By William Alegria, PharmD, BCIDP

Antimicrobial Stewardship Program, Stanford University School of Medicine

Dr. Alegria reports no financial relationships relevant to this field of study.

Cefiderocol is a novel siderophore cephalosporin with activity against several clinically relevant aerobic gram-negative bacteria, including carbapenem-resistant strains expressing serine- and metallo-β-lactamases. Cefiderocol received expedited approval by the Food and Drug Administration (FDA) in November 2019 for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis in adults with limited or no treatment options.1

Cefiderocol exerts an effect on cell wall synthesis through inhibition of penicillin binding proteins. Unlike earlier cephalosporins, cefiderocol’s siderophore moiety at C-3 complexes with ferric iron in the host and then is actively transported into the periplasmic space via iron transporters on the outer cell membrane of bacteria.2,3 This “Trojan horse” approach makes cefiderocol less susceptible to upregulation of efflux pumps and porin channel mutations.

Microbiology

Cefiderocol has demonstrated clinical efficacy and in vitro activity against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex.1 Additionally, in vitro activity has been demonstrated in multinational surveillance studies for several gram-negative clinical isolates, including carbapenem-resistant strains. Among carbapenem-nonsusceptible strains of Enterobacteriaceae, P. aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia, cefiderocol had a greater susceptibility ratio relative to ceftazidime-avibactam, ceftolozane-tazobactam, colistin, and ciprofloxacin.2,4,5 The FDA susceptibility breakpoint for cefiderocol is ≤ 2 mcg/mL and ≤ 1 mcg/mL for Enterobacteriaceae and P. aeruginosa, respectively.6 Cefiderocol does not have activity against gram-positive organisms.

Pharmacokinetics/Pharmacodynamics

The pharmacodynamic parameter most closely associated with bactericidal efficacy for cefiderocol is the fraction of the dosing interval during which the free drug concentration exceeds the minimum inhibitory concentration (MIC) (%fT>MIC). In vivo murine thigh and lung infection models demonstrated a bactericidal effect (i.e., ≥ 1 log10 reduction) at roughly 55% to 88% fT>MIC.7 In multiple rat lung infection models, prolonging the infusion time from one hour to three hours resulted in greater efficacy. Additionally, neutropenic murine thigh infection models meant to simulate humanized exposures of cefiderocol demonstrated consistent reductions in bacterial density for most of the pathogens tested (i.e., K. pneumoniae, E. coli, P. aeruginosa, and A. baumannii) with MICs ≤ 4 mcg/mL.7

Data regarding the pharmacokinetics, safety, and tolerability of cefiderocol are available from Phase I single- and multiple-dose studies in healthy volunteers and those with renal impairment. Additionally, data from patients with cUTIs with or without pyelonephritis or acute uncomplicated pyelonephritis also are available from licensing studies. Plasma and urine concentration data from subjects enrolled in Phase I studies were used to design a three-compartment model used to predict a target of 75% fT>MIC. A dose of 2 grams administered every eight hours (as either a one-hour or three-hour infusion) achieved the target in greater than 90% of patients for MICs ≤ 4 mcg/mL.7 In patients with renal impairment, dose adjustments were designed to simulate an area under the curve similar to that achieved with standard dosing in healthy volunteers. Cefiderocol is the first antibiotic to have FDA-approved dosing recommendations for patients with augmented renal clearance.1

Clinical Data

Cefiderocol was designated a Qualified Infectious Disease Product and approved by the FDA based on results of a multinational, noninferiority, double-blinded, randomized controlled trial in hospitalized adult patients with cUTI, with or without pyelonephritis or acute uncomplicated pyelonephritis.8 Patients were randomized to receive cefiderocol 2 g IV every eight hours (n = 300) or imipenem/cilastatin 1 g/1 g IV every eight hours (n = 148) for a period of seven to 14 days. The study protocol allowed for inclusion of immunocompromised patients, including renal transplant recipients, and excluded patients with carbapenem-resistant isolates. Cefiderocol demonstrated noninferiority against imipenem/cilastatin for the composite endpoint of microbiological eradication and clinical cure in the microbiological intent-to-treat population at test of cure (73% vs. 55%; P = 0.004).

