What are the best approaches for treating gram-negative multi-drug resistant (MDR) infections in the Intensive Care Unit (ICU)?

Best Approaches for Treating Gram-Negative MDR Infections in ICU

The optimal approach for treating gram-negative multi-drug resistant (MDR) infections in the ICU requires a risk-stratified approach with newer agents like ceftazidime-avibactam, meropenem-vaborbactam, or ceftolozane-tazobactam for carbapenem-resistant organisms, while implementing comprehensive infection control measures and antimicrobial stewardship. 1

Patient Risk Stratification

• Risk stratification is essential for appropriate empiric therapy selection, helping to avoid both undertreatment and overuse of broad-spectrum antibiotics 1
• Key risk factors for MDR gram-negative infections include: prior infection/colonization with MDR organisms, antibiotic therapy within past 90 days, poor functional status, hospitalization >2 days in past 90 days, current hospitalization ≥5 days, hemodialysis, and immunosuppression 1
• Prior receipt of carbapenems, broad-spectrum cephalosporins, and fluoroquinolones specifically increases risk for MDR Pseudomonas aeruginosa 1

Treatment Approaches by Pathogen Type

Carbapenem-Resistant Enterobacteriaceae (CRE)

• For KPC-carbapenemase-producing pathogens, newer β-lactam/β-lactamase inhibitor combinations like ceftazidime-avibactam and meropenem-vaborbactam are recommended as first-line options 1, 2
• Imipenem-relebactam is approved for complicated UTIs but has limited data against carbapenem-resistant pathogens 2
• For susceptible CRE infections, consider fluoroquinolones, aminoglycosides, or fosfomycin as alternatives 3

MDR Pseudomonas aeruginosa

• Ceftolozane-tazobactam is the preferred agent for MDR Pseudomonas aeruginosa infections 1, 2
• For carbapenem-resistant Pseudomonas aeruginosa (CRPA), use ceftolozane-tazobactam if active in vitro 4
• Double-covering therapy might be considered for severe infections, though evidence is of very low certainty 1

Carbapenem-Resistant Acinetobacter baumannii (CRAB)

• High-quality evidence suggests against carbapenem-polymyxin combination therapies for CRAB infections 1
• If CRAB is susceptible to multiple antibiotics, consider double-covering therapy (e.g., colistin plus ampicillin-sulbactam) 1
• Colistin-rifampin combination has not shown mortality benefit over colistin monotherapy in RCTs 1

Dosing Optimization

• Use optimal antibiotic dosing schemes with attention to adverse effects, especially with older agents like polymyxins and aminoglycosides 1
• Refer to EUCAST's recommended dosing (https://www.eucast.org/clinical_breakpoints/) for specific guidance 1
• Consider extended or continuous infusion for carbapenems when treating resistant organisms with lower MICs 1

Infection Control Measures

• Implement strong hand hygiene education programs with monitoring and feedback to healthcare workers 1
• Perform active screening cultures (ASC) at hospital admission for high-risk patients, followed by contact precautions 1
• Cohort patients with MDR gram-negative bacteria in designated areas 1
• Ensure proper environmental cleaning with specific protocols for disinfection 1

Antimicrobial Stewardship

• Implement in-ward antimicrobial stewardship programs to reduce selection pressure for resistance 1, 5
• Use procalcitonin-guided therapy to reduce unnecessary antibiotic exposure in respiratory infections and sepsis 1
• Preserve carbapenems by using carbapenem-sparing options for susceptible organisms when possible 4
• Limit cephalosporin use in settings with high ESBL prevalence to reduce selection pressure 4

Diagnostic Approaches

• Obtain microbiological cultures before initiating therapy to guide targeted treatment 4
• Implement rapid diagnostics and efficient laboratory workflows to anticipate diagnosis and enable de-escalation 6
• Consider periodic screening cultures for patients at high risk of MDR-GNB carriage due to ICU stay, prolonged antibiotic therapy, or presence of devices 1

Common Pitfalls and Challenges

• Relying on monotherapy for highly resistant pathogens when combination therapy may be needed 1
• Failing to optimize dosing regimens, particularly in critically ill patients with altered pharmacokinetics 1
• Neglecting source control, which should always be a priority to optimize outcomes and shorten antibiotic treatment durations 1
• Overlooking infection control measures, which are critical for preventing transmission of MDR organisms 1
• Delaying appropriate therapy, as effective treatment should be administered as soon as possible to improve outcomes 6

Emerging Therapies

• Several new antibiotic agents with activity against gram-negative MDROs have become available in recent years 1
• Cefiderocol, a siderophore β-lactam antibiotic, is effective against CRE and stable against many β-lactamases 3
• Eravacycline is another option for CRE infections 3
• These newer agents should be used judiciously to preserve their effectiveness and delay resistance development 1, 6