Why are newer combinations of beta-lactam (β-lactam) antibiotics with inhibitors, such as ceftazidime (Ceftazidime)-avibactam or ceftolozane (Ceftolozane)-tazobactam, used as first-line treatment in patients with Pseudomonas aeruginosa infections that have developed both porin closure and enzymatic resistance?

Why Newer Beta-Lactam/Inhibitor Combinations Are Used for Pseudomonas with Dual Resistance Mechanisms

Newer beta-lactam/inhibitor combinations like ceftolozane-tazobactam and ceftazidime-avibactam are specifically designed to overcome both porin closure and enzymatic resistance in Pseudomonas aeruginosa through enhanced beta-lactamase inhibition and improved penetration characteristics that bypass traditional resistance mechanisms. 1, 2

Mechanism-Based Rationale

Overcoming Enzymatic Resistance

• Avibactam is a non-beta-lactam beta-lactamase inhibitor that inactivates certain beta-lactamases that would otherwise degrade ceftazidime, including chromosomal AmpC enzymes commonly produced by Pseudomonas 1
• Tazobactam in the ceftolozane combination irreversibly inhibits some beta-lactamases (including certain penicillinases and cephalosporinases) through covalent binding, preventing enzymatic degradation 2
• Both combinations demonstrated in vitro activity against Pseudomonas isolates with chromosomal AmpC production, which is a primary enzymatic resistance mechanism 1, 2

Bypassing Porin Closure (OprD Loss)

• Ceftazidime-avibactam demonstrated in vitro activity against Pseudomonas aeruginosa strains lacking outer membrane porin (OprD), which is the primary mechanism of carbapenem resistance in Pseudomonas 1
• Ceftolozane-tazobactam similarly showed activity against isolates with loss of OprD porin, maintaining efficacy despite this permeability barrier 2
• In a study of 38 meropenem-resistant Pseudomonas isolates where 74% were OprD mutants and none harbored carbapenemases, both ceftazidime-avibactam and ceftolozane-tazobactam were active against 92% of isolates 3

Clinical Evidence Supporting Their Use

Guideline Recommendations

• The Journal of Microbiology, Immunology and Infection guidelines recommend that new beta-lactam/beta-lactamase inhibitors (ceftazidime-avibactam, ceftolozane-tazobactam, and imipenem-cilastatin-relebactam) may be considered for difficult-to-treat resistant Pseudomonas aeruginosa (DTR-PA) infections 4
• ESCMID guidelines suggest ceftolozane-tazobactam for severe infections due to difficult-to-treat carbapenem-resistant Pseudomonas aeruginosa (CRPA) when active in vitro 4

Superior Outcomes Compared to Older Agents

• One study reported better cure rates with less risk of acute kidney injury in the ceftolozane-tazobactam treatment group compared to polymyxin or aminoglycoside-combination groups when treating DTR-PA infections 4
• Data from Taiwan showed that 80% of imipenem-resistant Pseudomonas aeruginosa bloodstream isolates remained susceptible to ceftazidime-avibactam and ceftolozane-tazobactam 4

Specific Activity Against Dual Resistance

Molecular Mechanisms Addressed

• The molecular mechanisms of antimicrobial resistance in DTR-PA are complex, and these newer agents were specifically developed to address multiple simultaneous resistance mechanisms 4
• Ceftolozane demonstrates enhanced binding to penicillin-binding proteins (PBPs) of Pseudomonas aeruginosa (specifically PBP1b, PBP1c, and PBP3), maintaining activity even when enzymatic and permeability barriers are present 2
• Ceftazidime in combination with avibactam maintains activity against isolates that overexpress efflux pumps or have porin mutations, though activity may be reduced in some cases 1

Clinical Application Algorithm

When to Use These Agents

• For severe infections caused by CRPA or DTR-PA, these agents should be first-line when susceptibility testing confirms activity 4
• Antimicrobial susceptibility testing of new beta-lactam/beta-lactamase inhibitors is recommended to guide treatment 4

Agent Selection

• Ceftolozane-tazobactam is preferred for pneumonia (including hospital-acquired and ventilator-associated pneumonia) 5, 6, 7
• Ceftazidime-avibactam and ceftolozane-tazobactam can be used equally for non-pulmonary infections 5, 6, 7
• A comparative study of 200 patients showed no significant difference in mortality or clinical cure between ceftolozane-tazobactam and ceftazidime-avibactam for MDR Pseudomonas infections (44% vs 37% in-hospital mortality, p=0.314) 8

Critical Limitations and Pitfalls

Resistance Not Covered

• Neither ceftazidime-avibactam nor ceftolozane-tazobactam should be used for metallo-beta-lactamase-producing strains, as these enzymes confer resistance to both drugs 5, 1, 2
• Ceftazidime-avibactam is not active against bacteria that produce metallo-beta-lactamases and may not have activity against gram-negative bacteria that overexpress efflux pumps or have certain porin mutations 1

Monitoring Requirements

• In the study of meropenem-resistant Pseudomonas, 43% of ceftazidime-avibactam-susceptible isolates and 6% of ceftolozane-tazobactam-susceptible isolates exhibited MICs at the respective breakpoints, suggesting these agents should be used judiciously to preserve activity 3
• Resistance can develop during therapy, particularly with ceftazidime-avibactam monotherapy 6

Alternative Options When These Fail

• When resistance to ceftolozane-tazobactam and ceftazidime-avibactam is present, imipenem-relebactam may retain activity if metallo-beta-lactamases are absent 5, 6
• Cefiderocol is preferred when metallo-beta-lactamases are present 5, 6