Cefiderocol also was evaluated against meropenem for treatment of nosocomial pneumonia (i.e., hospital-acquired pneumonia [HAP], ventilator-associated pneumonia [VAP], or healthcare-associated pneumonia [HCAP]) in a Phase III, multinational, noninferiority, double-blinded, randomized controlled trial.9,10 Patients were randomized to receive either cefiderocol 2 g IV every eight hours (n = 148) or meropenem 2 g IV every eight hours (n = 150) for a period of seven to 14 days. At baseline, 59.7% of patients were ventilated, 32.6% had failure of prior antibiotic therapy, and 6.0% had concomitant gram-negative bacteremia. Cefiderocol demonstrated noninferiority against meropenem with respect to the primary outcome of 14-day all-cause mortality in the modified intention-to-treat population (12.4% vs. 11.6%, respectively).

In Europe, The European Medicines Agency allowed the manufacturer to move forward with a pathogen-focused, multinational, descriptive, open-label, randomized controlled trial in adult patients infected with carbapenem-resistant gram-negative organisms (n = 150).11 The study evaluated outcomes in patients receiving cefiderocol 2 g IV every eight hours (n = 101) or best available therapy (BAT) (n = 49) for a total treatment duration of up to 21 days. BAT was at the discretion of the treating provider and could include one, two, or three antibiotics used together. In contrast, cefiderocol-treated patients were allowed only one additional gram-negative antibiotic as adjunctive therapy (except for patients with cUTI, who received cefiderocol monotherapy). Given the unique trial design, patients with nosocomial pneumonia (i.e., HAP, VAP, HCAP), bloodstream infection and/or sepsis, and cUTI were enrolled. The most common baseline pathogens in both treatment groups included A. baumannii, K. pneumoniae, and P. aeruginosa. Although cefiderocol had similar rates of clinical cure, there was an increased rate of mortality noted in patients receiving cefiderocol at multiple timepoints.

The manufacturer concluded that in patients with adverse events leading to death, the difference between groups was driven by infections and infestations, representing the progression of or worsening of infection. Mortality appeared to be driven primarily by patients in the nosocomial pneumonia subgroup (n = 67) and bloodstream infection/sepsis. Compared to the Phase III trial in patients with nosocomial pneumonia mentioned previously, patients in this study had a higher rate of infections with A. baumannii (55.2% vs. 16%) and a higher rate of treatment failure prior to randomization (64% vs. 33%). Although cefiderocol currently is approved by the FDA for management of cUTI, results of this study prompted language in the prescribing information regarding an increase in all-cause mortality in patients with carbapenem-resistant gram-negative bacterial infections.

Conclusion

Cefiderocol is a novel siderophore cephalosporin with a wide spectrum of activity against difficult-to-treat gram-negative organisms for which there currently are limited treatment options. Although targeted antibiotics have been developed in recent years for Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae (e.g., ceftazidime/avibactam, meropenem/vaborbactam, imipenem/relebactam, etc.), there are limited treatment options for infections due to carbapenem-resistant organisms expressing Ambler Class B carbapenemases (i.e., NDM, IMP, VIM). Existing antibiotics with in vitro activity against NDM-producing gram-negative organisms have variable in vitro activity, pharmacokinetic limitations, and concerns regarding tolerability and toxicity. Additionally, novel beta-lactam/beta-lactamase inhibitors do not have activity against Ambler Class D (e.g., OXA-23) producing Acinetobacter. Given the mortality imbalance noted in a pathogen-focused study in Europe, however, the role of cefiderocol in clinical practice will require further exploration with a critical appraisal of real-world outcomes.

REFERENCES

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