Effectiveness and safety of cefiderocol treatment in patients with Gram-negative bacterial infections in Spain in the early access programme: results of the PERSEUS study

Abstract

Purpose: We assessed the effectiveness and safety of cefiderocol in patients with Gram-negative bacterial infections, excluding Acinetobacter spp., in the early access programme (EAP) in Spain.

Methods: The retrospective, multicentre PERSEUS study (2018-2022) enrolled hospitalised patients with serious Gram-negative infections, except Acinetobacter spp., who received first-time cefiderocol for ≥ 72 h following requests through the EAP. Clinical cure at end of treatment, all-cause mortality at Day 28, cefiderocol use, and adverse drug reactions (ADRs) were the key outcomes.

Results: Overall, 261 patients were eligible for analysis. Median (interquartile range) age was 61 (49-68) years, 202 (77.4%) were male and 165 (63.2%) were in the intensive care unit. The most frequent diagnoses were respiratory tract infection (47.9%), intra-abdominal infection (14.6%), and urinary tract infection (14.6%). The median (IQR) duration of cefiderocol treatment was 10 (7-14) days. Overall, the clinical cure rate was 80.5% (210/261) and the 28-day mortality rate was 21.5% (56/261). In patients with Pseudomonas aeruginosa infection (66.7% [n = 174], including 73 [42%] with metallo-β-lactamases), the clinical cure rate was 84.5% (147/174) and the 28-day mortality was 17.2% (30/174). Logistic regression analysis showed that prior antibiotic treatment for > 7 days (OR 0.19, 95% CI 0.05-0.56) and mechanical ventilation (OR 0.32, 95% CI 0.15-0.67) were independent negative predictive factors for clinical cure. ADRs occurred in seven patients, six events resolved, and one was fatal (toxic epidermal necrolysis).

Conclusions: Cefiderocol is a valuable option in the treatment of serious Gram-negative bacterial infections, particularly for those caused by P. aeruginosa.

Clinicaltrials: GOV: NCT05789199 (Registration date: 16 February 2023).

Keywords: Pseudomonas aeruginosa; Carbapenem resistance; Cefiderocol; Early appropriate therapy; Gram-negative; Limited treatment options; Multidrug resistance.

Fig. 1

Patient enrolment and flow through the study; ^aVerification between the infection site and the biospecimen was absent

Fig. 2

Rates of clinical cure at end of treatment and all-cause mortality at Day 28, in the overall primary analysis population (N = 261) and by baseline Gram-negative pathogen. NF-GN, non-fermenter Gram-negative; Other Enterobacterales (n): S. marcescens (5), E. cloacae (3), K. oxytoca (2), C. freundii (1), Serratia spp. (1); Pseudomonas spp. (n): P. putida (12), Pseudomonas fluorescens/putida group (1), P. fluorescens (1), P. nitroreducens (1); Other NF-GN (n): Burkholderia cepacia complex (8), Achromobacter spp. (5), Ralstonia mannitolilytica (1)

Fig. 3

Rates of clinical cure at end of treatment and all-cause mortality at Day 28 by infection site in the overall primary analysis population (N = 261). BSI, bloodstream infection; IAI, intra-abdominal infection; UTI, urinary tract infection; ^aIncludes central nervous system infection (n = 2) and mediastinitis (n = 2)

Fig. 4

Rates of clinical cure at end of treatment and all-cause mortality at Day 28 by infection site in patients with Pseudomonas aeruginosa (N = 174). BSI, bloodstream infection; IAI, intra-abdominal infection; UTI, urinary tract infection; ^aIncludes central nervous system infection (n = 2) and mediastinitis (n = 1)

Fig. 5

Kaplan–Meier analysis of probability of survival from initiation of cefiderocol treatment for up to 28 days in the overall primary analysis population (N = 261; missing n = 7) *This category includes three patients who did not receive at least one full calendar day of prior antibiotic treatment but received one or two doses