Comparison of cefiderocol and colistin-based regimens for the treatment of severe infections caused by carbapenem-resistant Acinetobacter baumannii: a systematic review with meta-analysis and trial sequential analysis

Abstract

Background

There are multiple antibiotic regimens for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) in clinical practice. We conducted this meta-analysis to compare the efficacy and safety of cefiderocol-based regimens and colistin-based regimens in the treatment of CRAB infections.

Methods

Two authors independently searched the PubMed, Web of Science, Embase, and Cochrane databases from their establishment to April 15, 2024, to search for randomized controlled trials (RCTs) or cohort studies, and compared the clinical efficacy and safety of cefiderocol-based regimens and colistin-based regimens in the treatment of CRAB infections. The Newcastle Ottawa Scale (NOS) checklist was used to evaluate the quality of the included studies. The primary outcome was all-cause mortality, and subgroup analysis was conducted on the basis of the site of infection and the risk of bias in the studies. Trial sequential analysis (TSA) was then conducted.

Results

Six observational studies were included, with 251 cases in the cefiderocol-based group and 372 cases in the colistin-based group. Compared to the colistin-based group, the cefiderocol-based group had lower all-cause mortality (RR = 0.71, 95% CI: 0.54–0.92, P = 0.01) and 30-day mortality (RR = 0.64, 95% CI: 0.43–0.95, P = 0.03). However, for the 14-day and 28-day mortality rates, there was no statistically significant difference between two groups. According to the subgroup analysis, among patients with bloodstream infection (BSI), the cefiderocol-based group had lower all-cause mortality, but it did not reduce the mortality of ventilator-associated pneumonia (VAP) patients. The result of TSA showed that our conclusions are reliable. There was no significant statistical difference in the microbiological cure rate, clinical cure rate, or duration of hospitalization. In addition, the cefiderocol-based group did not have an increased incidence of acute kidney injury (AKI).

Conclusions

Compared with the colistin-based regimens, the cefiderocol-based regimens were significantly associated with a lower risk of mortality in CRAB-infected patients, especially for patients with BSI. However, they did not show any advantages in terms of the clinical cure rate or microbiological cure rate, nor did they reduce the incidence of AKI.

PROSPERO registration number

CRD42023487213.

Introduction

Carbapenem-resistant Acinetobacter baumannii (CRAB) often results in severe hospital-acquired infections. CRAB infections can cause bloodstream infections (BSI), ventilator-associated pneumonia (VAP), skin and soft tissue infections, and various other types of infections. The treatment of CRAB presents a significant challenge in clinical practice because of its drug resistance. In Europe, the proportion of Acinetobacter baumannii resistant to carbapenem is close to or exceeds 50% [1]. In China, the proportion of CRAB strains is gradually increasing, rising from approximately 30% in 2005 to 70% in 2023. A national survey of drug-resistant strains in Intensive Care Unit (ICU) revealed that CRAB was present in 70% of ICUs [2]. Patients infected with CRAB are at high risk of a poor prognosis, depending on the patient’s condition, clinical severity, and type of infection. Research findings indicated that the mortality can range from 40 to 70% in these cases [3, 4].

This is a highly serious situation, as the available types of antibiotics are very limited, including antibiotics such as sulbactam, colistin, tigecycline, minocycline, and others [5]. According to the guidelines [6,7,8,9], the treatment options available for CRAB infections are represented by ampicillin/sulbactam or colistin, which can be used as monotherapy or in combination with other antibiotics such as high-dose tigecycline, aminoglycosides, minocycline, and high-dose meropenem. Our preference lies in the use of combination therapy with other antibiotics for treatment, particularly focusing on colistin-based regimens. Despite the administration of active antibiotics in accordance with established guidelines, randomized controlled trials (RCTs) have indicated a higher 28-day mortality rate among patients suffering from pneumonia and BSI caused by CRAB [10]. Furthermore, the combination of colistin therapy with meropenem, fosfomycin, or other antibiotics did not reduce the 28-day mortality risk in patients compared with colistin monotherapy [3, 11, 12]. Additionally, there is a notable incidence of nephrotoxicity associated with colistin treatment (28.2%) [13]. Consequently, there is an imperative need to develop and utilize novel antibiotics that demonstrate both effective therapeutic outcomes and enhanced safety profiles. As early as 2017, the World Health Organization (WHO) identified CRAB as one of the critical drug-resistant pathogens necessitating the advancement of new antibiotic therapies [14].

