What are the uses and substitutions for Zerbaxa (ceftolozane/tazobactam) in treating complicated infections?

Zerbaxa (Ceftolozane/Tazobactam): Clinical Uses and Substitutions

FDA-Approved Indications

Zerbaxa is indicated for three specific infection types: complicated intra-abdominal infections (in combination with metronidazole), complicated urinary tract infections including pyelonephritis, and hospital-acquired/ventilator-associated bacterial pneumonia. 1

Approved Uses by Patient Population:

• Complicated Intra-abdominal Infections (cIAI): Must be used in combination with metronidazole in both adults and pediatric patients (birth to <18 years) 1
• Complicated Urinary Tract Infections (cUTI) including Pyelonephritis: Adults and pediatric patients (birth to <18 years) 1
• Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia (HABP/VABP): Adults 18 years and older only 1

Standard Dosing Regimens

Adult Dosing (CrCl >50 mL/min):

• cIAI: 1.5 g IV every 8 hours for 4-14 days (with metronidazole 500 mg IV q8h) 1
• cUTI/Pyelonephritis: 1.5 g IV every 8 hours for 7 days 1
• HABP/VABP: 3 g IV every 8 hours for 8-14 days 1

Pediatric Dosing (eGFR >50 mL/min/1.73 m²):

• 30 mg/kg IV every 8 hours (maximum 1.5 g per dose) for both cIAI and cUTI 1, 2
• Duration: 5-14 days for cIAI, 7-14 days for cUTI 1

Primary Clinical Role: Multidrug-Resistant Gram-Negative Infections

Zerbaxa's most important clinical niche is treating difficult-to-treat Pseudomonas aeruginosa (DTR-PA) and carbapenem-resistant Pseudomonas aeruginosa (CRPA). 3

Specific Resistant Pathogen Coverage:

• DTR-PA and CRPA: Recommended at 1.5-3 g IV q8h (weak recommendation, low evidence) 3
• ESBL-producing Enterobacteriaceae: Active against most extended-spectrum beta-lactamase producers when combined with tazobactam 3, 4
• Multidrug-resistant P. aeruginosa: Including carbapenem, piperacillin/tazobactam, and ceftazidime-resistant strains 5, 6

Important Limitation:

• NOT active against carbapenemase-producing organisms (e.g., KPC, NDM, OXA-48) 5
• Susceptible to hydrolysis by carbapenemase enzymes 7

Appropriate Substitutions by Clinical Scenario

For Complicated Intra-Abdominal Infections:

First-Line Alternatives (Community-Acquired, Mild-to-Moderate):

• Piperacillin/tazobactam 3.375-4.5 g IV q6h (preferred single agent) 3, 8
• Ertapenem 1 g IV daily 3
• Cefazolin or cefuroxime + metronidazole 3, 8

High-Severity Community-Acquired Alternatives:

• Meropenem 1 g IV q8h 3
• Imipenem/cilastatin 500 mg IV q6h 3
• Cefepime or ceftazidime + metronidazole 3, 8

Hospital-Acquired/MDR Alternatives:

• Ceftazidime/avibactam 2.5 g IV q8h + metronidazole (for ESBL/KPC producers) 3
• Imipenem/cilastatin/relebactam 1.25 g IV q6h 3
• Meropenem/vaborbactam 4 g IV q8h (for CRE) 3

For Complicated Urinary Tract Infections:

Standard Alternatives (Non-MDR):

• Ceftriaxone 1-2 g IV daily 3
• Ceftazidime 2 g IV q8h 3
• Cefepime 2 g IV q8-12h 3
• Levofloxacin 750 mg IV daily (if local resistance <10%) 3

MDR/ESBL Alternatives:

• Ceftazidime/avibactam 2.5 g IV q8h 3
• Meropenem/vaborbactam 4 g IV q8h 3
• Aminoglycosides (amikacin 15 mg/kg IV daily, gentamicin 5-7 mg/kg IV daily) for UTI only 3

For Hospital-Acquired/Ventilator-Associated Pneumonia:

Anti-Pseudomonal Alternatives:

• Piperacillin/tazobactam 4.5 g IV q6h 8
• Cefepime 2 g IV q8h 3
• Ceftazidime 2 g IV q8h 3
• Imipenem/cilastatin 500 mg IV q6h or meropenem 2 g IV q8h 3

For DTR-PA/CRPA Pneumonia:

• Ceftazidime/avibactam 2.5 g IV q8h 3
• Imipenem/cilastatin/relebactam 1.25 g IV q6h 3
• Colistin-based combination therapy (5 mg CBA/kg loading, then 2.5 mg CBA × [1.5 × CrCl + 30] IV q12h) 3

Critical Antimicrobial Stewardship Considerations

Zerbaxa should be reserved for documented or high-risk multidrug-resistant Gram-negative infections, not used as routine empiric therapy. 3

When to Avoid Empiric Use:

• Community-acquired infections without MDR risk factors 3
• Settings with low ESBL/MDR prevalence 3
• When narrower-spectrum agents are appropriate 3, 8

Combination Therapy Requirements:

• Always add metronidazole for intra-abdominal infections due to limited activity against Bacteroides species 3, 1, 7
• Consider combination therapy (with colistin or meropenem) for severe DTR-PA to prevent resistance emergence 6

Common Pitfall:

Do NOT add metronidazole to piperacillin/tazobactam - this provides no additional anaerobic coverage, increases unnecessary antibiotic exposure, and violates stewardship principles 8

Renal Dose Adjustments

Dose reduction is mandatory for CrCl ≤50 mL/min:

• CrCl 30-50 mL/min: 750 mg IV q8h (cIAI/cUTI) or 1.5 g IV q8h (HABP/VABP) 1
• CrCl 15-29 mL/min: 375 mg IV q8h (cIAI/cUTI) or 750 mg IV q8h (HABP/VABP) 1
• ESRD on hemodialysis: Loading dose 750 mg (cIAI/cUTI) or 2.25 g (HABP/VABP), then maintenance 150 mg or 450 mg IV q8h respectively 1

Clinical Efficacy Data

Ceftolozane/tazobactam demonstrated non-inferiority to meropenem for cIAI (with metronidazole) and superiority to levofloxacin for cUTI in phase 3 trials. 4

• Clinical and microbiological success rates: 70-80% across multiple series 6
• Comparable safety profile to other cephalosporins 7, 5
• Common adverse effects: hypersensitivity, nausea, diarrhea, headache 7