What is the recommended treatment regimen for severe infections caused by multidrug-resistant gram-negative bacteria using polymyxin B (polymyxin B) and aztreonam (aztreonam) synergy?

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

Direct Recommendation

For severe infections caused by metallo-β-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE), use ceftazidime-avibactam 2.5 g IV every 8 hours (as a 3-hour prolonged infusion) PLUS aztreonam 2 g IV every 6 hours, NOT polymyxin-aztreonam combinations. 1, 2

Treatment Algorithm Based on Pathogen Type

For MBL-Producing CRE (NDM, VIM, IMP)

• Preferred regimen: Ceftazidime-avibactam plus aztreonam demonstrates 30-day mortality of 19.2% versus 44% with alternative regimens including colistin-based therapies. 1

• Do NOT use polymyxin-aztreonam for MBL-producers when ceftazidime-avibactam is available, as the ceftazidime-avibactam/aztreonam combination shows superior outcomes compared to colistin-containing regimens. 1, 2

• 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

For Carbapenem-Resistant Pseudomonas aeruginosa (CRPA)

• When treating severe CRPA infections with polymyxins, aminoglycosides, or fosfomycin, use two in vitro active drugs in combination (conditional recommendation, very low certainty of evidence). 3

• Polymyxin-aztreonam synergy is mechanistically sound: colistin disrupts the bacterial cell envelope initially (1 hour), while aztreonam inhibits cell wall biosynthesis at later time points (4-24 hours), creating time-dependent synergistic killing. 4

• In critically ill patients with XDR-P. aeruginosa, mortality was significantly lower with polymyxin combinations (0/3 deaths) versus polymyxin monotherapy (14/15 deaths). 3

For Carbapenem-Resistant Acinetobacter baumannii (CRAB)

• Polymyxin-based therapy remains the backbone for CRAB when sulbactam resistance exists. 3

• Colistin-aztreonam combination demonstrates synergistic bactericidal activity through complementary mechanisms: colistin causes immediate cell envelope disruption while aztreonam provides sustained cell wall synthesis inhibition. 4

Dosing Specifications

Polymyxin B Dosing

• Standard dosing: 15,000-25,000 units/kg/day divided every 12 hours (infused over 30 minutes). 5

• Polymyxin B demonstrates rapid bactericidal activity with serum clearance directly proportional to creatinine clearance, requiring dose adjustment in renal impairment. 6, 7

Aztreonam Dosing

• Standard regimen: 2 g IV every 6 hours. 1, 2

• Prolonged infusion strategy: 2 g IV every 6 hours infused over 4 hours achieves superior pharmacodynamic targets, maintaining concentrations above MIC for >40% of the dosing interval. 5

• Aztreonam clearance in critically ill patients (2.3 mL/kg/min) significantly exceeds adult reference values (1.3 mL/kg/min), potentially requiring higher or more frequent dosing. 5

Duration of Therapy

• Most severe infections: 7-14 days minimum, continuing at least 48 hours after clinical improvement or bacterial eradication. 8

• Bone/musculoskeletal infections: 4-6 weeks minimum. 2

• Respiratory tract infections: Mean duration 19 days (range 2-57 days) in critically ill patients. 9

Critical Pitfalls to Avoid

Never Use Aztreonam Monotherapy

• Aztreonam monotherapy will fail for MBL-producing organisms because these bacteria co-produce ESBLs and cephalosporinases that inactivate aztreonam, despite aztreonam's stability against metallo-β-lactamases. 1

Resistance Emergence

• Ceftazidime-avibactam resistance develops in 3.8-10.4% of patients during treatment of KPC-producing CRE. 2

• Obtain repeat cultures if clinical deterioration occurs within 48-72 hours to assess for resistance development. 2

Nephrotoxicity Monitoring

• Polymyxin B causes nephrotoxicity in approximately 10% of patients, though this rarely requires discontinuation. 9

• Colistin demonstrates higher nephrotoxicity than polymyxin B (adjusted HR 2.27,95% CI 1.35-3.82) in critically ill patients. 3

When Polymyxin-Aztreonam Is Appropriate

Use polymyxin-aztreonam combinations only when:

1. Ceftazidime-avibactam is unavailable or the organism is resistant to it. 1, 2

2. Treating CRPA or CRAB infections where alternative agents lack activity. 3

3. Antimicrobial synergy testing demonstrates synergistic activity and treatment options are severely limited. 3

Synergy Testing Considerations

• Antimicrobial synergy testing may guide combination selection when drug choices are limited or conventional susceptibility testing shows no effective options. 3

• Checkerboard method is preferred, followed by disc elution method or MIC strip crossing/stacking methods, all demonstrating 100% sensitivity and specificity for detecting synergy. 3

• Important caveat: One study showed in vitro synergism between colistin and meropenem did not translate into clinical benefit, highlighting the limitations of synergy testing. 3