidime, ceftriaxone, or cefepime). Despite their name, a few are more active on ceftazidime than cefotaxime. Rather than arising by mutation, they represent examples of plasmid acquisition of beta-lactamase genes normally found on the chromosome of Kluyvera species, a group of rarely pathogenic commensal organisms.
OXA beta-lactamases were long recognized as a less common but also plasmid-mediated beta-lactamase variety that could hydrolyze oxacillin and related anti-staphylococcal penicillins. Amino acid substitutions in OXA enzymes can also give the ESBL phenotype. OXA-type ESBLs have been found mainly in Pseudomonas aeruginosa isolates from Turkey and France. OXA beta-lactamases with carbapenemase activity have also been described.
- Length of hospital stay
- Length of ICU stay
- Presence of central venous or arterial catheters
- Emergency abdominal surgery
- Presence of a gastrostomy or jejunostomy tube
- Gut colonization
- Low birth weight
- Prior administration of any antibiotic
- Prior residence in a long-term care facility (eg, nursing home)
- Severity of illness
- Presence of a urinary catheter
- Ventilatory assistance
The choice of an appropriate antibiotic is essential since failure to treat with an antibiotic active against ESBL-producing K. pneumoniae is associated with lack of an adequate response and increased mortality. The potential magnitude of this effect was illustrated in a review of 85 patients with ESBL-producing K. pneumoniae infection from 12 hospitals in seven countries; 20 patients (24 percent) died . Failure to treat with an antibiotic that had in vitro activity against the cultured isolate during the first five days after the culture result was known was associated with a significantly higher mortality rate compared to treatment with active antibiotics (64 versus 14 percent). Administration of a carbapenem (imipenem, meropenem, and perhaps ertapenem) alone or with other antibiotics was associated with a significantly lower mortality than for those treated with active noncarbapenem antibiotics.
Treatment with a carbapenem produces the best outcomes in terms of survival and bacteriologic clearance. The efficacy of therapy with these agents is supported mainly by observational studies. In a prospective study of 85 episodes of bacteremia due to ESBL-producing K. pneumoniae, there was only one death at 14 days among 27 patients (3.7 percent mortality) treated with carbapenem monotherapy (imipenem in 24 and meropenem in 3)．In contrast, there were seven deaths among the 11 patients (64 percent) who did not receive any antibiotic active against these organisms and four deaths in nine patients (44 percent) treated with cephalosporin monotherapy or a beta-lactam/beta-lactamase inhibitor combination such as piperacillin-tazobactam. On multivariate analysis, carbapenem use was independently associated with reduced mortality (odds ratio 0.09, 95% CI 0.01-0.65). Similarly, in a retrospective study of patients with bacteremia due to an ESBL-producing organism, 14-day mortality was 8 percent among the 110 who received a carbapenem for empiric treatment compared with 17 percent among the 103 who received piperacillin-tazobactam．
There are no clear differences in efficacy between imipenem and meropenem. The choice to use one over the other is predominantly based on toxicity profiles in specific hosts. As an example, meropenem is favored in the setting of seizures or pregnancy because of the possible central nervous system toxicity and unknown safety in pregnancy of imipenem. Meropenem also may be easier to dose in the setting of changing or impaired renal failure.
Because doripenem is a relatively new carbapenem, the clinical data for its use in infections with organisms that produce ESBL are limited but overall suggest equivalent efficacy when compared with meropenem or imipenem．
Ertapenem has the advantage of once-daily dosing and has good in vitro activity, and clinical data regarding its use are growing. In two retrospective studies from the United States and Taiwan of patients with bloodstream infections due to Enterobacteriaceae that produced ESBL, treatment with ertapenem (n = 72 and 75, respectively) was associated with similar mortality rates as treatment with meropenem or imipenem (n = 132 and 176). Although patients treated with ertapenem in the study from the US had less invasive disease and a lower frequency of severe sepsis, adjusted analysis controlling for disease state and severity still showed equivalent mortality rates in the two groups. Smaller studies have reported favorable clinical response and microbiologic cure rates using ertapenem for ventilator-associated pneumonia and urinary tract infections due to ESBL-producing organisms. However, some ESBL-producing isolates are resistant to ertapenem, and resistance may also develop on therapy. We reserve the use of ertapenem for infections with susceptible ESBL-producing organisms that are not associated with severe sepsis. It can be a useful alternative for outpatient treatment of such infections.
Treatment of severe infections due to ESBL-producing K. pneumoniae with an oxyimino-beta-lactam (eg, cefotaxime, ceftazidime, ceftriaxone, or cefepime) is likely to result in treatment failure, even if the organism demonstrates in vitro susceptibility. However, cephalosporin-beta-lactamase inhibitors (namely ceftolozane-tazobactam and ceftazidime-avibactam) are novel agents that appear to have greater activity against ESBL-producing organisms.
