Cefiderocol for Carbapenem-Resistant Bacteria: Handle with Care! A Review of the Real-World Evidence

(1) Background: healthcare-associated infections are one of the most frequent adverse events in healthcare delivery worldwide. Several antibiotic resistance mechanisms have been developed, including those to carbapenemase. Cefiderocol (CFD) is a novel siderophore cephalosporin designed to treat carbapenem-resistant bacteria. (2) Methods: we performed a systematic review of all cases reported in the literature to outline the existing evidence. We evaluated real-world evidence studies of CFD in the treatment of carbapenem-resistant (CR) bacteria. (3) Results: a total of 19 publications treating cases of infection by CR bacteria were included. The three most frequent CR pathogens were Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. A regimen of 2 g every 8 h was most frequently adopted for CFD with a mean treatment duration of 25.6 days. CFD was generally well tolerated, with fewer side effects. The success rate of CFD therapy was satisfactory and almost 70% of patients showed clinical recovery; of these, nearly half showed negative blood cultures and infection-free status. (4) Conclusions: This review indicates that CFD is active against important GN organisms including Enterobacteriaceae, P. aeruginosa, and A. baumannii. CFD seems to have a safe profile.


Introduction
According to the World Health Organization (WHO), healthcare-associated infections (HAI) are one of the most frequent adverse events in healthcare delivery worldwide [1]. Around the world, hundreds of millions of patients are affected by HAI every year, leading to a significant impact on morbidity, mortality and quality of life and representing an economic burden on healthcare systems [1].
Antimicrobial resistance (AMR) is one of the greatest global public health challenges of our time [2]. The emergence and spread of pathogens that have acquired new drug resistance mechanisms, leading to antimicrobial resistance, are a threat to our ability to treat common infections [2].
Since the spread of Gram-negative (GN) bacteria that produce extended-spectrum ßlactamase (ESBL) enzymes, which, in addition to penicillins, confer resistance to cephalosporins and monobactam [3], carbapenems have been used as the rescue therapy to treat this type of infection [4]. Carbapenems belong to the class of β-lactam antibiotic agents which are very effective against severe and high-risk bacterial infections, and is normally a Drug of 2 of 17 Last Resort (DoLR) antibiotic for Multi-Drug-Resistant (MDR) bacterial infections. They bind to the penicillin-binding proteins, preventing the synthesis of the bacterial cell wall.
Unfortunately, shortly after the introduction of carbapenems, GN-bacteria rapidly developed resistance to these antibiotics and spread around the world [5]. These include the Carbapenemase-Producing Organisms (CPOs) and among them the Carbapenem-Resistant Enterobacteriaceae (CREs) [6]. CREs are a group of GN bacteria, from the family of Enterobacteriaceae, which have developed resistance to the carbapenem antibiotics. Other CPOs include some opportunistic bacteria that have the ability to produce carbapenemase enzymes, such as Pseudomonas aeruginosa and Acinetobacter baumannii.
In 2017, 8.3% of the patients who stayed in intensive-care units (ICUs) in Europe presented at least one acquired HAI (pneumonia, bloodstream infection, or urinary tract infection) [9]. Carbapenem resistance was reported in 15% of Klebsiella spp. isolates, 26% of P. aeruginosa isolates and 64% of Acinetobacter baumannii isolates [9]. These are a matter of national and international concern as they are an emerging cause of HAI that pose a significant threat to public health [10].
In 2017, the WHO developed a global priority pathogens list of antibiotic-resistant bacteria to help in prioritizing the research and development of new and effective antibiotic treatments. Carbapenem-resistant Enterobacteriaceae, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii are in the highest priority category [11].
It is important to identify patients with risk factors for developing MDR infections, to ensure early molecular or microbiological diagnoses and faster and more appropriate treatment [12]. The need for new antibiotics in carbapenem-resistant infections has been recognized globally. There are various antibiotics whose activity has been tested against carbapenemase-resistant microorganisms [13,14]. Cefiderocol (CFD), a novel siderophore cephalosporin designed to treat carbapenem-resistant bacteria, has shown potent in vitro activity against CPOs, including CREs [15][16][17][18][19].
In 2019, the U.S. Food and Drug Administration (FDA) granted CFD authorization to treat complicated urinary tract infections (cUTI) with limited or no alternative treatment options [20]. As of 2020, CFD is recommended for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP), caused by GN microorganisms [20].
Objectives. We performed a systematic review of the cases reported in the literature to outline the existing evidence. To our knowledge, there are no previously published systematic reviews that have evaluated real-world evidence studies of CFD in the treatment of carbapenem-resistant bacteria. A systematic review of case reports cannot support the efficacy of using CFD for the treatment of carbapenem-resistant bacterial infections, but it may identify rare or unrecognized associations and may generate hypotheses for subsequent studies.

