What defines difficult to treat Pseudomonas infections?

Definition of Difficult-to-Treat Pseudomonas (DTR-PA)

Difficult-to-treat Pseudomonas aeruginosa (DTR-PA) is defined as P. aeruginosa isolates that are non-susceptible to all of the following first-line, high-efficacy, low-toxicity agents: ceftazidime, cefepime, piperacillin-tazobactam, aztreonam, imipenem-cilastatin, meropenem, levofloxacin, and ciprofloxacin. 1

Background and Clinical Significance

The concept of difficult-to-treat resistance (DTR) was proposed to better characterize P. aeruginosa strains of significant clinical concern and to overcome the limitations of traditional classifications such as multidrug-resistant (MDR) and extensively drug-resistant (XDR) categories. This definition provides more practical clinical utility at the bedside when making treatment decisions 1.

DTR-PA is distinct from carbapenem-resistant P. aeruginosa (CRPA), which only refers to resistance to carbapenems but may retain susceptibility to other agents like piperacillin-tazobactam or ceftazidime 1. The DTR classification identifies truly problematic strains that have limited treatment options.

Key Characteristics of DTR-PA

• Resistance profile: Non-susceptible to all eight first-line antipseudomonal agents:

  • β-lactams: ceftazidime, cefepime, piperacillin-tazobactam, aztreonam
  • Carbapenems: imipenem-cilastatin, meropenem
  • Fluoroquinolones: levofloxacin, ciprofloxacin 1

• Clinical impact: Associated with:

  • Higher mortality rates
  • Limited treatment options
  • Need for newer or more toxic antimicrobial agents
  • Increased healthcare costs 2

Treatment Options for DTR-PA

When DTR-PA is identified, treatment options are limited but include:

1. First-line options (based on pre-clinical and clinical data):

   • Ceftolozane-tazobactam
   • Ceftazidime-avibactam 1

2. Alternative options:

   • Imipenem-cilastatin-relebactam
   • Cefiderocol
   • Colistin-based therapy 1

3. Combination therapy considerations:

   • Not recommended as routine choice
   • May be considered on case-by-case basis
   • Combination regimens including fosfomycin as companion agent could be considered 1

Clinical Approach to Suspected DTR-PA

1. Risk factor assessment for DTR-PA:

   • Recent hospitalization
   • Frequent administration of antibiotics (four or more courses in the last year)
   • Severe COPD (FEV₁ <30%)
   • Previous isolation of P. aeruginosa during exacerbation or colonization during stable period 1

2. Empiric therapy when DTR-PA is suspected:

   • Consider novel β-lactam agents (ceftolozane-tazobactam or ceftazidime-avibactam)
   • For critically ill patients, combination therapy may be appropriate initially 1

3. Definitive therapy once susceptibilities are known:

   • Tailor to the most active agent based on susceptibility testing
   • Consider extended infusion of β-lactams for isolates with high MICs 1

Pitfalls and Caveats

• DTR-PA should not be confused with CRPA, as treatment approaches differ significantly
• Empiric coverage for DTR-PA should be considered in patients with risk factors, especially in critically ill patients
• Consultation with infectious diseases specialists is strongly recommended when managing DTR-PA infections 1
• Combination therapy should not be used routinely but may be beneficial in specific scenarios (e.g., severe respiratory infections) 1
• Antimicrobial stewardship is essential to prevent further resistance development 3

By understanding the specific definition of DTR-PA and recognizing its clinical implications, clinicians can make more informed decisions about appropriate antimicrobial therapy, potentially improving outcomes in these challenging infections.