Ceftolozane-Tazobactam
Zerbaxa — ceftolozane 1 g / tazobactam 0.5 g per vial (2:1 ratio)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Complicated intra-abdominal infections (cIAI) | Adults & pediatrics (birth to <18 years) | Combination with metronidazole | FDA Approved |
| Complicated urinary tract infections (cUTI) including pyelonephritis | Adults & pediatrics (birth to <18 years) | Monotherapy | FDA Approved |
| Hospital-acquired / ventilator-associated bacterial pneumonia (HABP/VABP) | Adults ≥18 years only | Monotherapy | FDA Approved |
Ceftolozane-tazobactam was developed with particular potency against Pseudomonas aeruginosa, including many multidrug-resistant (MDR) strains. Ceftolozane’s unique pyrazole ring at the 3-position of the cephem ring confers stability against AmpC hydrolysis and enhanced binding to P. aeruginosa PBPs. The spectrum also covers E. coli, K. pneumoniae, P. mirabilis, E. cloacae, K. oxytoca, S. marcescens, H. influenzae, and B. fragilis (with metronidazole), as well as select gram-positive organisms in cIAI (Streptococcus anginosus group). Tazobactam extends coverage to many ESBL-producing Enterobacterales. Critically, ceftolozane-tazobactam does not cover KPC-producing carbapenem-resistant Enterobacterales, metallo-beta-lactamase producers, MRSA, Enterococcus, or Acinetobacter.
MDR Pseudomonas aeruginosa infections beyond approved sites: Ceftolozane-tazobactam is the IDSA 2023 AMR guidance preferred agent for difficult-to-treat (DTR) P. aeruginosa infections. It is used off-label for DTR P. aeruginosa bloodstream infections, osteoarticular infections, and other deep-seated infections. Evidence quality: High — IDSA guidance recommendation; supported by multiple observational studies.
Dosing
Adults (CrCl >50 mL/min)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| cIAI | 1.5 g (1 g/0.5 g) IV q8h | Same | 4.5 g/day | 4–14 days Must combine with metronidazole 500 mg IV q8h; infuse over 1 hour |
| cUTI including pyelonephritis | 1.5 g (1 g/0.5 g) IV q8h | Same | 4.5 g/day | 7 days Infuse over 1 hour |
| HABP/VABP | 3 g (2 g/1 g) IV q8h | Same | 9 g/day | 8–14 days Double dose vs cIAI/cUTI; requires 2 vials per dose; infuse over 1 hour |
Pediatric Patients (Birth to <18 Years; cIAI & cUTI Only)
| Clinical Scenario | Dose (eGFR >50) | Maximum Dose | Notes |
|---|---|---|---|
| cIAI | 30 mg/kg IV q8h | 1.5 g (>50 kg) | 5–14 days Add metronidazole; not recommended if eGFR ≤50; no peds HABP/VABP dosing |
| cUTI including pyelonephritis | 30 mg/kg IV q8h | 1.5 g (>50 kg) | 7–14 days |
Adult Renal Impairment (Indication-Specific)
| CrCl (mL/min) | cIAI & cUTI Dose | HABP/VABP Dose | Notes |
|---|---|---|---|
| >50 | 1.5 g q8h | 3 g q8h | Normal dosing |
| 30–50 | 750 mg (500/250) q8h | 1.5 g (1 g/0.5 g) q8h | 50% dose reduction for each indication |
| 15–29 | 375 mg (250/125) q8h | 750 mg (500/250) q8h | 75% dose reduction for cIAI/cUTI |
| ESRD on HD | LD 750 mg, then 150 mg (100/50) q8h | LD 2.25 g, then 450 mg (300/150) q8h | Loading dose + maintenance; administer post-HD on dialysis days |
The HABP/VABP dose (3 g q8h) is double the cIAI/cUTI dose (1.5 g q8h). Renal adjustments are also indication-specific — the dose at each CrCl tier for HABP/VABP is double the cIAI/cUTI dose. In the Phase 3 cIAI trial, clinical cure rates in patients with CrCl 30–50 were 47.8% (ZERBAXA + metro) vs 69.2% (meropenem). Monitor CrCl at least daily.