In a review of 28 patients with ESBL-producing Klebsiella pneumoniae with reported susceptibility to cephalosporins, 15 failed to respond to cephalosporin therapy. A possible explanation for the inferior outcomes in patients treated with apparently active cephalosporins may be the inoculum effect, in which there is a marked increase in MIC with increased inoculum．
While ESBL-producing bacteria generally test susceptible to cephamycins, resistance has developed after their use due to loss of porin channels for cephamycin entry, and there is little clinical experience to demonstrate their efficacy.
Cefepime may be effective against ESBL-producing organisms if administered in high doses rather than standard doses (1 g every 12 hours). In a European study of nosocomial pneumonia due to ESBL-producing pathogens, nine of thirteen patients treated with high-dose cefepime (2 g every eight hours) responded clinically．However, in a retrospective study that used an MIC ≤8 µg/ml as the breakpoint for cefepime susceptibility, cefepime was inferior to carbapenem for bacteremia due to ESBL-producing Enterobacteriaceae, and most available data do not encourage cefepime use for ESBL-producing pathogens.
With the addition of a beta-lactamase inhibitor, ceftolozane-tazobactam and ceftazidime-avibactam have extended spectra of activity to include most ESBL-producing Enterobacteriaceae. In a trial of patients with intraabdominal infections, ceftolozane-tazobactam plus metronidazole compared favorably to meropenem among those who had infections with ESBL-producing organisms (clinical cure rate in 23 of 24 [95 percent] versus 23 of 26 [89 percent] with meropenem).
We do not recommend piperacillin-tazobactam for severe infections with ESBL-producing organisms. Treatment failures have been described with piperacillin-tazobactam for treatment of infection due to ESBL isolates. In a retrospective study of over 200 individuals with bacteremia due to an ESBL-producing organism, empiric treatment with piperacillin-tazobactam (compared with a carbapenem) was associated with a higher risk of death within 14-days (adjusted HR 1.92, 95% CI 1.07-3.45) . In addition, resistance may develop during therapy.
In contrast, another retrospective study failed to demonstrate statistically significant differences in mortality outcomes in patients with ESBL-producing E. coli bacteremia based on whether piperacillin-tazobactam or carbapenems were used for empiric or definitive therapy.
Piperacillin-tazobactam may be effective for ESBL isolates with piperacillin-tazobactam MIC ≤16/4 mcg/mL and for urinary tract infections, regardless of susceptibility． The latter observation is a presumed reflection of the much higher drug concentrations achieved in urine compared to plasma.
Data on other agents, including quinolones and aminoglycosides, for use in for ESBL-producing organisms are sparse. One study evaluated bacteremia caused by ESBL-producing K. pneumoniae that were susceptible to ciprofloxacin. Among seven patients treated with ciprofloxacin, five failed treatment and two had a partial response; patients treated with imipenem had better outcomes (complete response in eight of ten).
Fosfomycin may be an oral option for complicated and uncomplicated urinary tract infections, although resistance to this drug has been documented during treatment. Additionally, increased use of this drug in the community has been associated with an increase rate of fosfomycin resistance among ESBL-producing isolates.
Tigecycline is another non beta-lactam drug that is a potential alternative for treatment of ESBL-producing strains, especially for patients with beta-lactam allergies, although data on its clinical use for this purpose are limited. In a systematic review of 10 studies that included 33 patients who received tigecycline for an ESBL infection, the response rate was 67 percent. Increasing tigecycline resistance does not yet appear to be a problem, as a 2014 microbiological surveillance showed unchanged resistance profiles in 2012 when compared to 2006 isolates.
There are no clinical data supporting the use of double antibiotic coverage for treatment of ESBL-producing organisms.
Lancet Infect Dis. 2010 Jan;10(1):43-50.
- Fosfomycin for the treatment of multidrug-resistant, including extended-spectrum beta-lactamase producing, Enterobacteriaceae infections: a systematic review.
- Rising rates of resistance to antimicrobial drugs among Enterobacteriaceae limit the choice of reliably active forms of these drugs. We evaluated the evidence on fosfomycin as a treatment option for infections caused by members of the family Enterobacteriaceae with advanced resistance to antimicrobial drugs, including producers of extended-spectrum beta-lactamase (ESBL). We systematically reviewed studies evaluating the antimicrobial activity, or the clinical effectiveness of fosfomycin. 17 antimicrobial-susceptibility studies were found and included in our Review, accounting for 5057 clinical isolates of Enterobacteriaceae with advanced resistance to antimicrobial drugs (4448 were producers of ESBL); 11 of the 17 studies reported that at least 90% of the isolates were susceptible to fosfomycin. Using a provisional minimum inhibitory concentration susceptibility breakpoint of 64 mg/L or less, 1604 (96.8%) of 1657 Escherichia coli isolates producing ESBL were susceptible to fosfomycin. Similarly, 608 (81.3%) of 748 Klebsiella pneumoniae isolates producing ESBL were susceptible to fosfomycin. In two clinical studies, oral treatment with fosfomycin-trometamol was clinically effective against complicated or uncomplicated lower urinary tract infections caused by ESBL-producing E coli in, cumulatively, 75 (93.8%) of the 80 patients evaluated. Initial clinical data support the use of fosfomycin for the treatment of urinary tract infections caused by these pathogens, although further research is needed.
