IDWeek 2024 Review: Shionogi's Antibiotic for Use in Adults with Certain Gram-negative Bacterial Infections
Sponsored by Shionogi Inc.
Disclaimers
- Real-world evidence is intended to complement data from randomized clinical trials. Observational retrospective analyses are not intended for direct comparison with clinical trials.
- In vitro activity does not necessarily correlate with clinical efficacy.
Introduction
At the IDWeek 2024 annual meeting, several posters and an oral presentation highlighted studies that explored the activity of the siderophore cephalosporin, cefiderocol, against various treatment-resistant Gram-negative infections1 caused by bacteria such as carbapenem-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii.2,3 Carbapenems are antibiotic agents commonly used for treatment of serious bacterial infections; however, resistance to these drugs continues to increase globally.4 This is a serious concern, as infections that involve carbapenem-resistant Gram-negative bacteria have a high mortality rate.5 Globally, antimicrobial resistance caused an estimated 1.14 million deaths in 2021.6 If not addressed, it could lead to more than 39 million deaths over the next 25 years. This highlights the need for antibiotic agents, such as cefiderocol.2,7-11 Cefiderocol’s unique mechanism of cell entry, in vitro activity against a broad range of Gram-negative bacteria, preclinical data, clinical efficacy and safety data establish it as an important treatment option for patients with or at risk of a carbapenem-resistant Gram-negative bacteria.12-14
The antibacterial properties of cefiderocol are based on its ability to overcome three major mechanisms of resistance.11,15-18 It enters cells via active transport through iron channels as well as passively through porin channels.11,19,20 It has stability against all classes of beta-lactamases and maintains activity despite efflux pump up-regulation.8,11,18
This review highlights key findings from cefiderocol studies presented at IDWeek last year, with a focus on the PROVE Chart Review Study.
Cefiderocol for Serious Gram-Negative Bacterial Infections: The PROVE Chart Review Study
PROVE is an international, multicenter, retrospective medical chart review study that was designed to evaluate real-world outcomes for patients with Gram-negative bacterial infections treated with cefiderocol for the first time.14 Criteria for patient charts included documented use of cefiderocol for at least 72 hours, cefiderocol starting dose, description of the Gram-negative bacterial infection, and discharge data following hospitalization.14
Patient Characteristics
This study enrolled seriously ill, hospitalized patients (1075 in total). The majority (56.6%) of patients were in the intensive care unit at the time of cefiderocol initiation and had a median age of 60. The study aimed to capture a broad, real-world patient population, reflecting a diversity of infection types and sites, disease severity, and geographic locations.14 The most common infection was respiratory tract infection (RTI; 53.1%), followed by a skin and skin structure infection (SSSI; 12.6%), urinary tract infection (UTI; 10.6%), bloodstream infection (BSI; 10.0%), intra-abdominal infection (IAI; 6.2%), bone and joint infection (BJI; 5.0%), and other (2.4%).14 Of note, while multiple infection sites were evaluated as part of the PROVE study, in the US, cefiderocol is indicated only in patients 18 years of age or older for the treatment of hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia (HABP/VABP), and complicated urinary tract infections (cUTIs) caused by certain susceptible Gram-negative microorganisms.11
In the PROVE study, most participants had infections caused by bacteria included in the World Health Organization’s list of priority pathogens.21 The most common Gram-negative pathogens in monomicrobial infections were P. aeruginosa (35.9%), A. baumannii (18.1%), Enterobacterales (13.1%), and S. maltophilia (5.9%). Approximately one-quarter (25.2%) of the infections were caused by multiple Gram-negative pathogens.14 Of the patients, 74.6% experienced resistance to carbapenems, 56.6% received cefiderocol in the intensive care unit, 38.5% required mechanical ventilation, and 25.3% received vasopressor support.14 Secondary bacteremia was present in 11.0% of patients.14 Most patients (61.8%) had not had a previous infection or colonization, whereas 15.5% had experienced previous colonization and 8.6% had experienced previous infection.14 Comorbidities present in more than 10% of patients included chronic pulmonary disease (20.4%), uncomplicated diabetes (18.5%), COVID-19 (17.0%), moderate-severe renal disease (16.9%), congestive heart failure (14.0%), and diabetes with end-organ damage (11.5%).14
Cefiderocol Treatment
The patients received cefiderocol for a median duration of 11 days (IQR 7-16) and 33.9% of the patients received combination therapy.14 As reported by the investigator, the reason for cefiderocol use was most frequently due to a documented infection (71.2%), followed by salvage (15.0%), empiric (11.3%), and other/unknown (2.5%).14
Efficacy and Safety Outcomes
