New Antimicrobial approval: cefiderocol (Fetroja).

BONUS QUESTION: Why is it called Fetroja?

This unique cephalosporin antibiotic utilizes Fe-siderophores to gain access to the cell. Access is between the inner and outer membrane. This explains the weak activity against Gram Positive bacteria (as well as anaerobes). This agent has good in vitro activity against Enterobacteraciae (ESBL and CRE), Pseudomonas, Acinetobacter and Stenotrophomonas.

How cefiderocol works:

The data where presented to the FDA and the agent was approved for complicated UTI.

Study 1: Approval study, published in Lancet ID 2018;18(12):1319-1328 study of comparing cefiderocol to imipenem-cilastin for the treatment of complicated UTI. This was a non-inferiority trial. Composite outcome of microbiologic cure and clinical cure at test for cure. 448 patients randomized. Primary endpoint was achieved in 73% of the cefiderocol vs 56% imipenem. For microbiologic cure 73% cefiderocol vs 56% imipenem. Clinic cure was similar at 90% cefiderocol vs 87% imipenem. Conclusion was that cefiderocol was superior to imipenem (not exactly sure on that one since driven by microbiologic cure and we do not get test of cure).

Study 2: No data, just mortality data.  CREDIBLE-CR: various drug resistant gram negative infections (HAP, VAP, Bacteremia) and compared cefiderocol to Best Available Therapy (CREDIBLE-CR study). Not much data on this study, other than the all-cause mortality was higher for cefiderocol vs BAT (mostly colistin based). For infection related mortality the organisms associated with mortality were Pseudomonas, Acinetobacter and Stenotrophomonas.

Study 3: Again not much data.  APEKS-NP Study looked at HAP/VAP and compared cefiderocol to meropenem. In the intent to treat group mortality at 14 days (12.8% v 11.4%)  and 28 days (21.2% v 20%) was similar for cefiderocol and meropenem. No other data is available.

My Take Home on this drug:

So this is another new antibacterial that has in vitro activity against drug resistant Enterobacteriaciae, Pseudomonas, Acientobacter and Stenotrophonomas. Clinically it seems that this agent has some issues with Acientobacter, Pseudomonas and Stenotrophomonas (unclear if drug resistant or susceptible) and I would not use for these organisms until more solid and published data. It works for cUTI and possible for HAP/VAP. I think this again adds to are armamentarium to fight gram negative bacteria, especially drug resistant. As with the other agents it is far from perfect, the studies are far from perfect and there may be many holes. What I like about this agent is the unique mechanism of entry into cells.

Interesting statement by the FDA advisory committee: “I thought the cUTI study was well-designed, and I did not think those data should be negated by the [CREDIBLE-CR] study, given its design and given the unmet need for treating these infections; I was also reassured by the [APEKS-NP] data,”