Extended-spectrum beta-lactamases

INTRODUCTION — Extended-spectrum beta-lactamases (ESBLs) are enzymes that confer resistance to most beta-lactam antibiotics, including penicillins, cephalosporins, and the monobactam aztreonam. Infections with ESBL-producing organisms have been associated with poor outcomes.

Community and hospital-acquired ESBL-producing Enterobacteriaceae are prevalent worldwide [1]. Reliable identification of ESBL-producing organisms in clinical laboratories can be challenging, so their prevalence is likely underestimated. Carbapenems are the best antimicrobial agent for infections caused by such organisms.

The types and detection of extended-spectrum beta-lactamases as well as the epidemiology and treatment of organisms that produce them are discussed in this topic. The clinical features and diagnosis of the infections that ESBL-producing organisms often cause are discussed elsewhere. (See "Gram-negative bacillary bacteremia in adults" and "Acute complicated urinary tract infection (including pyelonephritis) in adults and adolescents" and "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired and ventilator-associated pneumonia in adults" and "Clinical features, diagnosis, and treatment of Klebsiella pneumoniae infection".)

BETA-LACTAMASES — Beta-lactamases are enzymes that open the beta-lactam ring, inactivating the antibiotic. The first plasmid-mediated beta-lactamase in gram-negative bacteria was discovered in Greece in the 1960s. It was named TEM after the patient from whom it was isolated (Temoniera) [2]. Subsequently, a closely related enzyme was discovered and named TEM-2. It was identical in biochemical properties to the more common TEM-1 but differed by a single amino acid with a resulting change in the isoelectric point of the enzyme.

These two enzymes are the most common plasmid-mediated beta-lactamases in gram-negative bacteria, including Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus influenzae, and Neisseria gonorrhoeae. TEM-1 and TEM-2 hydrolyze penicillins and narrow-spectrum cephalosporins, such as cephalothin or cefazolin. However, they are not effective against higher generation cephalosporins with an oxyimino side chain, such as cefotaxime, ceftazidime, ceftriaxone, or cefepime. Consequently, when these antibiotics were first introduced, they were effective against a broad group of otherwise resistant bacteria. A related but less common enzyme was termed SHV, because sulfhydryl reagents had a variable effect on substrate specificity. (See "Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects" and "Cephalosporins".)

EXTENDED-SPECTRUM BETA-LACTAMASES — Not long after cefotaxime came into clinical use in Europe, strains of Klebsiella pneumoniae were discovered in Germany with transferable resistance to the oxyimino-cephalosporins (eg, cefotaxime, ceftazidime, and ceftriaxone) [3]. The enzyme responsible was related to SHV and was named SHV-2. TEM-related extended-spectrum beta-lactamases (ESBLs) were discovered in France in 1984 and in the United States in 1988.

The ESBL family is heterogeneous. SHV and TEM-type ESBLs arose by amino acid substitutions that allowed narrower-spectrum enzymes to attack the new oxyimino-beta-lactams. Others, notably members of the CTX-M family, represent plasmid acquisition of broad-spectrum beta-lactamases originally determined by chromosomal genes.

ESBLs vary in activity against different oxyimino-beta-lactam substrates but cannot attack the cephamycins (cefoxitin, cefotetan and cefmetazole) and the carbapenems (imipenem, meropenem, and ertapenem). They are also generally susceptible to beta-lactamase inhibitors, such as clavulanate, sulbactam, and tazobactam, which consequently can be combined with a beta-lactam substrate to test for the presence of this resistance mechanism.

ESBLs have been found exclusively in gram-negative organisms, primarily in Klebsiella pneumoniae, Klebsiella oxytoca, and Escherichia coli but also in Acinetobacter, Burkholderia, Citrobacter, Enterobacter, Morganella, Proteus, Pseudomonas, Salmonella, Serratia, and Shigella spp.

Infection due to ESBL-producing E. coli has become widespread in hospitals around the world [4]. Community-associated infection due to ESBL has also been recognized as an important clinical problem in the United States and Europe. In addition, a substantial portion of community-onset infection due to ESBL-producing E. coli has been observed among patients with no discernible health care-associated risk factors [5].

ESBL varieties

TEM beta-lactamases — 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. Not all behave as ESBL, and some, such as TEM-1 and TEM-2, only hydrolyze beta-lactams such as penicillins and narrow-spectrum cephalosporins [6]. Nevertheless, most are ESBLs, 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.