Of the patients included in the analysis (n = 1075), 75.1% had a favorable clinical response to cefiderocol at the end of treatment (defined as resolution or improvement of signs and symptoms as judged by the physician, excluding deaths while on therapy).14 Clinical response rates were 71.6% in patients with RTI (n = 571) and 91.2% in patients with UTIs (n = 114).14 Of the 1,075 patients, the rate of 30-day all-cause mortality (ACM) was 23.3%.14 There were 29 adverse drug reactions (ADRs) across 25 patients, including three serious ADRs.14 Thirteen patients discontinued treatment with cefiderocol due to adverse drug reactions.14
Overall, by including different infection sites and pathogens, the study provided comprehensive insights into the effectiveness of cefiderocol across diverse patient populations, infection sites, and types of difficult-to-treat bacteria.14 This real-world evidence complements and builds upon existing clinical trial data, providing a better understanding of responses to cefiderocol and may help instill confidence regarding cefiderocol efficacy in these environments.14,22 In conclusion, the PROVE study results further support cefiderocol as a treatment option for patients with difficult-to-treat Gram-negative bacterial infections.14
Cefiderocol Against Multidrug-Resistant P. aeruginosa and Enterobacterales Isolates
Novel β-lactam/β-lactamase inhibitor (BL/BLI) combinations have been used to treat infections caused by both carbapenem-resistant Enterobacterales and multidrug-resistant P. aeruginosa.23,24 However, cross-resistance has emerged among these combinations.23,24 Cross-resistance occurs when bacteria are resistant to multiple distinct antibiotics through the same mechanism(s); and it can further limit treatment options for multidrug-resistant bacteria.25,26 Cefiderocol showed in vitro activity against Enterobacterales and P. aeruginosa that are resistant to carbapenem and BL/BLI combinations in the outcomes from two additional studies presented at IDWeek 2024.23,24
Cefiderocol Against Resistant Bacteria Producing Metallo-β-Lactamases
Certain bacteria, such as isolates of P. aeruginosa and Enterobacterales, produce metallo-β-lactamases (MBLs), which can inactivate most antibiotics.2,3,27 Cefiderocol has showed stability against MBLs.11,28 Findings from two other studies presented at IDWeek 2024 showed that cefiderocol exhibited potent activity against carbapenem non-susceptible isolates of P. aeruginosa and Enterobacterales, including those with MBL genes.2,3 These data support cefiderocol as a treatment option for infections caused by P. aeruginosa and Enterobacterales isolates carrying MBL genes.1,2
Conclusions
The outcomes of the studies presented at IDWeek 2024 demonstrated that cefiderocol may play an important role in treating various carbapenem-resistant Gram-negative bacterial infections.2,14,23,24 In real-world settings, cefiderocol demonstrated efficacy and safety in treatment for carbapenem-resistant Gram-negative bacterial infections among patients who were critically ill.14 Cefiderocol has shown activity against Enterobacterales and P. aeruginosa that are resistant to carbapenem and BL/BLI combinations, including bacteria that carry MBL genes.2,23,24 Cefiderocol may help address the need for additional antibiotic treatment options, which is critical as certain difficult-to-treat bacteria are becoming more prevalent around the world.29
INDICATIONS
Fetroja® (cefiderocol) is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex.
Fetroja is indicated in patients 18 years of age or older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens.
USAGE
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Fetroja and other antibacterial drugs, Fetroja should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
Fetroja is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of Fetroja.
WARNINGS AND PRECAUTIONS
Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections
An increase in 28-Day all-cause mortality was observed in Fetroja-treated nosocomial pneumonia, bloodstream infections, or sepsis patients compared to those treated with best available therapy (BAT) in a clinical study (NCT02714595). Most BAT regimens contained colistin. All-cause mortality remained higher in patients treated with Fetroja than in patients treated with BAT through Day 49.
Generally, deaths were in patients with infections caused by Gram-negative organisms, including non-fermenters such as Acinetobacter baumannii complex, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established.
Closely monitor the clinical response to therapy in patients with cUTI and HABP/VABP.
Hypersensitivity Reactions
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Hypersensitivity was observed with Fetroja. Before Fetroja is instituted, inquire about previous hypersensitivity to cephalosporins, penicillins, or other beta-lactam drugs. If an allergic reaction occurs, discontinue Fetroja.
Clostridioides difficile-associated Diarrhea (CDAD)
CDAD has been reported with nearly all systemic antibacterial agents, including Fetroja. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued.