Cefiderocol is an injectable iron carrier cephalosporin developed in Japan and has been approved for the treatment of carbapenem-resistant gram-negative bacteria (CR-GNB), especially for carbapenem-resistant nonfermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. Cefiderocol has demonstrated efficacy against a range of carbapenemases, including classes A, B, C, and D, as well as β-lactamases, which include AmpC and extended-spectrum β-lactamases (ESBLs). Furthermore, it is highly stable [15]. Cefiderocol was approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2019 and 2020, respectively, for the treatment of multidrug-resistant, carbapenem-resistant, or extensively drug-resistant (XDR) gram-negative bacterial infections, including CRAB. In some in vitro activity experiments, clinical RCTs and retrospective studies, cefiderocol has good antibacterial activity and good clinical curative effects on CRAB [16]. Consequently, cefiderocol is regarded as a key therapeutic option for the management of CRAB infections in clinical settings. In the guideline, cefiderocol was recommended for patients with CRAB infections who are refractory to other antibiotics or patients who cannot tolerate other antibiotics [7], although the quality of evidence is relatively low.

In clinical practice, there are ongoing discussions concerning the optimal therapy for infections caused by CRAB. This meta-analysis was undertaken to evaluate the efficacy and safety of cefiderocol-based regimens in comparison to colistin-based regimens for patients with CRAB infections. The aim is to provide evidence-based medical insights to guide the clinical selection of antibiotic therapies for this specific infection.

Methods

Protocol and guidance

This meta-analysis was conducted in strict accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline. The protocol of this study was registered in PROSPERO (Registration Number: CRD42023487213).

Literature search strategy

According to the inclusion and exclusion criteria, two independent authors (WCM and DFL) searched PubMed, EMBASE, the Cochrane Library, and the Web of Science. The retrieval time ranged from the inception of the databases to April 15, 2024, and the language was not restricted. When we conducted a literature search in PubMed, the retrieval methods included medical subject heading (MeSH) term retrieval, liberal term retrieval, and Boolean logic operation. When we conducted literature searches in EMBASE, the Web of Science, and the Cochrane Library, we used keywords for retrieval. The search was performed using the following items: ((Cefiderocol) AND ((Colistin) OR (polymyxin) OR (Colistimethate Sodium)) AND ((CRAB) OR (Carbapenem Resistant Acinetobacter Baumannii))). Disagreements in the research were resolved through discussion. When disagreements were not resolved by discussion, the third author (QY) participated and made a decision.

Eligibility criteria

The eligibility criteria included the following: (1) The studies included observational studies, nonrandomized controlled trials (non-RCTs), and RCTs. (2) These studies evaluated the efficacy and safety of cefiderocol-based regimens in comparison to colistin-based regimens for the treatment of infections caused by CRAB. There were no restrictions placed on the specific sites of infection, which included VAP, BSI, and urinary tract infections (UTI). (3) The study included at least one of the following outcomes: all-cause mortality, 14-day mortality, 28-day mortality, 30-day mortality, clinical cure rate, microbiological cure rate, incidence of acute kidney injury (AKI), and duration of hospitalization. The exclusion criteria included animal studies, case reports, reviews, systematic reviews, meta-analyses, studies with incomplete original data, and duplicate publications.

Data extraction

The data included in the studies were extracted independently by 2 authors (DFL and WCM). We have read the articles that might met the inclusion criteria and extracted associated data using a self-made data extraction table. If there were any disagreements, the third author (QY) would participate and reach a consensus. The following information was extracted from each study: (1) Basic research information: including the name of the first author, the year of publication, the country where the research was conducted, and the type of research. (2) Baseline characteristics of patients: mainly including the number of patients included in the study and the specific site of infection of the patients. (3) Intervention measures: the specific medication regimen for the cefiderocol-based group and colistin-based group, and whether other types of antibiotics were used in combination. (4) Outcomes: all-cause mortality, 14-day mortality, 28-day mortality, 30-day mortality, clinical cure rate, microbiological cure rate, incidence of AKI, and duration of hospitalization.

