Real-life experience with compassionate use of cefiderocol for difficult-to-treat resistant Pseudomonas aeruginosa (DTR-P) infections

Abstract

Objectives To describe our real-life experience with cefiderocol in XDR and difficult-to-treat resistant Pseudomonas aeruginosa (DTR-P) infections without any other available treatment options. Methods We included patients with a proven infection due to an XDR/DTR-P, who had failed on previous regimens, and were treated with cefiderocol, following them prospectively to day 90 or until hospital discharge or death. Results Seventeen patients treated for >72 h with cefiderocol were included: 14 receiving combination regimens (82.4%) and 3 receiving monotherapy (17.6%). Fourteen patients were males (82%) with a median age of 64 years (IQR 58–73). Fifteen patients (88.2%) were admitted to the ICU and five had septic shock (29%). Seven cases (41.2%) were ventilator-associated pneumonia, of which 71% (5/7) occurred in COVID-19 patients. Four were complicated intrabdominal infections, one ecthyma gangrenosum, one nosocomial pneumonia and one empyema, one osteomyelitis, one primary bacteraemia, and one nosocomial external ventricular drainage meningitis. Clinical cure and microbiological cure rates were 70.6% and 76.5%, respectively. There were six deaths (35.3%) after a median of 8 days (IQR 3–10) from the end of treatment, but only two of them (11.7%) were associated with P. aeruginosa infection progression. Conclusions Our experience collecting this large case series of DTR-P treated with cefiderocol may help clinicians consider this new option in this hard-to-manage setting. Our results are even more relevant in the current scenario of ceftolozane/tazobactam shortage. Importantly, this is the first study providing real-life data indicating adequate cefiderocol concentrations in CSF.

Cefiderocol: Systematic Review of Mechanisms of Resistance, Heteroresistance and In Vivo Emergence of Resistance

“…In vivo emerging resistance has also been reported in small observational case series [ 26 , 34 , 35 , 36 ]. In one study, 17 patients were treated with cefiderocol for difficult-to-treat P. aeruginosa infection, and relapses occurred in 3 of the patients, but repeat MIC testing was available in only 1 patient (fourfold increase from 0.25 to 1 mg/L) [ 26 ].…”

“…The study flow chart is depicted in Figure 1 . A total of n = 52 relevant studies were reviewed [ 12 , 14 , 15 , 16 , 17 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 ]. All studies were published after 2018; n = 17 (33%) in 2022, n = 18 (35%) in 2021, n = 12 (23%) in 2020, n = 1 (2%) in 2019, and n = 4 (8%) in 2018.…”

“…Data about the prevalence of heteroresistance were available in only two studies [ 20 , 33 ]. Data about resistance emerging in vivo (during/after cefiderocol treatment) were available in 12 studies [ 21 , 22 , 23 , 24 , 25 , 26 , 32 , 34 , 35 , 36 , 38 , 39 ].…”

“…Nevertheless, cefiderocol resistance has been reported to be high in selected cohorts [ 14 , 15 , 16 , 17 , 18 , 19 ]. The prevalence of heteroresistance may also be high [ 20 ], and cases of resistance emerging during treatment are increasingly being reported [ 21 , 22 , 23 , 24 , 25 , 26 ]. The aim of this manuscript was to systematically review mechanisms of resistance to cefiderocol, prevalence of heteroresistance and reports of in vivo emerging resistance.…”

Outcomes with Cefiderocol Treatment in Patients with Bacteraemia Enrolled into Prospective Phase 2 and Phase 3 Randomised Clinical Studies

“…Our post hoc analysis data are complemented by efficacy findings for cefiderocol in real-life cases of difficult-to-treat severe gram-negative infections. Microbiological clearance from repeat blood cultures was seen in around 67% of a total of 60 patients with BSI due mainly to CR or XDR A. baumannii and difficult-to-treat resistant P. aeruginosa [34][35][36][37][38][39][40][41][42]. A more complete picture of the real-world efficacy of cefiderocol in gram-negative BSI patients will be provided by the ongoing Phase 2 GAMECHANGER study, an open-label, prospective, randomised, controlled, non-inferiority trial, comparing cefiderocol and standard of care in the treatment of healthcare-associated or hospital-acquired BSI (NCT03869437; [43]).…”