Written by Daylin Barranco, Pharm.D. Candidate, Class of 2021, Palm Beach Atlantic University Gregory School of Pharmacy
and
Elias B. Chahine, Pharm.D., FCCP, FASCP, FFSHP, BCPS, BCIDP, Professor of Pharmacy Practice, Palm Beach Atlantic University Gregory School of Pharmacy

Reviewed by Monica V. Mahoney, Pharm.D., BCPS-AQ ID, BCIDP, Clinical Pharmacy Specialist, Infectious Diseases, Outpatient ID/OPAT Clinics

Background: Antimicrobial resistance is one of the biggest threats to global health.1 The WHO has identified carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Pseudomonas aeruginosa (CRPA), and carbapenem-resistant Enterobacteriaceae (CRE) as well as extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae as critical priority pathogens for which new antibiotics are urgently needed.¹ Similarly, the CDC has identified CRPA and CRE as posing urgent threats and ESBL-producing Enterobacteriaceae and multidrug-resistant (MDR) P. aeruginosa as posing serious threats in the United States.² Cefiderocol (Fetroja) is a novel antibiotic with activity against a broad range of gram-negative organisms, including CRAB, CRPA, MDR P. aeruginosa, ESBL-producing Enterobacteriaceae, and CRE.³ Cefiderocol is stable in vitro in the presence of both serine β-lactamases such as CTX-M, KPC, and OXA and metallo-β-lactamases such as IMP, NDM, and VIM.³ Cefiderocol is FDA approved for adults who have limited or no alternative treatment options for complicated UTIs (cUTIs), including pyelonephritis caused by the following gram-negative organisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae complex, and P. aeruginosa.⁴

Clinical Trials: Several clinical trials have assessed the efficacy and safety of cefiderocol for the treatment of various infections.^5-10 Table 1 summarizes the results of these trials.^4,6,7,9

The APEKS-cUTI was a phase II, multicenter, randomized, double-blind, noninferiority study comparing cefiderocol with imipenem/cilastatin for the treatment of adults with cUTIs, including pyelonephritis.^4-7 Participants were randomized to receive either cefiderocol 2 g intravenously every 8 hours infused over 60 minutes or imipenem/cilastatin 1 g intravenously every 8 hours for 7–14 days. The primary outcome was a composite end point of clinical response and microbiologic eradication at test of cure in the modified intention-to-treat (mITT) population. The margin of noninferiority was minus 20%. A total of 448 participants received at least one dose of the study drug, and 371 participants with a qualifying gram-negative organism were included in the mITT population. The primary outcome was met in 73% of patients in the cefiderocol group and 55% of patients in the imipenem/cilastatin group, resulting in an adjusted treatment difference of 18.58% (95% CI, 8.23–28.92; p=0.0004), which met the prespecified criterion for noninferiority. There were no differences in clinical response or microbiologic eradication at early assessment or end of treatment between treatment groups. This trial showed that cefiderocol is noninferior to imipenem/cilastatin in the treatment of cUTIs, including pyelonephritis.

The APEKS-NP trial was a phase III, multicenter, randomized, double-blind, noninferiority study comparing cefiderocol with meropenem for the treatment of hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), and health care–associated bacterial pneumonia (HCABP).7-9 Participants were randomized to receive either cefiderocol 2 g intravenously every 8 hours or meropenem 2 g intravenously every 8 hours, both infused over 3 hours, for 7–14 days. Adjunctive linezolid 600 mg intravenously every 12 hours for at least 5 days was given to both treatment groups to cover gram-positive infections. The primary outcome was all-cause mortality (ACM) at day 14 in the mITT population. The noninferiority margin was minus 12.5%. A total of 291 participants received at least one dose of the study drug and were included in the mITT population. The primary outcome was met in 12.4% of patients in the cefiderocol group and 11.6% of patients in the meropenem group, resulting in a treatment difference of 0.8% (95% CI, -6.6 to 8.2), which met the prespecified criterion for noninferiority. There were no differences in clinical response or microbiologic eradication rates at test of cure between the treatment groups. This trial showed that cefiderocol is noninferior to meropenem in the treatment of HABP/VABP/HCABP with respect to ACM at day 14.