Seizures and Other Central Nervous System (CNS) Adverse Reactions
Cephalosporins, including Fetroja, have been implicated in triggering CNS adverse reactions such as seizures. Encephalopathy, coma, asterixis, and neuromuscular excitability have been reported with cephalosporins particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment. Adjust Fetroja dosing based on creatinine clearance. If focal tremors or seizures occur, evaluate patients to determine whether Fetroja should be discontinued.
Development of Drug-Resistant Bacteria
Prescribing Fetroja in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
ADVERSE REACTIONS
The most common adverse reactions occurring in ≥2% of patients receiving Fetroja in the cUTI trial were: diarrhea (4%), infusion site reactions (4%), constipation (3%), rash (3%), candidiasis (2%), cough (2%), elevations in liver tests (2%), headache (2%), hypokalemia (2%), nausea (2%), and vomiting (2%). The most common adverse reactions occurring in ≥4% of patients receiving Fetroja in the HABP/VABP trial were: elevations in liver tests (16%), hypokalemia (11%), diarrhea (9%), hypomagnesemia (5%), and atrial fibrillation (5%).
Please click here for Full U.S. Prescribing Information for Fetroja® (cefiderocol).
References
1. IDWeek 2024: Shionogi presents largest global real-world evidence study of cefiderocol demonstrating strong clinical response rates across seriously ill patients. Shionogi Press Release. Published October 16, 2024. Accessed November 27, 2024. https://www.shionogi.com/us/en/news/2024/10/idweek-2024-shionogi-presents-largest-global-real-world-evidence-study-of-cefiderocol-demonstrating-strong-clinical-response-rates-across-seriously-ill-patients.html.
2. Mendes RE, Kimbrough JH, Beekman D, et al. Cefiderocol activity against clinical Enterobacterales isolates carrying metallo-β-lactamase genes in United States and European hospitals (2020-2023). Poster 1363. Presented at: IDWeek 2024, Los Angeles, CA: October 16-19, 2024.
3. Mendes RE, Beekman D, Karr M, Kimbrough JH, Sader HS, Castanheira M. Cefiderocol Activity against Pseudomonas aeruginosa Clinical Isolates Carrying Metallo-β-lactamase Genes in United States and European Hospitals (2020–2023). Poster 1364. Presented at: IDWeek 2024, Los Angeles, CA: October 16-19, 2024.
4. Papp-Wallace KM, Endimiani A, Taracila MA, Bonomo RA. Carbapenems: past, present, and future. Antimicrob Agents Chemother. 2011 Nov;55(11):4943-60. doi:10.1128/AAC.00296-11.
5. Perez F, Van Duin D. Carbapenem-resistant Enterobacteriaceae: a menace to our most vulnerable patients. Cleve Clin J Med. 2013 Apr; 80(4):225-233. doi:10.3949/ccjm.80a.12182.
6. Naghavi M, Vollset SE, Ikuta KS, et al. Global burden of bacterial antimicrobial resistance 1990-2021: a systematic analysis with forecasts to 2050. Lancet. 2024 Sept 28;404(10459):1199-1226. doi:10.1016/S0140-6736(24)01867-1.
7. Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 2022 Feb 12; 399: 629–655.
8. Ito A, Sato T, Ota M, et al. In vitro antibacterial properties of cefiderocol, a novel siderophore cephalosporin, against Gram-negative bacteria. Antimicrob Agents Chemother. 2018 Jan;62(1):e01454-17.
9. Kazmierczak KM, Tsuji M, Wise MG, et al. In vitro activity of cefiderocol, a siderophore cephalosporin, against a recent collection of clinically relevant carbapenem-non-susceptible Gram-negative bacilli, including serine carbapenemase- and metallo-ϐ-lactamase-producing isolates (SIDERO-WT-2014 Study). Int J Antimicrob Agents. 2019 Feb;53(2):177-184.
10. Sheu C-C, Chang Y-T, Lin S-Y, et al. Infections caused by carbapenem-resistant Enterobacteriaceae: an update on therapeutic options. Front Microbiol. 2019 Jan 30;10:80. doi:10.3389/fmicb.2019.00080.
11. Fetroja (cefiderocol) [prescribing information]. Shionogi Inc. Accessed January 13, 2025. https://www.shionogi.com/content/dam/shionogi/si/products/pdf/fetroja.pdf.
12. Karlowsky JA, Hackel MA, Takemura M, Yamano Y, Echols R, Sahm DF. In Vitro Susceptibility of Gram-Negative Pathogens to Cefiderocol in Five Consecutive Annual Multinational SIDERO-WT Surveillance Studies, 2014 to 2019 [published correction appears in Antimicrob Agents Chemother. 2023 Jun 15;67(6):e0042723. doi:10.1128/aac.00427-23]. Antimicrob Agents Chemother. 2022 Feb 15;66(2):e0199021. doi:10.1128/AAC.01990-21.
