What antipseudomonal β‑lactam antibiotic can be used as an alternative to Zerbaxa (ceftolozane/tazobactam) in an adult with no drug allergies, normal renal function, and a suspected multidrug‑resistant gram‑negative infection?

Antipseudomonal β-Lactam Alternatives to Zerbaxa

For multidrug-resistant gram-negative infections in adults with normal renal function, ceftazidime-avibactam 2.5 g IV every 8 hours is the most comparable alternative to Zerbaxa (ceftolozane/tazobactam), offering similar spectrum coverage against ESBL-producing Enterobacteriaceae and carbapenem-resistant Pseudomonas aeruginosa. 1

Primary Alternative: Ceftazidime-Avibactam

Ceftazidime-avibactam represents the closest pharmacologic alternative to ceftolozane/tazobactam, as both are novel β-lactam/β-lactamase inhibitor combinations with activity against multidrug-resistant gram-negative pathogens. 1, 2

Spectrum of Activity

• Active against ESBL-producing Enterobacteriaceae, including those resistant to third-generation cephalosporins 1
• Retains activity against carbapenem-resistant Pseudomonas aeruginosa (CRPA) and difficult-to-treat resistant strains 1
• Uniquely active against KPC-producing organisms (Klebsiella pneumoniae carbapenemase), which distinguishes it from ceftolozane/tazobactam 1, 2
• Does NOT cover metallo-β-lactamase (MBL) producers - this is a critical limitation 1

Dosing

• Standard dose: 2.5 g IV every 8 hours (2 g ceftazidime + 0.5 g avibactam) infused over 2 hours 1
• No renal adjustment needed with normal kidney function 3

Clinical Evidence

• Similar efficacy to ceftolozane/tazobactam for non-pulmonary infections in observational studies 4
• Demonstrated lower 30-day mortality compared to other regimens in CRE bloodstream infections 1
• Well-tolerated safety profile comparable to other cephalosporins 2

Secondary Alternatives Based on Infection Site

For Non-Severe or Community-Acquired Infections

Piperacillin-tazobactam 3.375-4.5 g IV every 6 hours remains an option when susceptibility is confirmed, though its use in ESBL infections is controversial. 1

• Broad-spectrum coverage including anti-Pseudomonas activity and anaerobic coverage 1
• Reserve for stable patients with confirmed susceptibility 1
• Not reliable for ESBL producers despite in vitro susceptibility 1

For Carbapenem-Susceptible Organisms

Meropenem 2 g IV every 8 hours (extended infusion over 3 hours preferred) or imipenem-cilastatin 500 mg IV every 6 hours for confirmed susceptible pathogens. 1

• Group 2 carbapenems (meropenem, imipenem, doripenem) have activity against non-fermentative gram-negative bacilli including P. aeruginosa 1
• Should be reserved to preserve carbapenem activity due to emerging resistance 1

For Ceftazidime-Susceptible Pseudomonas

Ceftazidime 2 g IV every 8 hours when susceptibility is documented. 1

• Third-generation cephalosporin with anti-Pseudomonas activity 1
• Must combine with metronidazole for intra-abdominal infections (lacks anaerobic coverage) 1

Cefepime 2 g IV every 8-12 hours as a fourth-generation alternative. 1

• Broader spectrum than third-generation cephalosporins and effective against AmpC-producing organisms 1
• Also requires metronidazole for anaerobic coverage 1

Newer Alternatives for Highly Resistant Pathogens

Imipenem-Cilastatin-Relebactam

1.25 g IV every 6 hours for CRE infections when susceptible. 1

• Active against class A carbapenemases (KPC) and class C cephalosporinases 1
• Not active against class B (MBL) or class D carbapenemases 1

Meropenem-Vaborbactam

4 g IV every 8 hours for KPC-producing CRE. 1

• Specifically inhibits KPC enzymes (class A carbapenemases) 1
• Demonstrated lower mortality (15.6% vs 33.3%) compared to best available therapy in CRE bloodstream infections 1
• Reduced nephrotoxicity compared to polymyxin-based regimens 1

Critical Pitfalls and Caveats

Resistance Mechanisms to Avoid

• Never use ceftazidime-avibactam or ceftolozane/tazobactam for MBL-producing strains - both are inactive against metallo-β-lactamases 1
• For MBL producers, consider ceftazidime-avibactam PLUS aztreonam combination (HR 0.37 for mortality reduction) 1

Infection Site Considerations

• For pneumonia specifically, ceftolozane/tazobactam is preferred over ceftazidime-avibactam based on guideline recommendations 4, 5
• For non-pulmonary infections, both agents are equally effective 4

Resistance Development

• Resistance can emerge during therapy, particularly with ceftazidime-avibactam monotherapy (3.8-10.4% of cases) 1
• Combination therapy has not been proven superior to monotherapy for preventing resistance in most clinical studies 1

When to Use Older Agents

• Fluoroquinolones (ciprofloxacin 400 mg IV q8h, levofloxacin 750 mg IV daily) are no longer first-line due to widespread resistance, but remain options for β-lactam allergies 1
• Aminoglycosides (amikacin 15 mg/kg IV daily) should be reserved for combination therapy in MDR infections or β-lactam allergies due to nephrotoxicity 1
• Colistin (5 mg/kg loading dose, then maintenance dosing) is a last-resort option with significant nephrotoxicity risk 1

Treatment Algorithm

1. Obtain susceptibility testing immediately including novel β-lactam/β-lactamase inhibitor panels 4, 5
2. If ESBL or CRPA suspected: Use ceftazidime-avibactam 2.5 g IV q8h 1
3. If KPC-producing CRE: Prefer meropenem-vaborbactam 4 g IV q8h or ceftazidime-avibactam 1
4. If MBL-producing strain: Use ceftazidime-avibactam PLUS aztreonam combination 1
5. If susceptible to older agents: Consider piperacillin-tazobactam or carbapenems to preserve newer agents 1
6. Add metronidazole 500 mg IV q8h for intra-abdominal infections when using agents lacking anaerobic coverage 1