Highlights

Cefiderocol, developed by Japan’s Shionogi & Co., is a new antibiotic in the cephalosporin class that works against aerobic Gram-negative bacteria.

In mid-November 2019, Fetroja (cefiderocol) received FDA approval for the treatment of adult patients with complicated urinary tract infections (cUTI), including pyelonephritis, caused by Gram-negative microorganisms sensitive to this antibiotic (Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Enterobacter cloacae complex) when other therapy options are limited or unavailable. The positive verdict is based on limited data on the safety and efficacy of the drug.

  • Complicated urinary tract infections, being the second leading cause of hospitalization in the elderly after respiratory infections, are characterized by significant morbidity and poor outcomes, especially if the pathogens are resistant to carbapenems. The most frequent causes of cUTI are Escherichia coli (65%) and Klebsiella pneumoniae (8%). In some cases, there is a concomitant bloodstream infection known as urosepsis, with a mortality rate of 9–31%. Among the most common urosepsis pathogens resistant to carbapenems are Pseudomonas aeruginosa (44%), Klebsiella pneumoniae (22%), Enterobacter cloacae (8%), Proteus mirabilis (8%), Stenotrophomonas maltophilia (5%).
  • Yes, several new antibiotics combining beta-lactams with beta-lactamase inhibitors and addressing infections caused by carbapenem-resistant Enterobacteriaceae have recently emerged, but they cannot cope with all resistant pathogens. As a result, “last-resort” antibiotics like colistin are being prescribed much more frequently, even though they are accompanied by very serious toxicity. But bacterial resistance is also beginning to develop.

In late February 2020, Fetroja entered the U.S. market. The wholesale acquisition cost of Fetroja was $1100 per day. It is stated that cefiderocol has taken the position of the only available antibiotic that works in vitro against all Gram-negative pathogens on the WHO prepared list of global priorities for the development of new antibacterial drugs against the most dangerous drug-resistant bacteria.

At the end of April 2020, cefiderocol received marketing authorization in the European Union. The drug, which goes under the brand name Fetcroja (cefiderocol), is approved by the European Medicines Agency (EMA) to treat adult patients with infections caused by aerobic Gram-negative microorganisms when no other therapy options are available — read, after all available antibacterial drugs in the armamentarium have failed.

In September 2020, the FDA expanded the range of indications for Fetroja (cefiderocol). It is approved for the treatment of adult patients with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP) caused by drug-sensitive Gram-negative microorganisms such as Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, Serratia marcescens.

Fetroja (cefiderocol).

 

Problem of Antibiotic Resistance

Carbapenems are broad-spectrum beta-lactam antimicrobials commonly used as last-line therapy for infections caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and nonfermenting multidrug-resistant (MDR) Gram-negative microorganisms. The emergence and spread of carbapenem-resistant Enterobacteriaceae and nonfermenting Gram-negative bacteria like Pseudomonas aeruginosa and Acinetobacter baumannii is becoming a major public health problem worldwide.

None of the new combinations of beta-lactams with beta-lactamase inhibitors — Zerbaxa (ceftolozan + tazobactam), Avycaz/Zavicefta (ceftazidime + avibactam) and Vabomere/Vaborem (meropenem + vaborbactam) — or older drugs like aminoglycosides are not able to counteract Gram-negative bacterial isolates expressing Ambler class B metal-beta-lactamases (IMP, VIM, NDM, SPM, GIM) and are characterized by limited activity in the presence of class D beta-lactamases (OXA). The combination of ceftolozane with tazobactam is also inactive against Enterobacteriaceae and carbapenemase-producing Klebsiella pneumoniae (KPC).

Other antimicrobials for the treatment of infections caused by carbapenem-resistant Gram-negative microorganisms, such as amikacin, colistin, and tigecycline, are associated with toxicity, increased resistance and, in the case of the latter two, primary resistance or reduced activity against certain types of enterobacteria, including Morganella morganii, Proteus spp., Providencia spp., Serratia spp. In addition, tigecycline has primary resistance to Pseudomonas aeruginosa.

