Introduction
Antimicrobial resistance (AMR) poses a significant global health threat, driving morbidity and mortality worldwide (1,2). The emergence and spread of multidrug-resistant (MDR) Gram-negative bacteria, particularly carbapenem-resistant Enterobacterales, Acinetobacter baumannii (A. baumannii) and Pseudomonas aeruginosa (P. aeruginosa), are of critical concern, severely limiting therapeutic options for serious infections (1-4). The overuse of broad-spectrum antibiotics, including carbapenems, has contributed significantly to this challenge.
In response to this urgent need, new antimicrobial agents have been developed. Cefiderocol is a novel siderophore cephalosporin designed to overcome several common resistance mechanisms in Gram-negative bacteria (3). Its unique mechanism of action, utilizing bacterial iron transport systems for cell entry, allows it activity against numerous difficult-to-treat resistant (DTR) pathogens, including those producing carbapenemases (5,6).
While pivotal clinical trials such as CREDIBLE-CR (7), APEKS-NP (8) and APEKS-cUTI (9) have provided essential data on cefiderocol's efficacy and safety in specific patient populations, understanding its performance in routine clinical practice is crucial. Real-world settings often involve patients with complex comorbidities, polymicrobial infections, and prior treatment failures who may not have been fully represented in trial cohorts (3).
Therefore, the primary aim of the present study was to evaluate the real-life efficacy and safety of cefiderocol in treating patients hospitalized at the University Hospital ‘Gaetano Martino’ in Messina, Italy. The present study specifically focused on patients with proven mono- or poly-microbial infections caused by MDR/DTR Gram-negative bacteria, for whom cefiderocol was prescribed due to the failure of previous therapeutic lines or the absence of other suitable antibiotic options. The present retrospective observational study examines clinical outcomes and tolerability in this challenging patient population.
Discussion
The present retrospective observational study evaluated the real-life use of cefiderocol in a critically ill population infected with MDR Gram-negative bacteria, predominantly A. baumannii. The current findings suggest that cefiderocol may be a valuable therapeutic option in patients with limited treatment alternatives, particularly for bloodstream and soft tissue infections.
Clinical success was achieved in 66.7% of patients with BSI, closely aligning with findings from the CREDIBLE-CR trial (65.5%) (7) and the cohort study by Falcone et al (11). Similarly, a 100% success rate in skin and soft tissue infections (SSTI) mirrors the strong in vitro activity of cefiderocol against carbapenem-resistant pathogens documented in multiple studies (12,13). Conversely, the lower efficacy observed in VAP (40% success) reflects the ongoing challenges in treating this condition; this high mortality rate highlights an urgent need for optimized therapeutic strategies for VAP caused by MDR pathogens. Future studies should investigate whether alternative dosing regimens, such as prolonged or continuous infusion of cefiderocol, could improve pharmacokinetic/pharmacodynamic target attainment in the lung parenchyma and lead to improved clinical outcomes (14).
A key finding was that cefiderocol was predominantly used as part of a combination regimen (96.4%), with colistin being the most frequent partner antibiotic. This reflects a common clinical practice in treating severe infections caused by XDR pathogens such as A. baumannii, where combination therapy is often employed to achieve potential synergistic effects and mitigate the risk of resistance development (15,16). While the addition of colistin did not show a statistically significant mortality benefit in our analysis (P=0.104), the choice is often guided by the severity of illness and local resistance patterns, despite ongoing debates regarding colistin's efficacy and potential toxicity, particularly its limited pulmonary penetration.
The microbiological landscape in our cohort was dominated by A. baumannii (87.3%), a significantly higher prevalence than in previous trials such as CREDIBLE-CR (46%) (7), APEKS-NP (16%) (8) and Meschiari et al (5.9%) (17). The high rate of ICU admission and mechanical ventilation suggest these infections were primarily nosocomial, with VAP being a major source.
Notably, over 70% of the isolates were classified as XDR, with several cases potentially PDR. These findings emphasize the severity of infections managed in our setting and underscore the urgent need for effective antimicrobial options.
Septic shock was observed in 54.5% of patients and was significantly associated with mortality (P=0.001), consistent with global data estimating sepsis-related mortality at 30-40% (18). Colonization with MDR organisms at admission also associated with worse outcomes (P=0.028), highlighting the prognostic value of routine rectal swabs and active surveillance cultures in ICU settings.
The present study also sheds light on the positioning of cefiderocol in clinical practice. The indications for its use included both microbiologically confirmed infections and cases of strong clinical suspicion based on risk factors such as known colonization. This suggests a role for cefiderocol not only as a targeted therapy for confirmed DTR pathogens but also as a highly selective empiric option in critically ill patients with a high pre-test probability of having such an infection, particularly when prior broad-spectrum antibiotics have failed.
Cefiderocol demonstrated favorable tolerability in our cohort, with no serious adverse effects leading to discontinuation. Minor side effects (for example, rash, thrombocytopenia and myalgia) were infrequent and self-limiting. This safety profile aligns with published studies from randomized trials and pharmacokinetic-pharmacodynamic studies (7,19). Our findings are broadly consistent with prior clinical trials and real-world studies (20-24).
Despite these encouraging observations, the present study has important limitations. Its retrospective, single-center nature limits external validity and introduces selection bias. The absence of detailed molecular resistance testing (such as16S rRNA sequencing) and minimum inhibitory concentration (MIC) data restricts our ability to correlate outcomes with specific resistance mechanisms and precise susceptibility profiles. Additionally, the lack of a comparator arm precludes evaluation of cefiderocol's relative efficacy. Lastly, the small sample size, particularly within infection subgroups, limits the statistical power of some analyses.
Furthermore, due to the retrospective data collection, the precise timing of cefiderocol initiation relative to hospital admission or infection onset could not be consistently determined, although it was generally used after failure of prior therapies. Lastly, the small sample size, particularly within infection subgroups, limits the statistical power of some analyses. Nevertheless, our study adds valuable real-life evidence to the increasing body of literature supporting cefiderocol use in critically ill patients with few alternative treatment options. In particular, its observed efficacy in BSI and SSTI, combined with its tolerability, support its consideration in the management of infections caused by XDR A. baumannii and other MDR Gram-negative bacteria (25). Future prospective, multicenter studies are needed to further define optimal patient selection, combination therapy strategies, and the potential for resistance emergence. Moreover, long-term strategies to combat AMR will require a multifaceted approach, including robust antimicrobial stewardship, infection control, and the exploration of novel therapeutic paradigms beyond conventional antibiotics.
In conclusion, in the present real-life, retrospective study involving critically ill patients with infections caused by MDR Gram-negative bacteria-primarily A. baumannii-cefiderocol demonstrated promising efficacy and favorable tolerability, particularly in bloodstream and soft tissue infections. Despite the complexity of the cohort, which included a high prevalence of septic shock, ICU admission and XDR pathogens, clinical outcomes were comparable to those observed in controlled trials and recent observational data. Colonization with MDR organisms and septic shock were independently associated with higher mortality, emphasizing the importance of early identification and targeted antimicrobial therapy in high-risk settings. Cefiderocol was well tolerated, with no serious adverse events reported, further supporting its use in fragile and treatment-limited populations. While the retrospective, single-center design and lack of MIC data limit the generalizability of the present findings, our results contribute to the increasing body of real-world evidence supporting the role of cefiderocol as a valuable treatment option in severe infections caused by DTR Gram-negative bacteria. Future prospective, multicenter studies are needed to define optimal therapeutic strategies, including the role of combination therapy and resistance prevention.