What are the guidelines for polymyxin (Polymyxin B) based combination therapy in Carbapenem-Resistant Pseudomonas aeruginosa (CRPA) infections in the Intensive Care Unit (ICU)?

Guidelines for Polymyxin-Based Combination Therapy in CRPA Infections in the ICU

For severe CRPA infections in the ICU requiring polymyxin therapy, use combination therapy with two in vitro active drugs rather than polymyxin monotherapy. 1

Preferred Treatment Hierarchy

First-Line Agents (When Available and Susceptible)

• Ceftolozane-tazobactam is the preferred agent for severe difficult-to-treat CRPA infections if the organism is susceptible in vitro. 1, 2
• Consider newer beta-lactam/beta-lactamase inhibitors (imipenem-relebactam, cefiderocol, ceftazidime-avibactam) based on susceptibility testing, though evidence remains limited. 1, 2

When Polymyxin-Based Therapy is Required

Combination therapy approach:

• Use polymyxin B (or colistin) combined with a second in vitro active agent from: aminoglycosides, fosfomycin, or carbapenems (if MIC ≤8 mg/L). 1
• The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) provides a conditional recommendation for this approach, though the certainty of evidence is very low. 1
• No specific combination has proven superiority; selection must be guided by antimicrobial susceptibility testing. 1, 2

Polymyxin-Specific Combinations

Polymyxin-Containing Regimens with Highest Bactericidal Activity

• Polymyxin-containing combinations demonstrate 91% bactericidal activity against CRPA isolates in vitro. 3
• Polymyxin plus another active agent showed lower mortality compared to polymyxin monotherapy or polymyxin with inactive agents in observational studies. 1

Polymyxin-Sparing Alternatives (When Feasible)

• Fosfomycin + aztreonam or fosfomycin + cefepime represent promising polymyxin-sparing options, showing >60% bactericidal activity. 3
• These combinations should be considered when polymyxin toxicity is a concern and organisms are susceptible. 3

Dosing Considerations

Polymyxin B Dosing for ICU Patients

• Standard dosing: 15,000-25,000 units/kg/day divided every 12 hours (maximum 25,000 units/kg/day). 4
• A loading dose followed by maintenance dosing is recommended for critically ill patients. 5
• Adjust downward from 15,000 units/kg/day in patients with renal impairment. 4

Colistin Dosing Alternative

• Loading dose: 300 mg colistimethate sodium, followed by maintenance doses of 300-360 mg divided into two daily doses for patients with normal renal function. 2

Critical Management Principles

Essential Steps Before Initiating Therapy

• Obtain antimicrobial susceptibility testing immediately to guide combination selection. 1, 2
• Consult infectious disease specialists early in management. 2
• Ensure optimal source control (drainage of abscesses, removal of infected devices). 5
• Utilize therapeutic drug monitoring when available. 5

Evidence Limitations and Nuances

The AIDA and OVERCOME randomized controlled trials showed no significant mortality benefit for colistin-carbapenem combinations versus colistin alone in CRPA subgroups (21 and 43 patients respectively). 1 However, a retrospective study of 114 patients with XDR-P. aeruginosa nosocomial pneumonia found that colistin combined with another active antibiotic had significantly lower mortality (adjusted OR 6.63) compared to colistin alone or with inactive agents. 1

Common Pitfalls and Caveats

What NOT to Do

• Do not use polymyxin monotherapy for severe CRPA infections in the ICU—it is associated with higher treatment failure rates. 2, 6
• Do not use tigecycline for CRPA bacteremia—serum concentrations are inadequate for bloodstream infections. 2
• Avoid polymyxin-rifampin combinations—there is no evidence supporting this regimen for CRPA. 1

Toxicity Monitoring

• Monitor for nephrotoxicity—treatment-related acute renal failure occurs in approximately 14% of patients receiving polymyxin B. 7
• Baseline renal insufficiency is associated with a 6-fold increase in clinical failure. 6

Resistance Concerns

• Breakthrough infections with polymyxin-resistant organisms can occur during treatment. 6
• Approximately 25% of patients develop reinfection with CRPA, with 13-17% developing polymyxin resistance in subsequent isolates. 3, 6

Non-Severe or Low-Risk CRPA Infections

For non-severe CRPA infections, monotherapy with an in vitro active agent is acceptable, chosen based on susceptibility testing and infection source. 1 This represents good clinical practice under antibiotic stewardship principles. 1

Comparative Effectiveness Data

Recent observational data suggests ceftazidime-avibactam monotherapy demonstrates superior outcomes compared to polymyxin B-based therapy (30-day mortality 13.7% vs 47.1%, bacterial clearance 45.1% vs 12.9%), though this was not a randomized comparison. 8 This reinforces the preference for newer agents when available and susceptible. 2