SHV beta-lactamases — 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 [7]. Not all the SHVs are ESBL and some, such as SHV-1, only hydrolyze beta-lactams such as penicillins and narrow-spectrum cephalosporins [6].

CTX-M beta-lactamases — 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.

More than 160 CTX-M enzymes have been described [8]. They have been found in many different Enterobacteriaceae including Salmonella, are the most common ESBL type worldwide [9], and are increasingly prevalent in the United States [10]. The proliferation of CTX-M enzymes is due not to being better beta-lactamases than TEM or SHV varieties but to the capture and dissemination of CTX-M genes by mobile genetic elements that mediate rapid and efficient spread between replicons and from cell to cell, especially to highly successful lineages such as E. coli ST131 and ST405 and K. pneumoniae CC11 and ST147 [11].

OXA beta-lactamases — 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. (See "Carbapenem-resistant E. coli, K. pneumoniae, and other Enterobacterales (CRE)", section on 'Classifications and geographic distribution'.)

Not all OXA enzymes are ESBLs, and certain ones only hydrolyze beta-lactams such as penicillins, antistaphylococcal penicillins, and narrow-spectrum cephalosporins [6].

Others — Other plasmid-mediated ESBL families, such as PER, VEB, and GES, have been described but are uncommon and have been found mainly in P. aeruginosa and at a limited number of geographic sites [12]. In addition to conferring high-level resistance to antipseudomonal beta-lactams, these ESBLs also degrade cephalosporins, and monobactams. Other rare ESBLs found in Enterobacteriaceae are BES, SFO, and TLA. (See "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections".)

LABORATORY DETECTION — Detection of extended-spectrum beta-lactamases (ESBLs) is based upon the resistance they confer to oxyimino-beta-lactam substrates (eg, cefotaxime, ceftazidime, ceftriaxone, or cefepime) and the ability of a beta-lactamase inhibitor, usually clavulanate, to block this resistance. Other enzymes have different features that can be misleading in the laboratory. AmpC-type beta-lactamases, which are now determined by plasmid as well as chromosomal genes, can provide oxyimino-beta-lactam resistance, but they are resistant to inhibition by clavulanate and usually confer resistance to cephamycins (eg, cefoxitin, cefotetan, and cefmetazole), which ESBLs do not.

Problems in identification arise because ESBLs are heterogeneous. OXA-type ESBLs, for example, are poorly inhibited by clavulanate. Some ESBLs are best detected with ceftazidime and others with cefotaxime (such as most CTX-M enzymes). Consequently, susceptibility to several oxyimino-beta-lactams must be tested; criteria for ESBL detection have changed over time; and clinical laboratories vary in their success in diagnosis.

Previously, the Clinical and Laboratory Standards Institute (CLSI) recommended screening isolates of E. coli, K. pneumoniae, K. oxytoca, or Proteus mirabilis by disk diffusion or broth dilution for resistance, followed by a confirmatory test for increased susceptibility in the presence of clavulanate [13]. In 2010, however, the CLSI published new minimum inhibitory concentration (MIC) and disk diffusion breakpoints for the Enterobacteriaceae [14]. The new MIC breakpoints are one to three doubling dilutions lower than the original breakpoints, and the new disk diffusion criteria include larger zone diameters than those in previous guidelines. In 2010, the European Committee on Antimicrobial Susceptibility Testing (EUCAST) similarly changed the breakpoint criteria for susceptibility [15]. Thus, many organisms that previously would have been categorized as susceptible using the former breakpoints may now be considered intermediate or resistant [16]. Whether the evidence for these new breakpoints is sufficient [17] and if they eliminate the need to perform ESBL screening and confirmatory tests for making treatment decisions is controversial [18]. While the disk diffusion breakpoints can be implemented immediately, there are barriers to immediate implementation of the new MIC breakpoints; clinicians should review local practices with their own microbiology laboratories.

Nonetheless, ESBL testing may be performed for infection control purposes [19]. In addition to disk diffusion and broth dilution techniques, other techniques for ESBL detection include:

●Automated systems (Vitek, MicroScan, and BD Diagnostics)

●The double disk test, in which a disk with clavulanate placed near a disk with an oxyimino-beta-lactam enhances susceptibility to the latter compound

●An E-test strip with clavulanate added to one side of a dual oxyimino-beta-lactam gradient

●Pyrosequencing and microarray technologies [20]

Identification of the ESBL type present in a particular strain is generally a task for a research laboratory.

