Management of Multidrug-Resistant UPEC
For multidrug-resistant uropathogenic E. coli urinary tract infections, nitrofurantoin and fosfomycin remain first-line oral options for uncomplicated cystitis due to persistently low resistance rates, while ESBL-producing strains require carbapenems for severe infections or specific oral alternatives based on susceptibility testing. 1, 2
Uncomplicated Cystitis in MDR-UPEC
First-line oral agents that maintain efficacy:
- Nitrofurantoin (5-day course) - resistance remains low even among MDR strains 1, 3
- Fosfomycin tromethamine (3-g single dose) - maintains low resistance rates across MDR populations 1, 3
- Pivmecillinam (5-day course) - effective against many MDR strains including some ESBL-producers 1
Avoid empiric use of these agents due to high resistance:
- Trimethoprim-sulfamethoxazole shows 14.6-60% resistance in European countries and should not be used empirically 3
- Fluoroquinolones (ciprofloxacin, levofloxacin) demonstrate 43.6-47.3% resistance rates, with MDR strains showing nearly universal fluoroquinolone resistance 4
ESBL-Producing UPEC
Oral treatment options for ESBL-E. coli UTIs:
- Nitrofurantoin, fosfomycin, and pivmecillinam remain viable 1
- Amoxicillin-clavulanate can be used for ESBL-E. coli (but NOT for ESBL-Klebsiella) 1
- Newer fluoroquinolones: finafloxacin and sitafloxacin 1
Parenteral options for severe ESBL-UPEC infections:
- Carbapenems are the current mainstay (meropenem/vaborbactam, imipenem/cilastatin-relebactam) 1, 2
- Piperacillin-tazobactam (for ESBL-E. coli only, not other Enterobacterales) 1
- Novel β-lactam combinations: ceftazidime-avibactam, ceftolozane-tazobactam 1, 2
- Cefiderocol 1, 2
- Aminoglycosides including plazomicin 1
Critical caveat: Carbapenem overreliance is driving carbapenem-resistance emergence in UPEC populations, necessitating judicious use and consideration of carbapenem-sparing alternatives when possible 2
Carbapenem-Resistant UPEC
Treatment options for CRE-UPEC:
- Ceftazidime-avibactam 1, 2
- Meropenem/vaborbactam, imipenem/cilastatin-relebactam 1
- Cefiderocol 1, 2
- Aminoglycosides including plazomicin 1
- Fosfomycin (IV formulation) 1, 2
- Polymyxins (colistin) 1, 2
- Tigecycline 1, 2
For metallo-β-lactamase producers (NDM, IMP-4):
- Combination therapy: ceftazidime-avibactam PLUS aztreonam is the preferred approach 2
- Alternative combination: aztreonam plus amoxicillin-clavulanate 1
Clinical Algorithm
Step 1: Determine infection severity and site
- Uncomplicated cystitis → oral agents (nitrofurantoin, fosfomycin, pivmecillinam) 1
- Pyelonephritis or complicated UTI → consider parenteral therapy initially 3
Step 2: Assess resistance risk factors
- Recent antibiotic exposure (especially fluoroquinolones or TMP-SMX) 1
- Previous ESBL or MDR organism isolation 1
- Healthcare-associated infection 4
- Male gender (associated with fluoroquinolone resistance and MDR phenotype) 4
Step 3: Obtain cultures before treatment
- Essential for MDR-UPEC to guide definitive therapy 5
- Adjust therapy based on susceptibility results 1
Step 4: Antimicrobial stewardship
- Reserve carbapenems and novel agents for documented resistant infections to prevent further resistance development 1, 2
- Local antibiograms should guide empiric choices when available 1
Important Pitfalls
- Do not use fluoroquinolones or TMP-SMX empirically in communities with high resistance rates or in patients with recent exposure 1, 3
- Hospital-acquired infections show higher rates of third-generation cephalosporin and nitrofurantoin resistance 4
- Piperacillin-tazobactam only works for ESBL-E. coli, not other ESBL-producing Enterobacterales 1
- Continuous surveillance of local resistance patterns is mandatory to prevent treatment failure 4