How do we manage a complicated urinary tract infection that is pan-antibiotic resistant?

Management of Pan-Antibiotic Resistant Complicated Urinary Tract Infections

For pan-resistant complicated UTIs, treat with the least resistant antibiotic based on MICs relative to breakpoints, prioritizing newer beta-lactam/beta-lactamase inhibitor combinations (ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam) or cefiderocol as first-line agents, with combination therapy reserved for severe infections. 1

Initial Approach: Obtain Susceptibility Testing Immediately

• Obtain urine culture and susceptibility testing before initiating therapy to guide targeted treatment, as empiric therapy is unreliable in pan-resistant organisms 1
• Differentiate true infection from colonization before prescribing anti-resistant antimicrobials, as treatment of colonization drives further resistance 1
• Assess severity: severe infections (sepsis, septic shock, hemodynamic instability) require immediate empiric broad-spectrum therapy while awaiting cultures 1

First-Line Treatment Options for Carbapenem-Resistant Enterobacterales (CRE)

Newer Beta-Lactam Combinations (Preferred)

• Ceftazidime-avibactam 2.5 g IV every 8 hours is recommended for complicated UTIs caused by CRE, including KPC-producing strains 1
• Meropenem-vaborbactam 4 g IV every 8 hours demonstrated non-inferiority to best available treatment in the TANGO-II trial for CRE infections 1
• Imipenem-cilastatin-relebactam 1.25 g IV every 6 hours is active against most KPC-producing CRE and was well-tolerated in the RESTORE-IMI-1 trial 1
• These agents should be prioritized over older options due to superior activity against resistant mechanisms 1

Cefiderocol (Novel Siderophore Cephalosporin)

• Cefiderocol 2 g IV every 8 hours (infused over 1 hour) demonstrated 72.6% composite response rates in complicated UTIs, superior to imipenem-cilastatin (54.6%) 2
• Active against carbapenem-resistant organisms including CRE, Pseudomonas aeruginosa, and Acinetobacter baumannii 2
• Treatment duration: 7-14 days based on clinical response 2
• Critical caveat: European guidelines conditionally recommend AGAINST cefiderocol for CRAB infections due to mortality concerns, though it remains an option for CRE and CRPA 1

Aminoglycosides

• Plazomicin 15 mg/kg IV every 12 hours is recommended for complicated UTI due to CRE, with lower nephrotoxicity than colistin (16.7% vs 50% acute renal injury in CARE trial) 1
• Single-dose aminoglycoside (gentamicin or amikacin) achieves urinary concentrations 25-100 fold higher than plasma, with 87-100% microbiologic cure rates for simple cystitis due to CRE 1
• Amikacin remains the most active aminoglycoside against CRE isolates (38.2% susceptibility in Taiwan surveillance) 1

Treatment for Carbapenem-Resistant Pseudomonas aeruginosa (CRPA)

• Ceftolozane-tazobactam or ceftazidime-avibactam are preferred agents for CRPA infections 1
• For severe CRPA infections, use combination therapy with two in vitro active drugs (e.g., polymyxin plus aminoglycoside, or polymyxin plus fosfomycin) 1
• Monotherapy may be considered for non-severe infections under antibiotic stewardship principles 1

Treatment for Carbapenem-Resistant Acinetobacter baumannii (CRAB)

• Ampicillin-sulbactam is suggested for CRAB susceptible to sulbactam, particularly in hospital-acquired/ventilator-associated pneumonia 1
• Polymyxin or high-dose tigecycline can be used if active in vitro for sulbactam-resistant CRAB 1
• For severe CRAB infections, use combination therapy with two in vitro active antibiotics (polymyxin, aminoglycoside, tigecycline, or sulbactam combinations) 1
• Avoid polymyxin-meropenem or polymyxin-rifampin combinations as these are not recommended based on high/moderate quality evidence 1

Treatment for Vancomycin-Resistant Enterococcus (VRE) UTIs

For Complicated UTIs

• Fosfomycin is FDA-approved for UTI caused by E. faecalis and shows synergistic activity when combined with linezolid, tigecycline, or gentamicin 1
• Nitrofurantoin has good in vitro activity against VRE for lower urinary tract infections 1
• High-dose ampicillin (18-30 g IV daily) or amoxicillin (500 mg IV every 8 hours) can overcome ampicillin resistance in VRE UTIs due to high urinary concentrations, achieving 88.1% clinical cure and 86% microbiological eradication 1

For Serious VRE Infections with Bacteremia

• Daptomycin 8-12 mg/kg IV daily is preferred for bactericidal activity in serious VRE infections 1
• Tigecycline should NOT be used for VRE bacteremia due to large volume of distribution and low serum levels, despite being ideal for intra-abdominal VRE infections 1

Combination Therapy Considerations

• For severe infections or high-risk patients, combination therapy with two in vitro active antibiotics is suggested to prevent treatment failure 1
• The British Society for Antimicrobial Chemotherapy recommends considering ceftazidime-avibactam combined with a carbapenem or colistin for KPC-3 producers, though evidence for UTI is insufficient 1
• Avoid routine combination therapy for non-severe infections to preserve antibiotic stewardship 1

Critical Pitfalls to Avoid

• Do not use tigecycline for bloodstream infections despite its activity against resistant organisms, as serum levels are inadequate 1
• Do not use fluoroquinolones empirically due to high resistance rates in multidrug-resistant organisms 3, 4
• Do not treat asymptomatic bacteriuria even with resistant organisms, as this drives further resistance without clinical benefit 5
• Address underlying urological abnormalities (obstruction, stones, catheters) as antimicrobial therapy alone will fail without source control 6

Duration of Therapy

• Complicated UTIs: 5-10 days based on clinical response 5, 6
• Severe infections with bacteremia: 10-14 days may be required 1
• Individualize duration based on source control adequacy and clinical improvement 1

When All Options Are Exhausted (True Pan-Resistance)

• Treat with the antibiotic showing the lowest MIC relative to breakpoints, even if technically "resistant" 1
• Consider double carbapenem regimens using high-dose extended-infusion dosing for organisms with meropenem MIC ≤8 mg/L 1
• Ensure aggressive source control (drainage, catheter removal, obstruction relief) as antimicrobials alone are insufficient 1, 6