All-cause mortality included 28-day mortality, 30-day mortality, 90-day mortality and death at other time points. If multiple time point mortality rates were reported, mortality in the main analysis was recorded at the latest point in the study. Clinical cure is defined as the disappearance of a patient’s clinical symptoms, including fever, cough, phlegm, etc., after the completion of antibiotic treatment. Microbiological cure is defined as the removal of microorganisms from the corresponding infected area of patients after the use of antibiotics, which is obtained through microbial culture results. AKI is defined through the Kidney Disease Improving Global Guidelines (Kidgo) [17].

Methodological quality assessment

Because all the studies we ultimately included were observational, the Newcastle Ottawa Scale (NOS) was used to evaluate the quality of all the included studies [18]. The NOS checklist includes three quality parameters: selected population, group comparability, and evaluation of exposure or results of interest in case-control or cohort studies. The scores for each study ranges from 0 to 9. A study with a score of ≥ 7 is considered to be of high quality.

Statistical analysis

Review Manager 5.4 software provided by the Cochrane International Cooperation Organization and STATA version 17.0 (StataCorp., College Station, TX) were used for data analysis. The significance level for the 2-sided tests was 0.05, and P < 0.05 was considered statistically significant. The effect statistics for metrological data were analyzed by the mean deviation (MD) and standard deviation (SD), and those for counting data were analyzed by the relative risk (RR) and 95% confidence interval (CI). The Peto-modified Mantel-Haenszel fixed effects model was used if there was no significant heterogeneity (I² < 50%, P > 0.05). In contrast, the DerSimonian and Laird random effects model was used if the heterogeneity test was significant (I² ≥ 50%, P < 0.05). Since most of the articles included in this study were retrospective cohort studies, and the heterogeneity between the studies was significant, the random effects model was used for data consolidation in this study. The subgroup analysis plan was as follows: (1) According to the risk of bias of the studies (low risk of bias compared with high risk of bias). (2) A subgroup analysis was performed on the basis of the site of infection.

A trial sequential analysis (TSA, version 0.9.5.10 beta) was performed on the findings to reduce the risk of random errors caused by an insufficient sample size and repeated tests. The TSA computes the best statistics and appropriate significance boundaries for meta-analysis. When the cumulative Z curve passes through the TSA significance boundary, enters the invalid area or reaches the optimal sample size, clear conclusions can be drawn. If the cumulative Z curve does not cross any boundary, no clear conclusions can be drawn. In the TSA analysis, α = 0.05 (bilateral) and β = 0.20 were used to compute the optimal sample size, and the relative risk reduction was based on a 20% reduction in the control group.

A funnel plot was used to analyze potential publication bias. Egger’s and Begg’s tests were used to evaluate asymmetry in the funnel plot. In instances where publication bias was detected, the “trim and fill” method was applied to account for potentially omitted studies.

Results

Literature retrieval

A total of 210 articles were retrieved, of which 56 were from PubMed, 85 from EMBASE, 68 from Web of Science, and 1 from the Cochrane Library. After removing the duplicate articles, 114 articles remained. After the review, some articles, including systematic reviews, case reports, and comments, were excluded. Ultimately, the remaining 19 articles could be read thoroughly. Thirteen studies were excluded, because the control group was not treat with an antibiotic regimen based on colistin. Finally, 6 studies [19,20,21,22,23,24] met all the criteria for selection. The detailed PRISMA flow chart of the study is shown in Fig. 1.

Fig. 1

PRISMA flow diagram of the study selection process

Methodological quality evaluation

After carefully evaluating the methodological quality of the six included studies, we determined that four were classified as high-quality studies [19, 20, 22, 24], whereas the remaining two were low-quality studies [21, 23]. The specific methodological quality assessment for each study is shown in Table 1.

