Cefiderocol-Based Combination Therapy for “Difficult-to-Treat” Gram-Negative Severe Infections: Real-Life Case Series and Future Perspectives

Abstract

Cefiderocol is a new cephalosporin displaying against extensively resistant (XDR) Gram-negative bacteria. We report our experience with cefiderocol-based combination therapies as “rescue” treatments in immunocompromised or critically ill patients or in patients with post-surgical infections who had failed previous regimens. A total of 13 patients were treated from 1 September 2020 to 31 March 2021. In total, 5/13 (38%) patients were classified as critically ill, due to severe COVID-19 lung failure; 4/13 (31%) patients had post-surgical infections and 4/13 (31%) had severe infections in immunocompromised subjects due to solid organ transplantation (2/4) or hematological malignancy (2/4). Overall, 10/13 infections were caused by carbapenem-resistant Acinetobacter baumannii, one by KPC-positive ceftazidime/avibactam-resistant Klebsiella pneumonia and two by Pseudomonas aeruginosa XDR. Based on clinical, microbiological and hematobiochemical evaluation, cefiderocol was associated with different companion drugs, particularly with fosfomycin, high-dose tigecycline and/or colistin. Microbiological eradication was achieved in all cases and the 30-day survival rate was 10/13; two patients died due to SARS-CoV-2 lung failure, whereas one death was attributed to subsequent infections. No recurrent infections within 30 days were reported. Finally, we hereby discuss the therapeutic potential of cefiderocol and the possible place in the therapy of this novel drug.

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

“…All these factors could affect the antibiotic pharmacodynamic and pharmacokinetic aspects and may influence clinical outcome. Finally, these favourable outcomes are even more relevant since almost 90% of the patients were admitted to intensive care and they all had an extended follow-up of 90 days, significantly longer than other published case series, 11 , 13 and 30% of our cases were critically ill COVID-19 patients with a VAP due to XDR/DRT-P, associated per se with a significantly increased 28 day mortality rate. 14 …”

“…Although the rate of clinical cure reported in our study is in line with those previously reported in the larger RCTs, this result is relevant considering the peculiarity of our population. First of all, the prevalence of DRT-P infections was much higher than in previous studies: the rate was only 15% in the CREDIBLE-CR (including also MDR P. aeruginosa ) 5 , 6 and in the study by Bavaro et al ., 11 while no cases were reported by Falcone et al . 12 Only Bleibtreu et al .…”

“…It is important to highlight that two out of three patients treated with cefiderocol monotherapy experienced microbiological relapse and one of them (P3) reported an MIC creep. Currently, there is still no agreement about how to use cefiderocol, whether in monotherapy 12 or in combinations, 11 , 15 and further studies are needed.…”

COVID-19 and Antimicrobial Resistance: Data from the Greek Electronic System for the Surveillance of Antimicrobial Resistance—WHONET-Greece (January 2018–March 2021)

“…However, in blood isolates, we found consistently high non-susceptibility rates for the aforementioned antibiotics during both pre-pandemic and pandemic periods. P. aeruginosa has been identified as a common coinfecting pathogen in COVID-19 patients causing exacerbation of illness [ 29 , 56 , 60 , 61 , 62 ]. P. aeruginosa has shown high resistance to many antibiotics used during the COVID-period, such as carbapenems [ 48 , 63 , 64 ] and amikacin [ 48 , 65 , 66 ].…”

Impact of SARS-CoV-2 Epidemic on Antimicrobial Resistance: A Literature Review

“…Lastly, CRAB infection-related mortality is highly influenced by the low response to antimicrobials, particularly in the setting of critically ill patients. In fact, the backbone for treatment of CRAB infections is still represented by colistin, an antibiotic burdened by high toxicity and unpredictable pharmacokinetics/pharmacodynamics properties, and clinical data of new therapeutic options, such as cefiderocol, are still urgently needed [61,62].…”