By Abraham Chang, PharmD

Dr. Chang is a PharmD resident at Stanford University.

Dr. Chang reports no financial relationships relevant to this field of study.

GENERIC NAME: Ceftolozane/tazobactam

TRADE NAME: ZerbaxaTM

FDA APPROVAL DATE: December 19, 2014

U.S. FDA-APPROVED INDICATIONS

• Treatment of patients 18 years or older with the following infections caused by designated susceptible microorganisms:

• Complicated Intra-abdominal Infections: Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, and Streptococcus salivarius

• Complicated Urinary Tract Infections, including pyelonephritis: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa

PHARMACOLOGY

Ceftolozane is a cephalosporin with a chemical structure similar to ceftazidime. The modified side-chain confers steric hindrance between ceftolozane and entry gate to the 3-position side-chain binding pocket at β-lactamase active site, preventing hydrolysis and granting stability against AmpC β-lactamase-overproducing P. aeruginosa.

Ceftolozane has potent activity against P. aeruginosa due to its ability to evade many resistance mechanisms, including efflux pumps, reduced uptake through porins, and modifications of PBP. Ceftolozane has activity against Gram-negative bacteria with classical β-lactamases (TEM-1, SHV-1), but is compromised by ESBL and carbapenemases.

The addition of tazobactam extends activity to include most ESBL producers as well as some anaerobic species. However, ceftolozane/tazobactam is not active against bacteria that produce serine carbapenemases (KPC) and metallo-beta lactamases.

PHARMACOKINETICS

Plasma levels do not increase appreciably following multiple IV infusions of up to ceftolozane/tazobactam 2 g/1 g q8h for up to 10 days in healthy adults with normal renal function. The elimination half-life is independent of dose. The human plasma protein binding of ceftolozane and tazobactam is approximately 16-21% and 30%, respectively. The mean steady-state volume of distribution of ceftolozane and tazobactam was 13.5 L and 18.2 L, respectively, similar to extracellular fluid volume. Ceftolozane is eliminated in urine as unchanged parent drug and is not metabolized to any appreciable extent. The beta-lactam ring of tazobactam is hydrolyzed to form the pharmacologically inactive tazobactam metabolite M1.

Pharmacokinetics

PK parameters

Ceftolozane/Tazobactam (1 g/0.5 g q8h)

Ceftolozane

Tazobactam

Day 1 (n = 9)

Day 10 (n = 10)

Day 1 (n = 9)

Day 10 (n = 10)

Cmax (mcg/mL)

69.1

74.4

18.4

18

tmax (h)

1.02

1.07

1.02

1.01

AUC (mcg*h/mL)

172

182

24.4

25

t½ (h)

2.77

3.12

0.91

1.03

ADVERSE EFFECTS

The most common adverse reactions (greater than 5% of patients) in patients were nausea, diarrhea, headache, and pyrexia. In the cIAI trials (phase 2 and 3), death occurred in 2.5% of patients receiving ceftolozane/tazobactam and in 1.5% of patients receiving meropenem. The causes of death varied and included worsening and/or complications of infection, surgery, and underlying conditions.

CONTRAINDICATIONS/WARNINGS/PRECAUTIONS

Contraindications

• Contraindicated in patients with known hypersensitivity to ceftolozane/tazobactam, piperacillin/tazobactam, or other members of the beta-lactam class.

Warnings/Precautions

• Decreased efficacy in patients with baseline CrCl of 30 - ≤ 50 mL/min: Subgroup analysis of a phase 3 cIAI trial found clinical cure rates were lower in patients with baseline CrCl of 30 - ≤ 50 mL/min compared to those with CrCl ≥ 50 mL/min. A similar trend was also seen in the cUTI trial.

• Hypersensitivity: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterial drugs.

CLINICAL TRIALS/EVIDENCE SUMMARY

Trial

Patient Population

Intervention

Efficacy Results

Adverse Effects

ASPECT-cUTI

Phase 3, multi-center, prospective, double-blind, randomized study

N =1068 hospitalized, adult patients with cUTI, including pyelonephritis

Ceftolozane/ tazobactam 1.5 g IV q8

vs

Levofloxacin 750 mg IV q24h

x 7 days

TREATMENT ARMS

MMITT N

MMITT CURE

ME

N

ME CURE

Ceftolozane/ tazobactam

398

76.9%

341

83.3%

Levofloxacin

402

68.4%

353

75.4%

Ceftolozane/tazobactam met primary and secondary endpoints achieving non-inferiority to levofloxacin with regard to composite clinical and microbiological cure.