Protocol and Registration
Our systematic review is based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [21]. The protocol was not published, but is available if requested. The review was not registered with the international prospective register of systematic reviews (PROSPERO).

Literature Search Strategy
Medline, EMBASE, PubMed, Google Scholar, and The Cochrane Library-CENTRAL were screened to identify case reports of patients with carbapenem-resistant bacteria infections treated with CFD. Other studies were identified from the reference lists. We used a combination of terms such as "cefiderocol", "carbapenem resistant", "Enterobacteriaceae", "Pseudomonas aeruginosa" and "Acinetobacter baumannii". The titles and abstracts were screened by two researchers (P.S. and L.G.G.) to identify the keywords. The selected papers were read in full by the two independent reviewers, and if they disagreed a third reviewer (M.C.P.) was consulted.
The initial search was performed on 1 February 2022. All publications were included since inception up until the end of January 2022.
All the papers with available full text, reporting original data of patients with Carbapenemresistant bacteria infections treated with CFD, of any age, gender, and in any setting, were included. No language restrictions were applied.

Inclusion and Exclusion Criteria
Studies were included if they met all of the following criteria: - The full study was published; - The study described clinical use of CFD for HAI; - The agent responsible for the infection was carbapenem-resistant bacteria; - The study reported the clinical outcome of the patient(s) treated with CFD.
Exclusion criteria were: • The study did not report clinical outcome; • The study had duplicate data with others (in these cases, only the largest study was retained); • The study presented pooled data that did not allow for extrapolation of useful information.
According to an international expert proposal, the definition of Carbapenem-Resistant Organisms (CRO) is as follows [22,23]:
In Table 1, we reported the breakpoint values of minimum inhibitory concentration for carbapenems according to guidelines in Europe (EUCAST) and the United States (CLSI). Table 1. Breakpoint values of minimum inhibitory concentration (mg/L) for carbapenems according to guidelines in Europe (EUCAST) and the United States (CLSI).

Results
Based on the inclusion criteria, a total of 19 publications treating cases of infection by CR bacteria in patients were selected to conduct this review. Eight series (a randomized controlled trial [24], two retrospective monocentric [25,26], and five case series [26][27][28][29][30]) and eleven case reports published between 2017 and 2021 were included. As shown in Figure 1, the flow diagram reports the results from the literature search and the study selection process.

Results
Based on the inclusion criteria, a total of 19 publications treating cases of infection CR bacteria in patients were selected to conduct this review. Eight series (a randomiz controlled trial [24], two retrospective monocentric [25,26], and five case series [26-3 and eleven case reports published between 2017 and 2021 were included. As shown Figure 1, the flow diagram reports the results from the literature search and the stu selection process.  Table 2, all the studies are presented in alphabetical ord with a brief clinical description for each case.  Table 2, all the studies are presented in alphabetical order with a brief clinical description for each case.