Pharmacology
Mechanism of Action
Ceftolozane-tazobactam pairs a novel cephalosporin (ceftolozane) with the established beta-lactamase inhibitor tazobactam. Ceftolozane binds to PBPs and disrupts bacterial cell wall synthesis. Its structural modifications — including a pyrazole ring at the cephem 3-position and a dimethylacetic acid moiety — give it enhanced stability against AmpC beta-lactamases and chromosomal efflux pumps in P. aeruginosa, resulting in superior anti-pseudomonal potency compared to ceftazidime and piperacillin-tazobactam. Tazobactam is a penicillanic acid sulfone that irreversibly inhibits many class A beta-lactamases including ESBLs (CTX-M, SHV, TEM). Tazobactam does not inhibit KPC carbapenemases or class B/D enzymes, so ceftolozane-tazobactam is not active against KPC-producing CRE or MBL producers.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | IV only; Cmax and AUC dose-proportional for both components; linear PK; no accumulation over 10 days of q8h dosing in adults with normal renal function | 1-hour infusion for all doses; PK similar at single and multiple dosing |
| Distribution | Ceftolozane: Vss 13.5 L, protein binding 16–21%. Tazobactam: Vss 18.2 L, protein binding ~30%. Both distribute into extracellular fluid; good ELF penetration at 3 g dose | Adequate lung concentrations at the HABP/VABP dose support the higher 3 g regimen; ELF Cmin of ceftolozane 8.2 mcg/mL at end of dosing interval |
| Metabolism | Ceftolozane: not metabolized; >95% excreted unchanged in urine. Tazobactam: hydrolyzed to inactive M1 metabolite; >80% excreted unchanged + M1. No CYP involvement for either component. Tazobactam is an OAT1/OAT3 substrate | No hepatic dose adjustment; no CYP-mediated interactions; probenecid inhibits tazobactam renal elimination |
| Elimination | Ceftolozane t½ ~2.5–3 h; renal CL (3.41–6.69 L/h) ≈ plasma CL (glomerular filtration). Tazobactam t½ ~1 h. In augmented renal clearance (CrCl ≥180): ceftolozane t½ 2.6 h, tazobactam t½ 1.5 h | Dosing highly renal-dependent; no dose adjustment needed for augmented renal clearance in HABP/VABP; monitor CrCl at least daily |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Hepatic transaminase increased (ALT/AST) | 11.9% | Most common AE in HABP/VABP trial; monitor LFTs particularly in critically ill patients |
| Positive Coombs’ test seroconversion (HABP/VABP) | 31.2% | vs 3.6% meropenem; no evidence of hemolysis in any trial; can interfere with crossmatch; alert blood bank |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nausea | 7.9% | vs 5.8% meropenem; most common GI effect in cIAI |
| Diarrhea | 6.2% | vs 5% meropenem; 6.4% in HABP/VABP trial; monitor for C. difficile |
| Pyrexia | 5.6% | vs 4% meropenem; distinguish from treatment failure |
| Headache | 2.5% (cIAI) / 5.8% (cUTI) | Most common AE in cUTI trial (N=533) |
| Insomnia | 3.5% | vs 2.2% meropenem in cIAI |
| Vomiting | 3.3% | vs 4% meropenem in cIAI |
| Hypokalemia | 3.3% | vs 2% meropenem; monitor electrolytes |
| Constipation | 1.9% (cIAI) / 3.9% (cUTI) | More common in cUTI trial |
| Renal impairment / renal failure (HABP/VABP) | 8.9% | Second most common AE in HABP/VABP; led to discontinuation in 0.5% of cIAI/cUTI patients |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Anaphylaxis / serious hypersensitivity | Rare | Minutes to hours | Discontinue immediately; epinephrine and supportive care |
| C. difficile-associated diarrhea / colitis | Uncommon; ≥2% in HABP/VABP | During or up to 2+ months after therapy | Discontinue if confirmed; stool testing; treat with vancomycin or fidaxomicin |
| Renal impairment / acute renal failure | 8.9% in HABP/VABP; 0.5% discontinued in cIAI/cUTI | During therapy | Monitor CrCl at least daily; adjust dose; consider alternative if worsening |
| Intracranial hemorrhage (HABP/VABP) | ≥2% in HABP/VABP trial | Variable | Likely related to ICU population and underlying comorbidities rather than direct drug effect; monitor neurological status |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Renal impairment (cIAI+cUTI) | 0.5% (5/1015) | None in comparator arms; includes renal impairment, renal failure, and acute renal failure |
| All adverse reactions (cIAI+cUTI) | 2.0% (20/1015) | Similar to comparator (1.9%) |
| All adverse reactions (HABP/VABP) | 1.1% (4/361) | Lower than meropenem (1.4%) |
Drug Interactions
Ceftolozane-tazobactam has a very low drug interaction potential. Neither component is a CYP substrate, inhibitor, or inducer at therapeutic concentrations. Tazobactam is an OAT1/OAT3 substrate. The combination has not been tested for compatibility with other IV drugs and should not be mixed with other agents in the same infusion line.
