What is the recommended antibiotic regimen for treating patients with suspected Multi-Drug Resistant (MDR) Gram-Negative Bacteria (GNB) infections in an ICU with high MDR GNB prevalence?

Empiric Antibiotic Regimen for Suspected MDR GNB in High-Prevalence ICU

In an ICU with high MDR GNB prevalence, initiate broad-spectrum combination therapy with a polymyxin (colistin or polymyxin B) plus a carbapenem (meropenem or imipenem) administered by extended infusion, along with an aminoglycoside or tigecycline as a second active agent, pending culture results and susceptibility testing. 1, 2

Initial Empiric Regimen Components

Primary Beta-Lactam Coverage

• Administer meropenem 2g IV every 8 hours as a 3-hour extended infusion or imipenem 1g IV every 6 hours infused over 40-60 minutes for optimal pharmacodynamic coverage against organisms with elevated MICs 1, 2, 3
• Extended infusion of carbapenems is critical in high-MIC scenarios to maximize time above MIC 2, 4

Polymyxin Therapy

• Add polymyxin B with a loading dose of 2-2.5 mg/kg followed by maintenance dosing of 1.5-3 mg/kg/day divided into two doses based on total body weight 5, 2
• Polymyxin B is preferred over colistin due to lower nephrotoxicity rates and no requirement for prodrug conversion 5
• The loading dose must be administered even in patients with renal dysfunction 5

Second Active Agent for Combination Therapy

• For severe infections with suspected carbapenem-resistant organisms, add either:
  • An aminoglycoside (amikacin 15-20 mg/kg/day preferred over gentamicin for enhanced activity against non-fermenting GNB) 1, 2
  • OR high-dose tigecycline (100 mg IV loading dose, then 50 mg IV every 12 hours) if active in vitro 1, 6
• Combination therapy reduces treatment failure by approximately 119 cases per 1000 patients compared to monotherapy 5, 2

Pathogen-Specific Considerations

For Suspected Carbapenem-Resistant Enterobacterales (CRE)

• Reserve newer beta-lactam/beta-lactamase inhibitor combinations (ceftazidime-avibactam 2.5g IV q8h over 3 hours, meropenem-vaborbactam 4g IV q8h) for confirmed KPC-producing organisms rather than empiric use due to stewardship considerations 1, 2, 7
• These agents should be preserved for targeted therapy once resistance mechanisms are identified 7, 8

For Suspected Carbapenem-Resistant Pseudomonas aeruginosa (CRPA)

• The polymyxin-carbapenem-aminoglycoside combination provides coverage while awaiting susceptibilities 1
• Do NOT use polymyxin-rifampin combination as this has strong evidence against its use 1
• Consider ceftolozane-tazobactam as targeted therapy once CRPA is confirmed and susceptible 7, 8

For Suspected Carbapenem-Resistant Acinetobacter baumannii (CRAB)

• For CRAB pneumonia, add adjunctive inhaled colistin or polymyxin B (75-150 mg every 12 hours) to systemic therapy 2
• If meropenem MIC ≤8 mg/L (or ≤32 mg/L per some guidelines), continue high-dose extended-infusion carbapenem as part of combination therapy 1
• Do NOT use tigecycline monotherapy for CRAB pneumonia due to inadequate lung penetration 2, 6
• Conditionally recommend AGAINST cefiderocol for CRAB infections based on low-certainty evidence of inferior outcomes 1

Critical Monitoring and Adjustment Strategy

Immediate Actions (0-48 Hours)

• Obtain blood cultures, respiratory cultures, and site-specific cultures before initiating antibiotics 7
• Request urgent carbapenemase testing and MIC determination for any carbapenem-resistant isolates 1
• Use broth microdilution for colistin susceptibility testing (not automated methods) 9
• Implement therapeutic drug monitoring for polymyxin B when available, targeting Css,avg ≥1 mg/L 5

De-escalation Protocol (48-72 Hours)

• Reassess all antibiotic therapy at 48-72 hours based on culture results and clinical response 2, 7
• Narrow spectrum based on identified pathogens and susceptibility patterns 7, 4
• For pan-resistant organisms (resistant to polymyxins), treat with the least resistant antibiotic based on MICs relative to breakpoints 1

Nephrotoxicity Monitoring

• Monitor renal function closely as nephrotoxicity occurs in approximately 14% of patients with normal baseline function receiving polymyxin B 5
• Avoid concurrent nephrotoxic agents when possible 5

Common Pitfalls to Avoid

• Do NOT use polymyxin-meropenem combination for CRAB if the organism is highly carbapenem-resistant (MIC >8-32 mg/L) - two high-quality RCTs (AIDA and OVERCOME) showed no benefit over polymyxin monotherapy 1
• Do NOT delay the polymyxin loading dose - this is essential for rapidly achieving therapeutic concentrations 5
• Do NOT use monotherapy for severe infections or septic shock in high MDR prevalence settings 2, 7
• Avoid empiric use of newest agents (ceftazidime-avibactam, meropenem-vaborbactam) to preserve their effectiveness 1, 7

Source Control

• Ensure adequate source control (drainage of abscesses, removal of infected devices, debridement) as antibiotic therapy alone is insufficient without addressing the infection source 7, 4

Infection Control Measures

• Implement contact precautions immediately for all suspected MDR GNB cases 7
• Perform active surveillance cultures for high-risk patients to guide empiric therapy decisions 7