What is the recommended empiric treatment for a patient diagnosed with an Extended-Spectrum Beta-Lactamase (ESBL)-producing infection?

Treatment of ESBL-Producing Infections

For suspected or confirmed ESBL-producing infections, carbapenems (meropenem, imipenem-cilastatin, or doripenem) are the first-line empiric treatment for critically ill patients, while carbapenem-sparing alternatives like piperacillin-tazobactam or ceftazidime-avibactam should be considered for stable, non-ICU patients with adequate source control. 1, 2

Severity-Based Treatment Algorithm

Critically Ill or Septic Patients

• Initiate Group 2 carbapenems immediately as first-line therapy 1, 2:
  • Meropenem 1g IV every 6 hours by extended infusion 1, 3
  • Imipenem-cilastatin 500mg IV every 6 hours by extended infusion 2, 1
  • Doripenem 500mg IV every 8 hours by extended infusion 2, 1
• These agents have activity against non-fermentative gram-negative bacilli and are most appropriate for severe infections 1
• For beta-lactam allergies, eravacycline 1 mg/kg IV every 12 hours is an alternative 1, 3

Stable, Non-ICU Patients with Adequate Source Control

• Carbapenem-sparing strategies are appropriate in this population 1, 4:
  • Piperacillin-tazobactam 4g/0.5g IV every 6 hours or 16g/2g by continuous infusion 1, 5
  • Ceftazidime-avibactam plus metronidazole for intra-abdominal infections 1, 2
  • Ceftolozane-tazobactam plus metronidazole 1
• Recent data from non-ICU patients show no difference in time to clinical stability between empiric carbapenem and non-carbapenem therapy 4

Healthcare-Associated Intra-Abdominal Infections

• When local prevalence of ESBL-producing Enterobacteriaceae is ≥20%, carbapenems are recommended 2
• Alternative regimens include ceftazidime or cefepime, or piperacillin-tazobactam, each with metronidazole 2
• Empiric therapy must be driven by local microbiologic results 2

Site-Specific Considerations

Urinary Tract Infections

• Avoid fluoroquinolones empirically due to 60-93% resistance rates in ESBL-producing E. coli 3, 6
• For uncomplicated UTIs: nitrofurantoin (5-day course) or fosfomycin (3g single dose) 7
• For complicated UTIs/pyelonephritis: ertapenem 1g IV every 24 hours 3, 1
• Alternatives for mild-moderate UTIs include nitrofurantoin, fosfomycin, and aminoglycosides based on susceptibility 7

Skin and Soft Tissue Infections

• For ESBL-producing leg cellulitis with chronic kidney disease: ertapenem 1g IV every 24 hours for stable patients, or meropenem 1g IV every 8 hours for critically ill patients 6
• Ensure adequate wound care and debridement if necrotic tissue is present, as antimicrobials alone are insufficient without source control 6

Necrotizing Soft Tissue Infections

• In settings with high local prevalence of ESBL-producing Enterobacteriaceae, carbapenems (meropenem, imipenem-cilastatin, or doripenem) administered in adequate dosage are appropriate 2
• Piperacillin-tazobactam with optimized pharmacokinetic/pharmacodynamic parameters is appropriate only in settings without high ESBL prevalence 2

Special Resistance Mechanisms

Metallo-β-Lactamase (MBL) Producers

• Ceftazidime-avibactam plus aztreonam is strongly recommended for MBL-producing Enterobacterales 1
• Cefiderocol may be considered as an alternative 1
• MBLs hydrolyze all β-lactams except monobactams 1

Carbapenem-Resistant Enterobacteriaceae (CRE)

• Tigecycline at high doses plus carbapenem in continuous infusion may be considered 1
• Addition of IV colistin may be necessary in severe infections 2
• Ceftazidime-avibactam has activity against some KPC-producing organisms 1

De-escalation Strategy

Once culture and susceptibility results are available, de-escalation from carbapenem to narrower-spectrum agents is strongly recommended to preserve carbapenem effectiveness and reduce mortality 3, 1:

• Consider narrowing therapy if the organism shows susceptibility to non-carbapenem agents 6
• In clinical practice, less than 50% of patients with ESBL infections are successfully de-escalated, primarily due to antimicrobial resistance (44.7%), infection relapse (26.9%), and clinical instability (19.2%) 8
• E. coli-related infections are more amenable to de-escalation compared to other ESBL-producing organisms 8

Critical Pitfalls to Avoid

• Do not use fluoroquinolones empirically in regions with >20% resistance rates among E. coli isolates, as ESBL-producing E. coli exhibits 60-93% fluoroquinolone resistance 3, 1
• Do not use third-generation cephalosporins against ESBL producers due to high clinical failure rates 6, 9
• Do not delay parenteral therapy for complicated infections, as this increases treatment failure risk and mortality 3
• Do not rely on antimicrobials alone without adequate source control (drainage, debridement) 6, 3
• Do not overuse carbapenems in stable patients, as this leads to selection pressure and emergence of carbapenem-resistant organisms 1

Risk Factors Requiring Empiric ESBL Coverage

• Recent antibiotic exposure within 90 days, particularly third-generation cephalosporins or fluoroquinolones 3
• Healthcare exposure and chronic kidney disease 6, 3
• Prior ESBL infection or colonization 4
• Travel to Western Pacific, Eastern Mediterranean, or Southeast Asia regions 3
• Confirmed ESBL infection in the past 6

Monitoring and Duration

• Obtain cultures from the site of infection in higher-risk patients, particularly those with prior antibiotic exposure 2
• Susceptibility testing should be performed for Pseudomonas, Proteus, Acinetobacter, Staphylococcus aureus, and predominant Enterobacteriaceae 2
• Treatment duration for intra-abdominal infections: 7-10 days 5
• Treatment duration for nosocomial pneumonia: 7-14 days 5
• Procalcitonin monitoring may be useful to guide antimicrobial discontinuation 2