This is why there is such a high medical need for new antibiotics against Gram-negative bacteria — with a unique mechanism of action and low susceptibility to developing resistance.

 

Fetroja/Fetcroja: Cefiderocol’s Mechanism of Action

Cefiderocol, a cephalosporin, has a completely new mechanism of penetration through the outer membrane of Gram-negative pathogens, including multidrug-resistant strains.

Cefiderocol is able to bypass all three major mechanisms of resistance to beta-lactam antibiotics, such as mutations of porin channels, overexpression of efflux pumps, and enzymatic inactivation by beta-lactamases.

beta lactam resistance mechanisms - Fetroja/Fetcroja: New Cephalosporin That Bypasses All Antibiotic Resistance

The cefiderocol molecule includes a cephalosporin antibiotic and a catechol moiety. Due to the latter, cefiderocol works as a siderophore: binding to trivalent iron from the extracellular medium, it is actively transported to microorganism cells via bacterial carriers of iron, vital for them. In other words, cefiderocol, penetrating bacteria like a Trojan horse, may not turn to passive diffusion through porine channels.

Cefiderocol is a poor substrate for efflux pumps and therefore retains its activity against Gram-negative pathogens expressing large numbers of efflux pumps that pump antibiotics from the periplasmic space.

cefiderocol structure - Fetroja/Fetcroja: New Cephalosporin That Bypasses All Antibiotic Resistance
The chemical structure of cefiderocol is assembled from key parts of ceftazidime and cefepime, third- and fourth-generation cephalosporin antibiotics, with the addition of a catechol fragment. Drugs. 2019 Feb;79(3):271-289.

In the periplasmic space, cefiderocol works like a conventional beta-lactam antibiotic, destroying the bacterium by binding to penicillin-binding proteins (PBPs) and inhibiting the peptidoglycan synthesis of its cell wall. The side chains of cefiderocol give it both steric and ionic properties to resist all known classes of beta-lactamases (including ESBL, AmpC, and carbapenemases), bacterial enzymes that degrade the beta-lactam antibiotic ring. Clinically, this is reflected by the low minimum inhibitory concentration (MIC) for almost all Gram-negative pathogens: less than 1% of clinical isolates are insensitive to cefiderocol due to multiple factors, including some specific beta-lactamases. Cefiderocol does not work against Gram-positive or anaerobic bacteria.

cefiderocol moa - Fetroja/Fetcroja: New Cephalosporin That Bypasses All Antibiotic Resistance
Mechanism of action of cefiderocol against Gram-negative bacteria. Drugs. 2019 Feb;79(3):271-289.

 

Fetroja/Fetcroja: Efficacy and Safety of Cefiderocol

The APEKS-cUTI (NCT02321800) phase 2 (randomized, double-blind, active-controlled, multicenter, international) clinical trial enrolled adult patients (n=452) hospitalized with complicated urinary tract infection (cUTI), with or without pyelonephritis, or acute uncomplicated pyelonephritis (AUP).

Exclusion criteria included more than two uropathogens, fungal urinary tract infection, and carbapenem-resistant pathogens.

Participants were given intravenously every eight hours for 7–14 days either cefiderocol or a combination of imipenem and cilastatin.

The composite primary endpoint was stated to be the proportion of subjects who showed both clinical cure (elimination or improvement of disease symptoms) and microbiological eradication (pathogen titer in urine culture below 1×104 CFU/mL) after 7 days of therapy.

72.6% (n=183/252) of patients in the cefiderocol group reached the stated endpoint — versus 54.6% (n=65/119) in the control group. The adjusted treatment efficacy difference was 18.58% (95% CI: 8.23–28.92; p=0.0004) in favor of cefiderocol.

