In a critically ill patient with confirmed carbapenem‑resistant Acinetobacter baumannii infection, what is the recommended role, dosing regimen (including renal adjustment), treatment duration, and need for adjunctive agents of sulbactam‑durlobactam?

Sulbactam-Durlobactam for CRAB Infections

Sulbactam-durlobactam is now the preferred first-line agent for critically ill patients with confirmed carbapenem-resistant Acinetobacter baumannii infections, demonstrating superior 28-day mortality reduction compared to colistin (19.0% vs 32.3%) with significantly better tolerability. 1

Primary Role and Indications

Sulbactam-durlobactam should be used as definitive monotherapy for CRAB infections including hospital-acquired pneumonia, ventilator-associated pneumonia, and bacteremia. 1 The pivotal ATTACK trial established non-inferiority to colistin for 28-day all-cause mortality while achieving superior clinical cure rates (61.9% vs 40.3%) in the carbapenem-resistant population. 1

This agent represents a paradigm shift from traditional sulbactam-based regimens because:

• Durlobactam protects sulbactam from degradation by Acinetobacter-derived cephalosporinases (ADC) and oxacillinases (OXA), restoring sulbactam's intrinsic activity against CRAB. 2
• The combination demonstrates potent bactericidal activity specifically engineered for CRAB, unlike older β-lactam/β-lactamase inhibitors (ceftazidime-avibactam, ceftolozane-tazobactam) which lack activity against this pathogen. 3, 4

Standard Dosing Regimen

Administer 1 g sulbactam + 1 g durlobactam intravenously over 3 hours every 6 hours for patients with normal renal function. 1

Renal Dose Adjustments

For patients with creatinine clearance <50 mL/min, dose adjustments are mandatory: 1

• CrCl 30-49 mL/min: 1 g sulbactam + 1 g durlobactam IV over 3 hours every 8 hours
• CrCl 15-29 mL/min: 1 g sulbactam + 1 g durlobactam IV over 3 hours every 12 hours
• CrCl <15 mL/min or hemodialysis: Specific dosing requires consultation with renal dosing protocols 1

Critical pitfall: Unlike traditional high-dose ampicillin-sulbactam regimens (9-12 g/day sulbactam) used historically, sulbactam-durlobactam achieves therapeutic effect at lower sulbactam doses (4 g/day) due to durlobactam's protective mechanism. 5, 1

Treatment Duration

Treat for up to 14 days based on infection severity and clinical response. 1 The mean treatment duration in the ATTACK trial was 9 days for sulbactam-durlobactam. 1

• For severe infections with septic shock or bacteremia: Maintain therapy for a minimum of 14 days 3, 6
• For less severe pneumonia with good clinical response: 7-10 days may be sufficient 5

Adjunctive Agents: When to Add vs. Monotherapy

Sulbactam-durlobactam should be used as monotherapy for CRAB infections; combination therapy is NOT required. 1, 4 This represents a major departure from traditional CRAB management:

Evidence Against Routine Combination Therapy

• The ATTACK trial used imipenem-cilastatin as background therapy in BOTH arms (sulbactam-durlobactam and colistin groups) to cover potential non-CRAB pathogens, not to enhance CRAB activity. 1
• Clinical studies with cefiderocol demonstrate that combination treatment is not associated with improved outcomes compared to monotherapy for CRAB. 4
• Sulbactam-durlobactam's mechanism provides complete protection of sulbactam, eliminating the historical rationale for adding second agents to overcome resistance. 2

Specific Scenarios Requiring Adjunctive Coverage

Add imipenem-cilastatin 1 g IV every 6 hours (or meropenem 2 g IV every 8 hours) ONLY when polymicrobial infection is suspected or confirmed, to cover potential non-CRAB gram-negative pathogens. 1 This is particularly relevant in:

• Polymicrobial ventilator-associated pneumonia
• Intra-abdominal infections where Enterobacterales co-infection is likely
• Empiric therapy before CRAB confirmation when other pathogens remain possible

