What is the recommended treatment for a patient with a urinary tract infection (UTI) caused by Carbapenem-resistant Pseudomonas aeruginosa (CRPA)?

Treatment of Carbapenem-Resistant Pseudomonas aeruginosa (CRPA) Urinary Tract Infection

For non-severe CRPA UTI, use monotherapy with an in vitro active older antibiotic (aminoglycoside, fluoroquinolone, or polymyxin) based on susceptibility testing; for severe or complicated CRPA UTI, use ceftolozane-tazobactam if susceptible, or combination therapy with two in vitro active agents if resistant to newer beta-lactam/beta-lactamase inhibitors. 1

Treatment Algorithm Based on Infection Severity

Non-Severe or Low-Risk CRPA UTI

• Use monotherapy with older antibiotics chosen from in vitro active agents based on individual susceptibility testing and infection characteristics 1
• Single-dose aminoglycoside is highly effective for uncomplicated cystitis due to urinary concentrations exceeding peak plasma levels by 25- to 100-fold, with microbiologic cure rates of 87-100% 1
• Acceptable monotherapy options include:
  • Aminoglycosides (gentamicin, amikacin, or plazomicin 15 mg/kg IV q12h) - preferred for UTI due to excellent urinary concentration 1
  • Fluoroquinolones (ciprofloxacin 400 mg IV q8h or levofloxacin 750 mg IV daily) if susceptible 1
  • Polymyxins (colistin 5 mg CBA/kg IV loading dose, then 2.5 mg CBA × (1.5 × CrCl + 30) IV q12h) if other options unavailable 1

Severe or Complicated CRPA UTI

• First-line: Ceftolozane-tazobactam 1.5 g IV q8h if the isolate is susceptible in vitro 1
• Alternative newer beta-lactam/beta-lactamase inhibitors (insufficient evidence but may consider):
  • Ceftazidime-avibactam 2.5 g IV q8h 1, 2
  • Imipenem-cilastatin-relebactam 1.25 g IV q6h 1
  • Cefiderocol (evidence insufficient at time of guideline publication) 1

When Newer Agents Are Unavailable or Resistant

• Use combination therapy with two in vitro active drugs for severe infections 1
• Recommended combinations (no specific combination superiority established):
  • Polymyxin (colistin) + aminoglycoside 1
  • Polymyxin + fosfomycin (if susceptible or synergistic) 1
  • Polymyxin + carbapenem (only if meropenem MIC ≤8 mg/L using high-dose extended infusion) 1
• For fosfomycin combinations: Use 16-24 g/day as prolonged infusion combined with extended carbapenem infusion for carbapenem-resistant strains 3

Critical Dosing Considerations

• Use prolonged or extended infusions for beta-lactams when treating pathogens with high MICs to optimize pharmacodynamic targets 1
• Therapeutic drug monitoring (TDM) is strongly suggested for polymyxins, aminoglycosides, and carbapenems, especially in critically ill patients 1, 4
• High-dose extended-infusion meropenem (2 g IV q8h infused over >3 hours) may be used as part of combination therapy only if MIC ≤8 mg/L 1

Treatment Duration

• 5-10 days for complicated UTI without systemic involvement 1
• 10-14 days for pyelonephritis or UTI with bacteremia 1
• Duration should be adjusted based on source control, clinical response, and underlying comorbidities 1

Common Pitfalls to Avoid

• Never use polymyxin monotherapy for severe CRPA infections - associated with higher treatment failure rates 4
• Avoid tigecycline for UTI - it is not recommended due to low urinary concentrations 1
• Do not use carbapenem-based combinations unless meropenem MIC ≤8 mg/L with appropriate high-dose extended infusion 1, 4
• Avoid empiric use of newer agents without susceptibility confirmation - resistance can develop rapidly, particularly to ceftazidime-avibactam 1

Evidence Nuances

The ESCMID guidelines acknowledge very low certainty of evidence for combination therapy recommendations in CRPA, but suggest it over monotherapy for severe infections based on expert consensus 1. The guidelines explicitly state there is insufficient evidence to recommend for or against combination therapy with newer beta-lactam/beta-lactamase inhibitors (ceftazidime-avibactam, ceftolozane-tazobactam) or cefiderocol for CRPA 1. This reflects the limited head-to-head clinical trial data available 5.

For aminoglycosides specifically, plazomicin demonstrates stability against aminoglycoside-modifying enzymes and may be preferred when available, though it is primarily studied in CRE rather than CRPA 1. The recommendation for single-dose aminoglycosides in uncomplicated cystitis is based on favorable pharmacokinetics with urinary concentrations remaining therapeutic for days 1.

Antimicrobial Stewardship Considerations

• Infectious disease consultation is highly recommended for all CRPA infections 1
• Obtain susceptibility testing before finalizing therapy - local resistance patterns vary significantly 1
• Consider antibiotic stewardship principles when selecting between monotherapy and combination therapy for non-severe infections 1