What is the treatment regimen for a patient with a resistant carbapenem infection using Zerbaxa (ceftolozane/tazobactam)?

Zerbaxa (Ceftolozane/Tazobactam) for Resistant Carbapenem Infections

For carbapenem-resistant infections, Zerbaxa (ceftolozane/tazobactam) is primarily indicated for difficult-to-treat carbapenem-resistant Pseudomonas aeruginosa (CRPA), not carbapenem-resistant Enterobacterales (CRE), and should be dosed at 1.5g IV every 8 hours for most infections or 3g IV every 8 hours for hospital-acquired/ventilator-associated pneumonia. 1

Key Indication Distinction

Zerbaxa is NOT a first-line agent for carbapenem-resistant Enterobacterales (CRE). The evidence clearly shows:

• For CRE infections: Ceftazidime/avibactam, meropenem/vaborbactam, or imipenem/relebactam are the preferred new beta-lactam/beta-lactamase inhibitor combinations 2
• For carbapenem-resistant Pseudomonas aeruginosa (CRPA): Ceftolozane/tazobactam is a recommended option 2

This distinction is critical because ceftolozane/tazobactam is not active against metallo-β-lactamases or carbapenemase-producing Enterobacteriaceae (KPC producers), which are common mechanisms of carbapenem resistance in Enterobacterales 2

Dosing Regimens by Infection Type

Standard Dosing (CrCl >50 mL/min)

Complicated Intra-Abdominal Infections (cIAI):

• 1.5g IV every 8 hours over 1 hour for 4-14 days 1
• Must be combined with metronidazole 500mg IV every 8 hours for anaerobic coverage 1

Complicated Urinary Tract Infections (cUTI)/Pyelonephritis:

• 1.5g IV every 8 hours over 1 hour for 7 days 1

Hospital-Acquired/Ventilator-Associated Pneumonia (HABP/VABP):

• 3g IV every 8 hours over 1 hour for 8-14 days (higher dose required) 1
• This is specifically for difficult-to-treat Pseudomonas aeruginosa 2

Renal Dose Adjustments

CrCl 30-50 mL/min:

• cIAI/cUTI: 750mg IV every 8 hours 1
• HABP/VABP: 1.5g IV every 8 hours 1

CrCl 15-29 mL/min:

• cIAI/cUTI: 375mg IV every 8 hours 1
• HABP/VABP: 750mg IV every 8 hours 1

End-Stage Renal Disease on Hemodialysis:

• cIAI/cUTI: Loading dose 750mg, then 150mg maintenance every 8 hours 1
• HABP/VABP: Loading dose 2.25g, then 450mg maintenance every 8 hours 1
• Administer doses after dialysis on dialysis days 1

Clinical Efficacy Data

Real-world effectiveness for carbapenem-resistant infections:

• Clinical success rate of 74% for carbapenem-resistant Pseudomonas aeruginosa infections 3
• Clinical failure rate of 30.1% in difficult-to-treat multidrug-resistant Gram-negative infections, with most failures due to recurrence (16.1%) rather than persistent infection 4

Critical caveat: Treatment failure occurred in all cases where ceftolozane/tazobactam MIC ≥8 μg/mL, emphasizing the importance of susceptibility testing 3

Specific Clinical Scenarios

For Carbapenem-Resistant Pseudomonas aeruginosa (CRPA)

In severe infections with difficult-to-treat CRPA:

• Ceftolozane/tazobactam 1.5-3g IV every 8 hours is conditionally recommended if active in vitro 2
• Consider combination therapy with polymyxins or aminoglycosides for severe infections when using older agents, though no specific recommendation exists for combining with new beta-lactam/beta-lactamase inhibitors 2

For Carbapenem-Resistant Enterobacterales (CRE)

Zerbaxa is NOT recommended as first-line therapy. Instead, use:

• Ceftazidime/avibactam 2.5g IV every 8 hours 2
• Meropenem/vaborbactam 4g IV every 8 hours 2
• Imipenem/cilastatin/relebactam 1.25g IV every 6 hours 2

Important Limitations and Pitfalls

Metallo-β-lactamase producers:

• Ceftolozane/tazobactam is NOT active against metallo-β-lactamases, which are increasingly common mechanisms of carbapenem resistance in Pseudomonas aeruginosa in some geographic regions 2
• Always obtain susceptibility testing before relying on this agent 3

Anaerobic coverage:

• Zerbaxa has limited activity against Bacteroides species 2
• Mandatory co-administration of metronidazole for intra-abdominal infections 1

Bacteremia considerations:

• While effective for various infection sources, ensure adequate source control and monitor clinical response closely 4

Adverse events:

• Clostridium difficile infection (9% in real-world data) 4
• Cholestasis (8%) 4

Antimicrobial Stewardship Considerations

Carbapenem-sparing strategy:

• Ceftolozane/tazobactam serves as a valuable carbapenem-sparing alternative for ESBL-producing Enterobacteriaceae and multidrug-resistant Pseudomonas aeruginosa 2
• Particularly important in settings with high incidence of carbapenem-resistant K. pneumoniae to preserve carbapenem activity 2

When to use empirically:

• Critical patients with risk factors for ESBL isolation 2
• Known colonization with multidrug-resistant Pseudomonas aeruginosa 2
• Healthcare-associated infections in settings with high CRPA prevalence 2