The most commonly reported adverse events were headache (5.8%), constipation (3.9%), hypertension (3%), nausea (2.8%), and diarrhea (1.9%)

ASPECT-cIAI

Phase 3, multi-center, prospective, double-blind, randomized study

N = 993 hospitalized, adult patients with cIAI

Ceftolozane/ tazobactam 1.5 g IV q8 + Metronidazole 500 mg IV q8h

vs

Meropenem 1 g IV q8h

x 4-14 days

TREATMENT ARMS

MMITT N

MMITT CURE

ME

N

ME CURE

Ceftolozane/ tazobactam + metronidazole

389

83%

275

94.2%

Meropenem

417

87.3%

321

94.7%

Ceftolozane/tazobactam met primary and secondary endpoints achieving non-inferiority to meropenem with regard to clinical cure.

The most commonly reported adverse events were nausea (7.9%), diarrhea (6.2%), pyrexia (5.2%), insomnia (3.5%), and vomiting (3.3%).

cUTI = complicated urinary tract infection; cIAI = complicated intra-abdominal infection; mMITT = microbiological modified intent-to-treat; MITT = microbiological intent-to-treat; ME = microbiologically evaluable

Clostridium difficile-associated diarrhea: Clostridium difficile-associated diarrhea has been reported for nearly all systemic antibacterial agents, including ceftolozane/tazobactam.

• Development of Drug-Resistant Bacteria: Prescribing ceftolozane/tazobactam in the absence of a proven or strongly suspected bacterial infection is unlikely to benefit the patient and risks the development of drug-resistant bacteria.

Pregnancy and Lactation Information

• Pregnancy category B: Embryo-fetal development studies performed with IV ceftolozane in mice and rats revealed no evidence of harm to fetus.

• It is not known whether ceftolozane or tazobactam is excreted in human milk.

DRUG INTERACTIONS

No significant drug-drug interactions are anticipated between ceftolozane/tazobactam and substrates, inhibitors, and inducers of cytochrome P450 enzymes.

DOSAGE AND ADMINISTRATION1

Recommended dose

• cIAI: 1.5 g IV every 8 hours infused over 1 hour for 4-14 days.

• cUTI: 1.5 g IV every 8 hours infused over 1 hour for 7 days.

• Patients with renal impairment

o CrCl: 30-50 mL/min: 750 mg IV every 8 hours.

o CrCl: 15-20 mL/min: 375 mg IV every 8 hours.

o ESRD on HD: A single loading dose of 750 mg IV followed by 150 mg IV every 8 hours. On hemodialysis days, administer dose at the earliest time following completion of dialysis.

Cost

 

How Supplied

Average Wholesale Price (each vial)

Usual Dose

Cost of Therapy per day

Ceftolozane/ tazobactam

1.5 g vials

$99.60

1.5 g q8h

$298.80

Meropenem

1 g vials

$18.48

1 g q8h

$55.44

CONCLUSIONS

Ceftolozane/tazobactam is a cephalosporin and β-lactamase inhibitor combination with activity against multidrug-resistant gram-negative bacilli, including ESBL-producing Enterobacteriaceae and drug-resistant P. aeruginosa. It possesses a safety and tolerability profile similar to other β-lactam antibiotics. However, its lack of activity against KPC and MBL enzymes is a limitation.

REFERENCES

  1. Zerbaxa TM [Package Insert]. Lexington, MA: Cubist Pharmaceuticals, Inc. 2014.
  2. Lexi-Comp, Inc. (Lexi-DrugsTM). Lexi-Comp, Inc.
  3. Wagenlehner F, et al. Efficacy and safety of ceftolozane/tazobactam versus levofloxacin in the treatment of complicated urinary tract infections (cUTI) including pyelonephritis in hospitalized adults: Results from the Phase 3 ASPECT-cUTI trial. In: Proceeding of the 24th European Congress of Clinical Microbiology and Infectious Diseases. May 10-13, 2014. Barcelona, Spain. Abstract #eP449.
  4. Eckmann C, et al. Efficacy and safety of ceftolozane/tazobactam versus meropenem in the treatment of complicated intra-abdominal infections (cIAI) in hospitalized adults: results from the Phase 3 ASPECT-cIAI Trial. In: Proceeding of the 24th European Congress of Clinical Microbiology and Infectious Diseases. May 10-13, 2014. Barcelona, Spain. Abstract #P0266a.
  5. Zhanel GG, et al. Ceftolozane/Tazobactam: A novel cephlaosporin/beta-lactamase inhibitor combination with activity against multidrug-resistant gram-negative bacilli. Drugs 2014:74:31-51.