Steph’s Note: This week, we welcome back our resident ID expert, Dev Chatterji, PharmD, BCPS, BCIDP. You may remember him from previous tl;dr posts like this one about pneumonia, this one about urinary tract infections, or this one about how to be a successful resident. Here’s back this time to give you all the heads up about the newest antibiotic on the block. (Of course, don’t be shy about reviewing the others here first.) Tell us what we need to know, Dev!

Cefiderocol (Fetroja)

Cefiderocol, a new cephalosporin antibiotic recently FDA-approved in the United States in November 2019, offers an additional treatment option in our armamentarium of agents against antimicrobial resistant pathogens.

The FDA approval coincidentally came right before the Covid-19 pandemic hit, so the agent probably didn’t get as much traction in early 2020. But with its novel mechanism and ability to evade a number of different drug resistance mechanisms, cefiderocol is definitely worth a tl;dr pharmacy post.

Plus, I get to use some cool pictures of a Trojan horse and Greek solider (rationale to be explained later below), so it’s a win-win for everyone!

FDA-Approved Indication

Cefiderocol is approved for treatment of complicated urinary tract infections (cUTIs) caused by susceptible Gram-negative microorganisms.

How Does Cefiderocol Work?

Cefiderocol is a unique cephalosporin in that it functions as a siderophore. Siderophores (from the Greek word for ‘iron carrier”) are small, high-affinity, iron-chelating compounds that are produced by bacteria and fungi to help transport iron across cell membranes. During an infection, the immune system naturally creates an iron-poor environment, which makes bacteria extremely hungry for iron.

Nothing worse than hangry bacteria.

In any case, the bacteria have to come up with mechanisms to help them get as much iron as possible. Since siderophores are among the strongest soluble Fe3+ binding agents known, they are the ideal type of molecule to help the bacteria do this. Siderophores bind to iron molecules, and these combination molecules are then detected and actively transported into the hungry bacterial cell.

One potentially useful pharmacological application of siderophores is to exploit their transportation abilities to carry drugs.

By combining an antibiotic with a siderophore, we sort of trick the bacteria into taking the antibiotic into the cell since the bacteria believes these siderophores are bound to iron. This approach has been coined the ‘Trojan Horse’ strategy.

Analogous to Greek mythology where Greek soldiers hid inside Trojan horses for a ‘surprise attack’, the siderophore is smuggling the antibiotic into the bacterial cell—very sneaky!

This leads to high intracellular antibiotic concentrations that would otherwise not occur. It also allows the antibiotic to bypass a number of different resistance mechanisms designed to halt entry into the cell. Once inside the cell, similar to other cephalosporins, cefiderocol exhibits bactericidal action via inhibition of cell wall synthesis through binding to penicillin-binding proteins (PBPs).

Lastly, to throw some good ole ‘med chem’ in there…below is the structure of the compound. For those of you ‘med chem’ nerds, you’ll notice that the cephalosporin side of this compound is painstakingly similar to ceftazidime (with a sprinkle of cefepime thrown in there), and then a siderophore side chain is added to the mix.

Spectrum of Cefiderocol’s Activity

Cefiderocol is active against aerobic Gram-negative bacteria only. It has no activity against Gram-positive or anaerobic bacteria.

Gram-negative activity both in vitro and in clinical infections includes:

Enterobacteriales
- E. coli
- Klebsiella spp.
- Proteus mirabilis
Pseudomonas aeruginosa

Gram-negative activity demonstrated in vitro (with unknown clinical significance) includes:

Stenotrophomonas maltophilia
Acinetobacter baumannii
Citrobacter freundii complex
Citrobacter koseri
Klebsiella aerogenes, Klebsiella oxytoca
Morganella morganii
Proteus vulgaris
Providencia rettgeri
Serratia marcescens

As mentioned earlier, the ‘sneak attack’ mechanism allows cefiderocol to bypass a number of different mechanisms designed to halt entry into the cell. It can overcome the 3 main mechanisms of beta lactam resistance:

Porin channel mutations, decreased porin channels
1. Cefiderocol overcomes the porin channel mechanism of resistance by using the iron transport function of the cell to gain entry and bypass the porin channel.
2. However, cefiderocol can also enter the cells using porin channels despite the mutations that may exist.
Production of β-lactamases
1. Cefiderocol is stable against β-lactamase degradation. The side chains (specifically C3 and C7) provide this stability.
2. As shown in the table below, it has demonstrated in vitro stability against all 4 classes of clinically significant β-lactamases.
Efflux pumps
1. Increased expression of efflux pumps removes β-lactams and other antibiotics from the periplasmic space.
2. Cefiderocol is a poor substrate for these efflux pumps and therefore retains its activity in pathogens that express higher numbers of efflux pumps.