Patients.
A total of 172 patients were included in this review. Bassetti et al., reported 101 patients with serious infections caused by carbapenem-resistant Gram-negative bacteria, but of these only 80 completed CFD therapy. The mean age was 58.8 ± 15.8 years (15-92 years). Sex was reported for 160 patients: males were 111 (69.4%) and females were 49 (30.6%).
Baseline characteristics of patients are reported in Table 3.
Significant risk factors frequently associated with carbapenem resistance were: longer hospital stays and ICU hospitalization (n = 80), at least three types of antimicrobial therapy received (n = 106), previous use of carbapenem (n = 70), septic shock or immunocompromised conditions (n = 57), and invasive life support (n = 11).
Significant risk factors frequently associated with carbapenem resistance were: longer hospital stays and ICU hospitalization (n = 80), at least three types of antimicrobial therapy received (n = 106), previous use of carbapenem (n = 70), septic shock or immunocompromised conditions (n = 57), and invasive life support (n = 11).
Adverse Events (AEs) and outcome. As shown in Figure 3, a total of 98 treatmentemergent adverse events (TEAE) were reported. The most frequently reported TEAEs were diarrhea (n = 19), pyrexia (n = 14), septic shock (n = 13), and vomiting (n = 13). In Bassetti et al., TEAEs led to study drug discontinuation in three patients due to pyrexia, aminotransferase increase, and skin rash. In Bodro et al., cefiderocol was discontinued due to thrombocytopenia.