The CREDIBLE-CR was a phase III, multicenter, randomized, open-label study comparing cefiderocol with best available therapy (BAT) for severe infections caused by carbapenem-resistant (CR) gram-negative pathogens, including HABP, VABP, HCABP, bloodstream infections (BSIs)/sepsis, and cUTIs.^7,10 Participants were randomized to receive either cefiderocol 2 g intravenously every 8 hours infused over 3 hours or BAT, which consisted of one to three antibiotics active against CR gram-negative pathogens, for 7–14 days. The primary outcomes were clinical outcomes of HABP, VABP, HCABP, and BSI/sepsis and microbiologic outcomes of cUTI at test of cure. The study was descriptive without formal testing of statistical hypotheses. A total of 150 participants received at least one dose of study drug, and 118 were included in the CR mITT population. Clinical cure rates were 52.5% in the cefiderocol group and 50.0% in the BAT group, resulting in a difference of 2.5% (95% CI, -16.8 to 21.8). Microbiologic eradication rates were 31.3% in the cefiderocol group and 23.7% in the BAT group, resulting in a difference of 7.6% (95% CI, -9.3 to 24.5). Assessments of microbiologic eradication rates were limited because around 50% of patients in each treatment group were classified as having an indeterminate outcome. Assessments within the cUTI subgroup were also limited by the sample size of only five patients in the BAT group. The ACM rates as shown in Table 1 were higher in the cefiderocol group than in the BAT group at days 14, 28, and 49. The greatest mortality imbalance occurred in the HABP/VABP/HCABP subgroup at day 49, followed by the BSI/sepsis subgroup at day 49. The cUTI subgroup had a higher mortality rate in the BAT group, but the difference was difficult to interpret because of the small sample size. This trial showed that cefiderocol has a higher mortality rate than BAT in the treatment of severe infections caused by CR gram-negative pathogens.

Table 1. Summary of Results of Phase II and III Clinical Trials of Cefiderocol

^aResolution of or improvement in cUTI symptoms present at study entry and absence of new symptoms.

^bBacterial pathogen at study entry at > 10⁵ CFU/mL reduced to ≤ 10⁴ CFU/mL.

^c7 days (±2 days) after EOT.

^dDay 4 of treatment.

^eClinical outcome of clinical cure.

^f7 days after EOT.

^gMicrobiologic outcome of eradication.

^hConsisted of one to three antibiotics to treat carbapenem-resistant gram-negative infections.

iResolution of or substantial improvement in baseline signs and symptoms of HABP/VAPB/HCABP and BSI/sepsis or lack of progression of chest radiography abnormalities.

^jGram-negative uropathogen at study entry at ≥ 10⁵ CFU/mL reduced to < 10⁴ CFU/mL. ACM = all-cause mortality; BAT = best available therapy; BSI = bloodstream infection; CO = clinical outcomes; CR = clinical response; cUTI = complicated UTI; EA = early assessment; EOT = end of treatment; FDC = cefiderocol; HABP = hospital-acquired bacterial pneumonia; HCABP = health care–associated bacterial pneumonia; IPM = imipenem/cilastatin; IV = intravenous(ly); LZD = linezolid; ME = microbiologic eradication; MEM = meropenem; mITT = modified intention-to-treat; MO = microbiologic outcomes; NR = not reported; q = every; TOC = test of cure; VABP = ventilator-associated bacterial pneumonia.

Information from: Fetroja [package insert]. Florham Park, NJ: Shionogi, 2019; Portsmouth S, van Veenhuyzen D, Echols R, et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by gram-negative uropathogens: a phase 2, randomized, double-blind, non-inferiority trial. Lancet Infect Dis 2018;18:1319-28; U.S. Food and Drug Administration (FDA). Cefiderocol Injection. Briefing Document. October 16, 2019. Available at https://www.fda.gov/media/131703/download. Accessed September 18, 2020; Wunderink RG, Matsunaga Y, Ariyasu M, et al. Efficacy and safety of cefiderocol vs. high-dose meropenem in patients with nosocomial pneumonia – results of a phase 3, randomized, multicenter, double-blind, non-inferiority study. Open Forum Infect Dis 2019;6(suppl 2):S994.

Safety and Adverse Events: Cefiderocol is structurally related to ceftazidime and cefepime and is contraindicated in patients with severe hypersensitivity to β-lactams.^3,4 Cefiderocol carries warnings regarding increased ACM in patients with CR gram-negative infections, hypersensitivity reactions, Clostridioides difficile infection (CDI), and seizures and other CNS adverse reactions.⁴ The most common adverse reactions of cefiderocol in the APEKS-cUTI trial were diarrhea (4%), infusion site reactions (4%), constipation (3%), rash (3%), candidiasis (2%), cough (2%), elevated liver function tests (2%), headache (2%), hypokalemia (2%), nausea (2%), and vomiting (2%).^4,7 Other, less-common adverse reactions were thrombocytosis, congestive heart failure, bradycardia, atrial fibrillation, abdominal pain, dry mouth, stomatitis, pyrexia, peripheral edema, cholelithiasis, cholecystitis, gallbladder pain, drug hypersensitivity, CDI, prolonged PT, elevated INR, positive RBCs in the urine, elevated creatine phosphokinase, decreased appetite, hypocalcemia, fluid overload, dysgeusia, seizure, dyspnea, pleural effusion, pruritus, insomnia, and restlessness.⁴ The most common adverse reactions of cefiderocol in the CREDIBLE-CR trial were diarrhea (19%), elevated liver function tests (18%), pyrexia (14%), decubitus ulcer (10%), pneumonia (9%), candidiasis (9%), hypomagnesemia (9%), anemia (8%), fluid overload (8%), constipation (8%), hypotension (8%), pleural effusion (8%), dyspnea (7%), nausea (7%), chest pain (7%), oliguria (5%), and agitation (5%).⁷ Cefiderocol has a low potential for CYP and drug transporter–mediated drug interactions but yields false-positive results in dipstick tests.⁴

