Extended Spectrum Beta-Lactamases

OVERVIEW

Extend Spectrum b-lactamases (ESBLs) are enzymes capable of conferring resistance to most penicillins, cephalosporins and aztreonam.  They are typically found in E. coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis.  These organisms are typical bowel flora and cause a variety of common infections including but not limited to urinary tract infections (UTIs), bloodstream infections, intra-abdominal infections.  The incidence of infections caused by ESBL producing organisms has increased significantly in both community and nosocomial infections over the last two decades.  Infection with an ESBL producing organism is associated with increased morbidity, mortality, cost of care and length of hospitalization.1-5

Extend Spectrum β-lactamases have, in large part, evolved due to point mutations of previously existing more ‘narrow-spectrum’ β-lactamases.  This type of resistance is plasmid mediated, meaning it can be acquired from and then passed to other organisms on mobile genetic elements.  The presence of this plasmid-mediated resistance in pathogens that colonize the bowel is of special concern, creating great potential for spread and serving as a constant colonizing source.

ESBL producing bacteria are often multi-class resistant with multiple resistance genes genetically linked thereby severely limiting susceptibility to available antibiotics.  These can include modifying enzymes (aminoglycosides resistance), alternate folate pathways (trimethoprim/sulfamethoxazole resistance), DNA-gyrase and topoisomerase target mutations (fluoroquinolone resistance).

CHALLENGES IN DETECTION OF ESBL-PRODUCING ORGANISMS

Spread of Antibiotic ResistanceThe microbiologic detection of ESBL-producing organisms can be problematic and testing controversial.6  Most physicians, nurse practitioners and physician assistants are not adequately trained to identify a potential ESBL absent a confirmatory test report by a microbiology laboratory.   E. coli, K. pneumoniae, K. oxytoca and P. mirabilis bacteria should be highly susceptible to 3rd generation cephalosporins (MIC<1), 4th generation cephalosporins (MIC<1), aztreonam (MIC<1) and piperacillin/tazobactam (MIC<4).  Deviations from these susceptibility patterns can signal ESBL production.  A variety of gene mutations exist, producing discordant susceptibility results between individual 3rd generation cephalosporins when using routine testing methods. Consider organisms with 3rd or 4th generation cephalosporin MICs > 1 as potential ESBL producing bacteria, until confirmatory testing is performed.

Routine susceptibility testing of an ESBL without confirmatory testing can lead to misleading determinations of susceptibility and subsequent errors in therapy.  ESBLs are not reliably susceptible to aztreonam, 3rd and 4th generation cephalosporins and piperacillin/tazobactam.  Carbapenem antibiotics remain active.  Treatment of an infection with aztreonam, cephalosporin or penicillin antibiotics, even if reported susceptible, can lead to poor outcomes.7  Carbapenem antibiotics when dosed appropriately are preferred treatment.

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Although confirmatory testing is necessary to avoid poor outcomes, it is not uniformly performed in all labs or circumstances.  Some techniques are not automated, can be time consuming, costly and difficult to interpret.  Confirmatory tests are not always immediately available, may give indeterminate results, and may not be performed on some clinical samples (example, urine cultures). The clinician should recognize two broad ESBL enzyme categories:

  • One preferentially displays resistance to cefotaxime/ceftriaxone
  • One preferentially displays resistance to ceftazidime

Lacking in vitro confirmatory testing clinicians must assume ESBL production as the cause of elevated MICs to 3rd and 4th generation cephalosporins.  Once again preferred therapy is a carbapenem antibiotic, unless the organism is lacking multi-drug resistance genes linked to the ESBL gene thereby conferring susceptibility to a non-beta-lactam antibiotic (trimethoprim-sulfamethoxazole, aminoglycosides, fluoroquinolones).

The production of ESBLs in combination with other inducible resistance mechanisms, such as outer membrane porin repression, efflux pump induction, and AmpC β-lactamases, can lead to carbapenem resistance even in the absence of carbapenemase (enzyme inactivation of carbapenem antibiotic) production.  This combination of resistance mechanisms may contribute to overall carbapenem resistance but is not actively surveilled.

