It was another dull and dreary afternoon giving advice when an excited Dermatologist phoned about a patient with funny skin lumps. (Microbiologists get excited about bugs, Dermatologists get excited about rashes, so lumps and bumps together… what can I say…we were very excited!!)
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Their patient was a keen gardener who had been clearing a large number of blackthorn trees (good for making sloe gin) and despite wearing thick gloves had managed to get pricked and scratched all the way up their arms. At the site of one of those puncture wounds they had developed a small red lump which had eventually turned into a small ulcer. The ulcer hadn’t got much better and over the next few weeks the patient had noticed a number of other lumps appearing up their arm and then hard swellings in their armpit.

I was recently asked about antibiotics to treat a difficult infection caused by an extremely resistant Gram-negative bacterium and so I thought it was time to go back and look at what antibiotics are being developed for these situations. One antibiotic caught my eye, Cefiderocol, and I thought I ought to read more about it and see why it might be useful in the future.
 
What is Cefiderocol?
Cefiderocol is a cephalosporin antibiotic currently in clinical trials. It is a hybrid of Ceftazidime and a siderophore side chain… but what the heck does that mean and why does this matter?
 
A siderophore, from the Greek for “iron carrier”, is a small molecule produced by bacteria to help them scavenge iron from their environment. Iron is essential for bacteria, they cannot survive without it, and so they have come up with mechanisms like siderophores to help them get as much iron as possible. Siderophores bind to iron molecules and these combined molecules are then detected and actively transported into the bacterial cell; it’s like the iron needs a ticket to get in and the siderophore is the ticket.

​By combining an antibiotic with a siderophore the bacterium can be tricked into actively taking the antibiotic into the it’s cell, a process Microbiologists have termed a “Trojan horse” strategy (remember in Greek mythology Greek warriors hid in a wooden horse that was taken into the city of Troy as a “gift” and then the Greeks snuck out at night, opened the gates and sacked the city). The siderophore is “hiding” the antibiotic allowing it to be taken into the bacterial cell where it can damage the bacterium. This clever strategy leads to much higher intracellular antibiotic concentration than would occur without the siderophore and cunningly it bypasses mechanisms of resistance that might stop the antibiotic from entering as well… very clever!
 
Laboratory studies
Cefiderocol is very active against Gram-negative bacteria such as the enterobacteriales (previously called the enterobacteriaceae) E. coli and Klebsiella spp. as well as Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Acinetobacter baumannii including strains that showed resistance to the carbapenem antibiotics such as Meropenem and Imipenem.
 
It seems that the siderophore side chain also provides 10-100x more stability against breakdown by carbapenemases of Ambler classes A, B and D than for Ceftazidime without the siderophore, including those from the “big five” such as KPC, VIM, IMP, NDM and OXA. Cefiderocol is usually active (reported to be about 99%) against these bacteria but that’s not 100% and it doesn’t seem to be entirely predictable but remember no antibiotic is 100% reliable.
 
Recent studies have also shown potential for Cefiderocol in the treatment of AmpC producing Gram-negative bacteria. The siderophore seems to give a low affinity for AmpC enzymes as well as a low risk of inducing the production of AmpC in bacteria that have the ability, but do not always have the ability switched on, such as P. aeruginosa and Enterobacter cloacae. Over production of AmpC when combined with a loss of a porin (hole) in the cell membrane of Gram-negative bacteria can lead to carbapenem resistance so having less ability to induce AmpC and bypassing the porin as a way to get into the cell seems like a pretty good strategy for getting around this mechanism of carbapenem resistance as well.
 
Clinical studies
In clinical studies Cefiderocol was shown to be well tolerated at doses of 2g TDS intravenously; unfortunately there is no oral version of this antibiotic but then there is no oral version of Ceftazidime on its own either. Like other Cephalosporins it is mainly eliminated by renal excretion.
 
There is an on-going Phase 3 clinical trial using Cefiderocol openly to treat serious infections caused by carbapenem resistant Gram-negative bacteria and another randomised and blinded study comparing against Meropenem in the treatment of hospital or ventilator associated pneumonia with Gram-negative bacteria. Many of us are waiting to see how these go and hoping that Cefiderocol will “pass” these tests with shining colours!
 
Tissue penetration
Cefiderocol at 2g TDS IV has been shown to give good serum levels with a maximum concentration of 140mg/L. The serum half-life is about 2 hours.
 
Cefiderocol is 60-70% excreted unchanged via the kidneys and so has excellent levels in urine.
 
In studies looking at the ability of Cefiderocol to treat pneumonia it has been shown that bronchoalveolar fluid concentrations are about 10% of serum concentrations (maximum 14mg/L) with the same half-life.
 
Most bacterial MICs for Cefiderocol are <2mg/L so these pharmokinetic and pharmacodynamic studies show that Cefiderocol should be good at treating systemic, urinary tract and pulmonary infections.
 
Cefiderocol resistance
Cefiderocol resistance has unfortunately already been seen in laboratory studies, especially with P. aeruginosa isolates. It is not common and so far >99% of isolates are sensitive, but it is worrying none-the-less as this antibiotic hasn’t yet been used widely and resistance already occurs. The mechanism of Cefiderocol resistance isn’t completely understood but is thought to be due to mutation in the siderophore transport mechanism (no longer accepting wooden horses as gifts!) in combination with other mechanisms that traditionally give resistance to Ceftazidime when it is used in its normal form e.g. mutation of the penicillin-binding protein to which Ceftazidime normally binds.
 
Cefiderocol won’t be the only answer to all of our antibiotic problems. Resistance will develop; it’s inevitable, as bacteria evolve to overcome the next challenge for their survival. In addition, Cefiderocol is only active against Gram-negative bacteria so is no use against the Gram-positives such as Staphylococcus aureus or Enterococcus spp. and let’s not mention the increasing “popularity” of beta-lactam allergy; Cefiderocol is a beta-lactam and so if you are allergic then you won’t be able to have it anyway!
 
Having said all of that I am still excited about the possibilities of Cefiderocol, we need more anti-Gram-negative antibiotics and this one seems to have promise. Let’s see what happens in the clinical trials…
 
Another word of caution
Whilst I may want to get hysterical about the potential value of Cefiderocol it is important to note that all of the primary research into Cefiderocol so far has been done by Shionogi & Co. Ltd from Japan, who is the producer of Cefiderocol! Now this is the way it will be at first as it is their drug and they won’t want to disclose trade secrets but it does mean we’ll have to wait for further, more open and robust, clinical trials and experience of its use by those without potential conflicts of interest before we finally yell “hooray for Cefiderocol”… but fingers crossed this won’t be long.

Last weekend the Nuts & Bolts team (except cats!) went to the cinema to watch the new film about the early life of J.R.R Tolkien. I have been a fan of Tolkien since reading The Hobbit at the age of 5 years old and The Lord of the Rings when I was 6… okay this is early to read this book; I didn’t understand much of the dark bits but I was captured by the heroic story and have read it again many times since… the ECIC cannot understand this, she thinks it’s weird to read a book when you already know how it’s going to end… maybe she’s right, but that won’t stop me, where did I leave my copy, or my second copy or that third copy or…
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Surely you can’t connect Tolkien with microbiology!? Read on to find out more…

​Tolkien enlisted in the Lancashire Fusiliers and was sent to the Western Front in June 1916 to join the Somme offensive. He was assigned as a Lieutenant in the signal corps and put in charge of enlisted men; there is a great quote from him, "the most improper job of any man... is bossing other men, …not one in a million is fit for it, and least of all those who seek the opportunity”… a sentiment I share.