What is the initial approach to treating patients diagnosed with multidrug-resistant Urinary Pathogen Escherichia coli (UPEC)?

Initial Approach to Multidrug-Resistant UPEC

For multidrug-resistant (MDR) UPEC infections, initiate empiric therapy with carbapenems for severe infections or urosepsis, while nitrofurantoin or fosfomycin remain viable options for uncomplicated cystitis with resistance rates below 20%. 1, 2

Definitions and Classification

MDR UPEC is defined as resistance to three or more antibiotic classes, with the most concerning phenotype being ESBL-producing strains that demonstrate resistance to penicillins, cephalosporins, fluoroquinolones, and trimethoprim-sulfamethoxazole. 2, 3

• ESBL-producing UPEC: 96.3% of ESBL-producers are MDR, with CTX-M being the most prevalent resistance gene (100% of ESBL strains), followed by SHV (63%) and TEM (11.1%). 2
• Carbapenem-resistant UPEC: The most severe form requiring alternative strategies including novel β-lactam-β-lactamase inhibitor combinations or cefiderocol. 1
• Mobile genetic elements (transposons, integrons, conjugative plasmids) drive the rapid spread of resistance genes across UPEC populations. 3

Prevalence in Different Healthcare Settings

Community-acquired UTIs show alarming resistance patterns, with significant geographic variation:

• Trimethoprim-sulfamethoxazole resistance: 14.6-60% across European countries, making it unreliable as first-line therapy in many regions. 4
• Fluoroquinolone resistance: Dramatically higher in developing countries (55.5-85.5%) compared to developed nations (5.1-32.0%). 4
• Amoxicillin-clavulanic acid resistance: Ranges from 5.3% in Germany to 37.6% in France. 4
• ESBL prevalence: 34.6% of community-acquired UPEC isolates in some regions, with 93.6% of all isolates demonstrating MDR patterns. 2

Clinical Outcomes and Treatment Challenges

Severity and Mortality Impact

MDR ESBL-producing UPEC increases UTI severity, reduces first-line antibiotic efficacy, and elevates morbidity and mortality rates. 2

• High virulence factor prevalence persists even in MDR strains, particularly adhesins (82.1% csgA, 73.1% fimH) and siderophores (73.1% sitA), facilitating tissue invasion and persistence. 2
• Treatment failure rates increase substantially when empiric therapy doesn't cover resistance patterns. 2

Treatment Algorithm by Clinical Scenario

For uncomplicated cystitis with suspected MDR:

• First-line: Nitrofurantoin (resistance <20% in most settings) or fosfomycin (low resistance rates maintained). 1, 4, 2
• These agents retain activity even against ESBL-producers. 2

For complicated UTI or pyelonephritis with MDR:

• Empiric therapy: Carbapenems remain the cornerstone for MDR UPEC when ESBL-production is suspected or confirmed. 1
• Alternative options: β-lactam-β-lactamase inhibitor combinations, cephamycin, or temocillin for strains with documented susceptibility. 1

For carbapenem-resistant UPEC:

• Novel combinations: Ceftazidime-avibactam, meropenem-vaborbactam, or imipenem-relebactam. 1
• Cefiderocol: Siderophore cephalosporin with activity against carbapenem-resistant strains. 1
• For metallo-β-lactamase producers (NDM, IMP-4): Ceftazidime-avibactam combined with aztreonam. 1
• Last-resort options: Polymyxins, tigecycline, aminoglycosides, or fosfomycin (often in combination therapy). 1

Critical Pitfalls to Avoid

Do not use fluoroquinolones or trimethoprim-sulfamethoxazole empirically for MDR UPEC given resistance rates exceeding 50% in most regions and approaching 85% in developing countries. 4, 2

Avoid carbapenem overreliance as this accelerates carbapenem-resistance dissemination; reserve for severe infections or documented ESBL-producers. 1

Obtain urine cultures with susceptibility testing before initiating therapy whenever possible, as resistance patterns vary dramatically by geographic region and healthcare setting. 4, 2

Monitor for ESBL production in all UPEC isolates, as this phenotype predicts resistance to multiple antibiotic classes and necessitates carbapenem therapy for serious infections. 2