To satisfy the criterion that the experimental therapy was as good as the standard therapy, cefiderocol needed to meet the prespecified 15% and 20% margins, respectively, for clinical response and microbiological response. On these two measures, cefiderocol showed superiority over imipinem with cilastatin in clinical response (the difference was 17.25%) but not in microbiological response (2.39%).

apeks cuti results 01 - Fetroja/Fetcroja: New Cephalosporin That Bypasses All Antibiotic Resistance

Negative adverse reactions were experienced by 41% (n=122/300) of patients in the cefiderocol group and 51% (n=76/148) in the control group; most were characterized by mild to moderate severity. The most common adverse events with cefiderocol administration were diarrhea (4%), hypertension (4%), constipation (3%), injection site pain (3%), headache (2%), nausea (2%), cough (2%), vomiting (2%), hypokalemia (2%). Serious adverse reactions were noted in 4.7% (n=14/300) of patients receiving cefiderocol and 8.1% (n=12/148) in the imipinem group with cilastatin. Pseudomembranous colitis caused by Clostridium difficile was reported in one patient in the cefiderocol group and two in the control group.

The CREDIBLE-CR (NCT02714595) phase 3 (randomized, open-label, active-controlled, multicenter, international) clinical trial evaluated how safely and effectively cefiderocole deals with Gram-negative bacterial infections resistant to carbapenems.

Three types of infections were tested, such as hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), or healthcare-associated pneumonia (HCAP); bloodstream infections (BSI) and/or sepsis; and complicated urinary tract infections (cUTI).

Adult patients (n=150) were administered either cefiderocol (with an optional additional antibiotic) or the best available therapy (one, two, or three antibiotics).

carbapenem resistant drug regimen - Fetroja/Fetcroja: New Cephalosporin That Bypasses All Antibiotic Resistance

Administration of cefiderocol resulted in higher rates of clinical cure (66% versus 58%) and microbiological eradication (48% vs. 26%) compared to the control group. However, this is true from a cumulative point of view, whereas the results may vary from case to case.

The regulator’s concern was the increased all-cause mortality in the cefiderocol group at all time points: 14 days, 28 days, 49 days, and completion of the clinical trial.

Meanwhile, neither the side effects of cefiderocol nor its lack of efficacy were found to be directly responsible for the increased mortality rate.

The APEKS-NP (NCT03032380) phase 3 (randomized, double-blind, active-controlled, multicenter, international) clinical trial testing the safety and efficacy of cefiderocol in the treatment of nosocomial pneumonia (HAP, VAP, or HCAP) among adult patients (n=300) found that it performed as well as meropenem in the treatment.

In both groups, linezolid was additionally administered to cover methicillin-resistant Staphylococcus aureus (MRSA) and Gram-positive bacteria (not affected by cefiderocol).

There is no significant difference in mortality, which was not in favor of cefiderocol in the CREDIBLE-CR clinical trial.

credible cr death 06 - Fetroja/Fetcroja: New Cephalosporin That Bypasses All Antibiotic Resistance

 

Extras

Fetroja (cefiderocol). Prescribing information. US. [PDF]

Fetcroja (cefiderocol). Prescribing information. Europe. [PDF]

Cefiderocol. Multi-discipline review. FDA CDER. [PDF]

Cefiderocol. EMA EPAR. [PDF]

Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2018 Dec;18(12):1319-1328. [source]

Structured patient interview to assess clinical outcomes in complicated urinary tract infections in the APEKS-cUTI study: pilot investigation. Ther Adv Infect Dis. 2021 Nov 24;8:20499361211058257. [source]

US Food and Drug Administration (FDA): benefit-risk considerations for cefiderocol (Fetroja). Clin Infect Dis. 2021 Jun 15;72(12):e1103-e1111. [source]

Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis. 2021 Feb;21(2):226-240. [source]

Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2021 Feb;21(2):213-225. [source]

Cefiderocol: a siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant Gram-negative bacilli. Drugs. 2019 Feb;79(3):271-289. [source]

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