Burkholderia pseudomallei clinical isolates are highly susceptible in vitro to cefiderocol, a novel siderophore cephalosporin

Abstract

Cefiderocol is a novel 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 (S-649266) against a total of 271 clinical isolates of Burkholderia pseudomallei from Australia. The collection was comprised of primary isolates (92.3%) and subsequent isolates (7.7%). Minimum inhibitory concentrations (MIC) of cefiderocol ranged from ≤0.03 to 32 mg/L, where the MIC90 was 1 mg/L and 16 mg/L for primary and subsequent isolates, respectively. Based upon non-species specific (Gram-negative bacilli) clinical breakpoints for cefiderocol (MIC ≤ 4 mg/L), twelve isolates (4.4%) would be classified as non-susceptible. Further testing for co-resistance to meropenem, ceftazidime, trimethoprim-sulfamethoxazole, amoxicillin-clavulanate and doxycycline was performed on a subset of isolates with elevated cefiderocol MICs (≥2 mg/L, 4.8%) and 84.6% of these isolates exhibited resistance to at least one of these antimicrobials. Cefiderocol was found to be highly active in vitro against B. pseudomallei primary clinical isolates. This novel compound shows great potential for the treatment of melioidosis in endemic countries and should be explored further.

Achromobacter Infections and Treatment Options

“…Cefiderocol is a new-generation cephalosporin with in vitro activity against carbapenem-resistant Gram-negative nonfermenters such as P. aeruginosa, A. baumannii, and Burkholderia spp. (83,84). Although in vitro data on cefiderocol activity against Achromobacter spp.…”

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][16][17][18][19][20].…”

Class C β-Lactamases: Molecular Characteristics

“…Cefiderocol is an advanced injectable siderophore cephalosporin active against MDR and XDR Gram-negative rods, including producers of various -lactamases, including members of Enterobacterales, P. aeruginosa, A. baumannii, Stenotrophomonas maltophila, B. cepacia and B. pseudomallei (395)(396)(397)(398). Through its catechol siderophore moiety, cefiderocol exploits iron-transport systems via a Trojan-horse strategy, navigating the bacterial periplasm and evading various -lactamases, including ESBLs, KPC (class A), NDM, IMP, VIM (class B) and various class C and D enzymes (OXA-23, OXA-24, OXA-48 and OXA-51), as well as other mechanisms of resistance (399)(400)(401).…”