13. Shortridge D, Streit JM, Mendes R, Castanheira M. In Vitro Activity of Cefiderocol against U.S. and European Gram-Negative Clinical Isolates Collected in 2020 as Part of the SENTRY Antimicrobial Surveillance Program. Microbiol Spectr. 2022 Apr 27;10(2):e0271221. doi:10.1128/spectrum.02712-21.
14. Clancy CJ, Cornely OA, Slover CM, et al. Real-world effectiveness and safety of cefiderocol in the treatment of patients with serious Gram-negative bacterial infections: results of the PROVE chart review study. Poster 1475. Presented at: IDWeek 2024, Los Angeles, CA: October 16-19, 2024.
15. Davies TA, Queenan AM, Morrow BJ, et al. Longitudinal survey of carbapenem resistance and resistance mechanisms in Enterobacteriaceae and non-fermenters from the USA in 2007–09. J Antimicrob Chemother. 2011 Oct;66(10):2298-2307.
16. Perez F, Hujer AM, Hujer KM, Decker BK, Rather PN, Bonomo RA. Global challenge of multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2007 Oct;51(10):3471-3484.
17. Rodríguez-Martínez J-M, Poirel L, Nordmann P. Molecular epidemiology and mechanisms of carbapenem resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2009 Nov;53(11):4783-4788.
18. Iregui A, Khan Z, Landman D, Quale J. Activity of cefiderocol against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii endemic to medical centers in New York City. Microb Drug Resist. 2020 Jul;26(7):722-726.
19. Zhanel GG, Golden AR, Zelenitsky S, et al. Cefiderocol: a siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant Gram-negative bacilli. Drugs. 2019 Feb;79(3):271-289.
20. Ito A, Nishikawa T, Matsumoto S, et al. Siderophore cephalosporin cefiderocol utilizes ferric iron transporter systems for antibacterial activity against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2016 Nov 21;60(12):7396-7401.
21. WHO Bacterial Priority Pathogens List, 2024. World Health Organization. Accessed January 13, 2025. https://iris.who.int/bitstream/handle/10665/376776/9789240093461-eng.pdf?sequence=1.
22. Williams DM, Evans M. The evolution of real-world evidence in healthcare decision making. Expert Opin Drug Saf. 2023 Jan-Jun;22(6):443-445. doi:10.1080/14740338.2023.2224559.
23. DeJonge BL, Nguyen ST, Bryowsky JJ, et al. Cefiderocol retains in vitro activity against Enterobacterales non-susceptible to β-lactam–β-lactamase inhibitor combinations. Oral presentation #513. Presented at: IDWeek 2024, Los Angeles, CA: October 16-19, 2024.
24. Nguyen ST, DeJonge BL, Bryowsky JJ, et al. Evaluation of phenotypic cross-resistance between cefiderocol and β-lactam/β-lactamase inhibitor combinations against Pseudomonas aeruginosa isolates from US medical centers. Poster 1530. Presented at: IDWeek 2024, Los Angeles, CA: October 16-19, 2024.
25. Colclough A, Corander J, Sheppard SK, Bayliss SC, Vos M. Patterns of cross-resistance and collateral sensitivity between clinical antibiotics and natural antimicrobials. Evol Appl. 2019 Jan 28;12(5):878-887. doi:10.1111/eva.12762.
26. Anderson M, Panteli D, van Kessel R, Ljungqvist G, Colombo F, Mossialos E. Challenges and opportunities for incentivising antibiotic research and development in Europe. Lancet Reg Health Eur. 2023 July 26;33:100705. doi:10.1016/j.lanepe.2023.100705.
27. Timsit JF, Paul M, Shields RK, et al. Cefiderocol for the Treatment of Infections Due to Metallo-B-lactamase-Producing Pathogens in the CREDIBLE-CR and APEKS-NP Phase 3 Randomized Studies. Clin Infect Dis. 2022 Sep 29;75(6):1081-1084. doi:10.1093/cid/ciac078.
28. Ito-Horiyama T, et al. Stability of novel siderophore cephalosporin S-649266 against clinically relevant carbapenemases. Antimicrob Agents Chemother. 2016 Jun 20;60(7):4384-4386. doi:10.1128/AAC.03098-15.
29. Domingues S, Lima T, Saavedra MJ, Da Silva GJ. An overview of cefiderocol’s therapeutic potential and underlying resistance mechanisms. Life (Basel). 2023 Jun 21;13(7):1427. doi:10.3390/life13071427.
