Burkholderia pseudomallei Clinical Isolates Are Highly Susceptible In Vitro to Cefiderocol, a Siderophore Cephalosporin

Abstract

Cefiderocol is a cephalosporin designed to treat multidrug resistant Gram-negative infections. By forming a chelated complex with ferric iron, cefiderocol is transported into the periplasmic space via bacterial iron transport systems and primarily binds to penicillin-binding protein 3 (PBP3) to inhibit peptidoglycan synthesis. This mode of action results in cefiderocol having greater in vitro activity against many Gram-negative bacilli than currently used carbapenems, β-lactam/β-lactamase inhibitor combinations, and cephalosporins. Thus, we investigated the in vitro activity of cefiderocol against a total of 246 clinical isolates of Burkholderia pseudomallei from Queensland, Australia. The collection was comprised primarily of bloodstream (56.1%), skin and soft tissue (16.3%) and respiratory isolates (15.9%). Minimum inhibitory concentrations (MIC) of cefiderocol ranged from ≤0.03 to 16 mg/L, where the MIC90 was 0.125 mg/L. Based upon CLSI clinical breakpoints for cefiderocol against Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia, three isolates (1.2%) would be classified as non-susceptible (MIC >4 mg/L). Using EUCAST non-species specific (PK/PD) clinical breakpoints, or those set for Pseudomonas aeruginosa, four isolates (1.6%) would be resistant (MIC >2 mg/L). Further testing for co-resistance to meropenem, ceftazidime, trimethoprim-sulfamethoxazole, amoxicillin-clavulanate and doxycycline was performed on the four isolates with elevated cefiderocol MICs (>2 mg/L), all isolates exhibited resistance to amoxicillin-clavulanic acid, while three isolates also displayed resistance to at least one other antimicrobial. Cefiderocol was found to be highly active in vitro against B. pseudomallei primary clinical isolates. This compound shows great potential for the treatment of melioidosis in endemic countries and should be explored further.

Cefiderocol for the Treatment of Multidrug-Resistant Gram-Negative Bacteria: A Systematic Review of Currently Available Evidence

“…Thirty-eight studies reporting on the in vitro activity of cefiderocol against Gram-negative bacteria were included ( Ito et al, 2015 ; Ito et al, 2016 ; Kohira et al, 2015 ; Falagas et al, 2017 ; Dobias et al, 2017 ; Hackel et al, 2017 ; Kanazawa et al, 2017 ; Yamano et al, 2017 ; Hackel et al, 2018 ; Ito et al, 2018a ; Jacobs et al, 2018 ; Karlowsky et al, 2019 ; Kazmierczak et al, 2019 ; Hsueh et al, 2019 ; Iregui et al, 2019 ; Albano et al, 2020 ; Biagi et al, 2020 ; Delgado-Valverde et al, 2020 ; Golden et al, 2020 ; Johnston et al, 2020 ; Kresken et al, 2020 ; Longshaw et al, 2020 ; Morris et al, 2020 ; Mushtaq et al, 2020 ; Rolston et al, 2020 ; Trebosc et al, 2020 ; Abdul-Mutakabbir et al, 2021 ; Bhagwat et al, 2021 ; Bianco et al, 2021 ; Burnard et al, 2021 ; Cercenado et al, 2021 ; Gant et al, 2021 ; Candel et al, 2022 ; Johnston et al, 2021 ; Lee et al, 2021 ; Liu et al, 2021 ; Stracquadanio et al, 2021 ; Zalacain et al, 2021 ). A total of 53,416 isolates, including 34,805 Enterobacterales , 8297 P. aeruginosa , 7249 Acinetobacter spp , 2508 Stenotrophomonas maltophilia and 549 Burkholderia spp , mainly collected from North America, Europe and East Asia excluding Chinese mainland, were tested for cefiderocol susceptibility.…”

Cefiderocol to manage chronic, multi-drug-resistant Burkholderia cepacia complex infection in a patient with cystic fibrosis: a case report

“…The management of pulmonary infections, and Bcc infection specifically, requires that clinicians assess each person individually, taking into account symptomatic changes , previous clinical responses and their own experiences [3]. Evidence from the literature, which to date is largely founded on in vitro studies or case reports, supports that cefiderocol is an antibiotic that appears to expand the treatment options for CF patients colonized with MDR Gram-negative bacilli [15–20].…”

In vitro and in vivo activity of GT-1, a novel siderophore cephalosporin, and GT-055, a broad-spectrum β-lactamase inhibitor, against biothreat and ESKAPE pathogens

“…The combination of GT-1 and GT-055 was particularly effective in vitro against the biothreat pathogens B. pseudomallei and Y. pestis. Cefiderocol has also demonstrated potent in vitro activity against these biothreat pathogens [22,23], although there are no published studies of its in vivo activity against these pathogens in the mouse models of infection. Our present studies demonstrate that GT-1 alone or in combination with GT-055 has potent activity against Y. pestis in a murine model of intranasal infection.…”