Monitoring
- Renal FunctionAt least daily
RoutineBoth components are renally eliminated. CrCl determines dose for both indications. Renal impairment/failure occurred in 8.9% of HABP/VABP patients and caused treatment discontinuation in 0.5% of cIAI/cUTI patients. Decreased efficacy was observed in cIAI patients with CrCl 30–50. - Hepatic PanelBaseline + weekly
RoutineHepatic transaminase elevation was the most common AE in the HABP/VABP trial (11.9%). ALT and AST elevations also occurred in 1–2% of cIAI/cUTI patients. Monitor especially in critically ill patients receiving the 3 g dose. - Clinical Response48–72 h
RoutineIf inadequate response, reassess cultures. Consider that ceftolozane-tazobactam does not cover KPC-producing organisms or MBL producers. In elderly cIAI patients, cure rates were lower (69% vs 82.4% meropenem in patients ≥65 years). - Coombs’ TestBefore transfusion
Trigger-basedSeroconversion to positive direct Coombs’ test was 31.2% in the HABP/VABP trial (vs 3.6% meropenem). Clinically significant hemolysis was not observed. Alert the blood bank if transfusion is anticipated. - GI SymptomsThroughout therapy
RoutineDiarrhea occurred in 6.2% (cIAI) and 6.4% (HABP/VABP). C. difficile colitis was reported at ≥2% in the HABP/VABP trial. Test if diarrhea is persistent or bloody.
Contraindications & Cautions
Absolute Contraindications
- Known serious hypersensitivity to ceftolozane, tazobactam, piperacillin/tazobactam, or other beta-lactams
Relative Contraindications (Specialist Input Recommended)
- CrCl 30–50 mL/min in cIAI patients — clinical cure rates were significantly lower (47.8% vs 69.2% meropenem) in this subgroup
- Infections caused by KPC-producing or MBL-producing organisms — tazobactam does not inhibit KPC or class B/D beta-lactamases
Use with Caution
- Elderly patients (≥65 years) — higher incidence of adverse events; lower cure rates in cIAI trial (69% vs 82.4% meropenem); age-related renal decline
- Penicillin or other beta-lactam allergy — cross-hypersensitivity may occur
- Pediatric patients with eGFR ≤50 mL/min/1.73 m² — no dosing established; ZERBAXA not recommended
- History of GI disease, especially colitis — C. difficile risk
In the Phase 3 cIAI trial, clinical cure rates in patients with baseline CrCl 30–50 mL/min were 47.8% (11/23) for ZERBAXA plus metronidazole compared to 69.2% (9/13) for meropenem. A similar trend was seen in the cUTI trial. Monitor CrCl at least daily in patients with changing renal function and adjust dosing accordingly.
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibiotics. Cross-sensitivity has been established among beta-lactam classes. If an anaphylactic reaction occurs, discontinue ZERBAXA and institute appropriate therapy.
Patient Counselling
Purpose of Therapy
Ceftolozane-tazobactam (Zerbaxa) is a powerful IV antibiotic specifically designed to treat serious bacterial infections, including those caused by hard-to-treat Pseudomonas bacteria. It combines an antibiotic with a protective agent that helps the antibiotic work against resistant bacteria. It is given as an IV infusion over 1 hour, usually every 8 hours.
