(1/11) Immunocompromised adult pt with liver abscess + bacteremia, Cx(+) XDR Pseudomonas aeruginosa. 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/
(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
(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/
(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/
(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
(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
(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
(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/
(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
(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 MBLs
However, its unique MOA limits it to gram (-) ONLY
AST is challenging & time consuming
Several breakpoints exist MIC interpretation = challenging