EPIDEMIOLOGY

Distribution — Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae have been reported worldwide, most often in hospital specimens but also in samples from the community. Prevalence rates vary from hospital to hospital and from country to country as illustrated by the following observations:

●In a sample of 5739 isolates from 72 US hospitals collected in 2012, the overall frequency of ESBLs was 16 percent in K. pneumoniae, 11.9 percent in E. coli, 10 percent in K. oxytoca, and 4.8 percent in P. mirabilis [21]. CTX-M-15 was the most common ESBL identified, followed by SHV- and TEM-type enzymes. Two or more β-lactamase genes were identified in 63 percent of the isolates, including non-ESBLs and carbapenemases.

Rates of ESBLs have also been increasing in the US, as reflected by a study that reported an increase in the incidence of ESBL-producing infections in southeastern US hospitals from 11.1 to 22.1 infections per 100,000 patient days between 2009 and 2014 [22].

●ESBL prevalence is even higher in isolates from Asia, Latin America, and the Middle East [23], reaching 60 percent in K. pneumoniae isolates from Argentina and 48 percent in E. coli isolates from Mexico [24,25].

●Increasing community-acquired ESBL infections led to the discovery of concomitant high and increasing rates of fecal colonization by ESBL-producing bacteria worldwide [26,27].

Children are also increasingly affected by ESBL-producing organisms [28]. In a surveillance study from the US, the prevalence of ESBL-producing gram-negative rod isolates in pediatric specimens increased from 0.28 percent in 1999 to 2001 to 0.92 percent in 2010 to 2011 [29].

When the frequency of ESBL-positive isolates is high in a single institution, it is more likely that a single ESBL type is involved. Outbreaks have been due both to a single ESBL-producing strain and to a single ESBL plasmid carried by unrelated strains. A resistant strain or plasmid may cause problems in several hospitals locally or involve a large geographic area. Community clinics and nursing homes have also been identified as potential reservoirs for ESBL-producing K. pneumoniae and E. coli [30].

Transmission — Although ESBL-producing organisms are a growing cause of nosocomial infections and outbreaks as well as community-acquired infections, data on the actual risk of transmission of ESBLs within and outside the hospital setting are limited.

In one observational study from a tertiary care hospital in Switzerland, active surveillance cultures for ESBL carriage were performed in patients who shared a hospital room for at least 24 hours (contact patients, n = 133) with patients found to be infected or colonized with an ESBL-producing organism (index patients, n = 93) [31]. Only seven contacts (5.3 percent) were found to be colonized with an ESBL-producing organism, and only two harbored a strain that was genetically identical to that in the index patient, suggesting a low overall transmission rate (1.5 percent).

A study from a separate tertiary care hospital in Switzerland reported slightly higher in-hospital transmission rates of 4.5 percent for ESBL-producing E. coli (4 of 88 contacts exposed to 40 index patients) and 8.3 percent for ESBL-producing K. pneumoniae (2 of 24 contacts exposed to 8 index patients) [32]. Even higher rates of transmission were observed among household contacts of index patients (23 and 25 percent for E. coli and K. pneumoniae, respectively). One report described a household in which two young children had ESBL-producing E. coli urinary tract infections, and all four of the other household members had intestinal colonization with the same strain [33].

Additionally, environmental, animal, and food contamination with ESBL-producing gram-negative organisms has been extensively documented. As examples, ESBL producers have been detected in city rivers (eg, the River Thames in London, England), sewage [34,35], sink pipes [36], wild seagulls (eg, in Porto and Miami Beach [37,38]), livestock [39,40], and companion animals [41,42]. Alarmingly, ESBL-producing gram-negative organisms have also been identified in retail meat obtained from supermarkets [43-45]. A foodborne nosocomial outbreak among 156 patients in Spain provided evidence that food can be a transmission vector for ESBL-producing Enterobacteriaceae [46]. Up to 35 percent of the kitchen surfaces were colonized, and 14 percent of food handlers were fecal carriers of a single strain of SHV-1 and CTX-M-15 producing K. pneumoniae.

