When to add colistin to ceftazidime (Ceftazidime) + avibactam (Avibactam) + aztreonam (Aztreonam) in patients with Klebsiella infections?

When to Add Colistin to Ceftazidime-Avibactam + Aztreonam in Klebsiella Infections

Do not add colistin to ceftazidime-avibactam plus aztreonam for Klebsiella infections, as current guidelines strongly recommend against combination therapy when treating with newer beta-lactam/beta-lactamase inhibitors, and clinical evidence shows no mortality benefit from adding colistin to this regimen. 1

Primary Recommendation: Avoid Colistin Addition

For MBL-Producing Carbapenem-Resistant Klebsiella

• Use ceftazidime-avibactam plus aztreonam without colistin for metallo-beta-lactamase (NDM, VIM) producing Klebsiella pneumoniae infections 1
• This dual combination demonstrated significantly lower 30-day mortality (19.2% vs 44%) compared to colistin-containing regimens in a prospective study of 102 patients with MBL-producing CRE bacteremia 1, 2
• The hazard ratio for mortality with ceftazidime-avibactam-aztreonam was 0.37 (95% CI 0.13-0.74) compared to other therapies, which predominantly included colistin combinations 1
• Highest mortality rates were specifically observed in patients receiving colistin-containing regimens 1

For KPC-Producing or OXA-48-Producing Klebsiella

• Guidelines strongly recommend against combination therapy when ceftazidime-avibactam is active in vitro 1
• Five retrospective cohorts totaling 824 patients showed no difference in mortality or clinical failure between ceftazidime-avibactam monotherapy versus combination therapy for KPC and OXA-48 producers 1
• The largest study (577 patients with KPC-producing K. pneumoniae) found no association between monotherapy versus combination and development of resistance (10.4% vs 3.8%) 1

Specific Clinical Scenarios Where Colistin Should NOT Be Added

Severe Infections with Susceptible Isolates

• When ceftazidime-avibactam plus aztreonam shows in vitro activity against MBL-producers, adding colistin provides no additional benefit 1
• For severe CRE infections susceptible to ceftazidime-avibactam or meropenem-vaborbactam, combination therapy is not recommended 1

Bloodstream Infections

• In MBL-producing K. pneumoniae bacteremia, ceftazidime-avibactam-aztreonam without colistin achieved superior outcomes compared to colistin-based regimens 1
• Clinical case reports document successful treatment of NDM-1-producing K. pneumoniae bacteremia with aztreonam-ceftazidime-avibactam after colistin failure 3

Rare Exception: Consider Colistin Addition Only When

Pan-Resistant Isolates with Limited Options

• Only consider adding colistin when the isolate is susceptible in vitro only to polymyxins, aminoglycosides, tigecycline, or fosfomycin AND newer beta-lactam combinations are unavailable or resistant 1
• In this scenario, treatment with more than one drug active in vitro is suggested, though no specific combination is recommended over another 1

Concern for Ceftazidime-Avibactam Resistance Development

• The British Society for Antimicrobial Chemotherapy suggests considering ceftazidime-avibactam with carbapenem or colistin for KPC-3 producers when resistance emergence is a concern 1
• However, this recommendation lacks strong clinical evidence and contradicts the primary guideline recommendations 1

Critical Pitfalls to Avoid

Do Not Add Colistin Based on Severity Alone

• Severity of infection is not an indication for adding colistin to ceftazidime-avibactam-aztreonam 1
• In vitro synergy studies showing potential benefit of colistin combinations have not translated to clinical benefit 1

Do Not Add Colistin to Prevent Resistance

• Two large retrospective studies found no association between monotherapy versus combination therapy and resistance development to ceftazidime-avibactam 1
• Resistance development occurred in 3.8-10.4% regardless of combination use 1

Optimize Dosing Instead of Adding Agents

• Use prolonged infusion (3-hour) of ceftazidime-avibactam, which has been associated with improved 30-day survival 1, 4
• Ensure appropriate renal dose adjustment 1

Summary Algorithm

1. Identify carbapenemase type (MBL vs KPC vs OXA-48)
2. For MBL-producers: Use ceftazidime-avibactam + aztreonam (without colistin) 1, 2
3. For KPC/OXA-48 producers: Use ceftazidime-avibactam or meropenem-vaborbactam monotherapy (without colistin) 1
4. Only if pan-resistant with no other options: Consider multi-drug regimen including colistin 1
5. Optimize administration: Use prolonged infusion and appropriate renal dosing 1, 4