What is the recommended treatment for infections caused by Extended-Spectrum Beta-Lactamase (ESBL)-producing bacteria?

Treatment of ESBL-Producing Bacterial Infections

Immediate First-Line Treatment Based on Severity

For critically ill patients with serious ESBL infections, initiate Group 2 carbapenems (meropenem, imipenem, or doripenem) immediately as first-line therapy. 1, 2

Critically Ill Patients or Septic Shock

• Meropenem 1g IV every 6 hours by extended infusion is the preferred agent 2
• Alternative options include:
  • Imipenem/cilastatin 500mg IV every 6 hours by extended infusion 2
  • Doripenem 500mg IV every 8 hours by extended infusion 2
• These Group 2 carbapenems have activity against non-fermentative gram-negative bacilli and are most appropriate for high bacterial loads or elevated β-lactam MICs 1

Stable Patients with Mild-to-Moderate Infections

Carbapenem-sparing alternatives should be prioritized to reduce selection pressure for carbapenem resistance. 1, 3

• Piperacillin/tazobactam 6g/0.75g loading dose, then 4g/0.5g IV every 6 hours or 16g/2g by continuous infusion 2, 4
• Ceftolozane/tazobactam plus metronidazole is effective against ESBL-producing Enterobacteriaceae 1
• Ceftazidime/avibactam plus metronidazole demonstrates activity against ESBL-producers and some KPC-producing organisms 1

Site-Specific Treatment Algorithms

Urinary Tract Infections (UTIs)

For uncomplicated UTIs caused by ESBL-producers, oral carbapenem-sparing options are highly effective. 3, 5

Oral Options for Uncomplicated UTIs:

• Fosfomycin shows 98% sensitivity against E. coli ESBL-producers 5
• Pivmecillinam shows 96% sensitivity against E. coli and 83% against Klebsiella ESBL-producers 5
• Nitrofurantoin shows 93% sensitivity against E. coli ESBL-producers 5
• Treatment duration: 3-5 days for uncomplicated UTIs 3

Complicated UTIs or Pyelonephritis:

• Intravenous fosfomycin has high-certainty evidence for complicated UTIs with or without bacteremia 3
• Aminoglycosides (including plazomicin) are effective but duration should be limited to avoid nephrotoxicity 3
• Meropenem-vaborbactam or imipenem-cilastatin-relebactam for carbapenem-resistant Enterobacteriaceae 3
• Treatment duration: 7-14 days guided by clinical response 3

Intra-Abdominal Infections

For non-critically ill, immunocompetent patients with adequate source control, amoxicillin/clavulanate 2g/0.2g IV every 8 hours is appropriate. 2

• For critically ill or immunocompromised patients: piperacillin/tazobactam at doses listed above 2
• For high risk of ESBL or inadequate source control: ertapenem 1g IV every 24 hours 2
• Delayed source control leads to treatment failure—ensure surgical intervention when indicated 2

Nosocomial Pneumonia

Start with 4.5g piperacillin/tazobactam every 6 hours plus an aminoglycoside for empiric coverage. 4

• Total daily dose: 18.0g (16.0g piperacillin and 2.0g tazobactam) 4
• Continue aminoglycoside if P. aeruginosa is isolated 4
• Treatment duration: 7-14 days 4

Special Resistance Mechanisms Requiring Alternative Therapy

Metallo-β-Lactamase (MBL)-Producing Organisms

Ceftazidime/avibactam plus aztreonam is strongly recommended for MBL-producing Enterobacterales. 6, 1, 2

• MBLs hydrolyze all β-lactams except aztreonam, but aztreonam cannot be used alone due to co-production of ESBLs 6
• This combination showed 30-day mortality of 19.2% vs. 44% with other regimens (P = 0.007) 6
• Cefiderocol may be considered as an alternative with 75% clinical cure rate in MBL subgroup 6, 1

KPC-Producing Organisms

Ceftazidime/avibactam or meropenem/vaborbactam are first-line options for KPC-producing carbapenem-resistant Enterobacteriaceae. 1, 2

• For severe infections, consider combination therapy with high-dose tigecycline plus carbapenem in continuous infusion 1
• Add IV colistin in severe infections 1

OXA-48-Like Producing Organisms

Ceftazidime/avibactam shows promising results but evidence is limited. 6

• Very limited clinical data available from observational studies with small sample sizes 6
• Further studies needed to confirm efficacy 6

Dosage Adjustments for Renal Impairment

Reduce piperacillin/tazobactam dosing based on creatinine clearance. 4

Creatinine Clearance	All Indications (except pneumonia)	Nosocomial Pneumonia
>40 mL/min	3.375g every 6 hours	4.5g every 6 hours
20-40 mL/min	2.25g every 6 hours	3.375g every 6 hours
<20 mL/min	2.25g every 8 hours	2.25g every 6 hours
Hemodialysis	2.25g every 12 hours + 0.75g post-dialysis	2.25g every 8 hours + 0.75g post-dialysis

4

Critical Pitfalls to Avoid

Antibiotic Selection Errors

• Never use first-generation cephalosporins—they lack activity against ESBL-producing organisms 1, 2
• Avoid fluoroquinolones in regions with >20% resistance rates among E. coli isolates 1, 2, 3
• Do not use extended-spectrum cephalosporins even if susceptibility testing suggests sensitivity—clinical failure rates are high 7, 8
• Avoid trimethoprim and ciprofloxacin—they show poor efficacy against ESBL-producers 5

Carbapenem Stewardship

• Minimize carbapenem overuse to prevent selection pressure for carbapenem-resistant organisms 1, 2
• In areas with high carbapenem-resistant Klebsiella pneumoniae prevalence, strongly favor carbapenem-sparing regimens 1, 2
• Reserve newer agents (ceftolozane/tazobactam, ceftazidime/avibactam) for multidrug-resistant infections to preserve their activity 1, 2

Clinical Management Errors

• Delayed source control is a common cause of treatment failure in intra-abdominal infections 1, 2
• Monitor aminoglycoside and vancomycin serum levels closely to decrease renal failure risk 1, 2
• Reassess when microbiological results are available and consider de-escalation 3

Local Epidemiology Considerations

Local antimicrobial resistance patterns must guide empiric therapy choices. 1, 2

• ESBL carriage rates exceed 10% in Western Pacific, Eastern Mediterranean, and Southeast Asia 2
• ESBL carriage rates remain <10% in Europe 2
• Rapid identification of the specific resistance mechanism is crucial for optimizing therapy 1

Risk Factors Warranting Empiric ESBL Coverage

Initiate empiric anti-ESBL therapy when patients have: 2

• Recent antibiotic exposure (especially cephalosporins or fluoroquinolones) 2
• Known colonization with ESBL-producing Enterobacteriaceae 2
• Travel to high-prevalence regions 2
• Admission from long-term care facilities 2

Alternative and Emerging Options

Tigecycline

• Viable for complicated intra-abdominal infections with favorable activity against ESBL-producing Enterobacteriaceae 1, 2
• Lacks activity against P. aeruginosa and should be used cautiously in suspected bacteremia 1, 2

Polymyxins and Fosfomycin

• Colistin and fosfomycin have been revived for carbapenem-resistant infections but require judicious use 1, 2
• Should be reserved for salvage therapy when other options are exhausted 1

Eravacycline

• Alternative for beta-lactam allergies at 1 mg/kg IV every 12 hours 2