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

Burnard, D.; Robertson, G.; Henderson, A.; Falconer, C.; Bauer, M.; Cottrell, K.; Gassiep, I.; Norton, R.; Paterson, D. L.; Harris, P. N. A.

doi:10.1101/2020.03.26.009134

bioRxiv · 10.1101/2020.03.26.009134

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

Burnard, D.·Robertson, G.·Henderson, A.·Falconer, C.·Bauer, M.·Cottrell, K.·Gassiep, I.·Norton, R.·Paterson, D. L.·Harris, P. N. A.

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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, {beta}-lactam/{beta}-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.

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Burnard, D., Robertson, G., Henderson, A., Falconer, C., Bauer, M., Cottrell, K., Gassiep, I., Norton, R., Paterson, D. L., Harris, P. N. A.. 2020-03-27. Burkholderia pseudomallei clinical isolates are highly susceptible in vitro to cefiderocol, a novel siderophore cephalosporin. https://doi.org/10.1101/2020.03.26.009134

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