Table 1 The detailed characteristics of the included studies

Basic characteristics of the included studies

The meta-analysis included six observational studies, including one prospective study [22] and the remaining five retrospective studies [19,20,21, 23, 24]. All included studies were published from 2021 to 2023, and all studies were conducted in Italy. The use of cefiderocol in all studies included monotherapy or combination therapy with other antibiotics. Regarding the infection sites of the patients involved in the study, two studies [22, 24] focused on patients with VAP, one study [21] focused on patients with BSI, and the remaining three studies [19, 20, 23] did not restrict their scope to particular infection sites, including the BSI, UTI and VAP. All the studies reported mortality data, with three studies [19, 22, 24] reporting 14-day mortality data, two studies [19, 22] reporting 28-day mortality data, four studies [20, 21, 23, 24] reporting 30-day mortality data, and one study [21] reporting 90-day mortality data. For secondary outcomes, two studies reported data on the clinical cure rate [19, 23] and microbiological cure rate [19, 23], respectively. Five studies [19,20,21,22,23] reported data on the incidence of AKI. Three studies [20, 22, 24] reported data on the duration of hospitalization. All baseline characteristics included in the study are listed in detail in Table 2.

Table 2 Methodological quality assessment of the included studies

Results of the meta-analysis and TSA

Primary outcomes: all-cause mortality, 14-day mortality, 28-day mortality and 30-day mortality

All included studies [19,20,21,22,23,24] reported data on all-cause mortality. Among the 623 patients, 251 were in the cefiderocol-based group and 372 were in the colistin-based group. The random effects model was used for the meta-analysis. The meta-analysis results revealed that for CRAB-infected patients, the cefiderocol-based regimens outperformed the colistin-based regimens and had a lower all-cause mortality rate (RR = 0.71, 95% CI: 0.54–0.92, P = 0.01). We performed subgroup analysis according to the risk of bias of the included studies. The results indicated that in the low-risk bias studies, the cefiderocol-based group presented a lower all-cause mortality rate (RR = 0.63, 95% CI: 0.42–0.95, P = 0.03). However, in the high-risk bias studies, the cefiderocol-based regimens did not reduce the all-cause mortality rate (RR = 0.82, 95% CI: 0.57–1.18, P = 0.29) (Fig. 2).

Fig. 2

Forest plot comparing the all-cause mortality in the cefiderocol-based group to that of in the colistin-based group

The result of the TSA reveled that a total of 623 patients were included in the analysis, with a required information size (RIS) of 1280. The cumulative Z-curves crossed both the conventional boundary and the trial sequential monitoring boundary, which indicated the reliability of the meta-analysis results. Although the cumulative sample size did not reach the expected sample size, the TSA result suggested that compared with the colistin-based regimens, the cefidocol-based regimens could reduce all-cause mortality in patients infected by CRAB (Fig. 3).

Fig. 3

Trial sequential analysis (TSA) for all-cause mortality

Three studies [19, 22, 24] involving a total of 270 patients, with 101 in the cefiderocol-based group and 169 in the colistin-based group, provided data on 14-day mortality. The results indicated that there was no significant difference in the 14-day mortality between the two groups (RR = 0.30, 95% CI: 0.07–1.27, P = 0.10) (Fig. 4a). For the 28-day mortality, only 2 studies reported 28-day mortality [19, 22]. A total of 197 patients were enrolled, with 82 in the cefiderocol-based group and 115 in the colistin-based group. The results of the meta-analysis revealed that, compared with colistin-based regimens, cefiderocol-based regimens did not reduce 28-day mortality (RR = 0.84, 95% CI: 0.61–1.14, P = 0.26) (Fig. 4b). Nevertheless, cefiderocol-based regimens showed an advantage in reducing the 30-day mortality rate. A meta-analysis of the 4 studies [20, 21, 23, 24] including 426 patients suggested that cefiderocol-based regimens could reduce the risk of 30-day mortality compared with colistin-based regimens (RR = 0.64, 95% CI: 0.43–0.95, P = 0.03)(Fig. 4c).