Antimicrob Agents Chemother. 2012 Nov;56(11):5744-8. Epub 2012 Aug 27.
- Experience with fosfomycin for treatment of urinary tract infections due to multidrug-resistant organisms.
- Fosfomycin has shown promising in vitro activity against multidrug-resistant (MDR) urinary pathogens; however, clinical data are lacking. We conducted a retrospective chart review to describe the microbiological and clinical outcomes of urinary tract infections (UTIs) with MDR pathogens treated with fosfomycin tromethamine. Charts for 41 hospitalized patients with a urine culture for an MDR pathogen who received fosfomycin tromethamine from 2006 to 2010 were reviewed. Forty-one patients had 44 urinary pathogens, including 13 carbapenem-resistant Klebsiella pneumoniae (CR-Kp), 8 Pseudomonas aeruginosa, and 7 vancomycin-resistant Enterococcus faecium (VRE) isolates, 7 extended-spectrum beta-lactamase (ESBL) producers, and 9 others. In vitro fosfomycin susceptibility was 86% (median MIC, 16μg/ml; range, 0.25 to 1,024μg/ml). Patients received an average of 2.9 fosfomycin doses per treatment course. The overall microbiological cure was 59%; failure was due to either relapse (24%) or reinfection UTI (17%). Microbiological cure rates by pathogen were 46% for CR-Kp, 38% for P. aeruginosa, 71% for VRE, 57% for ESBL producers, and 100% for others. Microbiological cure (n = 24) was compared to microbiological failure (n = 17). There were significantly more solid organ transplant recipients in the microbiological failure group (59% versus 21%; P = 0.02). None of the patients in the microbiological cure group had a ureteral stent, compared to 24% of patients within the microbiological failure group (P = 0.02). Fosfomycin demonstrated in vitro activity against UTIs due to MDR pathogens. For CR-KP, there was a divergence between in vitro susceptibility (92%) and microbiological cure (46%). Multiple confounding factors may have contributed to microbiological failures, and further data regarding the use of fosfomycin for UTIs due to MDR pathogens are needed
J Antimicrob Chemother. 2010 Nov;65(11):2459-63. Epub 2010 Sep 16.
- Parallel increase in community use of fosfomycin and resistance to fosfomycin in extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli.
- OBJECTIVES: To document fosfomycin susceptibility of extended-spectrumβ-lactamase-producing Escherichia coli (ESBL-EC), analyse trends in fosfomycin use and investigate fosfomycin resistance in ESBL-EC isolated from urinary tract infections (UTIs).
- METHODS: Twenty-seven Spanish hospitals participating in the European Antimicrobial Resistance Surveillance Network were requested to collect up to 10 sequential ESBL-EC for centralized susceptibility testing and typing. EUCAST guidelines were followed for antibiotic susceptibility testing, and bla(ESBL) type, phylogroups and O25b serotype were determined by PCR and sequencing. In addition, the trend in fosfomycin resistance among ESBL-EC causing UTIs was determined in 9 of the 27 hospitals. Total fosfomycin use for ambulatory care was established by WHO-recommended methods.
- RESULTS: A total of 231 ESBL-EC (42.4% CTX-M-15, 34.2% SHV-12 and 23.4% CTX-M-14) were collected. The overall rate of fosfomycin resistance was 9.1%, but varied according to ESBL type (5.6% of CTX-M-14 isolates, 5.1% of SHV-12 and 15.3% of CTX-M-15). Of 67 O25b/B2 isolates, 11 (16.4%) were fosfomycin resistant. Predictors of infection with fosfomycin-resistant ESBL-EC were O25b/phylogroup B2 isolates, female gender and nursing home residence. Among 114 197 UTIs caused by E. coli 4740 (4.2%) were due to ESBL-EC. Fosfomycin resistance increased in these isolates from 4.4% (2005) to 11.4% (2009). The use of fosfomycin grew from 0.05 defined daily doses per 1000 inhabitants per day (1997) to 0.22 (2008), a 340% increase.
- CONCLUSIONS: Key factors related to increased fosfomycin resistance in ESBL-EC causing UTIs could be the rapid growth in community use of fosfomycin, the widespread distribution of the 025b/B2 E. coli clone and the existence of a susceptible population comprising women residing in nursing home facilities.