Usual Dose: The cefiderocol dose is 2 g intravenously every 8 hours infused over 3 hours for 7–14 days.⁴ Dosage adjustment is recommended in patients with augmented renal clearance and those with renal impairment. Cefiderocol is one of the few antibiotics that comes with a recommendation in the prescribing information to increase the dose in patients with augmented renal clearance. The recommended dose is 2 g every 6 hours for patients with a CrCl of 120 mL/minute or greater; 1.5 g every 8 hours for a CrCl of 30–59 mL/minute; 1 g every 8 hours for a CrCl of 15–29 mL/minute; and 0.75 g every 12 hours for a CrCl less than 15 mL/minute, including in patients receiving hemodialysis.

Advantages: Cefiderocol is active against a broad range of gram-negative organisms, including CRAB, CRPA, MDR P. aeruginosa, CRE, and ESBL-producing Enterobacteriaceae.3 Cefiderocol is FDA approved for adults with cUTIs including pyelonephritis, is well tolerated, and has a low potential for drug interactions.⁴

Disadvantages: Cefiderocol is FDA approved only for adults with cUTIs who have limited or no alternative treatment options and was associated with increased ACM in patients with CR gram-negative infections.⁴ Cross-reactivity is possible in patients with an allergy to other β-lactam antibiotics. Like other systemic antibiotics, cefiderocol carries a warning regarding the development of CDI. Like some other cephalosporins, cefiderocol also carries a warning regarding seizures and other CNS adverse reactions. Finally, cefiderocol is only available in an intravenous formulation.

Conclusion: Cefiderocol represents an addition to the armamentarium of antibiotics active against MDR gram-negative organisms. Given the increased ACM observed in one clinical trial and until more data become available, cefiderocol should be reserved for the treatment of cUTIs caused by MDR gram-negative organisms in patients with limited or no alternative treatment options.

References:

1. World Health Organization (WHO). Global Priority List of Antibiotic-Resistant Bacteria to Guide Research, Discovery, and Development of New Antibiotics, 2017. Available at https://www.who.int/medicines/publications/global-priority-list-antibiotic-resistant-bacteria/en/. Accessed September 18, 2020.
2. Centers for Disease Control and Prevention (CDC). Antibiotic Resistance Threats in the United States, 2019. Available at https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf. Accessed September 18, 2020.
3. Wu JY, Srinivas P, Pogue JM. Cefiderocol: a novel agent for the management of multidrug-resistant gram-negative organisms. Infect Dis Ther 2020;9:17-40.
4. Fetroja [package insert]. Florham Park, NJ: Shionogi, 2019.
5. ClinicalTrials.gov. A Study of Efficacy and Safety of Intravenous Cefiderocol (S-649266) versus Imipenem/Cilastatin in Complicated Urinary Tract Infections (APEKS-cUTI). Available at https://clinicaltrials.gov/ct2/show/NCT02321800. Accessed September 18, 2020.
6. Portsmouth S, van Veenhuyzen D, Echols R, et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by gram-negative uropathogens: a phase 2, randomized, double-blind, non-inferiority trial. Lancet Infect Dis 2018;18:1319-28.
7. U.S. Food and Drug Administration (FDA). Cefiderocol Injection. Briefing Document. October 16, 2019. Available at https://www.fda.gov/media/131703/download. Accessed September 18, 2020.
8. ClinicalTrials.gov. Clinical Study of S-649266 for the Treatment of Nosocomial Pneumonia Caused by Gram-negative Pathogens (APEKS-NP). Available at https://clinicaltrials.gov/ct2/show/NCT03032380. Accessed September 18, 2020.
9. Wunderink RG, Matsunaga Y, Ariyasu M, et al. Efficacy and safety of cefiderocol vs. high-dose meropenem in patients with nosocomial pneumonia – results of a phase 3, randomized, multicenter, double-blind, non-inferiority study. Open Forum Infect Dis 2019;6(suppl 2):S994.
10. ClinicalTrials.gov. Study of S-649266 or Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-Resistant Gram-negative Pathogens (CREDIBLE-CR). Available at https://clinicaltrials.gov/ct2/show/NCT02714595. Accessed September 18, 2020.