Fig. 4

Forest plot comparing the mortality in the cefiderocol-based group to that of in the colistin-based group (a: 14-day mortality, b: 28-day mortality, c: 30-day mortality)

Subgroup analysis for infection site

Specific infection sites were reported in 5 studies, of which 2 focused on BSI [20, 21] and 3 focused on VAP [20, 22, 24]. A total of 395 patients were included, with 141 patients in the cefiderocol-based group and 254 patients in the colistin-based group. In the analysis of all-cause mortality, the cefiderocol-based group had a lower all-cause mortality (RR = 0.61, 95% CI: 0.43–0.87, P = 0.006). However, in the subgroup analysis, for patients with BSI, a decrease in all-cause mortality was observed in the cefiderocol-based group (RR = 0.61, 95% CI: 0.41–0.90, P = 0.01), whereas for VAP patients, there was no statistically significant difference in all-cause mortality between the two groups (RR = 0.62, 95% CI: 0.33–1.17, P = 0.14) (Fig. 5).

Fig. 5

Forest plot of the subgroup analysis comparing all-cause mortality in the cefiderocol-based group to that of the colistin-based group stratified by different infection sites

The secondary outcomes: clinical cure rate, microbiological cure rate, duration of hospitalization

Only two studies reported data on the clinical cure rate [19, 23]. A total of 218 patients were included, including 102 patients in the cefiderocol-based group and 116 patients in the colistin-based group. We found that there was no significant statistical difference between the two groups in terms of the clinical cure rate (RR = 1.10, 95% CI: 0.88–1.37, P = 0.40) (Fig. 6a).

Fig. 6

Forest plot comparing the secondary outcomes in the cefiderocol-based group to those in the colistin-based group (a: clinical cure rate, b:microbiological cure rate, c:duration of hospitalization.)

For the microbiological cure rate, only two studies included relevant data [19, 23]. The result of the meta-analysis showed that there was no significant difference in the microbiological cure rate between the two groups (RR = 1.13, 95% CI: 0.78–1.63, P = 0.52) (Fig. 6b).

Three studies reported data on the duration of hospitalization [20, 22, 24]. A total of 287 patients were included, of whom 106 were in the cefiderocol-based group and 181 were in the colistin-based group. The result revealed that there was no significant difference in the length of duration of hospitalization between the two groups (MD = 7.23, 95% CI: -2.02 to 16.47, P = 0.13) (Fig. 6c).

Adverse events: AKI

For the analysis of adverse events, only AKI data were analyzed, and five studies were included [19,20,21,22,23]. A total of 550 patients were included, of which 232 were in the cefiderocol-based group and 318 were in the colistin-based group. The results suggested that there was no significant difference in the incidence of AKI between the cefiderocol-based group and the colistin-based group (RR = 0.71, 95% CI: 0.44–1.14, P = 0.16). The subgroup analysis revealed that there was no significant statistical difference in the incidence of AKI between the cefiderocol-based group and the colistin-based group, regardless of whether studies had a high or low risk of bias (Fig. 7).

Fig. 7

Forest plot comparing the AKI in the cefiderocol-based group to that in the colistin-based group

Sensitivity analysis and publication bias

We perform a leave-one-out sensitivity analysis to assess the robustness of our meta-analysis. In the analysis of all-cause mortality, there was significant heterogeneity among the included studies. When we removed the trail “Russo 2023”, the I² value could be reduced to less than 50%. In this study, there was a significant difference in sample size between the cefiderocol-based group and colistin-based group, and the mortality of patients in the colistin-based group was extremely high, close to 100%. This may be the reason for the significant heterogeneity between studies. When we deleted the study “Russo 2023” and conducted a meta-analysis, we found that the all-cause mortality of the cefiderocol-based group was still lower (RR = 0.78, 95% CI: 0.65–0.95, P = 0.01). Another reason is that we included studies with s high risk of bias, after removing two studies with high risk of bias, our meta-analysis results did not change (Fig. 2). We also assessed the publication bias for all-cause mortality through a funnel plot. In the funnel plot, we chose RR as the abscissa and standard error as the ordinate. The funnel plot was visually asymmetrical (Fig. 8), indicating potential publication bias. We further evaluated potential publication bias through Egger’s and Begg’s tests. The results of Egger’s test (Z=-2.61, P = 0.0090) and Begg’s test (Z=-1.88, P = 0.1329) indicated the presence of publication bias. Using the “trim and fill” method, one potentially missing study was included (Fig. 9), and the result showed an adjusted effect size (RR) of 0.78 (95% CI: 0.55–1.08), suggesting that the current research results are not robust enough.

