FDA approves new antibiotic combo for two complicated infections

March 10, 2015

Ceftolozane/tazobactam was approved to treat complicated urinary tract infections and to treat - in combination with metronidazole - complicated intra-abdominal infections.

Kathryn WheelerCeftolozane/tazobactam (Zerbaxa; Cubist Pharmaceuticals) received FDA approval in December 2014. This medication is a combination of a new cephalosporin type of antibiotic and a beta-lactamase inhibitor. The bactericidal agent ceftolozane binds penicillin-binding proteins, inhibiting cell-wall synthesis. Tazobactam is a beta-lactamase inhibitor. In combination with ceftolozane, it increases the spectrum of activity to include some bacteria that produce beta-lactamase and would otherwise resist ceftolozane’s antimicrobial activity. 

Ceftolozane/tazobatam was approved for the treatment of two types of complicated infections: urinary tract infections, including pyelonephritis, and - in combination with metronidazole - intra-abdominal infections. As many infections have become more difficult to treat due to the increase in antibiotic resistance, the Infectious Disease Society of America implemented the “10 by 20” initiative, which calls for 10 new antibiotics to be developed by the year 2020. This drug, the fifth new antibiotic to be approved, offers a new option for fighting resistant pseudomonal infections. 

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Efficacy

FDA based its approval for use of the drug combination in treatment of intra-abdominal infections on a single study comparing ceftolozone/tazobactam plus metronidazole to meropenem in 979 participants hospitalized with complicated intra-abdominal infections. The primary endpoint, clinical response, was measured at 24 to 32 days after the first dose of study drug was administered. Ceftolozone/tazobactam plus metronidazole was demonstrated to be non-inferior to meropenem.

While ceftolozone/tazobactam provides excellent coverage against Pseudomonas aeruginosa, it has limited anaerobic activity.  For this reason, it is used in combination with metronidazole in the treatment of intra-abdominal infections.  

Approval for its use in treatment of complicated urinary infections was based on the findings of a single study in 1,068 adults randomized to receive ceftolozane/tazobactam or levofloxacin. The primary endpoint was defined as the resolution or marked improvement of symptoms and eradication of microbial infection at the test-of-cure visit. This visit occurred within one week (+/- 2 days) of administration of the last dose of study drug. Ceftolozane/tazobactam demonstrated comparable efficacy to levofloxacin in the treatment of complicated urinary tract infections.

Ceftolozane/tazobactam was designated a Qualified Infectious Disease Product (QDIP) as allowed by the Generating Antibiotic Initiatives Now (GAIN) title of the FDA Safety and Innovation Act.  In accordance with these rules, FDA approved ceftolozane/tazobactam on the basis of a priority and expedited review, because the drug is an antimicrobial product intended to treat serious or life-threatening infections.

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Safety

A total of 1,015 patients received ceftolozane/tazobatam in clinical trials. Generally, ceftolozane/tazobactam appeared well tolerated. The most common adverse effects seen in clinical trials included nausea, diarrhea, headache, and fever. Ceftolozane/tazobactam should be used with caution in any patient with a known sensitivity to beta-lactam antibiotics, as cross-sensitivity has been established. The manufacturer lists known serious hypersensitivity to ceftolozane/tazobactam, piperacillin/tazobactam, or other beta-lactam antibiotics as a contraindication to the use of the product. As with other systemic antibiotics, Clostridium difficile-associated diarrhea has been reported with ceftolozane/tazobactam use. Patients experiencing diarrhea should be evaluated.

Dosage

Zerbaxa is available in a single-dose vial of ceftolozane/tazobactam 1 g/0.5 g powder for reconstitution. The approved dose for adults with a creatinine clearance greater than 50 mL/min is 1.5 g (1 g/ 0.5 g), administered every eight hours via intravenous infusion over the course of one hour. Dose adjustments are required for renal impairment. For creatinine clearance of 30 to 50 mL/min and 15 to 29mL/min, the appropriate doses are 750 mg every eight hours and 375 mg every eight hours, respectively. Patients who have end-stage renal disease or who are on hemodialysis should receive a single 750-mg dose followed by 150-mg doses administered every eight hours. Ceftolozane/tazobactam is not a substrate of the CYP450 enzymes. It is pregnancy category B.

References

1. Zerbaxa [package insert]. Lexington, MA: Cubist Pharmaceuticals U.S; Revised December 2014.

2. 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: 31-51.

Kathryn Wheeler is associate clinical professor, Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, Conn.