What is the recommended treatment regimen for severe infections caused by multi-drug resistant gram-negative bacteria using polymyxin (antibiotic) and aztreonam (monobactam antibiotic) in combination?

Polymyxin and Aztreonam Synergy for Multidrug-Resistant Gram-Negative Infections

Direct Recommendation

For severe infections caused by metallo-β-lactamase (MBL)-producing carbapenem-resistant Enterobacterales, use ceftazidime-avibactam plus aztreonam instead of polymyxin-aztreonam combinations, as this regimen achieves 19.2% mortality versus 44% with polymyxin-based alternatives. 1

Treatment Algorithm Based on Pathogen and Resistance Mechanism

For MBL-Producing Carbapenem-Resistant Enterobacterales (CRE)

• Preferred regimen: Ceftazidime-avibactam 2.5 g IV every 8 hours (as 2-hour infusion) PLUS aztreonam 2 g IV every 6-8 hours 2, 1, 3
• The Italian Society of Infection and Tropical Diseases provides a STRONG recommendation with MODERATE certainty of evidence for ceftazidime-avibactam/aztreonam over polymyxin-based regimens 1
• This combination demonstrates synergistic activity in 90% of MBL-producing strains 3
• Critical mechanism: Aztreonam alone fails for MBL-producers because these bacteria co-produce ESBLs and cephalosporinases that inactivate aztreonam; avibactam inhibits these co-produced enzymes, restoring aztreonam activity 1, 4

For Carbapenem-Resistant Pseudomonas aeruginosa (CRPA)

• When polymyxins are the only active option: Use polymyxin PLUS a second in vitro active drug (conditional recommendation, very low certainty of evidence) 2
• In critically ill patients with XDR-P. aeruginosa, polymyxin combinations showed dramatically lower mortality (0/3 deaths) versus polymyxin monotherapy (14/15 deaths) 1
• Specific combinations: Polymyxin with aminoglycosides or fosfomycin when both are active in vitro 2
• No recommendation can be provided for or against specific polymyxin-aztreonam combinations for CRPA 2

For Non-MBL-Producing CRE (KPC or OXA-48)

• Do NOT use polymyxin-aztreonam combinations 1, 3
• Use ceftazidime-avibactam monotherapy 2.5 g IV every 8 hours as prolonged 3-hour infusion 3
• Nearly 100% of KPC-producing and OXA-48-producing strains are susceptible to ceftazidime-avibactam alone 3

Dosing Specifications

Standard Dosing for Severe Infections

• Aztreonam: 2 g IV every 6-8 hours 1, 5, 3
• Polymyxin B or Colistin: Dose according to institutional protocols with loading dose
• Duration: Minimum 7-14 days for most severe infections, continuing at least 48 hours after clinical improvement 1, 5
• Bone/musculoskeletal infections: Minimum 4-6 weeks 1, 3

Renal Adjustment

• Aztreonam clearance is directly proportional to creatinine clearance; dosage adjustment required in renal impairment 6
• Polymyxins require complex dosing adjustments based on renal function

Critical Pitfalls to Avoid

Resistance Development

• Ceftazidime-avibactam resistance develops in 3.8-10.4% of patients during treatment of KPC-producing CRE 1, 3
• Obtain repeat cultures if clinical deterioration occurs within 48-72 hours to assess for resistance emergence 1, 3
• Resistance to polymyxins may emerge during treatment of P. aeruginosa infections 7

Toxicity Considerations

• Colistin demonstrates significantly higher nephrotoxicity than polymyxin B (adjusted HR 2.27,95% CI 1.35-3.82) in critically ill patients 1
• Early reports suggested polymyxin nephrotoxicity rates of 20% and neurotoxicity of 7%, though recent studies suggest lower rates 8
• Aztreonam is not nephrotoxic and is weakly immunogenic 7, 6

Inappropriate Combination Use

• Do NOT add polymyxin or fosfomycin routinely to ceftazidime-avibactam plus aztreonam for MBL-producers, as the dual β-lactam combination alone demonstrates superior outcomes 3
• For patients with CRE infections susceptible to and treated with ceftazidime-avibactam, meropenem-vaborbactam, or cefiderocol, do NOT use combination therapy (strong recommendation, low certainty) 2

Synergy Testing Limitations

• Antimicrobial synergy testing may guide combination selection when drug choices are limited 1
• Checkerboard method is preferred for detecting synergy, demonstrating 100% sensitivity and specificity 1
• Major caveat: One study showed in vitro synergism between colistin and meropenem did not translate into clinical benefit, highlighting the limitations of synergy testing 1
• There are currently no standardized antimicrobial susceptibility testing methods or clinical breakpoints approved for the ceftazidime-avibactam plus aztreonam combination 3

Monitoring Parameters

• Assess clinical improvement within 48-72 hours of initiating therapy 1, 5
• Monitor renal function closely when using polymyxins 8
• Obtain repeat cultures if clinical deterioration occurs to detect resistance development 1, 3