Infectious Diseases II
Cefepime-enmetazobactam
FDA approved in 2024 for treatment of complicated UTIs including pyelonephritis caused by
ESBL-producing gram-negative organisms, including organisms that produce CTX-M, SHV,
TEM, and VEB
ii.
Target bacteria include E coli, K pneumoniae, P aeruginosa, P mirabilis, and E cloacae.
iii.
Does not have activity against KPC, metallo-Ξ²-lactamases, or some oxacillinases
iv.
Cefepime-enmetazobactam, compared with piperacillin-tazobactam, met noninferiority as
well as superiority for clinical cure and microbiologic eradication in patients with complicated
UTIs or acute pyelonephritis.
Confer resistance to penicillins and narrow-spectrum cephalosporins
Ξ²-Lactamase inhibitor resistant; hence, tazobactam and clavulanic acid would not provide
additional coverage
Innate low-level production in many gram-negative bacteria (i.e., Enterobacter, Citrobacter,
Serratia, Morganella, Providencia, and Pseudomonas). This low-level production leads to
resistance against penicillin, ampicillin, and first-generation cephalosporins.
| d. | Genetic mutation leading to sustained high-level production is possible (derepressed mutants). |
|---|
Theoretically,
treatment
with
third-generation
cephalosporins
or
broad-spectrum
cephalosporins for non-derepressed mutants may select species with the mutation. The actual
incidence of breakthrough infections is unknown with derepressed mutants when bacteria
with innate AmpC Ξ²-lactamase production are treated with third-generation cephalosporins or
extended-spectrum penicillins. However, it is believed to be low.
ii.
Several epidemiologic studies have linked the use of third-generation cephalosporins with the
increase in pathogenic species of AmpC hyperproducing Enterobacterales.
iii.
Derepression confers resistance to third-generation cephalosporins and broad-spectrum
penicillins (piperacillin, ticarcillin).
iv.
Commonly occurs in E. cloacae and Citrobacter freundii, Hafnia alvei, Klebsiella
(Enterobacter) aerogenes, Yersinia enterocolitica
Cefepime generally retains activity against derepressed mutants.
vi.
Carbapenem and cefepime should be considered the drugs of choice in severe infections.
vii.
Because derepression results from the mutation of a chromosomal-mediated Ξ²-lactamase, and
not from transmitted plasmids, many pathogens with this mutation maintain sensitivity to
other nonΞ²-lactam antimicrobials (e.g., fluoroquinolones, aminoglycosides).