Risk factors — The gastrointestinal tract is the main reservoir for ESBL-producing Enterobacteriaceae, and colonization with such organisms is a strong risk factor for subsequent infection with them. Most clinical factors associated with colonization and infection with ESBL-producing organisms involve healthcare exposure, such as hospitalization, residence in a long-term care facility, hemodialysis use, and presence of an intravascular catheter [6,47-51]. However, community-acquired infections are not uncommon; risk factors for these include recent antibiotic therapy, use of corticosteroids, and the presence of a percutaneous feeding tube [52].

Additionally, for individuals living in the United States and Europe, travel to Asia has emerged as a major risk factor for colonization with ESBL-producing Enterobacteriaceae [53-57]. As an example, in a study of Dutch individuals who had no ESBL colonization prior to international travel, 34 percent overall and 75 percent of those who went to southern Asia acquired ESBL colonization following their travels. Colonization persisted for 30 days, on average, and 11 percent remained colonized after a year [54]. Among travelers, travelers’ diarrhea and antibiotic use has been associated with an increased risk of ESBL acquisition [57].

Predicting when an Enterobacteriaceae infection is with an ESBL-producing isolate, though, remains difficult. In one retrospective study from the United States, among 1288 cases of bacteremia, the features most strongly associated with ESBL infection (detected in 15 percent) were prior history of ESBL colonization or infection in the prior six months and colonization with an ESBL isolate [58]. Incorporation of these features, in addition to the presence of a chronic indwelling vascular device, age ≥43 years, and six or more days of antibiotic exposure within the prior six months, into a decision tree was able to identify ESBL-producing infections with a positive and negative predictive value of 91 and 92 percent, respectively.

TREATMENT OPTIONS

Preferred agents — The preferred, proven therapeutic options for severe infections caused by extended-spectrum beta-lactamase (ESBL)-producing organisms are carbapenems (imipenem, meropenem, 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. (See 'Carbapenems' below.)

The combination cephalosporin-beta-lactamase inhibitor agents (ceftolozane-tazobactam and ceftazidime-avibactam) and the broad-spectrum tetracycline eravacycline appear promising [59-62], although data on their clinical efficacy are too limited at this time to recommend their routine use, and it is not clear that they provide additional benefit over carbapenems. In the United States, ceftolozane-tazobactam, ceftazidime-avibactam, and eravacycline have been approved by the US Food and Drug Administration (FDA) for use in complicated intra-abdominal infections (with metronidazole for the cephalosporin-beta-lactamase inhibitor combinations). Ceftolozane-tazobactam and ceftazidime-avibactam are also approved for complicated urinary tract infections (UTIs); trials evaluating their use for treatment of ventilator-associated pneumonia are ongoing. Eravacycline was not successful in trials for complicated UTIs. (See 'Cephalosporins' below and 'Other drugs' below.)

For complicated UTI, plazomicin is another option that can be active against ESBL-producing isolates that are resistant to other aminoglycosides. We generally reserve this for patients who cannot use a carbapenem, and risk of renal dysfunction is a consideration. Similarly, parenteral fosfomycin is a potential option for complicated UTI due to susceptible ESBL-producing isolates when carbapenems cannot be used, but it is not widely available. (See 'Other drugs' below.)

For simple cystitis, oral fosfomycin and nitrofurantoin are other potential options that may retain activity against ESBL-producing isolates. These are discussed elsewhere. (See "Acute simple cystitis in adult and adolescent females", section on 'Patients with MDR risk factors'.)

In vitro susceptibility — ESBL-producing organisms vary in their susceptibility to different oxyimino-beta-lactams; despite resistance to some, they may appear sensitive to others. Strains making TEM and SHV-type ESBLs usually appear susceptible to cefepime and to piperacillin-tazobactam, but both drugs show an inoculum effect with diminished susceptibility as the inoculum is raised from 10⁵ to 10⁷ organisms [63]. Some CTX-M- and OXA-type ESBLs test resistant to cefepime despite use of a low inoculum.

Strains producing only ESBLs test susceptible to cephamycins (eg, cefoxitin, cefotetan, and cefmetazole) and carbapenems in vitro and show little if any inoculum effect with these agents [64].

ESBL-producing isolates typically show greater than average resistance to other agents including aminoglycosides and fluoroquinolones. These relationships were illustrated in a review of 85 episodes of bacteremia due to ESBL-producing K. pneumoniae from 12 hospitals in seven countries [65]. All isolates were susceptible to imipenem or meropenem, while 71 percent were resistant to gentamicin, 47 percent to piperacillin-tazobactam, and 20 percent to ciprofloxacin.