Summary of the resistance mechanisms cefiderocol has demonstrated activity against:

Notable Adverse Effects of Cefiderocol

Similar to other β-lactams, cefiderocol seems to be a well-tolerated medication overall.

Adverse effects listed in the package insert with an incidence > 2%:
- Candidiasis
- Constipation
- Cough
- Diarrhea
- Headache
- Hypokalemia
- Infusion site reactions
- Increased AST/ALT
- Nausea
- Rash
- Vomiting

Also, importantly, cefiderocol does not have any clinically significant drug interactions with cytochrome P450. It also doesn’t have any drug transport-mediated drug-drug interactions. Now THAT’S a pharmacy win!

Cefiderocol’s Current Place in Therapy

Cefiderocol is the newest kid on the block as far as treatment options for multi drug resistant (MDR) Gram-negative pathogens. Its novel mechanism (which is a super cool concept in the field of drug delivery, by the way) and microbiological activity profile make it a promising therapeutic option. It is the first antibiotic conferring in vitro stability against all 4 classes of beta-lactamases, including metallo-carbapenamases such as NDM-1.

Although the drug looks fantastic on paper, results from clinical studies have been variable and bring to question its true place in therapy at the moment…

The cUTI trial that secured cefiderocol’s FDA indication can be found here. This study demonstrated that, in hospitalized patients with multiple comorbidities and difficult-to-treat UTIs, cefiderocol was non-inferior to a standard-of-care antibiotic comparator, imipenem/cilastatin. Although the study was only designed to demonstrate non-inferiority, the findings of a post-hoc analysis were consistent with superiority.

As you would expect, the most common Gram-negative pathogens identified in the patients were E.coli (60-64%) and K. pneumoniae (18-21%). To solidify the drug’s role in treating MDR pathogens, it is reassuring that 28-30% of the isolates were producers of Extended Spectrum Beta Lactamases (ESBLs). While the post hoc analysis did demonstrate superiority of cefiderocol in this UTI trial, this is not exactly the ‘big ticket’ data I was looking for when first learning about this drug.

Nonetheless, this trial basically got the drug FDA-approved and assured its safety and efficacy. So there’s that.

A couple of studies with results that have not been published but were presented to the FDA as part of the drug approval process are the CREDIBLE-CR (NCT02714595) and the APEKS-NP (NCT03032380) trials. These trials better paint the more likely picture of the agent’s eventual place in therapy.

The CREDIBLE-CR study was a randomized, open-label study to assess the efficacy and safety of cefiderocol and best available therapy (BAT) in patients with carbapenem-resistant Gram-negative bacterial infections. Unlike most antibiotic clinical trials, this study was not limited to a single infection site, but rather it included multiple infection sites as long as there was evidence of carbapenem resistance.
While clinical cure rates were comparable between the groups overall as well each individual disease state (HAP/VAP, bloodstream infections, cUTIs), all cause mortality was numerically higher in the cefiderocol group. This was obviously concerning and led to a notation in the package insert under the Warnings and Precautions section. A third party blinded committee reviewed the deaths, and none could be traced back to a single factor…so I think looking more closely at the detailed patient level information should be considered.
APEKS-NP is a phase III, double-blind, randomized, active-controlled, non-inferiority trial of cefiderocol for the treatment of HAP, VAP, or HCAP caused by Gram-negative pathogens. Patients were randomized to cefiderocol 2 g every 8 h or meropenem 2 g every 8 h, both as a 3-hour infusion. Both arms received linezolid for Gram-positive coverage.
Cefiderocol was non-inferior with respect to all cause mortality compared to meropenem at day 14. So this data does increase our confidence and excitement that promising aspects of the drug seen pre-clinically may translate over to the clinical setting. But as usually holds true, we always need more data to make a strong conclusion.

There are other case reports of cefiderocol being used for real word clinical situations, as well as a number of on-going phase III trials underway, including studies in the pediatric population.

The tl;dr of Cefiderocol

So as we await the results of these data, I think the place in therapy for cefiderocol, at least the tl;dr version of it, is as such:

Cefiderocol is definitely an important agent to have in our armamentarium of agents due to its ability to avoid all three major resistance mechanisms of β-lactam resistance, its relatively minimal adverse effect profile, and its low risk of drug-drug interactions.
Given some of the unknowns from a clinical efficacy standpoint and some of the concerns raised in the CREDIBLE-CR study, we really can’t put cefiderocol in the same category as some of our other novel β-lactams such as ceftazidime/avibactam, ceftolozane/tazobactam, etc. I think these agents should be given preference over cefiderocol at the moment.
Reserve cefiderocol for patients with MDR Gram-negative infections with limited or no other treatment options:
- Known resistance to other novel β-lactams or where those agents are suboptimal options.
- Infections due to NDM-1 carbapenemases.

And there you have it! The “what you should know” about this new cephalosporin antibiotic.

New FDA Approval: Fetroja