What is the recommended treatment for carbapenem-resistant Acinetobacter infections?

Treatment of Carbapenem-Resistant Acinetobacter baumannii (CRAB)

For CRAB pneumonia, use colistin with a carbapenem (meropenem 2g IV q8h or imipenem 500mg IV q6h) as combination therapy, with adjunctive inhaled colistin for at least 7 days. 1

Recommended Treatment by Infection Site

Pneumonia (Hospital-Acquired/Ventilator-Associated)

Primary Regimen:

• Colistin IV: 5 mg CBA/kg loading dose, then 2.5 mg CBA × (1.5 × CrCl + 30) IV q12h 1
• PLUS Carbapenem (if MIC ≤32 mg/L): Meropenem 2g IV q8h OR Imipenem 500mg IV q6h (infuse over >3 hours) 1
• PLUS Adjunctive inhaled colistin: 1.25-15 MIU/day in 2-3 divided doses 1
• Duration: At least 7 days 1

Alternative Regimens (if primary not feasible):

• Sulbactam monotherapy: 6-9 g/day IV in 3-4 divided doses (if MIC ≤4 mg/L) 1
• Triple combination: Colistin IV + Tigecycline (100mg loading, then 50mg IV q12h) + Sulbactam 6-9 g/day (if tigecycline MIC ≤2 mg/L) 1

Critical Pitfall: Tigecycline monotherapy is NOT recommended for pneumonia due to higher treatment failure rates compared to colistin-based regimens 1, 2

Bloodstream Infections

Primary Regimen:

• Colistin-carbapenem combination: Same colistin dosing as above PLUS carbapenem (meropenem or imipenem at same doses) 1
• Duration: 10-14 days 1

This combination showed the highest SUCRA ranking (83.6%) for clinical cure in network meta-analysis 1

Alternative Regimens:

• Colistin + Tigecycline: Colistin (as above) + Tigecycline 100mg loading, then 50mg IV q12h 1
• Colistin + Sulbactam: Colistin (as above) + Sulbactam 6-9 g/day IV 1

Critical Evidence: Colistin monotherapy was significantly associated with increased 7-day and 28-day mortality in a multicentre Korean study 3. Combination therapy with colistin-carbapenem significantly reduced 7-day mortality 3

Dosing Specifications

Colistin Dosing Algorithm

1. Loading dose: 9 MIU (5 mg CBA/kg) IV - essential to rapidly achieve therapeutic levels 1, 4
2. Maintenance dose: 4.5 MIU (2.5 mg CBA × [1.5 × CrCl + 30]) IV q12h 1
3. Monitor renal function closely - nephrotoxicity occurs in up to 33% of patients 5, 6

Note: 1 MIU colistin methanesulfonate ≈ 33 mg colistin base activity 1

Carbapenem Dosing for Combination Therapy

• Meropenem: 2g IV q8h by extended infusion (>3 hours) 1
• Imipenem: 500mg IV q6h by extended infusion (>3 hours) 1
• Only use if carbapenem MIC ≤32 mg/L - synergistic benefit demonstrated at this threshold 1

Sulbactam Dosing

• High-dose regimen: 6-9 g/day IV in 3-4 divided doses 1
• Optimal administration: As ampicillin-sulbactam 3g sulbactam component q8h via 4-hour infusion 5, 7
• Use only if MIC ≤4 mg/L 5, 7

Combination Therapy Rationale

When to use combination therapy (two active agents): 1, 5

• Severe infections with septic shock
• Ventilator-associated pneumonia
• Bacteremia with severe sepsis
• Clinical failures on monotherapy
• Isolates with MIC at upper limit of susceptibility

Evidence supporting combinations:

• Colistin-carbapenem combination achieved higher microbiological eradication rates and reduced mortality in XDR-AB bloodstream infections 1
• Combination therapy prevents emergence of colistin resistance during treatment 7
• Sulbactam-containing regimens significantly reduced 28-day mortality 3

Combinations to AVOID

Never use these combinations: 1, 5

• Colistin + rifampin: No clinical benefit demonstrated in randomized trials despite microbiological eradication; increased hepatotoxicity 1
• Colistin + vancomycin (or other glycopeptides): Significantly increased nephrotoxicity without added benefit 1, 5
• Polymyxin-meropenem for high-level carbapenem resistance (MIC >16 mg/L): No benefit demonstrated 5

Monitoring Requirements

Renal function monitoring: 1, 5, 6

• Check creatinine clearance before each dose adjustment
• Monitor for RIFLE criteria (Risk, Injury, Failure, Loss, End-stage)
• Nephrotoxicity risk: 33-39% with colistin therapy 5, 6
• Adjust colistin maintenance dose based on CrCl using formula: 2.5 mg CBA × (1.5 × CrCl + 30) 1

Hepatotoxicity monitoring: 3

• Monitor liver function tests if using tigecycline (associated with increased hepatotoxicity) 3

Microbiological monitoring: 2

• Obtain repeat cultures to document clearance
• Monitor for emergence of resistance, particularly with colistin (heteroresistance reported in 18.7-100% of isolates) 8, 2

Alternative Agents (Limited Role)

Tigecycline

• Only use in combination, never as monotherapy for bacteremia or pneumonia 5, 2
• High-dose regimen: 200mg loading, then 100mg IV q12h for severe infections 1
• Standard dose: 100mg loading, then 50mg IV q12h 1
• Use only if MIC ≤2 mg/L 1
• Warning: Suboptimal serum concentrations lead to higher treatment failure rates in bacteremia 5

Minocycline

• Showed best microbiological responses at 7 days, 28 days, and end of treatment in Korean multicentre study 3
• Susceptibility rates: 60-80% against CRAB 1
• Limited clinical data; not included in primary guidelines 1

Treatment Duration

• Pneumonia: At least 7 days, typically 10-14 days for HAP/VAP 1
• Bloodstream infections: 10-14 days 1
• Severe sepsis/septic shock: Maintain for 2 weeks 1, 5

Key Clinical Pitfalls

1. Inadequate colistin loading dose: Failure to use 9 MIU loading dose delays achievement of therapeutic levels 1, 4
2. Colistin monotherapy in severe infections: Associated with significantly increased mortality 3, 4
3. Using carbapenems when MIC >32 mg/L: No synergistic benefit demonstrated 1
4. Tigecycline monotherapy for pneumonia: Higher failure rates than combination therapy 1, 2
5. Ignoring renal function adjustments: Leads to either subtherapeutic levels or increased nephrotoxicity 1, 6