EM@3AM: ESBL-Producing Organisms and Their Management

  • Oct 5th, 2024
  • Devin Morris
  • categories:
    em@3am

Authors: Devin Morris, MD (EM Resident Physician, UT Southwestern – Dallas, TX); Samia Farooqi, MD (Assistant Professor, UT Southwestern – Dallas, TX) // Reviewed by: Sophia Görgens, MD (EM Physician, BIDMC, MA), Cassandra Mackey, MD (Assistant Professor of Emergency Medicine, UMass Chan Medical School); Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Welcome to EM@3AM, an emDOCs series designed to foster your working knowledge by providing an expedited review of clinical basics. We’ll keep it short, while you keep that EM brain sharp.

A 62-year-old female patient with a history of recurrent urinary tract infections (UTIs) presents to the emergency department with fever, chills, and dysuria. Her recent urine culture results show growth of Escherichia coli resistant to third-generation cephalosporins but susceptible to carbapenems.

Question: When ordering an antibiotic, what type of organism should the physician ensure is covered based on previous cultures?

Answer: ESBL-producing organisms

 

Background 1-3

  • Extended spectrum beta-lactamases (ESBL) are enzymes produced by certain bacteria that can break down a broad range of beta-lactam antibiotics.
    • The “extended spectrum” label refers specifically to their ability to hydrolyze and render ineffective not only standard beta-lactam antibiotics, such as penicillins (e.g., amoxicillin) and first-generation cephalosporins (e.g., cephalexin), but also a broader range of beta-lactam antibiotics, including many second-, third-, and fourth-generation cephalosporins (e.g., ceftriaxone, cefepime).
  • ESBL are found exclusively in Gram-negative organisms, including:
    • Klebsiella pneumoniae
    • Klebsiella oxytoca
    • Escherichia coli
    • Proteus mirabilis
    • Pseudomonas aeruginosa
  • The first reported beta-lactamase enzyme was reported in 1963, and today there are well over 350 ESBL enzyme variants.3

 

Epidemiology4-8

  • ESBL-producing Enterobacteriaceae (ESBL-E) have been reported worldwide.
    • They are found primarily in hospital specimens but are increasing in frequency in samples from the community.4
    • The incidence of ESBL-E identified in bacterial cultures in the United States increased by 53% from 2012 to 2017.
      • Increased incidence is largely due to increasing community spread.
    • E. coli is the most common cause of ESBL infection worldwide.

 

Transmission

  • ESBL spread via plasmid and transposon encoded genes.
    • Theses plasmids can also carry genes for resistance to other antimicrobial agents including aminoglycosides, trimethoprim, and tetracyclines.5
  • Common modes of transmission include via direct contact between individuals or via indirect contact with fomites.
    • ESBL-E spread most commonly occurs in the healthcare setting via contaminated hands or during invasive procedures.
  • The gastrointestinal tract is the main reservoir for ESBL-E.
    • Colonization with ESBL-E is a strong risk factor for subsequent infection.6

 

Risk factors

  • Healthcare associated risk factors include:
    • Hospitalization
    • Residence in a long-term care facility
    • Hemodialysis
    • Presence of an intravascular catheter7
  • Community-acquired infection risk factors include:
    • Antibiotic therapy
    • Use of corticosteroids
    • Presence of a percutaneous feeding tube7
  • 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.8

 

Workup and Diagnosis

  • Evaluation should be tailored to the patient presentation, but may include studies such as:
    • CBC, CMP, UA, lactate (if concern for sepsis),
    • Cultures (blood, urine, etc.)
    • Imaging studies targeting the area of concern (CXR, CT abdomen and pelvis, etc.)
  • Diagnosis of ESBL producing organism is made based on sampling from the presumed site of infection (urine, blood, sputum, wound swabs, etc.).
  • Cultures and subsequent phenotypic confirmatory testing or genotypic testing are the standard for determining ESBL-producing organism presence.
  • Most clinic microbiology labs do not perform routine ESBL testing. Instead, non-susceptibility to Ceftriaxone is often used as a proxy.9
    • Organisms that are non-susceptible to Ceftriaxone for reasons other than ESBL production may be falsely presumed to be ESBL-producers using this method.

 

Management9-12

  • Patients such receive standard resuscitation care including:
    • Antipyretics such as Tylenol (650-1000 mg PO), Ibuprofen (600 mg PO), or Toradol (15mg IV).
    • IV fluid resuscitation as needed.
    • Pressors where indicated for septic shock (typically Norepinephrine starting at 0.05 mcg/kg/min and titrated to MAP >65).