Clinical efficacy — 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 [65,66]. 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 [65]. 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 with 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.

Carbapenems — Treatment with a carbapenem produces the best outcomes in terms of survival and bacteriologic clearance. The efficacy of therapy with these agents is supported by a randomized trial in which meropenem resulted in lower mortality rates compared with piperacillin-tazobactam among patients with bacteremia with ESBL-producing Enterobacteriaceae [67]. (See 'Piperacillin-tazobactam' below.)

Preferential use of carbapenems is also supported by observational studies [65,68,69]. 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) [65]. 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 [69].

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. (See "Combination beta-lactamase inhibitors, carbapenems, and monobactams", section on 'Carbapenems'.)

Ertapenem has the advantage of once-daily dosing and has good in vitro activity [64], and clinical data regarding its use are growing [70-75]. 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) [70,71]. 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 UTIs due to ESBL-producing organisms [72-74]. However, some ESBL-producing isolates are resistant to ertapenem, and resistance may also develop on therapy [72,76]. 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. (See "Combination beta-lactamase inhibitors, carbapenems, and monobactams", section on 'Ertapenem'.)

Cephalosporins — 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 [65,66,77]. However, cephalosporin-beta-lactamase inhibitor combinations (namely ceftolozane-tazobactam and ceftazidime-avibactam) are novel agents that appear to have greater activity against ESBL-producing organisms [78]. (See "Combination beta-lactamase inhibitors, carbapenems, and monobactams", section on 'Ceftolozane-tazobactam' and "Combination beta-lactamase inhibitors, carbapenems, and monobactams", section on 'Ceftazidime-avibactam'.)

In a review of 28 patients with ESBL-producing Klebsiella pneumoniae with reported susceptibility to cephalosporins, 15 failed to respond to standard-spectrum cephalosporin therapy (ie, not novel, expanded-spectrum cephalosporins) [66]. 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 minimum inhibitory concentration (MIC) with increased inoculum [63]. Additionally, although 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.

Most available data do not encourage cefepime use for ESBL-producing pathogens [79]. Although some observational data have suggested that high-dose cefepime (eg, 2 g every eight hours) can be effective [80-82], in a randomized trial of patients with UTI caused by ESBL-producing pathogens, treatment failure with cefepime was higher than with ertapenem or piperacillin-tazobactam [83]. Similarly, in a retrospective study, definitive cefepime therapy for monomicrobial bacteremia due to ESBL-producing Enterobacteriaceae with an MIC ≤8 mcg/mL was associated with a higher rate of clinical and microbiologic failure and mortality compared with carbapenem therapy [77]. Among those treated with cefepime, mortality rates due to sepsis rose as the MIC exceeded 1 mcg/mL.

With the addition of a beta-lactamase inhibitor, ceftolozane-tazobactam and ceftazidime-avibactam have extended spectra of activity to include most ESBL-producing Enterobacteriaceae [84,85]. As an example, in a trial of patients with intraabdominal infections, ceftolozane-tazobactam plus metronidazole compared favorably with 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) [84].

Piperacillin-tazobactam — We do not recommend piperacillin-tazobactam for severe infections with ESBL-producing organisms. However, piperacillin-tazobactam may be effective and a reasonable alternative for isolated UTIs due to ESBL-producing organisms given the much higher drug concentrations achieved in the urine compared with plasma [86].

Although some ESBL isolates have MICs for piperacillin-tazobactam that are in the susceptible range, treatment of serious infections with piperacillin-tazobactam appears to result in worse outcomes than with a carbapenem. In an international, randomized, open-label trial of 379 adults with bacteremia due to E. coli or Klebsiella species that were nonsusceptible to ceftriaxone or cefotaxime (most confirmed to produce an ESBL), the 30-day, all-cause mortality rate was higher with directed therapy with piperacillin-tazobactam compared with meropenem (12.3 versus 3.7 percent) [67]. There was also a trend toward higher rates of clinical and microbiologic resolution by day 4 with meropenem (75 versus 68 percent with piperacillin-tazobactam, although the difference was not statistically significant). The vast majority of isolates tested susceptible to piperacillin-tazobactam (median MIC 2 mcg/mL; interquartile range 1.5 to 4), and there was no relationship between mortality and MIC value. This study had a number of limitations, including the lack of blinding of treating clinicians and investigators, the variable empiric regimens used prior to randomization, and an imbalance in patient characteristics between groups. Nevertheless, the findings support our suggestion not to use piperacillin-tazobactam for serious infections with ESBL-producing bacteria. A recent multicenter, randomized controlled trial of 72 patients with AmpC beta-lactamase-producing gram-negative rod bacteremia, compared piperacillin tazobactam against meropenem [87]. Despite more than 95 percent of isolates being piperacillin-tazobactam susceptible by microdilution, the microbiological failure among the group that received piperacillin-tazobactam was greater (5 of 38; 13 percent) than the group that received meropenem (0 of 34).

