Cefiderocol: An Overview of Its in-vitro and in-vivo Activity and Underlying Resistant Mechanisms

Abstract

Treatment of multidrug-resistant (MDR) Gram-negative bacteria (GNB) infections has led to a global public health challenging due to the bacterial resistance and limited choices of antibiotics. Cefiderocol (CFDC), a novel siderophore cephalosporin possessed unique drug delivery systems and stability to β-lactamases, has the potential to become first-line therapy for most aggressive MDR Gram-negative pathogens infection. However, there have been reports of drug resistance in the course of using CFDC. This study provides an overview of the in-vitro and in-vivo activity of CFDC and potential resistance mechanism was also summarized. In general, CFDC shows excellent activity against a broad range of MDR GNB pathogens including Enterobacteriaceae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia. The expressions of metallo-β-lactamases such as inosine 5'-monophosphate (IMP), Verona integron-mediated metallo-β-lactamase (VIM), and New Delhi metallo-β-lactamase (NDM) are associated with a higher resistance rate of CFDC. Carbapenem-resistant phenotype has little effect on the resistance rate, although the acquisition of a particular carbapenemase may affect the susceptibility of the pathogens to CFDC. For potential resistance mechanism, mutations in β-lactamases and TonB-dependent receptors, which assist CFDC entering bacteria, would increase a minimum inhibitory concentration (MIC)90 value of CFDC against MDR pathogens. Since the development of CFDC, resistance during its utilization has been reported thus, prudent clinical applications are still necessary to preserve the activity of CFDC.

Chelation in Antibacterial Drugs: From Nitroxoline to Cefiderocol and Beyond

“…This “Trojan horse” approach is very efficient in circumventing certain intrinsic or acquired antibiotic resistance mechanisms [ 64 , 130 ]. Cefiderocol was successfully approved in 2019 for the treatment of complicated urinary tract infections and hospital-acquired bacterial pneumonia, and in 2020, for ventilator-associated bacterial pneumonia caused by GNB [ 25 ].…”

“…Then, Fe 3+ is reduced to Fe 2+ , which has a diminished affinity for siderophore ligands, and is thus released from the chelate inside the cell. Novel cephalosporin antibiotic cefiderocol owes its potent activity to the ability to act as a siderophore [ 24 , 25 ]. Chelating agents are thus able to control in vivo infection progression by selectively disturbing the essential metal metabolism of the microorganism, such as the blockage of microbial nutrition, development and growth, or by disturbing the adhesion to biotic and abiotic surfaces [ 26 , 27 , 28 , 29 , 30 ].…”

Extended‐spectrum β‐lactamase‐producing and carbapenem‐resistant Enterobacterales bloodstream infection after solid organ transplantation: Recent trends in epidemiology and therapeutic approaches

“…In addition, it actively enters the periplasmic compartment—where high concentrations are achieved—by exploiting the bacterial siderophore‐iron complex pathway as a “Trojan horse” 119 . This mode of action overcomes common mechanisms of β‐lactam resistance such as loss of porin expression or up‐regulation of efflux pumps and results in stability against hydrolysis by various types of carbapenemases, including most serine enzymes (e.g., KPC, OXA type) and MBLs 120 . Cefiderocol also retains antibacterial activity against ESBL‐ and AmpC‐producing strains 121 .…”

“…and MBLs. 120 Cefiderocol also retains antibacterial activity against ESBL-and AmpC-producing strains. 121 Its clinical development program comprised three non-inferiority phase II/III RCTs.…”

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“…Finally, with the increase in recent decades in the prevalence of infections by ESBL-producing Enterobacterales, carbapenems became the empirical therapy of first choice in areas with an unfavorable epidemiological situation, and in high-risk patients, which has made carbapenemase-producing Enterobacteriaceae an even greater problem [26,36], with very limited treatment options. While tigecycline and colistin have historically, and out of necessity in the absence of other options, been considered the first-choice treatment for infections caused by carbapenemase-producing Enterobacteriaceae [37,38], resistance to these drugs is now being added [38], forcing, as previously, the use of combinations with fosfomycin or aminoglycosides or, on the other hand, increasing the shock and maintenance doses of drugs such as tigecycline, given their safety profile [1,26,36]. However, dual therapy with carbapenems at higher doses, in extended perfusion, and/or in combination regimens may be useful in carbapenemase-producing Enterobacteriaceae with MICs lower than 8 mg/L of meropenem.…”