INTRODUCTION:

In 2019, the FDA approved cefiderocol to treat hospital-acquired and ventilator-associated bacterial pneumonia, as well as complex urinary tract infections (cUTIs) like kidney infections caused by susceptible Gram-negative pathogens when there are few or no other treatment choices¹.

The Japanese pharmaceutical company Shionogi and Co., Ltd. created Cefiderocol, previously known as S-649266. It is a new catechol-substituted siderophore cephalosporin antibiotic. Many bacteria create iron-chelating compounds called siderophores², which are essential for the absorption of iron into the bacterial cell. In the year 2020, the European Union gave its clearance for the treatment of infections caused by aerobic Gram-negative bacteria in people who had few therapeutic choices available to them³. In terms of molecular structure, Cefiderocol is quite close to Cefepime and Ceftazidime^{4, 5}. It penetrates the bacterial periplasm via binding to iron transport channels, much like bacterial siderophores. A "trojan horse" is a term for this kind of setup. Cefiderocol's antibacterial action is a result of the molecule dissociating within the cell from the iron transport channel⁶. Cefiderocol's siderophore activity, improved stability against beta-lactamases, and ease of transport over the outer membrane of Gram-negative bacteria (Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii) are all the result of the molecule's functional groups⁷. Stability against serine and metallo-type carbapenemases and extended-spectrum β-lactamases contributes to cefiderocol's potent action⁸. Carbapenem-resistant (CR) Gram-negative bacteria, such as carbapenem-resistant Enterobacterales and non-fermenters, are effectively inhibited by cefiderocol in vitro⁹. Antibiotics known as carbapenems are among the most efficient antimicrobials available for treating illnesses brought on by bacteria with the highest level of resistance¹⁰. Yet resistance to the antibiotic carbapenem in gram-negative bacteria has become an issue on a global scale¹¹. On the most recent version of the global priority list of pathogens that was published by the World Health Organization (WHO), carbapenem-resistant Enterobacteriaceae (CRE), carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii are placed in the highest priority category¹².

OBJECTIVE:

Differences in the mechanisms of action of cefiderocol and carbamepen are summarized in this article. Studies published between 2007 and 2023 are the primary focus of the debate. This review's supporting materials were sourced via a combined search of PubMed, PubChem, and Google Scholar, including the terms “Cefiderocol,” “Carbapenem,” “Gram-negative Bacteria,” “Carbapenem Resistance,” and “Cefiderocol clinical trials” from 2007 until May 2023.

MECHANISMS OF CARBAPENEM:

Antibiotics such as carbapenems are generally regarded as the treatment of choice for illnesses caused by bacteria (Pseudomonas aeruginosa, Enterobacteriaceae, and Acinetobacter baumannii) with the highest level of resistance¹³. Carbapenems, like penicillin, are a type of beta-lactam antibiotic (cephalosporins and monobactams)¹⁴. These antibiotics have the highest global use. The beta-lactam ring is a common structural element of β-lactam antibiotics¹⁵. Carbapenems, like other beta-lactam antibiotics, limit cell-wall production by blocking transpeptidation, an essential process for maintaining the bacterial cell wall's structural integrity. Carbapenems are considered bactericidal because they kill bacteria by inhibiting peptidoglycan crosslinking, which is essential for their survival. For the most part, carbapenems are unable to penetrate the outer membrane of gram-negative bacteria¹⁶. To get access to Gram-negative bacteria, carbapenems need the presence of outer membrane protein (OMP) porins; for instance, OprD is identified as a critical transport route for carbapenems, allowing them to enter Pseudomonas aeruginosa. The penicillin-binding-protein (PBP) family of enzymes is inactivated by carbapenems because they are acylated. The structural differences between gram-negative and gram-positive PBPs account for the wide range of carbapenem affinities seen for these proteins in bacteria. Carbapenems target a variety of PBPs, with meropenem's principal target in Escherichia coli being PBP-2, and with Staphylococcus aureus showing high-affinity binding to PBP-1, PBP-2, and PBP-4. The peptidoglycan substrate is inhibited due to its resemblance to the d-Ala-d-Ala terminus of the β-lactam core. Due to their shared structural features, they are able to form covalent bonds and block their target enzymes permanently¹⁷.

Figure 1: Mechanism of Carbapenem Resistance. Here, Fe = ferric ions, Carb = Carbapenem, PBPs = Penicillin-Binding Proteins.

Carbapenem Resistance:

When bacteria that normally cause infections are able to survive after being exposed to a medicine that would normally kill them or hinder their growth, this is known as antibiotic resistance¹⁸. As there are no other strains around that are susceptible to the same medicine, the ones that make it continue to proliferate and spread. Antibiotic-resistant microorganisms are a global health problem because of careless prescribing and overuse¹⁹. In fact, the problem of antibiotic-resistant bacteria has become so bad that the World Health Organization (WHO) now predicts that infections caused by resistant bacteria will overtake cancer, diabetes, and cardiovascular disease as the leading cause of mortality globally over the next few decades²⁰.

Figure 2: Types of the different mode of action of drug resistance in Carbapenem^{28, 29}.

Enterobacteriaceae can become resistant to carbapenems in one of three main ways: by making enzymes, making efflux pumps, or getting mutations in their porins²¹. The synthesis of enzymes is a primary defense mechanism among them. In most cases, gram-negative bacteria produce ß-lactam-hydrolyzing enzymes to acquire resistance^{22, 23}. When first discovered, these enzymes were only able to deactivate penicillin; however, when other antibiotics became available, their spectral range expanded to include other antimicrobials^{24, 25}. As a result, several carbapenemases, such as extended-spectrum beta-lactamases (ESBLs), metallo-ß-lactamases (MBLs), etc., emerged. Carbapenemase-producing CRE (CP-CRE) and non-carbapenemase-producing CRE are the two basic categories into which CRE are typically sorted (non-CP-CRE)^{26, 27}.