Discussion
During the last decade, there has been an alarming global increase in the incidence and prevalence of carbapenem-resistant GN bacteria. The three most frequent carbapenemresistant pathogens in this review were Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. This is in accord with the European Centre for Disease Prevention and Control (ECDC) epidemiological report for 2020 [43]. Carbapenem resistance was common in Acinetobacter species (38%), Pseudomonas aeruginosa (17.8%), and Klebsiella pneumoniae (10%). In 2019, the U.S. Centers for Disease Control and Prevention (CDC) reported 13,100 cases of carbapenem-resistant Enterobacteriaceae and 8500 cases of carbapenem-resistant Acinetobacter; multidrug-resistant Pseudomonas aeruginosa were isolated in 32,600 cases [44].
According to our data, the most effective carbapenemases, in terms of carbapenem hydrolysis and geographical spread, are OXA, NDM, VIM, and KPC [8]. Among carbapenemresistant OXA-type β-lactamase, OXA-23 and OXA-48 were the most recurrent. The most dominant groups of Metallo-β-Lactamases (MBLs) were NDM and VIM. Cases of KPC have also been reported, frequently associated with Klebsiella Pneumoniae.
The risk factors for the development of resistance to carbapenems are the same as reported in the literature [45]; moreover, at present, with the ongoing COVID19 pandemic, the presence of multi-resistant bacteria is widespread among patients admitted to intensive care with SARS-CoV-2 infection [46].
In this review, we discuss the cases of patients who developed several types of infections by carbapenem-resistant GN bacteria, and failed several antibiotic therapy lines. Finally, 70% of them recovered after compassionate treatment with CFD.
CFD is authorized for the treatment of the complicated urinary tract infections (cUTI), and hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible GN microorganisms [20]. The studies we have included report cases due to other conditions, such as osteo-articular infections, bacteremia or sepsis, intra-abdominal infections, skin infection, and endocarditis. During the clinical course, treatment options were extremely limited, and phenotypic testing was carried out on several antibiotics to explore any alternative treatment options. In the included studies, CFD MICs of the tested strains were inferior to the susceptibility breakpoint of ≤4 mg/L accepted for Enterobacteriaceae, Pseudomonas and Acinetobacter, and proposed by the Clinical & Laboratory Standards Institute (CLSI) (see Table 5) [23]. As reported in this review, the proposed dosing regimen for CFD is 2 g intravenously every 8 h and dosage adjustments for altered renal function are required [20]. For CFDtreated patients with a creatinine clearance of more than 120 mL/min, a regimen of 2 g every 6 h is used; in case of renal impairment or dialysis, the dosing regimen for CFD is reduced [20]. The proposed treatment duration is 7-14 days [20]. In the included studies, the duration of therapy was further prolonged up to 102 days in Dragher M et al. The mean duration of therapy was approximately 26 days and was guided by the patient's clinical status.
The role of combination therapy for the treatment of severe multi-resistant GN infections has long been debated. In 31.8% of total cases, CFD was associated with different drugs, particularly with colistin. Colistin has been long considered the first-line therapy against MDR GN bacteria; however, alternative antimicrobials or combination regimens have been investigated in order to increase success rates due to the unpredictable pharmacodynamic/pharmacokinetic properties and the considerable kidney toxicity [47]. Additionally, in recent years colistin resistance significantly increased, causing a reduction in possible treatment options for multi-resistant GN infections.
Resistance to CFD was reported in six patients, all regarding Pseudomonas aeruginosa. Mechanisms through which resistance to CFD develops remain unclear. No direct correlation was observed between resistance to CFD and acquired carbapenemases. CFD is transported into the periplasmic space through siderophore iron transporters known as TonB-dependent receptors; mutations in the genes encoding for these transporters can lead to a loss of function for the receptors that are required for CFD import [48]. Associations between elevated cefiderocol MIC and β-lactamases have also been reported. B-lactamases associated with CFD resistance are NDM and Pseudomonas-extended-resistant (PER) βlactamases [49]. Mutations in the chromosomal ampC β-lactamase also are responsible for the development of resistance to CFD [50]. Among risk factors for resistance to CFD, empiric CFD use is discouraged unless there is a known risk factor for infection due to the presence of extensively drug-resistant pathogens. As with all other antimicrobials, failure to exercise careful antimicrobial stewardship may also compromise the long-term efficacy of CFD, as in the case of excessive use of ceftazidime/avibactam responsible to select for metallo-β-lactamases and for NDM [51]. Finally, the patient's travel history and geographical location may represent risk factors for resistance to CFD.
CFD was generally well tolerated, with fewer side effects than existing alternative treatments for carbapenem-resistant bacteria. Among the patients under consideration, a total of 97 adverse reactions were observed. Only in three cases, CFD administration was discontinued, although a long treatment duration was prescribed. In cefiderocol trials, some data about adverse drug reactions are available. The most frequently reported AEs are elevated liver tests and hypokalemia, all reported in more than 10% of subjects receiving CFD [52]. Diarrhea, hypomagnesemia, atrial fibrillation, thrombocytopenia, and many others have been reported with an incidence ranging from 1% to 10% [52]. Severe or serious AEs are rare, corresponding to 2% and 4.7%, respectively. An increase in all-cause mortality is observed in CFD-treated patients compared to those treated with the best available therapy [20]. Concerning mortality, a total of 48 deaths were reported.
In conclusion, the success rate of CFD therapy was satisfactory. Almost 70% of patients showed clinical recovery, and of these nearly half showed negative blood cultures and infection-free status.
Limitations. This review presents some limitations. First, it was based on observational studies, the majority of which were case series or case reports. They are often excluded from systematic reviews due to the greater potential for bias. In this report, case series and observational studies contribute to the available evidence base, and their results supplement the limited evidence available from other studies. Second, a meta-analysis was not performed, due to the design of most of the studies (case report, case series) and the lack of a comparator.

Conclusions
Despite recent advances in the development of antibacterial agents, there is still an unmet need for antibacterial agents with an acceptable safety profile that are active against carbapenem-resistant GN organisms, especially against organisms producing carbapenemases. This review indicates that CFD is active against important GN organisms including Enterobacteriaceae, P. aeruginosa, and A. baumannii. CFD seems, moreover, to have a safe profile. Therefore, CFD could provide a useful alternative for the treatment of most infections due to carbapenem-resistant GN bacteria.