The findings of this trial are also consistent with earlier reports of treatment failure with piperacillin-tazobactam and some observational studies suggesting inferiority to carbapenems [65,88-91]. As an example, in a retrospective study of over 200 individuals with bacteremia due to an ESBL-producing organism, empiric treatment with piperacillin-tazobactam was associated with a higher risk of death within 14 days compared with a carbapenem (adjusted hazard ratio [HR] 1.92, 95% CI 1.07-3.45) [69].

However, other observational studies had suggested no difference in mortality among patients (including neutropenic patients) with ESBL-producing E. coli bacteremia treated with either piperacillin-tazobactam or a carbapenem for empiric or definitive therapy [92,93]. In light of the trial findings above and the greater potential for confounding in observational studies, these results should not be used to support use of piperacillin-tazobactam for bloodstream infections.

In addition to concerns about efficacy of piperacillin-tazobactam for ESBL-producing isolates, resistance may develop during therapy [89].

Other drugs — Data on other agents for use in for ESBL-producing organisms are sparse.

●Tigecycline is a 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 [94]. Increasing tigecycline resistance does not yet appear to be a problem, as a 2014 microbiological surveillance showed unchanged resistance profiles in 2012 when compared with 2006 isolates [95].

●Eravacycline also appears effective against ESBL-producing isolates, based on limited clinical data. In an analysis of two randomized trials that demonstrated comparable clinical outcomes for complicated intra-abdominal infections with either intravenous eravacycline or a carbapenem, microbiologic and clinical cure rates with eravacycline for the 36 infections due to an ESBL-producing Enterobacteriaceae were 89 and 86 percent, respectively [62].

●Plazomicin is an advanced aminoglycoside that often retains activity against ESBL-producing isolates despite the presence of aminoglycoside-modifying enzymes that inactivate other aminoglycosides. In a randomized trial of 609 patients with acute complicated urinary tract infection (including pyelonephritis and infections complicated by bacteremia), early clinical cure rates with plazomicin were similar to those with meropenem (88 versus 91 percent); among the 120 patients with infection caused by an isolate with an ESBL phenotype, microbial eradication rates at two weeks were also similar (82 versus 75 percent with meropenem) [96]. A ≥0.5 mg/dL increase in serum creatinine over baseline occurred in 7 versus 4 percent with plazomicin and meropenem, respectively.

●Fosfomycin retains activity against many ESBL-producing isolates, and oral fosfomycin can be effective for cystitis caused by ESBL-producing E. coli, although emergent resistance may be a concern [97,98]. This is discussed elsewhere (see "Acute simple cystitis in adult and adolescent females", section on 'Patients with MDR risk factors'). Intravenous fosfomycin is also a potential option that is active against many ESBL-producing organisms and is effective in complicated UTIs, but it is not widely available [99].

There are no clinical data supporting the use of double antibiotic coverage for treatment of ESBL-producing organisms.

DURATION OF THERAPY — Infection with an extended-spectrum beta-lactamase (ESBL)-producing organism usually does not warrant a longer course of therapy than generally indicated for the type of infection. Duration of therapy for specific infections is discussed separately in the corresponding topic reviews. (See "Gram-negative bacillary bacteremia in adults", section on 'Duration and route of therapy' and "Acute complicated urinary tract infection (including pyelonephritis) in adults and adolescents", section on 'Management' and "Treatment of hospital-acquired and ventilator-associated pneumonia in adults", section on 'Duration'.)

PROGNOSIS — 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 [65,100-102]. 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) [103]. 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 percent]) and with cephalosporin monotherapy or a beta-lactam/beta-lactamase inhibitor combination such as piperacillin-tazobactam (4 of 9 [44 percent]) [65].

