Salvage therapy with sulbactam/durlobactam against cefiderocol-resistant Acinetobacter baumannii in a critically ill burn patient: clinical challenges and molecular characterization

Abstract

Background Carbapenem-resistant Acinetobacter baumannii (CRAB) infections are associated with high mortality rates. The optimal treatment regimen for CRAB has not been defined. Cefiderocol has been recently introduced in the armamentarium against CRAB but there is concern about treatment-emergent resistance. Since mortality rates in CRAB infections remain high, further antibiotic options are needed. Methods We report a case of severe infection by CRAB resistant to both colistin and cefiderocol treated with sulbactam/durlobactam and describe the molecular features of the strain. Susceptibility to cefiderocol was detected by disc diffusion according to EUCAST breakpoints. Susceptibility to sulbactam/durlobactam was determined by Etest according to preliminary breakpoints provided by Entasis Therapeutics. Whole Genome Sequencing (WGS) of the CRAB isolate was performed. Results A burn patient with ventilator-associated pneumonia by CRAB resistant to colistin and cefiderocol received sulbactam/durlobactam as compassionate use. She was alive after 30 days from the end of therapy. Complete microbiological eradication of CRAB was achieved. The isolate harboured blaADC-30, blaOXA-23 and blaOXA-66. A missense mutation in PBP3 was detected. The isolate harboured a mutation in the TonB-dependent siderophore receptor gene piuA that showed a frameshift mutation causing a premature stop codon (K384fs). Moreover, the fepA gene, which is orthologous to pirA, was interrupted by a transposon insertion P635-ISAba125 (IS30 family). Conclusions Further treatment options for severe infections by CRAB resistant to all available antibiotics are urgently needed. Sulbactam/durlobactam may be a future option against MDR A. baumannii.

What is the clinical significance of ‘heteroresistance’ in nonfermenting Gram-negative strains?

“…Resistant subpopulations with significant fitness cost may be unstable and not sustained over time. Emergence of cefiderocol resistance among CRAB is of clinical concern [62 ▪ ,63]. It is not known if underlying mechanisms are shared between heteroresistant subpopulations and fully resistant isolates.…”

Cefiderocol and Sulbactam-Durlobactam against Carbapenem-Resistant Acinetobacter baumannii

“…At present, there is no published real-life experience that has assessed SUL-DUR efficacy. However, a few case reports have been published (Table 4) [81][82][83]. Zaidan et al [81] described a 55-year-old woman with pneumonia due to COVID-19, complicated by respiratory failure and on mechanical ventilation, with sputum cultures negative after extubation and clinical improvement.…”

“…Tiseo et al [83] described treatment with SUL-DUR in a young woman who suffered a severe burn injury with 45% of body involvement. She developed a central line BSI due to CRAB isolate, which showed resistance to FDC and susceptibility to colistin.…”

Specificity and mechanism of TonB-dependent ferric catecholate uptake by Fiu

“…In Acinetobacter baumannii , for example, iron acquisition strongly correlates with bacterial pathogenesis ( Gaddy et al, 2012 ; Penwell et al, 2015 ; Fleming et al, 2017 ; Luna et al, 2019 ; Ramirez et al, 2019 ; Escalante et al, 2023 ). Furthermore, orthologs of E. coli Fiu and Cir (PiuA and PirA, respectively) were implicated in the uptake of the novel Trojan horse antibiotic cefiderocol (FDC) in both Pseudomonas aeruginosa ( Luscher et al, 2018 ; Gupta et al, 2022 ) and A. baumannii ( Luscher et al, 2018 ; Malik et al, 2020 ; Asrat et al, 2023 ; Smoke et al, 2023 ; Tiseo et al, 2023 ). Siderophore antibiotics use native, TonB-dependent iron uptake pathways for entry into bacterial cells ( Miller et al, 1991 ; Ji et al, 2012 ; Miller and Liu, 2021 ).…”