Medication Approvals

by Paul Brumley, Pharm.D., PGY1 pharmacy resident, St. Joseph Mercy Ann Arbor 

According to the Infectious Diseases Society of America (IDSA), antimicrobial resistance has become an imminent threat in the health care world, and the tangible evidence of this is becoming more apparent every year. Antibiotic-resistant pathogens lead to devastating consequences, including nearly 99,000 deaths per year resulting in $21 billion in health care costs. To help combat the insufficient rate at which new antibiotics are being brought to market, the IDSA implemented the “10 X ‘20 Initiative,” a global movement to develop 10 new agents by the year 2020. One new agent that has made its way to market is Zerbaxa®

On Dec. 19, 2014, Cubist Pharmaceuticals’ new product Zerbaxa® (ceftolozane/ tazobactam) became the latest Food and Drug Administration (FDA)-approved antibiotic in this battle against growing antimicrobial resistance. With its antipseudomonal coverage, ceftolozane now joins the ranks of ceftazidime and cefepime in cephalosporins with this property; the addition of the β-lactamase inhibitor tazobactam was found to increase activity against both gram-positive and gram-negative organisms in vitro. In regard to resistant strains of Pseudomonas aeruginosa, ceftolozane/tazobactam has demonstrated in vitro activity against isolates with up-regulation of efflux pumps, presence of chromosomal AmpC and loss of outer membrane porin. Other resistant bugs, which have been shown to have in vitro susceptibility to ceftolozane/tazobactam, include some strains of β-lactamase-producing E. coli and K. pneumoniae. To what extent this activity holds up in vivo will be an important aspect to monitor over time. Although studies for other indications are under way, Cubist’s product is currently only indicated for complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs). 

For use in cUTI’s, ceftolozane/tazobactam 1,500 mg IV q8h was compared with levofloxacin 750 mg IV q24h in a phase III, multicenter, prospective, randomized, double-blind, double-dummy study. Included patients were required to have two or more symptoms of a UTI (dysuria, fever, suprapubic/flank pain, nausea or vomiting) plus at least one complicating factor (males with documented history of urinary retention, an indwelling catheter, obstructive uropathy, or any urogenital tract functional or anatomical abnormality). After seven days of therapy, ceftolozane/tazobactam was found to be non-inferior to levofloxacin, with composite microbiological and clinical cure rates (the primary outcome) of 76.9 percent and 68.4 percent, respectively. Safety profiles were comparable between the two groups, with treatment-related adverse events occurring in 10.3 percent of the ceftolozane/tazobactam group and 12 percent of the levofloxacin group. Studies have shown ceftolozane/tazobactam to be effective against cUTI’s caused by the following bugs: E. coli, K. pneumoniae, P. mirabilis and P. aeruginosa

With a similar non-inferiority study design for patients with cIAIs, ceftolozane/tazobactam 1,500 mg IV q8h plus metronidazole 500 mg IV q8h was compared with meropenem 1,000 mg IV q8h. For study inclusion, patients had to require surgical intervention (e.g., laparotomy, laparoscopic surgery or percutaneous draining of an abscess) within 24 hours of the first dose of study drug. After four to 14 days of therapy, ceftolozane/tazobactam plus metronidazole achieved non-inferiority to meropenem with clinical cure rates (the primary outcome) of 83 percent and 87.3 percent, respectively. Adverse event rates for ceftolozane/tazobactam were comparable with the cUTI study, with the most common observed adverse effects being nausea (7.9 percent) and diarrhea (6.2 percent). Studies have shown ceftolozane/tazobactam plus metronidazole to be effective against cIAI’s caused by the following microorganisms: E. cloacae, E. coli, K. oxytoca, K pneumoniae, P mirabilis, P. aeruginosa, B. fragilis, S. anginosus, S. constellatus and S. salivarius

With its recent FDA approval, Zerbaxa® is the fifth new antibiotic available since the IDSA’s introduction of the 10 X ‘20 Initiative. In a December 2014 progress statement, the organization indicated that it “applauds Cubist and other public and private industry enterprises dedicated to helping combat the rise of antibiotic-resistant bacteria – a true public health crisis – for their efforts to mitigate the sharp decline in the development of new antibiotics.” Exactly what the new product’s place in therapy will be is yet to be determined, but the incorporation of a new weapon in the arsenal against resistant bacteria is an exciting advancement. 

References available upon request from MPA office.


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