Sources
- ZERBAXA (ceftolozane and tazobactam) Prescribing Information. Merck Sharp & Dohme LLC. Revised May 2022. DailyMedCurrent FDA PI; source for all dosing tables (adults, pediatrics, renal), adverse events (N=1015 cIAI/cUTI; N=361 HABP/VABP), PK parameters, and Coombs data.
- ZERBAXA FDA Label, NDA 206829 (2019 supplement). FDA.govLabel revision adding HABP/VABP indication with ASPECT-NP trial data; 3 g dosing for pneumonia.
- ZERBAXA FDA Label, NDA 206829 (2022 supplement). FDA.govLabel adding pediatric cIAI and cUTI indications (birth to <18 years) based on PK modeling and pediatric safety data.
- Solomkin J, Hershberger E, Miller B, et al. Ceftolozane/tazobactam plus metronidazole for complicated intra-abdominal infections in an era of multidrug resistance: results from a randomized, double-blind, Phase 3 trial (ASPECT-cIAI). Clin Infect Dis. 2015;60(10):1462-1471. DOIPhase 3 cIAI trial demonstrating non-inferiority to meropenem; source for cIAI adverse event rates and CrCl 30–50 subgroup efficacy data.
- Wagenlehner FM, Umeh O, Steenbergen J, et al. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, Phase 3 trial (ASPECT-cUTI). Lancet. 2015;385(9981):1949-1956. DOIPhase 3 cUTI trial demonstrating superiority over levofloxacin; source for cUTI adverse event rates.
- Kollef MH, Nóvak R, Engel AM, et al. Ceftolozane-tazobactam versus meropenem for treatment of nosocomial pneumonia (ASPECT-NP). Lancet Infect Dis. 2019;19(12):1299-1311. DOIPhase 3 HABP/VABP trial establishing non-inferiority to meropenem; basis for 3 g dosing approval and HABP/VABP adverse event data.
- Tamma PD, Aitken SL, Bonomo RA, et al. Infectious Diseases Society of America 2023 guidance on the treatment of antimicrobial resistant gram-negative infections. Clin Infect Dis. 2023;ciad428. DOIIDSA AMR guidance recommending ceftolozane-tazobactam as the preferred agent for difficult-to-treat (DTR) P. aeruginosa infections.
- Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the IDSA and ATS. Clin Infect Dis. 2016;63(5):e61-e111. DOIATS/IDSA HAP/VAP guideline; ceftolozane-tazobactam as anti-pseudomonal option.
- Moya B, Zamorano L, Juan C, et al. Affinity of the new cephalosporin CXA-101 to penicillin-binding proteins of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2010;54(9):3933-3937. DOIKey mechanistic study demonstrating ceftolozane’s enhanced binding to P. aeruginosa PBP1b, PBP1c, and PBP3 compared to ceftazidime.
- Zhanel GG, Chung P, Adam H, et al. Ceftolozane/tazobactam: a novel cephalosporin/beta-lactamase inhibitor combination with activity against multidrug-resistant gram-negative bacilli. Drugs. 2014;74(1):31-51. DOIComprehensive review of ceftolozane-tazobactam pharmacology, spectrum, and early clinical data.
- Caro L, Nicolau DP, De Waele JJ, et al. Lung penetration, bronchopulmonary pharmacokinetic/pharmacodynamic profile and safety of 3 g of ceftolozane/tazobactam administered to ventilated, critically ill patients with pneumonia. J Antimicrob Chemother. 2020;75(6):1546-1553. DOIELF penetration study supporting the 3 g dose for HABP/VABP; demonstrated ceftolozane ELF Cmin of 8.2 mcg/mL.
- Miller B, Hershberger E, Guo Y, et al. Pharmacokinetics and safety of ceftolozane/tazobactam in subjects with varying degrees of renal function. J Clin Pharmacol. 2017;57(12):1613-1621. DOIRenal impairment PK study supporting dose adjustments; documented 1.5-fold, 2-fold, and 4-fold tazobactam AUC increases at CrCl 80–51, 50–30, and 29–15 mL/min respectively.
- Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41. DOICrCl estimation formula referenced in the ZERBAXA PI for adult renal dose adjustments.