Fig. 8

Funnel plot of publication bias analysis included in all-cause mortality analysis literature

Fig. 9

Funnel plot of publication bias analysis after the “trim and fill” method

Discussion

To our knowledge, this is the first meta-analysis to assess the efficacy and safety of cefiderocol-based regimens in comparison with colistin-based regimens in the treatment of CRAB infections. Our findings indicate that, with respect to the primary outcomes, the cefiderocol-based regimen is associated with lower all-cause mortality and 30-day mortality rates when than the colistin-based regimens. However, no statistically significant differences were observed in 14-day or 28-day mortality. Subgroup analyses revealed that the cefiderocol-based regimen demonstrated superior therapeutic efficacy and reduced all-cause mortality in patients with BSI, whereas in patients with VAP, the efficacy of the cefiderocol-based regimen was not found to be superior to that of the colistin-based regimen. Furthermore, the TSA result for all-cause mortality support the reliability of our conclusions. In terms of secondary outcomes, there was no significant differences were observed in the microbiological cure rate, clinical cure rate, or duration of hospitalization between the two groups. Additionally, in terms of adverse events, compared with the colistin-based group, the group based on cefiderocol did not have a lower incidence of AKI.

CRAB is a prevalent pathogen associated with hospital-acquired infections, especially in intensive care units. The mortality rate among patients infected with CRAB is significantly elevated, with reports showing a mortality rate of up to 70% [3, 4]. Patients infected with CRAB presented a markedly greater disease burden, an elevated risk of mortality, extended duration of hospital stay days, increased rates of readmission, and higher healthcare costs than did those infected with carbapenem-susceptible strains of the organism [25]. Although CRAB infections often lead to serious consequences, the best available therapy (BAT) for CRAB-infected patients is not yet clear. The latest guideline from the American Society of Infectious Diseases (IDSA) recommend the use of ampicillin/sulbactam in combination with at least one additional antimicrobial agent for the management of infections caused by CRAB. Alternatively, polymyxin B, high-dose minocycline, high-dose tigecycline, or cefiderocol can be used. It is recommended that at least two drugs should be used in combination before clinical improvement [7]. In patients requiring treatment, anti-infective regimens that include colistin, often in combination with tigecycline, sulbactam, and other agents, are commonly employed. However, this combination therapy was associated with a significant incidence of nephrotoxicity and a high rate of clinical failure [26, 27]. Concurrently, the widespread use of colistin has resulted in the emergence of colistin-resistant CRAB (col-R CRAB), which presents a greater threat to patients, and some studies have reported higher mortality rate in patients infected with col-R CRAB. Therefore, the BAT for CRAB is particularly important [28, 29].

Notably, the IDSA guideline recommend cefiderocol for the treatment of CRAB, which is refractory to other antibiotics, or is used in cases where other drugs are intolerant or resistance precludes their use [7]. When treating CRAB infections, its use in combination with other antibiotics is also recommended, as monotherapy is not recommended. Cefiderocol, a newly approved β-lactam antibiotic by the FDA, has demonstrated potential for the treatment of infections caused by CRAB. While in vitro studies have indicated a high efficacy rate of 94.9% for cefiderocol against CRAB infections [30], its clinical utilization is significantly constrained by the findings from the CREDIBLE-CR study [31]. This study evaluated the efficacy and safety of cefiderocol or the BAT for severe infections caused by CR-GNB. Compared with that of the BAT group, the mortality rate of the cefiderocol group was higher (18% VS 34%), with the majority of these fatalities occurring within the subgroup of patients with CRAB infections. However, it should be noted that the subgroup infected with CRABpresented a greater frequency of septic shock, a higher frequency of hospitalization in the ICU, and a higher proportion of moderate and severe renal dysfunction. These factors are significantly associated with an increased risk of mortality. Consequently, the elevated mortality rate observed within the CRAB infection subgroup may not be attributable to variations in therapeutic interventions. Nonetheless, this RCT has a significant impact on the utilization of cefiderocol in the management of infections caused by CRAB. Another RCT revealed that cefiderocol was not inferior to high-dose, prolonged infusion of meropenem (2 g by 3-h every 8 h) in the treatment of CRAB infections, and there was no significant difference in all-cause mortality between the two groups (12.4% vs. 11.6%) [32]. Following the incorporation of several retrospective studies into the meta-analysis, it was observed that the all-cause mortality in the cefiderocol group was significantly lower than that in the BAT group [33]. Considering the significant heterogeneity among studies and the fact that the vast majority of studies are retrospective, more large sample size RCTs are needed to validate this viewpoint.

