ESBL Infections: Risk Factors and Treatment Approaches

Common ESBL-Producing Organisms

Klebsiella pneumoniae, Klebsiella oxytoca, and Escherichia coli are common ESBL-producing organisms, with other Enterobacteriaceae including Proteus mirabilis, Enterobacter species, and Citrobacter species also being affected 1

Recent exposure to antibiotics, particularly beta-lactams or fluoroquinolones, within 90 days is a risk factor for ESBL infections, along with known colonization with ESBL-producing Enterobacteriaceae and healthcare-associated infections 2

The prevalence of ESBL-producing bacteria varies significantly by geographic region, with higher rates observed in Asia, Latin America, and the Middle East compared to North America and Europe 3

Newer agents such as ceftazidime-avibactam have activity against ESBL-producing organisms and may be valuable for treating infections to preserve carbapenems 4
For community-acquired intra-abdominal infections (CA-IAIs), agents with a narrower spectrum of activity are preferred, but in patients at risk for ESBL infections, anti-ESBL-producer coverage may be warranted, and for healthcare-associated intra-abdominal infections (HA-IAIs), antibiotic regimens with broader spectra of activity are preferred 2, 4
In the setting of high ESBL prevalence, extended use of cephalosporins should be discouraged and limited to pathogen-directed therapy 4

The American College of Physicians recommends carbapenems as the treatment of choice for serious infections caused by ESBL-producing organisms, with alternative treatments for uncomplicated infections including fosfomycin, nitrofurantoin, and aminoglycosides, depending on susceptibility and infection type 5
Rapid molecular identification methods can significantly reduce time to appropriate therapy, according to the Clinical and Laboratory Standards Institute 6

Recent antibiotic exposure, particularly beta-lactams or fluoroquinolones, within 90 days is a risk factor for ESBL infections, as is known colonization with ESBL-producing Enterobacteriaceae and healthcare-associated infections 6
Hospitalization, especially in intensive care units, is also a risk factor for ESBL infections 7

Active surveillance in high-risk patients can help identify colonization and prevent dissemination of ESBL-producing organisms, as recommended by the Journal of Hepatology 8
The emergence of carbapenem-resistant Enterobacteriaceae represents a potential shift from multi-drug resistant (MDR) to extensively drug-resistant (XDR) or even pandrug-resistant (PDR) bacteria, highlighting the need for judicious use of antibiotics and infection control measures 8

Prolonged hospitalization exceeding 5 days is a risk factor for ESBL-producing Klebsiella infections 9
The presence of risk factors for multidrug-resistant organisms, such as recent antibiotic exposure, may necessitate broader coverage than ceftriaxone alone, as recommended by the ATS guidelines 9

For suspected or confirmed ESBL-producing Klebsiella infections, carbapenems are the treatment of choice, according to the American Heart Association, as published in Circulation 10
A combination of a third-generation cephalosporin and an aminoglycoside is recommended for Klebsiella endocarditis, as suggested by the American Heart Association, as published in Circulation 10

ESBL-producing bacteria are resistant to all penicillins, all cephalosporins, aztreonam, and extended-spectrum penicillins, but remain susceptible to carbapenems, as reported by the American Thoracic Society 11
ESBL enzymes hydrolyze all cephalosporins, including ceftriaxone, cefotaxime, ceftazidime, and cefepime, according to the American Thoracic Society 11

ESBL-producing organisms frequently carry additional resistance mechanisms, including aminoglycosides, trimethoprim-sulfamethoxazole, and fluoroquinolones, as noted by the European Society of Clinical Microbiology and Infectious Diseases 12
Co-resistance to aminoglycosides, such as gentamicin and tobramycin, is frequently observed in ESBL-producing organisms, as reported by the European Society of Clinical Microbiology and Infectious Diseases 12

Carbapenems, including imipenem, meropenem, and ertapenem, remain fully active against ESBL producers and are the primary therapeutic choice, according to the American Thoracic Society 11

When ESBL producers also express AmpC beta-lactamases, they gain additional resistance to cephamycins, but carbapenems remain effective, as reported by the American Thoracic Society 11

The Clinical and Laboratory Standards Institute (CLSI) guidelines state that routine ESBL testing is no longer necessary before reporting results when using newer interpretive criteria for cephalosporins, but ESBL testing remains valuable for epidemiological and infection control purposes 13, 14
The CLSI guidelines recommend that the new ceftazidime and cefepime susceptible breakpoints should be used with caution, as they may fail to identify many ESBL-producing bacteria, such as E. coli, K. pneumoniae, and K. oxytoca 15

ESBL-producing bacteria demonstrate resistance to all penicillins, all cephalosporins, and aztreonam, but preserved susceptibility to carbapenems, and are inhibited by clavulanic acid 13, 15

Approximately 5-10% of oxyimino-lactam-resistant K. pneumoniae produce a plasmid-mediated AmpC-type enzyme rather than (or in addition to) an ESBL, and these strains may show cefoxitin resistance, according to the American Thoracic Society 16

The strength of evidence for ESBL detection methods, including MIC determination and double-disk synergy testing (DDST), is not specified, but these methods are commonly used for ESBL detection, as recommended by the Clinical and Laboratory Standards Institute (CLSI) is not available, however, 16

In nosocomial settings, ESBL production is the predominant mechanism of β‑lactam resistance among E. coli isolates. This observation is based on surveillance of hospital‑acquired strains and highlights the high prevalence of ESBL genes in clinical environments. 17
ESBL‑encoding plasmids frequently co‑carry resistance determinants for aminoglycosides and other drug classes, rendering β‑lactam/β‑lactamase‑inhibitor combinations ineffective. The co‑location of multiple resistance genes on the same plasmid explains why ESBL‑producing E. coli are often multidrug‑resistant. 17

Hyperexpression of chromosomal AmpC β‑lactamase in E. coli can occur sporadically and confers resistance to first‑ and second‑generation cephalosporins. Laboratory studies demonstrated that overproduction of AmpC reduces susceptibility to these agents, even though the enzyme is not typically inducible in E. coli. [17][18]

Carbapenems remain the most reliable therapeutic option for infections caused by ESBL‑producing E. coli, as these isolates retain susceptibility to carbapenem agents. Clinical guidelines recommend carbapenems as first‑line empiric therapy when ESBL risk factors are present. 17