What is the recommended treatment for a urinary tract infection (UTI) caused by Extended-Spectrum Beta-Lactamase (ESBL)-producing bacteria?

Treatment of ESBL-Producing UTIs

For uncomplicated cystitis caused by ESBL-producing bacteria, use oral nitrofurantoin, fosfomycin, or pivmecillinam; for complicated UTIs or pyelonephritis without severe sepsis in hemodynamically stable patients, use piperacillin-tazobactam as a carbapenem-sparing option; reserve carbapenems (ertapenem, meropenem) for bacteremic infections with severe sepsis, septic shock, or critically ill patients. 1

Uncomplicated Cystitis (Lower UTI)

• Oral first-line options include nitrofurantoin (5-day course), fosfomycin (3g single dose), or pivmecillinam (5-day course) 1, 2
• These agents demonstrate >95% sensitivity against ESBL-producing Enterobacteriaceae, with E. coli showing 98% sensitivity to fosfomycin, 96% to pivmecillinam, and 93% to nitrofurantoin 3
• Single-dose aminoglycosides are an alternative option for simple cystitis due to their high urinary concentrations (25-100 fold above plasma levels) and microbiologic cure rates of 87-100%, though evidence for ESBL-specific infections is limited 4

Complicated UTIs and Pyelonephritis (Without Bacteremia)

Carbapenem-Sparing Strategy (Preferred When Appropriate)

• Piperacillin-tazobactam is the recommended carbapenem-sparing option for hemodynamically stable patients with complicated UTIs or pyelonephritis caused by ESBL-producing organisms 1
• The European Society of Clinical Microbiology and Infectious Diseases provides moderate-certainty evidence showing no statistically significant differences between piperacillin-tazobactam and carbapenems for clinical cure, microbiological cure, mortality, or recurrence in pyelonephritis caused by third-generation cephalosporin-resistant Enterobacteriaceae 1
• This approach is appropriate when the patient is not critically ill, not immunocompromised, and has not failed prior piperacillin-tazobactam therapy 1

Alternative Parenteral Options

• Fosfomycin IV demonstrates non-inferiority to meropenem for bacteremic UTIs due to E. coli (high-certainty evidence), though carries an 8.6% risk of heart failure versus 1.4% with meropenem 1
• Aminoglycosides (including plazomicin) are effective for complicated UTIs with moderate-certainty evidence, but duration should be limited to <7 days due to nephrotoxicity risk 1, 2
• Ceftolozane-tazobactam with metronidazole may be valuable for ESBL infections to preserve carbapenems, though primarily studied in intra-abdominal infections 4

Bacteremic UTIs and Severe Infections

When to Use Carbapenems

Carbapenems are indicated when:

• Bacteremia with severe sepsis or septic shock is present 1
• Patient is critically ill or immunocompromised 1
• Previous therapeutic failure with piperacillin-tazobactam 1
• Hemodynamic instability exists 4

Carbapenem Options

• Ertapenem 1g IV once daily is FDA-approved for complicated UTIs including pyelonephritis caused by E. coli (including concurrent bacteremia) and K. pneumoniae 5
• Ertapenem is stable against ESBL hydrolysis and demonstrates high clinical efficacy with mean treatment duration of 7-9 days 5, 6, 7
• Meropenem-vaborbactam 4g IV q8h or imipenem-cilastatin-relebactam 1.25g IV q6h are recommended for complicated UTIs caused by carbapenem-resistant Enterobacteriaceae (weak recommendation, low quality evidence) 4
• For pediatric patients 3 months to 12 years, ertapenem 15 mg/kg twice daily (not exceeding 1g/day) is appropriate 5

Carbapenem-Resistant Enterobacteriaceae (CRE)

• Ceftazidime-avibactam 2.5g IV q8h is recommended for complicated UTIs caused by CRE (weak recommendation, very low quality evidence) 4
• Plazomicin 15 mg/kg IV q12h is an option for CRE-UTI, with the CARE trial showing lower mortality (24% vs 50%) and less acute renal injury (16.7% vs 50%) compared to colistin-based regimens 4
• Other options include colistin, polymyxin B, tigecycline, and fosfomycin, though these are reserved for limited therapeutic options 8, 2

Critical Pitfalls to Avoid

• Do not use third-generation cephalosporins (ceftriaxone, cefotaxime) for ESBL infections due to high resistance rates and selective pressure for further resistance 4
• Avoid fluoroquinolones for empiric therapy due to high resistance rates in ESBL-producing organisms and selective pressure for MRSA and additional ESBL emergence 4, 8
• Do not use piperacillin-tazobactam in critically ill patients, those with septic shock, or bacteremic infections requiring definitive therapy—use carbapenems instead 1
• Limit aminoglycoside duration to <7 days to minimize nephrotoxicity risk 1
• Monitor for heart failure (8.6% incidence) when using IV fosfomycin 1

Duration of Therapy

• For complicated UTIs with adequate source control, 3-5 days of post-operative therapy is appropriate in non-severely ill patients 4
• Ertapenem therapy typically ranges 7-9 days for ESBL-producing UTIs 6, 7
• Patients with ongoing signs beyond 5-7 days warrant investigation for uncontrolled infection source or treatment failure 4