Our meta-analysis results suggested that compared with the colistin-based group, the cefiderocol-based group had lower all-cause mortality and 30-day mortality rates, which is consistent with the latest meta-analysis results [33]. Since most “best available therapies” include colistin, such findings are reasonable. Among the six studies included, four [19, 21,22,23] reported lower all-cause mortality in the cefiderocol-based group than in the colistin-based group, but the difference was not statistically significant. The other two studies [20, 24] reported significantly lower all-cause mortality. Compared with the regimens based on colistin, the cefiderocol-based group had lower all-cause mortality, and the TSA result also confirmed the reliability of our findings. The regimens based on cefiderocol offers new hope for the treatment of CRAB infections. However, it should be noted that only one of the included studies was a prospective observational study, while the remaining studies were retrospective studies, with significant heterogeneity between studies, resulting in a lower quality of evidence. Regarding 14-day mortality, two studies [22, 24] reported lower mortality rates, whereas one study [19] reported no significant difference in mortality. Owing to the limited research data and significant heterogeneity among studies, the interpretation of these results should be cautious, and more data may be needed to support them.

Subgroup analysis of different infection sites revealed that BSI patients have lower mortality rates. In VAP patients, cefiderocol is not superior to colistin, and there is no significant difference in mortality rate between the two groups. What factors may have contributed to this outcome? A large part of the reason is attributed to the characteristics of antibiotics. Cefiderocol is a type of β-lactam antibiotic, and the binding rate of plasma protein is approximately 58%, which is mainly excreted through the kidney in its original state. Therefore, the concentration of cefiderocol in the plasma is relatively high, whereas the concentration in the lung epithelial lining fluid (ELF) is lrelatively low. As recorded in healthy volunteers, the low cefiderocol ELF to total/free plasma ratios are shown (0.101/0.239, respectively) [34]. Moreover, as a time-dependent antibiotic, the key pharmacodynamic parameter that is most closely related to the bactericidal efficacy of cefiderocol is the fraction of the dosing interval during which the free drug concentration exceeds the minimal inhibitory concentration (MIC) (% fT > MIC) [35]. In a case report that included 13 patients who received treatment with cefiderocol for XDR-AB infection (6 patients with BSI plus VAP, 5 patients with VAP, and 2 patients with BSI), 7 patients experienced microbiological failure, with 6 patients in the VAP group and 1 patient with VAP plus BSI. All BSI patients achieved an optimal or quasi-optimal fCmin/MIC ratio, whereas only 50% of VAP patients achieved this pharmacokinetic/pharmacodynamic (PK/PD) target [36]. Owing to the sub-optimal penetration of cefiderocol in ELF, higher doses of cefiderocol may be required to achieve effective concentrations in the ELF of VAP patients [37].

The necessity of combining cefiderocol with other antibiotics for the treatment of CRAB infections still seems to be a debated issue. A multicenter prospective observational study revealed no differences in mortality (51.7% vs. 45.5%), clinical failure (41.4% vs. 63.7%), or microbiological failure (24.1% vs. 9.1%) between monotherapy and combination therapy with cefiderocol in the treatment of infections caused by CRAB [38]. A retrospective study [39] revealed that critically ill patients suffering from CRAB infections who received cefiderocol monotherapy had a higher clinical success rate (61.2% vs. 49%) than did those who were treated with combination therapy. In our study, the use of cefiderocol in all studies encompass both monotherapy and combination therapy with other antibiotics. Therefore, we are unable to conduct further subgroup analysis to determine whether the use of cefiderocol monotherapy is superior or inferior to combination therapy in terms of efficacy and safety.

