What treatment options are available for Acinetobacter infections resistant to cefaperazone (Cefaperazone) sulbactam (Sulbactam)?

Treatment of Cefoperazone-Sulbactam Resistant Acinetobacter Infections

For Acinetobacter infections resistant to cefoperazone-sulbactam, polymyxins (colistin or polymyxin B) represent the primary treatment option, with high-dose tigecycline as an alternative if the isolate demonstrates in vitro susceptibility. 1

First-Line Treatment Selection

When sulbactam resistance is confirmed, treatment selection follows this hierarchy:

• Polymyxins (colistin or polymyxin B) are the recommended first-line agents for carbapenem-resistant Acinetobacter baumannii (CRAB) that is also sulbactam-resistant 1
• High-dose tigecycline can be used as an alternative if active in vitro, though no specific recommendation exists for which agent is preferred between polymyxins and tigecycline 1
• The 2022 ESCMID guidelines explicitly state that lacking evidence, they cannot recommend the preferred antibiotic between polymyxins and tigecycline for sulbactam-resistant CRAB 1

Critical Dosing Considerations

Polymyxin Dosing

• Colistin: Loading dose of 6-9 million IU followed by 9 million IU/day divided into 2-3 doses, with renal function adjustment 2
• Polymyxin B: Loading dose of 9 MU (5 mg/kg) followed by 4.5 MU twice daily for critically ill patients 3

Tigecycline Dosing

• Loading dose: 100 mg intravenously 4
• Maintenance: 50 mg every 12 hours 4
• Note: Tigecycline resistance in Acinetobacter is associated with multidrug-resistant efflux pumps, and resistance can develop during standard treatment 4

Combination Therapy Strategy

For severe infections or high-risk patients with sulbactam-resistant CRAB, combination therapy with two in vitro active antibiotics is suggested. 1

Specific Combination Recommendations

• Polymyxin-meropenem combination is recommended when the meropenem MIC is ≤8 mg/L, despite carbapenem resistance 1, 3
• The 2022 ESCMID guidelines strongly recommend against polymyxin-rifampin combination therapy (strong recommendation, high/moderate evidence) 1
• Combination options include polymyxin with aminoglycosides, tigecycline, or high-dose extended-infusion carbapenems when MIC ≤8 mg/L 1

Evidence Against Certain Combinations

• Polymyxin-rifampin combinations are explicitly not recommended based on high-quality evidence 1
• Colistin combined with anti-Gram-positive agents increases nephrotoxicity and should be avoided 2

Emerging Treatment Option: Sulbactam-Durlobactam

• Sulbactam-durlobactam demonstrated non-inferiority to colistin for carbapenem-resistant ABC infections in the 2023 ATTACK trial 5
• 28-day mortality: 19% with sulbactam-durlobactam versus 32% with colistin (difference -13.2%, 95% CI -30.0 to 3.5) 5
• Nephrotoxicity was significantly lower: 13% versus 38% (p<0.001) 5
• Dosing: 1.0 g sulbactam + 1.0 g durlobactam over 3 hours every 6 hours 5

Toxicity Monitoring and Safety

Nephrotoxicity Considerations

• Colistin nephrotoxicity occurs in up to 33-38% of patients 1, 2, 5
• Polymyxin B appears to have lower nephrotoxicity than colistin (adjusted HR 2.27 for colistin, 95% CI 1.35-3.82) 3
• Regular renal function monitoring is mandatory during polymyxin therapy 3

Resistance Development

• Heteroresistance to colistin has been reported in 18.7-100% of isolates in some series 2, 6
• Previous colistin use is a risk factor for higher heteroresistance rates 2
• Tigecycline resistance can develop during standard treatment in Acinetobacter infections, requiring more frequent monitoring for relapse 4

Treatment Algorithm for Sulbactam-Resistant Acinetobacter

1. Confirm resistance: Obtain susceptibility testing; MIC >4 mg/L by Etest indicates sulbactam resistance 1

2. Assess infection severity:

   • Severe infections (septic shock, VAP, bacteremia with severe sepsis): Use combination therapy with two in vitro active agents 1, 2
   • Non-severe infections: Monotherapy with polymyxin or tigecycline may be appropriate based on source and individual factors 1

3. Select primary agent:

   • First choice: Polymyxin (colistin or polymyxin B) if susceptible 1
   • Alternative: High-dose tigecycline if susceptible 1
   • Consider sulbactam-durlobactam if available 5

4. Add combination partner for severe infections:

   • High-dose extended-infusion meropenem if MIC ≤8 mg/L 1
   • Aminoglycoside if susceptible 1
   • Avoid rifampin combinations 1

5. Monitor closely:

   • Renal function every 2-3 days 3
   • Clinical response at day 7 5
   • Consider repeat cultures if clinical failure 4

Common Pitfalls to Avoid

• Do not use monotherapy with polymyxins for severe infections when combination therapy is feasible 1
• Avoid polymyxin-rifampin combinations despite historical use 1
• Do not underdose polymyxins; use appropriate loading doses 2, 3
• Do not ignore local resistance patterns; heteroresistance to colistin is increasingly common 2, 6
• Avoid cefiderocol for CRAB infections (conditional recommendation against use) 1
• Do not combine colistin with anti-Gram-positive agents due to increased nephrotoxicity 2

Special Considerations by Infection Site

Pneumonia/VAP

• Consider adjunctive aerosolized polymyxin in addition to intravenous therapy for respiratory infections 3, 6
• Colistin concentrations in epithelial lining fluid are negligible after IV administration alone 1

Meningitis

• Ampicillin-sulbactam with intrathecal amikacin has shown success even for sulbactam-intermediate strains 7
• Consider intrathecal or intraventricular polymyxin for CNS infections 8