Do NOT add colistin, tigecycline, or rifampin to sulbactam-durlobactam for CRAB coverage. 3, 4 These combinations:

• Increase nephrotoxicity without added benefit (colistin + any agent) 5, 3
• Lack proven clinical benefit (colistin + rifampin) 3
• Are unnecessary given sulbactam-durlobactam's demonstrated efficacy as monotherapy 1, 4

Safety Profile and Monitoring

Sulbactam-durlobactam demonstrates markedly superior tolerability compared to colistin-based regimens, with nephrotoxicity rates of approximately 15% versus 33% for colistin. 5, 1

Common Adverse Effects

• Headache, nausea, and injection-site phlebitis are the most frequent side effects, all generally mild. 2
• No dose-limiting toxicity or severe hematologic effects occur. 2

Monitoring Requirements

• Baseline and periodic renal function monitoring (serum creatinine, CrCl calculation) for dose adjustment 1
• No hepatic monitoring required (unlike rifampin-containing regimens which need weekly liver function tests) 3
• No therapeutic drug monitoring necessary (unlike colistin or aminoglycosides) 1

Clinical Efficacy Data

The ATTACK trial enrolled 177 patients with documented Acinetobacter baumannii-calcoaceticus complex infections: 1

• Patient population: 74% male, mean age 63 years, mean APACHE II score 17 (26% with APACHE II ≥20)
• Infection severity: 75% mechanically ventilated, 64% in ICU ≥5 days, 53% VABP and 43% HABP
• Primary endpoint: 28-day all-cause mortality was 19.0% (12/63) for sulbactam-durlobactam vs 32.3% (20/62) for colistin, representing a 13.2% absolute risk reduction 1
• Secondary endpoint: Clinical cure at test-of-cure visit (7±2 days post-treatment) was 61.9% vs 40.3% 1

Positioning Relative to Traditional Agents

When Sulbactam-Durlobactam is Unavailable

If sulbactam-durlobactam cannot be obtained, revert to traditional algorithms: 5, 3, 6

1. Check sulbactam MIC by E-test or broth microdilution (automated methods are unreliable) 5
2. If sulbactam MIC ≤4 mg/L: Use high-dose ampicillin-sulbactam 3 g sulbactam IV over 4 hours every 8 hours (9-12 g/day total) 5, 3, 6
3. If sulbactam MIC >4 mg/L or sulbactam-resistant: Use colistin with weight-based dosing (loading dose 9 million IU, then 4.5 million IU every 12 hours for CrCl >50 mL/min) 5, 3
4. For severe infections or septic shock: Add a second in vitro active agent (tigecycline 100 mg load then 50 mg every 12 hours, or rifampin 600 mg daily) 5, 3

Critical Advantage Over Ampicillin-Sulbactam

Sulbactam-durlobactam eliminates the need for MIC testing and susceptibility confirmation before initiation, whereas traditional ampicillin-sulbactam should only be used for directed therapy after confirming sulbactam MIC ≤4 mg/L. 5, 7 This allows earlier appropriate therapy in critically ill patients.

Common Pitfalls to Avoid

• Do not use sulbactam-durlobactam empirically before confirming Acinetobacter baumannii-calcoaceticus complex infection – it has no activity against other pathogens 1, 2
• Do not add colistin "for extra coverage" to sulbactam-durlobactam – this increases toxicity without benefit 3, 4
• Do not use tigecycline as monotherapy for CRAB bacteremia – serum concentrations are insufficient even when sulbactam-durlobactam is unavailable 3
• Do not forget renal dose adjustments – 39% of ATTACK trial patients had CrCl <90 mL/min at baseline, requiring dose modification 1
• Do not confuse sulbactam-durlobactam with cefiderocol – cefiderocol showed higher mortality in CRAB subgroup analysis and is conditionally recommended AGAINST 3