In one predictive model for mortality among patients with bloodstream infections with ESBL-producing organisms, factors with a major impact on mortality include age older than 50 years, infection due to Klebsiella spp, source other than urinary tract, fatal underlying disease, Pitt score >3, severe sepsis or septic shock at presentation, and inappropriate empirical antibiotic choice [104].

Some individuals infected or colonized by ESBL-producing organisms continue to shed bacteria for prolonged periods [105]. 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.

INFECTION CONTROL AND ANTIBIOTIC STEWARDSHIP — As with other clonal outbreaks caused by multidrug-resistant gram-negative rods, interventions aimed at controlling the horizontal spread of extended-spectrum beta-lactamase (ESBL)-producing organisms should target the transmission pathways within the hospital. Two main strategies to control outbreaks due to ESBL-producing bacteria have been described: barrier protection of infected or colonized patients (contact precautions), and restriction of beta-lactam use [101,106]. The optimal implementation of contact precautions is uncertain. We agree with guidelines from the Society for Healthcare Epidemiology that recommend contact precautions for the duration of the hospitalization during which ESBL infection or colonization was identified [107]. Discontinuation of inpatient contact precautions can be considered once six months have passed since the last positive culture, the patient does not have an active infection and is not on active treatment of an ESBL infection, and at least two consecutive negative rectal swabs at least one week apart, off antibiotics, have been obtained.

Institution of both barrier protection and restriction of cephalosporin use in one study was associated with a decrease in the number of infections caused by ESBL-producing K. pneumoniae (4.9 episodes to 0.6 episodes per 1000 patient-days) [106]. In a 2017 meta-analysis, antimicrobial stewardship programs reduced the incidence of ESBL-producing Enterobacteriaceae colonization and infection by 48 percent [108]. The institution of barrier methods without antibiotic restriction has also been evaluated [31,109]. All personnel in contact with patients infected with or carriers of ESBL-producing Enterobacteriaceae were required to use gowns and gloves. In one study, barrier production was associated with a decrease in the incidence of hospital-acquired ESBL from 172 patients to 19 over three years, despite increased use of cephalosporins [109].

A subsequent study modeled the impact of improved hand hygiene, patient cohorting, and antibiotic restrictions [110]. Improving hand hygiene compliance from 60 to 80 percent would be associated with a 91 percent reduction in colonization with ESBL-producing gram-negative rods at 90 days. Cohorting patients would be associated with a further 7 percent decrease in colonization rates. However, antibiotic restriction would not affect colonization rates.

Since there are environmental reservoirs for resistant gram-negative organisms (eg, sink pipes), ensuring the cleanliness of medical equipment and patient care areas are also important measures for prevention and reduction of healthcare-associated infection. (See "Infection prevention: General principles", section on 'Cleaning, disinfection, and sterilization'.)

SUMMARY AND RECOMMENDATIONS

●Antibiotic resistance due to extended-spectrum beta-lactamases (ESBLs) – 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. (See 'Introduction' above and 'Extended-spectrum beta-lactamases' above.)

●Identifying ESBLs – 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. (See 'Laboratory detection' above.)

●Epidemiology and risk factors – 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. (See 'Epidemiology' above.)

●Antibiotic selection

•Carbapenems as preferred agents – We suggest meropenem or imipenem for ESBL infections, rather than other beta-lactam agents such as cefepime and piperacillin-tazobactam (Grade 1B). Ertapenem is an acceptable option in the absence of resistance or severe sepsis and can be particularly useful in the outpatient setting. (See 'Preferred agents' above and 'Clinical efficacy' above.)

Use of cephalosporins and piperacillin-tazobactam has been associated with treatment failures or higher mortality rates. Fluoroquinolones can be used to treat susceptible isolates but resistance is common.

•Alternative agents – Plazomicin often retains activity despite resistance to other aminoglycosides and is effective for complicated urinary tract infection (UTI). Ceftolozane-tazobactam, ceftazidime-avibactam, and eravacycline 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. (See 'Treatment options' above.)

●Prognosis – 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. (See 'Prognosis' above.)

●Infection control – The spread of ESBL-producing organisms within institutions can be slowed by the use of barrier protection and restriction of later generation cephalosporins. (See 'Infection control and antibiotic stewardship' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges George A Jacoby, MD, who contributed to an earlier version of this topic review.