Table 1: Antibiotic Management of ESBL-E Infections

 

  • An uncomplicated UTI is typically an infection in an afebrile non-pregnant immune-competent female patient.
  • A complicated UTI (cUTI) is an infection that carries a higher risk of treatment failure.11
    • Complicated UTIs a UTIs that occur in immunocompromised patients, males, pregnant patients, and those with associated factors such as fevers, stones, sepsis, urinary obstruction, or catheters.
  • Meropenem, imipenem-cilastatin, or ertapenem are preferred for the treatment of infections outside of the urinary tract caused by ESBL-E.
    • For patients who are critically ill and/or experiencing hypoalbuminemia, meropenem or imipenem-cilastatin are the preferred carbapenems.
  • Current IDSA guidelines recommend against empiric use of piperacillin-tazobactam for ESBL-E infections
    • A study demonstrated a 12% vs 4% 30 day mortality between Zosyn and Meropenem when used for ESBL-E bloodstream infections.12

 

Complications

  • Inadequate empiric therapy can lead to treatment delays and worse outcomes.
  • Carbapenems can have significant side effects including nephrotoxicity and neurotoxicity.
    • Imipenem confers highest risk of seizures
  • ESBL-E are often hospital acquired infections and can prolong hospital stay or lead to worse outcomes.
  • Phenotypic confirmation of ESBL type can take time leading to delayed diagnosis and insufficient empiric coverage.

 

Disposition

  • Patients with complicated UTI, pyelonephritis, bacteremia, or other ESBL-E infections should be admitted for IV antibiotic treatment and would benefit from Infectious Disease consultation.
  • Consider Infectious Disease consultation prior to any potential discharges.

 

Pearls

  • Be aware of risk factors for both in-hospital and community spread of ESBL-E infections including long-term care facility residence, hemodialysis patients, antibiotic use, steroid use, and invasive lines.
  • ESBL-E have higher rates of antibiotic resistance; review prior cultures before initiating empiric coverage to cover for ESBL-E in patients with history of prior infections or colonization.
  • Non-septic patients with UTI, cUTI, or pyelonephritis do not need empiric carbapenem coverage according to the most recent IDSA guidelines.
  • In septic or non-urinary tract ESBL-E infection, cover with IV carbapenems as opposed to higher-generation cephalosporins.

An 84-year-old man with a medical history of hypertension, benign prostatic hyperplasia, and recurrent multidrug-resistant urinary tract infections presents to the hospital with altered mental status. His vital signs are BP 89/55 mm Hg, HR 110 bpm, RR 20/min, and T 38°C. He was admitted to the hospital 3 weeks ago to receive intravenous antibiotics for pneumonia. Today, his physical exam is notable for suprapubic and costovertebral tenderness. You note a serum lactate of 3.2 mmol/L on his initial point-of-care lab tests. His urinalysis demonstrates pyuria, and a urine culture was sent to the microbiology lab. Intravenous vancomycin is ordered. What additional antibiotic is the best choice for this patient?

A) Cefepime

B) Ceftriaxone

C) Levofloxacin

D) Meropenem

E) Piperacillin-tazobactam

 

 

 

 

 

Answer: D

This patient is presenting with signs and symptoms consistent with sepsis. His vital signs, elevated lactate, and altered mental status are concerning for systemic infection with evidence of end-organ damage. His medical history is notable for recurrent urinary tract infections (UTIs). Patients with benign prostatic hyperplasia are at increased risk for bladder outlet obstruction, which predisposes them to the development of UTIs and prostatitis. Acute UTIs commonly present with dysuria, urinary frequency, or suprapubic pain. If the infection has spread beyond the bladder, the patient may present with symptoms of pyelonephritis, such as flank pain, fever, nausea, and vomiting. An acute UTI is consideredcomplicated in the presence of fever, systemic signs of infection, flank pain, costovertebral tenderness, or symptoms of prostatitis in men. In addition to suprapubic pain and pyuria, this patient also has systemic signs of infection, fever, and costovertebral tenderness. Therefore, his presentation is most consistent with sepsis due to acute complicated UTI.

The most common bacteria associated with acute complicated UTI isEscherichia coli. However, it may also be caused by other pathogens, such as Klebsiella, Proteus, and Pseudomonas. Recent antibiotic use, recent hospitalizations, or travel to regions with high rates of drug-resistant organisms increases the likelihood of drug-resistant pathogens. In a patient with an acute complicated UTI, the presence of critical illness or a known urinary tract obstruction should prompt treatment with broad–spectrum gram–positive coverage, such as vancomycin, as well as a carbapenem for broad-spectrum gram–negative coverage and coverage for extended–spectrum beta–lactamase (ESBL). Because this patient has sepsis and known urinary tract obstruction due to his enlarged prostate, the most appropriate antibiotic for empiric coverage is vancomycin and meropenem. ESBL is an enzyme produced by some gram-negative bacteria that lends resistance to beta-lactam antibiotics, such as penicillins, cephalosporins, and aztreonam. ESBL-producing organisms are becoming more prevalent and are commonly the cause of complicated UTIs. Risk factors for ESBL infection include prior history of ESBL infection, hospitalizations, recent antibiotic use, residence in long–term health care facilities, and presence of indwelling catheters. Antibiotic selection for patients with these risk factors who present with systemic signs of infection should include ESBL coverage. Carbapenems such as meropenem or imipenem are first–line therapy for ESBL organisms.