Cefiderocol In The Replacement Of Carbapenem:

Worldwide, there has been an increase in the number of reports of Gram-negative bacteria that are both extensively drug-resistant (XDR) and pandrug-resistant^{30, 31, 32}. Attributable mortality seems to be high, and treatment choices are relatively restricted^{33, 34}. Synergistic combinations of in vitro inactive (alone) antimicrobials are commonly used as a last resort therapeutic strategy^{35, 36}. The fact that cefiderocol is able to overcome the majority of the processes that lead to -lactam resistance is very encouraging. These mechanisms include -lactamases, porin mutations, and efflux pumps³⁷.

In the realm of cephalosporins, the newcomer cefiderocol stands out as a siderophore. Similar to cefepime and ceftazidime, it features a pyrrolidinium group on the C-3 side chain that makes it more stable against beta-lactamases,³⁸ and it also shares the C-7 side chain of ceftazidime, which makes it more stable against beta-lactamases and facilitates its transport over the outer membrane. The C-3 side chain has been extended with a chlorocatechol group, which increases beta-lactamase stability and adds siderophore action³⁹. Bacteria rely on natural iron-chelating molecules called siderophores to transfer iron. Two natural iron-chelating siderophores, enterobactin (E. coli) and pyoverdine (P. aeruginosa), have a common structural feature: a catechol group^{40, 41}. Cefiderocol is actively transported through the outer membrane of Gram-negative bacteria, bypassing resistance mediated by porin loss or efflux pumps, thanks to the use of natural iron transportation mechanisms (commonly referred to as a "Trojan horse" technique). Cefiderocol is now more stable against beta-lactamases, making it a promising option for treating infections caused by extensively drug-resistant and pan-drug-resistant Gram-negative bacteria⁴².

Figure 3: Mechanism of Cefiderocol (CFDC). Here, Fe = ferric ions, Carb = Carbapenem, PBPs = Penicillin-Binding Proteins.

CLINICAL EVALUTION OF CFDC:

In 2019, the Food and Drug Administration (FDA) approved CFDC to treat complicated urinary tract infections (cUTI), hospital-acquired bacterial pneumonia (HAP), and ventilator-associated bacterial pneumonia (VAP).After consulting with an infectious disease specialist, the European Medicines Agency (EMA) approved CFDC in 2020 to treat infections caused by aerobic GNB in adults who don't have many treatment options. CFDC was approved for these indications in 2019⁴³.

Three types of clinical tests were taken for these studies. The tests were taken to evaluate the effectiveness against carbapenem-resistant bacteria, urinary tract infection, and nosocomial pneumonia⁴⁵. These tests were taken in 17 countries at different centers. Patients having a clinical diagnosis of cUTI with or without pyelonephritis or acute uncomplicated pyelonephritis were included in the APEKS-cUTI trial, a phase 2, multicentre, double-blind study conducted at 67 institutions in 15 countries. In this trial, CFDC showed a better result than imipenem-cilastin⁴⁵. Between 2016 and 2019, the CREDIBLE-CR trial was conducted in 95 hospitals across 16 countries as a randomized, open-label, multicenter, parallel-group, pathogen-focused, descriptive, phase 3 investigation. Individuals with a diagnosis of NP, BSI (Blood Steam Infection), sepsis, or UTI caused by a GNB resistant to carbapenems were included. Cifiderocol was much more effective than a combination of other antibiotics, with 66% of patients achieving clinical cure compared to 58% of patients receiving the combination⁴⁶.

APEKS – cUTIs (67 Hospitals and 15 Countries)
Cefiderocol 2gm IV	Imipenem-cilastin 1gm IV
303	149
Efficacy – 73%	Efficacy – 55%
CREDIBLE – CR (95 Hospitals and 16 Countries)
Cefiderocol 1gm IV	Other Combinational Antibiotics
101	49
Efficacy – 66%	Efficacy – 58%
APEKS – NP (76 Hospitals and 17 Countries)
Cefiderocol 1gm IV	Meropenem 2gm IV
145	147
TEAE	TEAE

Table 1: Clinical evaluation of CFDC. Here, NP = Nosocomial pneumonia, CR = Carbapenem Resistance, UTIs = Urinary tract infections, TEAE = Treatment-emergent adverse event⁴⁴.

CONCLUSION:

Even though new compounds that are more effective are being made available for clinical use, the number of germs that can't be killed by these medicines keeps going up. The spread of carbapenem-resistant Gram-negative organisms, which in some cases show pan-drug resistance, makes it hard for our society to keep up a high level of public health⁴⁷. The fight against infectious diseases is likely one of the biggest reasons for this. Cefiderocol is a new cephalosporin that has been shown to have a promising action against MDR (multidrug-resistant) GNB (gram-negative bacteria), particularly carbapenem-resistant GNB. It would be particularly helpful for the treatment of GNB in patients who have limited therapeutic choices, such as those who produce metallo-β-lactamases, if this could be done.

ACKNOWLEDGMENTS:

Benzene Research Center, Bangladesh designed the project and revised the paper.

CONFLICTS OF INTEREST:

The authors declare no conflict of interest.

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Received on 10.03.2023 Modified on 05.06.2023

Research J. Pharm. and Tech 2023; 16(11):5492-5496.

DOI: 10.52711/0974-360X.2023.00888