Treatment of MDR and ESBL-Producing UPEC Infections
For MDR and ESBL-producing UPEC infections, nitrofurantoin and fosfomycin should be prioritized as first-line oral agents for uncomplicated cases, while carbapenems remain the definitive treatment for complicated infections and urosepsis, with emerging alternatives including cefiderocol and novel β-lactam-β-lactamase inhibitor combinations reserved for carbapenem-resistant strains.
Virulence and Resistance Correlation
MDR and ESBL-producing UPEC strains demonstrate distinct virulence profiles compared to susceptible isolates:
ESBL-producers show paradoxically lower virulence scores with reduced prevalence of hemagglutinin (tsh), hemolysin toxin (hlyD), and invasin (ibeA) genes compared to non-MDR strains, though they maintain high levels of adhesins (82.1% csgA, 73.1% fimH) and siderophores (73.1% sitA) 1
96.3% of ESBL-producing UPEC are multidrug-resistant, with 100% harboring blaCTX-M genes, 63% harboring blaSHV, and 11.1% harboring blaTEM 1
All MDR UPEC isolates demonstrate resistance to penicillins, with resistance rates exceeding 50% for two-thirds of tested antibiotics 1
Treatment Algorithm by Clinical Scenario
Uncomplicated UTI (Outpatient)
First-line options:
Nitrofurantoin demonstrates the highest efficacy with <20% resistance rates among ESBL-producers and 72.5% sensitivity overall 2, 1
Fosfomycin shows 14.1% resistance in ESBL-producing strains, making it a viable alternative 3
Complicated UTI or Urosepsis
Definitive therapy:
Carbapenems remain the cornerstone for treating MDR ESBL-producing UPEC in severe infections, with zero resistance observed in recent surveillance 4, 3
Amikacin retains 70% sensitivity and should be considered for combination therapy 2
Carbapenem-Resistant UPEC
Salvage options in order of preference:
Cefiderocol as a novel siderophore cephalosporin 4
Novel β-lactam-β-lactamase inhibitor combinations including ceftazidime-avibactam 4
For metallo-β-lactamase producers (NDM, IMP-4): combination of ceftazidime-avibactam with aztreonam 4
Alternative agents: polymyxins, tigecycline, or aminoglycosides in combination regimens 4
Regional Resistance Patterns to Avoid
High-resistance antibiotics that should NOT be used empirically:
- Ampicillin (97.5% resistance) 2
- Nalidixic acid and cefelexin (95% resistance) 2
- Amoxicillin (92.5% resistance) 2
- Cotrimoxazole (82.5% resistance) 2
- Ciprofloxacin (80% resistance) 2
- Third-generation cephalosporins show variable resistance with 70% of resistant isolates being ESBL-producers 2
Critical Clinical Pitfalls
Cefoxitin resistance occurs in 29.3% of ESBL-producers, limiting second-generation cephalosporin utility 3
Aminoglycoside resistance affects 50% of ESBL-producing strains, requiring susceptibility testing before use 3
Fluoroquinolone co-resistance is prevalent in ESBL-producers, making empiric quinolone therapy inappropriate 1
Treatment failure risk is substantially elevated with ESBL-producers due to the combination of MDR patterns and persistent virulence factors, particularly adhesins that facilitate biofilm formation 1, 5
Resistance Pattern Heterogeneity
Thirty different antibiotic resistance patterns have been documented among MDR UPEC isolates, with eleven distinct patterns among ESBL-producers specifically 2. This heterogeneity varies by: