What is the recommended treatment for a patient with a multidrug-resistant Gram-negative urinary tract infection (UTI) as indicated by urine culture results?

Treatment of Multidrug-Resistant Gram-Negative UTI

For multidrug-resistant Gram-negative urinary tract infections, newer beta-lactam/beta-lactamase inhibitor combinations—specifically ceftazidime-avibactam, meropenem-vaborbactam, or imipenem-cilastatin-relebactam—are the preferred first-line agents for carbapenem-resistant organisms, while aminoglycosides or fosfomycin serve as effective alternatives for non-severe infections or simple cystitis. 1

Treatment Algorithm Based on Infection Severity and Resistance Pattern

For Carbapenem-Resistant Enterobacterales (CRE)

Severe/Complicated UTI:

• Ceftazidime-avibactam 2.5 g IV every 8 hours is recommended as first-line therapy if the organism is susceptible in vitro 1
• Meropenem-vaborbactam 4 g IV every 8 hours is an equally effective alternative with similar evidence quality 1, 2
• Imipenem-cilastatin-relebactam 1.25 g IV every 6 hours represents another first-line option for CRE complicated UTIs 1, 2
• Treatment duration should be 5-7 days for uncomplicated pyelonephritis and 5-10 days for complicated UTIs, with extension to 7-14 days if bacteremia is present 3

Non-Severe UTI or Simple Cystitis:

• Single-dose aminoglycosides (gentamicin 5-7 mg/kg IV once daily or amikacin 15 mg/kg IV once daily) are recommended for simple cystitis due to CRE 1, 2
• Plazomicin 15 mg/kg IV every 12 hours is an alternative aminoglycoside option for complicated UTI due to CRE 1, 2
• Fosfomycin (oral 3 g every 48-72 hours for 3 doses, or IV 6 g every 8 hours for 7 days) demonstrates excellent activity against multidrug-resistant organisms including ESBL-producing and carbapenem-resistant Enterobacterales 4, 5, 6

For Metallo-Beta-Lactamase Producers

• Cefiderocol is conditionally recommended when organisms are resistant to ceftazidime-avibactam and meropenem-vaborbactam 1
• Aztreonam plus ceftazidime-avibactam combination is suggested for severe infections caused by metallo-beta-lactamase-producing CRE 1

For Extended-Spectrum Beta-Lactamase (ESBL) Producers

• Carbapenems remain the gold standard for ESBL-producing organisms causing severe UTI 3, 7
• For non-severe ESBL UTIs, consider older agents based on susceptibility: piperacillin-tazobactam, fluoroquinolones (if local resistance <10%), fosfomycin, or nitrofurantoin 1, 7
• Reserve newer beta-lactam/beta-lactamase inhibitors for extensively resistant bacteria due to antimicrobial stewardship considerations 1

For Multidrug-Resistant Pseudomonas aeruginosa

• Treatment options include ceftazidime, cefepime, piperacillin-tazobactam, carbapenems, aminoglycosides, ceftazidime-avibactam, or ceftolozane-tazobactam based on susceptibility 7
• Colistin (dosed per package insert) serves as a last-resort option for organisms resistant to all other agents 8, 7

Critical Clinical Considerations

Combination Therapy:

• Do NOT use combination therapy for CRE infections susceptible to and treated with ceftazidime-avibactam, meropenem-vaborbactam, or cefiderocol 1
• Consider combination therapy only for severe infections when organisms are susceptible in vitro only to polymyxins, aminoglycosides, tigecycline, or fosfomycin 1
• Combination selection should be based on susceptibility testing results 1

Agents to Avoid:

• Tigecycline is NOT recommended for bloodstream infections or hospital-acquired/ventilator-associated pneumonia, though high-dose tigecycline may be considered for pneumonia if necessary 1
• Fluoroquinolones should be restricted for empiric treatment due to increasing resistance rates 7
• Avoid carbapenem-based combination therapy for CRE unless meropenem MIC is ≤8 mg/L and newer agents are unavailable 1

Antimicrobial Stewardship:

• Always obtain urine culture and susceptibility testing before initiating therapy when possible 1, 9
• De-escalate to targeted therapy once susceptibility results are available, using older agents (beta-lactam/beta-lactamase inhibitors, quinolones, cotrimoxazole) when appropriate 1
• Local resistance patterns must guide empiric therapy selection 3, 7

Common Pitfalls:

• Aminoglycoside monotherapy should only be used for urinary tract infections, not systemic infections, due to inadequate tissue penetration 3, 9
• Extended infusion of meropenem over 3 hours is necessary if the pathogen's MIC is ≥8 mg/L 2
• Treatment failure by 72 hours requires urologic evaluation and consideration of alternative diagnosis or resistant organisms 10