Cefepime (A) is a fourth-generation cephalosporin. Efficacy data does not support its use for the treatment of infections caused by ESBL-producing organisms, even if cefepime susceptibility is demonstrated.

Ceftriaxone (B) is a third-generation cephalosporin that would be an appropriate choice for an acute complicated UTI if there was no suspicion for drug-resistant organisms. This patient has risk factors for drug resistance, so he requires broader antibiotic coverage.

In addition to carbapenems, fluoroquinolones such as levofloxacin (C) or trimethoprim-sulfamethoxazole are options for the treatment of complicated UTIs caused by ESBL-producing organisms. However, carbapenems are the preferred empiric therapy for this patient, who is likely bacteremic.

Piperacillin-tazobactam (E) is not recommended for the treatment of infections caused by ESBL-producing organisms due to conflicting evidence regarding their efficacy compared to carbapenems.

References

  1. Laudy AE, Róg P, Smolińska-Król K, Ćmiel M, Słoczyńska A, Patzer J, Dzierżanowska D, Wolinowska R, Starościak B, Tyski S. Prevalence of ESBL-producing Pseudomonas aeruginosa isolates in Warsaw, Poland, detected by various phenotypic and genotypic methods. PLoS One. 2017 Jun 28;12(6):e doi: 10.1371/journal.pone.0180121. PMID: 28658322; PMCID: PMC5489192.
  2. Jacoby GA, Medeiros AA, O’Brien TF, Pinto ME, Jiang H. Broad-spectrum, transmissible beta-lactamases. N Engl J Med. 1988;319(11):723-724. doi:10.1056/NEJM198809153191114
  3. Bajpai T, Pandey M, Varma M, Bhatambare GS. Prevalence of TEM, SHV, and CTX-M Beta-Lactamase genes in the urinary isolates of a tertiary care hospital. Avicenna J Med. 2017 Jan-Mar;7(1):12-16. doi: 10.4103/2231-0770.197508. PMID: 28182026; PMCID: PMC5255976.
  4. Paterson DL, Bonomo RA. Extended-Spectrum β-Lactamases: a Clinical Update. Clin Microbiol Rev 18: https://doi.org/10.1128/cmr.18.4.657-686.2005
  5. Paterson DL. Recommendation for treatment of severe infections caused by Enterobacteriaceae producing extended-spectrum β-lactamases (ESBLs) Clin Microbiol Infect. 2000; 6:460–3.
  6. Lee JA, Kang CI, Joo EJ, et al. Epidemiology and clinical features of community-onset bacteremia caused by extended-spectrum β-lactamase-producing Klebsiella pneumoniae. Microb Drug Resist 2011; 17:267.
  7. Hooper DC. Extended-spectrumbeta-lactamases. In: PostTW, ed. UpToDate.https://www.uptodate.com/contents/extended-spectrum-beta-lactamases. Accessed July 13, 2024.
  8. Arcilla MS, van Hattem JM., Haverkate MR, et al. Import and spread of extended-spectrum [beta]-lactamase-producing Enterobacteriaceae by international travelers (COMBAT study): a prospective, multicentre cohort study. The Lancet Infectious Diseases. 2017/01/01/;17(1):78-85. doi:https://doi.org/10.1016/S1473-3099(16)30319-X
  9. Tamma PD, Heil EL, Justo JA, Mathers AJ, Satlin MJ, Bonomo RA, Infectious Diseases Society of America Antimicrobial-Resistant Treatment Guidance: Gram-Negative Bacterial Infections. Infectious Diseases Society of America 2024; Version 4.0. Available at https://www.idsociety.org/practice-guideline/amr-guidance/. Accessed July 22, 2024.
  10. Park SH, Choi SM, Chang YK, et al. The efficacy of non-carbapenem antibiotics for the treatment of community-onset acute pyelonephritis due to extended-spectrum beta- lactamase-producing Escherichia coli. J Antimicrob Chemother. Oct 2014;69(10):2848-56. doi:10.1093/jac/dku215
  11. Sabih A, Leslie SW. Complicated Urinary Tract Infections. [Updated 2023 Nov 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK436013/
  12. Harris PA, Tambyah PA, Lye DC, et al. Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients with E colior Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance: A Randomized Clinical Trial.  2018;320(10):984–994. doi:10.1001/jama.2018.12163

 

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