It is time once again to visit the twisted world of pharmaceutical advertorials, this time in the Lancet. Our subject is ceftolozane-tazobactam, a 5th-generation cephalosporin, approved and marketed as Zerbaxa. It joins an ever-growing arsenal of antibiotics whose intention is to fight the growing tide of antimicrobial resistance.
And, thus, welcome – and let us never use it.
Of course, this study will be the basis of many mailers, presentations, and lunch visits imploring its use. This is a phase 3 trial, comparing intravenous ceftolozane-tazobactam versus intravenous levofloxacin for treatment of complicated UTI/pyelonephritis, designed as a non-inferiority trial. The results, as expected in any such paid advertorial, show “composite cure” favoring ceftolozane-tazobactam – a cure rate of 76.8%, versus 68.4% with levofloxacin. The authors declare superiority based on confidence intervals, and the accompanying editorial further celebrates its availability and success.
Of course, this is “composite cure”, an endpoint based solely on differences in microbiological eradication of the original pathogens; clinical cure showed a non-significant difference. And, the cohort for evaluation was only a “microbiological modified intention to treat population”, which ultimately excluded over 300 patients from this 1000 patient trial. And, even then, the supposed difference in efficacy was based solely on the treatment failures in patients with pathogens with levofloxacin resistance.
So, yes, this is non-inferior to levofloxacin – except in price, where this new agent will likely cost $200-$300 per day per patient. Superior? No. Its only utility will be in those locations where resistance is very high, and, even then, there will likely be other, cheaper alternatives with efficacy.
But, Cubist Pharmaceuticals, the sponsor and co-author of this paper, has no interest in use of such cheaper options.
“Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI)”
http://www.ncbi.nlm.nih.gov/pubmed/25931244
It is the ideal way to start a non-inferiority trial- pick a clearly inferior comparitor. Levofloxacin is exhibiting resistance rates of 20% and more in E Coli. There is a reason the comparison was not against ceftriaxone or pip/ tazo.
I feel you may not fully comprehend the risks of just throwing around all of those "cheap" options – Resistence is on the increase and people like you often only think about the immediate effectiveness of the drug and not the long term consequences!
Local resistance patterns do vary, but, yes, e. coli resistance is definitely on the rise.
I am puzzled by your comment. The "cheaper" options should stay as the first line, despite their resistance increases, until they are utterly ineffective. Widespread use of Zerbaxa would simply mean eventual resistance to it, with fewer options remaining.
I am too puzzled by the comments of Anonymous. Mr. Radecki you are right on the point. Zerbaxa is garbage by Cubist and now that Merck has bought them…Well lets just say the Merckettes know how to sell drugs.