What is the “Niche” for Ceftolozane / Tazobactam?

There are currently a total of 6 beta-lactam + beta-lactamase inhibitor combinations in clinical trials.

It will be a steep learning curve for the pharma reps (and physicians) to understand the resistance classifications, the confusing ESBL definitions, the CRE nomenclature, and how this all matters in clinical practice, on the backdrop of the local hospital resistance situation. There will be a lot of misunderstandings and misrepresentations because we have not done a good job preparing ourselves for the claims and counter-claims that will certainly come once the competition heats up.

Let’s look at the most advanced project, Ceftolozane / Tazobactam, and review first what each component has to offer before putting the 2 ingredients back into the bottle together again, so to speak.

Ceftolozane, aka CXA-101, is a cephalosporin with excellent P. aeruginosa (PA) coverage.  It is more powerful than ceftazidime, cefepime, meropenem, ciprofloxacin, and as potent as amikacin or colistin by virtue of a set of unique features:  it is not a substrate of several PA efflux systems and its uptake is independent of the OmpD porin channel.  In addition, it has a low affinity for the AmpC B-lactamase.[1]

Like other 3^rd generation cephalosporins, it covers many other gram-negative rods but without any stand-out features that make it so compelling for PA.  Activity against B. fragilis is not reliable enough to forgo metronidazole in cIAI.

With this set of features alone, we would certainly want ceftolozane in our antibiotic quaver.

Tazobactam is a good old friend, in use for some 20+ years by now, in combination with piperacillin.  It is a B-lactamase inhibitor (BLI) inhibiting Ambler Class A BLs, which have been around since the 90ies, but it is not as potent an inhibitor for AmpC BL and other ESBLs which have been driving up carbapenem use lately.

In summary, ceftolozane/tazobactam looks like a great pseudomonas drug.  It is also a cephalosporin with nice 3^rd generation gram-negative activity.  The addition of tazobactam has the benefit of widening the spectrum to include some but not all ESBL producers[2].  Maybe the large daily doses of 4.5 g (for cUTI and cIAI) and 9 g (for VABP) will help ensure coverage.  It is a significant improvement over piperacillin / tazobactam [3].

Will it be relegated to a 2^nd line drug or “rescue” drug for intractable PA infections?  It would certainly be a safer drug than colistin or any aminoglycoside, including plazomicin.  Certainly, Cubist does not want a “niche” indication for this drug but rather present us a “PA plus ESBL” profile.

It is difficult to collect sufficient numbers of ESBL patients in a clinical trial program and prove beyond a doubt that ceftolozane/tazobactam is en par with carbapenems.  But to be fair:  not everything can be demonstrated in a registration program.  Once marketed, there will be more studies and we will hear  ‘the rest of the story’.

Other BL/BLI combination will benefit from avibactam’s broader profile with solid ESBL and KPC coverage.  This will not displace ceftolozane/tazobactam as the premier anti-pseudomonas drug but it suggests that the ESBL claim may get hammered by the competition.

Adverse events so far are not a major concern or differentiating factor.  There seem to be more CNS events with ceftolozane than with ceftazidime (headaches, sleep disorders, and possibly infusion site reactions).  Also, there are the odd “pyrexia” cases which pop up occasionally.   At this stage, it remains unclear if these are spurious clusters or, if real, of clinical relevance.

Cubist has submitted the NDA in May 2014 and will get FDA Priority Review.  The drug already has Fast Track and QIDP status.

On Dec. 22, 2014, FDA approved Zerbaxa®, the combination of ceftolozane and tazobactam for the indications cUTI and cIAI.

References:

[1] Shlaes.  Ann. N.Y. Acad. Sci. (2013); 105: 1277
[2] Paterson.  https://www.asid.net.au/documents/item/65
[3] Hong.  Infection and Drug Resistance 2013:6 215