Compared with the colistin-based regimens, cefiderocol-based regimens demonstrated superior clinical cure rates (59.8% vs. 50%) and microbiological cure rates (37.3% vs. 30.2%). However, these differences did not reach statistical significance. Given that only two studies with a limited sample size were included in the meta-analysis, the conclusions are not necessarily reliable. The resistance rates of CRAB to cefiderocol and colistin appear to be comparable. According to recent findings, 94.9% of Acinetobacter baumannii strains demonstrate an MIC of cefiderocol at or below 2 mg/L, whereas 93.6% of isolatesare sensitive to colistin. Furthermore, in contrast to other pathogens, cefiderocol exhibits widespread heterogeneous resistance to CRAB, which may result in the failure of cefiderocol treatment [40].

Data on the incidence of AKI was available for analyse in terms of adverse events. It is evident that the cefiderocol group has a lower incidence of AKI than the colistin group did, although the difference was not statistically significant. The significant nephrotoxicity associated with colistin is a primary concern. A meta-analysis indicated that the overall incidence of nephrotoxicity during the administration of colistin is 28.2% [13].

Consequently, there is presently insufficient evidence to determine the necessity of cefiderocol in the treatment of infections caused by CRAB. The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guideline [9] recommend against the use of cefiderocol for the treatment of infections caused by CRAB(conditional recommendations against use, low certainty of evidence). The guideline of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) suggest that cefiderocol can be used as part of combination therapy when treatment options are limited. Pandrug-resistant Acinetobacter baumannii (PD-RAB) can be treated with colistin, high-dose meropenem, or high-dose sulbactam in combination with other antibiotics [41]. Some new suggestions were subsequently proposed in the IDSA guidelines [7]. The current standing of cefiderocol in the management of CRAB is relatively low, mainly due to the limited number of related RCT studies and even negative RCT results [31, 32].

Our meta-analysis has the following advantages. First, we systematically evaluated the efficacy and safety of regimens based on the cefiderocol and regimens based on colistin in the treatment of CRAB infections. We conducted sensitivity analysis and trial sequential analysis to assess the reliability of our findings. Second, we conducted several meaningful subgroup analyses to comprehensively evaluate the impact of different infection sites, which may provide insights for clinical antibiotic regimen selection. However, our meta-analysis has several limitations. First, most of the included studies were retrospective, with only one being prospective. Second, the sample sizes varied among the included studies, leading to significant heterogeneity. Although we used a random effects model to reinforce the results, caution is still needed when interpreting our findings. Third, different studies have inconsistent antibiotic combination therapy regimens, which poses significant challenges to our interpretation of the results. Fourth, we are aware that colistin is associated with pronounced nephrotoxicity and neurotoxicity, which are directly linked to the dosage administered. Moreover, the therapeutic effectiveness of colistin is intricately tied to its dosage levels. However, as only two articles provide specific details on the dosage of colistin, we are unable to elucidate the influence of colistin dosage on the efficacy and safety within the colistin-based group. Fifth, we employed the Newcastle-Ottawa Scale for methodological quality assessment, which may also be a limitation in our manuscript. While it is widely used in meta-analysis, its standardization level is relatively modest. Finally, there is publication bias in our meta-analysis, and our results are not reliable enough. These findings need to be interpreted carefully.

Conclusion

Cefiderocol, as a novel iron carrier cephalosporin, demonstrates high in vitro antibacterial activity against CRAB and can be utilized clinically for the treatment of CRAB infections in adult patients when alternative therapeutic options are scarce. According to our research, a regimen containing cefiderocol has superior clinical efficacy and greater safety in treating CRAB infection than does a colistin-based regimen, but this benefit has not been reflected in the microbiological cure rate. It is anticipated that cefiderocol will emerge as a viable therapeutic option for CRAB infections, although further RCTs are necessary to clarify its clinical role.