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(1/11) Immunocompromised adult pt with liver abscess + bacteremia, Cx(+) XDR Pseudomonas aeruginosa. 
Your DOC:
Your DOC:
(2/11) Let’s explore the newest cephalosporin on the block 
cefiderocol (Fetroja™) - a 1st in class synthetic β-lactam = cefepime + ceftazidime + siderophore https://pubmed.ncbi.nlm.nih.gov/30712199/
cefiderocol (Fetroja™) - a 1st in class synthetic β-lactam = cefepime + ceftazidime + siderophore https://pubmed.ncbi.nlm.nih.gov/30712199/
(3/11) The siderophore sidechain complexes with Fe+ to smuggle the cephalosporin across the bacterial membrane 
This “Trojan 
” circumvents porin channel changes that cause β-lactam resistance 
This “Trojan ” circumvents porin channel changes that cause β-lactam resistance
(4/11) Cefiderocol has modifications at C-3 and C-7 to 
stability against β-lactamases and increase transport across the outer membrane https://pubmed.ncbi.nlm.nih.gov/31724047/
stability against β-lactamases and increase transport across the outer membrane https://pubmed.ncbi.nlm.nih.gov/31724047/
(5/11) Cefiderocol has 
GNR coverage and withstands Ambler class A, C, D, & even B β-lactamases 
It is typically reserved for MDR GNR & is FDA approved for cUTI, pyelonephritis, & HAP&VAP https://pubmed.ncbi.nlm.nih.gov/22850518/
GNR coverage and withstands Ambler class A, C, D, & even B β-lactamases It is typically reserved for MDR GNR & is FDA approved for cUTI, pyelonephritis, & HAP&VAP https://pubmed.ncbi.nlm.nih.gov/22850518/
(6/11) Gram positive and anaerobic bacteria leave cefiderocol out in the cold 
as active ferric uptake via siderophores is mostly unique to aerobic gram-negative bacteria https://aac.asm.org/content/62/1/e01454-17
as active ferric uptake via siderophores is mostly unique to aerobic gram-negative bacteria https://aac.asm.org/content/62/1/e01454-17
(7/11) The Challenge: Cefiderocol’s unique MOA makes antimicrobial susceptibility testing (AST) difficult 
The AST media must mimic in vivo iron conc. to recreate the environment that encourages uptake of iron and therefore, cefiderocol
The AST media must mimic in vivo iron conc. to recreate the environment that encourages uptake of iron and therefore, cefiderocol
(8/11) MIC using iron-depleted (ID) media ≠ standard cation-adjusted Muller-Hinton Medium (CAMHB). CLSI approved ID-CAMHB but it is challenging to perform 
Other options: AST disk-diffusion methods 
and FDA 
lyophilized Sensitire BMD
Other options: AST disk-diffusion methods and FDA lyophilized Sensitire BMD
(9/11) Susceptibilities are usually a send out test 
so options are empiric use or alt agent and await susceptibilities 
, 
case report raises concern of P. aeruginosa resistance to cefiderocol https://pubmed.ncbi.nlm.nih.gov/33411899/
so options are empiric use or alt agent and await susceptibilities , case report raises concern of P. aeruginosa resistance to cefiderocol https://pubmed.ncbi.nlm.nih.gov/33411899/
(10/11) The Challenge part 2: discordance between the FDA, CLSI, and EUCAST breakpoints. The current FDA breakpoint for P. aeruginosa </=1, EUCAST breakpoint is </=2. CLSI breakpoints are “investigational” with an update expected in 2021 
https://jcm.asm.org/content/59/1/e00951-20
https://jcm.asm.org/content/59/1/e00951-20
(11/11) Recap:
Cefiderocol’s Trojan MOA + structure = activity against MDR GNR including MBLs
However, its unique MOA limits it to gram (-) ONLY
AST is challenging & time consuming
Several breakpoints exist MIC interpretation = challenging
Cefiderocol’s Trojan MOA + structure = activity against MDR GNR including MBLsHowever, its unique MOA limits it to gram (-) ONLYAST is challenging & time consumingSeveral breakpoints exist MIC interpretation = challenging
