What is the recommended treatment regimen for a patient with extensive drug-resistant Pseudomonas infection using Zavicefta (ceftazidime and avibactam) and polymyxin B (Poly B)?

Treatment of Extensive Drug-Resistant Pseudomonas with Zavicefta and Polymyxin B

For extensive drug-resistant Pseudomonas aeruginosa infections, use ceftazidime-avibactam (Zavicefta) as monotherapy rather than combining it with polymyxin B, as combination therapy shows no mortality benefit and increases toxicity risk. 1

Primary Treatment Approach

Monotherapy is Preferred for Ceftazidime-Avibactam

• Five retrospective cohorts totaling 824 patients demonstrated no difference in mortality or clinical failure between ceftazidime-avibactam monotherapy versus combination therapy for carbapenem-resistant infections. 1

• The largest study of 577 patients with resistant infections showed that ceftazidime-avibactam monotherapy was equally effective as combination regimens, with no increased resistance development (3.8% resistance emergence with monotherapy). 1

• ESCMID guidelines explicitly state: "For patients with CRE infections susceptible to and treated with ceftazidime-avibactam, we do not recommend combination therapy" (Strong recommendation, low certainty). 1

When to Consider Polymyxin B

• Reserve polymyxin B-based therapy only when ceftazidime-avibactam is not available or the organism is resistant to all newer beta-lactam/beta-lactamase inhibitors. 1

• If polymyxin B must be used for severe infections, combine it with at least one other in vitro active agent (not ceftazidime-avibactam). 1

• Polymyxin B monotherapy for difficult-to-treat resistant Pseudomonas shows survival rates of only 39-83%, significantly lower than newer agents. 1

Optimal Dosing Strategy for Ceftazidime-Avibactam

Administration Schedule

• Use prolonged infusion (3-hour infusion) of ceftazidime-avibactam, which was independently associated with 30-day survival in the largest cohort study. 1

• Ensure appropriate renal dose adjustment, as this was also associated with improved survival. 1

• Standard dosing: 2.5g (2g ceftazidime + 0.5g avibactam) every 8 hours, adjusted for creatinine clearance. 1

Timing Considerations

• Initiate ceftazidime-avibactam therapy as early as possible—each day of delay reduces clinical cure odds by 35% (aOR: 0.65,95% CI: 0.49-0.86). 2

• Early source control is critical—each day of delay reduces clinical cure odds by 16% (aOR: 0.84,95% CI: 0.72-0.98). 2

Alternative Agents for Extensive Drug-Resistant Pseudomonas

First-Line Alternatives

• Ceftolozane-tazobactam is the preferred agent for severe difficult-to-treat carbapenem-resistant Pseudomonas infections when active in vitro (ESCMID conditional recommendation). 1, 3

• Ceftolozane-tazobactam is specifically preferred for pneumonia (including hospital-acquired and ventilator-associated pneumonia). 3, 4

• For non-pulmonary infections, ceftazidime-avibactam and ceftolozane-tazobactam can be used equally based on susceptibility. 3, 4

Second-Line Options

• Imipenem-relebactam and cefiderocol may retain activity when resistance to ceftazidime-avibactam and ceftolozane-tazobactam develops. 4

• For metallo-beta-lactamase-producing strains, cefiderocol is the preferred agent, as ceftazidime-avibactam and ceftolozane-tazobactam are ineffective. 3, 4

• Alternative for metallo-beta-lactamase producers: ceftazidime-avibactam combined with aztreonam (not polymyxin B), which showed significant mortality reduction (HR 0.37,95% CI 0.13-0.74). 1

Critical Pitfalls to Avoid

Combination Therapy Misconceptions

• Despite in vitro synergy data showing reduced resistance development with polymyxin and ceftazidime-avibactam combinations, these results are NOT confirmed in clinical studies. 1

• The evidence for combination therapy with newer beta-lactam/beta-lactamase inhibitors is insufficient—ESCMID states "we cannot recommend for or against" combination therapy for carbapenem-resistant Pseudomonas. 1

• One study paradoxically showed combination therapy with ceftazidime-avibactam was associated with worse outcomes (aOR: 0.02,95% CI: 0.01-0.38 for clinical cure). 2

Polymyxin B Toxicity Concerns

• Monitor renal function closely during polymyxin B therapy—acute kidney injury is a significant risk that can compromise outcomes. 1, 5

• Polymyxin B dosing: loading dose of 2.5 mg/kg followed by maintenance of 1.5 mg/kg every 12 hours, adjusted for renal function. 1

• Ceftazidime-avibactam demonstrates significantly lower nephrotoxicity compared to polymyxin B-based regimens. 6

Comparative Effectiveness Data

Ceftazidime-Avibactam versus Polymyxin B

• A propensity-matched study of 136 patients showed ceftazidime-avibactam had significantly lower 30-day mortality (14.3% vs 42.9%, p=0.018) and higher bacterial clearance (42.9% vs 14.3%, p=0.018) compared to polymyxin B. 6

• 14-day mortality was also significantly lower with ceftazidime-avibactam (5.9% vs 27.1%, p=0.002). 6

• Ceftazidime-avibactam therapy emerged as an independent predictor of 30-day survival in multivariate analysis. 6

Resistance Monitoring

• Resistance to ceftazidime-avibactam can develop during therapy (3.8-10.4% of cases), but is NOT associated with monotherapy versus combination use. 1

• If resistance develops to ceftolozane-tazobactam during therapy, switch to ceftazidime-avibactam plus aztreonam (not polymyxin B). 5

• Repeat susceptibility testing if clinical failure occurs after 72 hours of appropriate therapy. 2