CONTRIBUTING RISK FACTORS

It is important to recognize factors that increase the risk of ESBL producing organisms to prevent, effectively identify and empirically treat individuals at risk.  Overuse of 3rd generation cephalosporins and fluoroquinolones increase risk of ESBLs in the patient care environment. Patient related risks include antibiotic use within 90 days, recent hospital, nursing facility or LTAC stay, ICU hospitalization, use of invasive devices, and multiple existing comorbidities.8-10

Remain aware that ESBLs are found in normal bowel flora and resistant organisms can colonize the bowel for up to 9-12 months.  This colonization serves as a potential recurring source for infection, especially for UTIs, intra-abdominal infections and lower body wound infections.  Know local susceptibility rates, especially for acute and post-acute care settings, in addition to reviewing prior culture data for patients at risk.  Avoid indiscriminate use of 3rd generation cephalosporins and fluoroquinolones especially in patients at risk for recurrent UTIs.

DISEASE STATES

ESBL-related resources for the following disease states were developed to build awareness and provide educational resources.

  • Bacteremia/Sepsis
  • Intra-abdominal Infections
  • Nosocomial Pneumonia
  • Urinary Tract Infections
  • Wounds/Skin and Soft Tissue Infections

SELECTED REFERENCES

  1. Ling W, Paterson DL, Harris PNA, Furuya-Kanamori L, Edwards F, Laupland KB. Mortality, hospital length of stay, and recurrent bloodstream infections associated with extended-spectrum beta-lactamase-producing Escherichia coli in a low prevalence region: a 20-year population-based large cohort study. Int J Infect Dis. 2024;138:84-90.
  2. Bonten M, Johnson JR, van den Biggelaar AHJ, Georgalis L, Geurtsen J, de Palacios PI, et al. Epidemiology ofEscherichia coli bacteremia: a systematic literature review. Clin Infect Dis. 2021; 72: 1211-1219. https://doi.org/10.1093/cid/ciaa210
  3. Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. 2022; 399: 629-655. https://doi.org/10.1016/S0140-6736(21)02724-0
  4. Shamsrizi P, Gladstone BP, Carrara E, Luise D, Cona A, Bovo C, et al. Variation of effect estimates in the analysis of mortality and length of hospital stay in patients with infections caused by bacteria-producing extended-spectrum beta-lactamases: a systematic review and meta-analysis. BMJ Open.2020;10 https://doi.org/10.1136/bmjopen-2019-030266
  5. Wozniak TM, Bailey EJ, Graves N.Health and economic burden of antimicrobial-resistant infections in Australian hospitals: a population-based model. Infect Control Hosp Epidemiol. 2019;40:320-327. https://doi.org/10.1017/ice.2019.2
  6. Livermore DL, Andrews JM, Hawkey PM, Ho PL, Keness Y, Doi Y, Patterson D, Woodford N. Are susceptibility tests enough, or should laboratories still seek ESBLs and carbapenemases directly. J Antimicrob Chemother 2012;67:1569-1577.
  7. Harris PNA, Tambyah PA, Lye DC, Mo Y, Lee TH, Yilmaz M, … MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN) (2018). Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial.JAMA;320(10):984–994. https://doi.org/10.1001/jama.2018.12163
  8. Banerjee R., et al., Escherichia coli sequence type 131 is a dominant, antimicrobial-resistant clonal group associated with healthcare and elderly hosts. Infect Control Hosp Epidemiol, 2013. 34(4): p. 361–9. pmid:23466908
  9. Vance MK, Cretella DA, Ward LM, Vijayvargiya P, Garrigos ZE, Wingler MJB. Risk factors for bloodstream infections due to ESBL-producing Escherichia coli, Klebsiella spp., and Proteus mirabilis. Pharmacy.2023;11(2),74. http://doi.org/10.3390/pharmacy11020074
  10. Rodríguez-Baño J, Picón E, Gijón P, Hernández JR, Ruíz M, Peña C, et. al. Community-onset bacteremia due to extended-spectrum β-lactamase-producing Escherichia coli:risk factors and prognosis. Clin Infect Dis 2010;50(1):40–48. https://doi.org/10.1086/649537

IMPORTANT DISCLAIMER—THIS WEBPAGE DOES NOT PROVIDE MEDICAL ADVICE

The information provided on this webpage is intended as general overview and background information. It is not intended to be, and should not be considered to be, medical advice or used in any way for the diagnosis or treatment of any specific medical condition. As to any specific medical condition, you should always seek the advice of a physician or other qualified health care provider. You also should not disregard professional medical advice given directly to you based on information contained on this webpage.

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