fourth-generation cephalosporin

**Mechanism:** Like all beta-lactams, cephalosporins bind penicillin-binding proteins (PBPs), inhibiting transpeptidase cross-linking of peptidoglycan. This blocks cell wall synthesis and is bactericidal. Cefepime is a zwitterion, so it penetrates the outer membrane of gram-negative bacteria well. It is also relatively stable against hydrolysis by chromosomal AmpC beta-lactamases.

**Representative drug:** Cefepime (IV/IM). Cefpirome is used outside the US.

**Spectrum:** - Gram-positive: Streptococci and MSSA (comparable to ceftriaxone, sometimes better for staphylococci). - Gram-negative: Enterobacterales, including AmpC producers such as Enterobacter, Citrobacter, and Serratia. Also *Pseudomonas aeruginosa*, which is a key distinguishing feature. - Gaps: MRSA, enterococci, *Listeria*, *Clostridioides difficile*, and anaerobes (add metronidazole if needed). It is unreliable against ESBL producers, so carbapenems are preferred. It does not cover atypicals.

**Cephalosporin generation cheat sheet:** - 1st (cefazolin, cephalexin): gram-positive cocci, plus *Proteus*, *E. coli*, *Klebsiella* (PEcK). Used for surgical prophylaxis and skin infections. - 2nd (cefoxitin, cefotetan, cefuroxime, cefaclor): added gram-negative and *H. influenzae*. Cefoxitin and cefotetan also cover anaerobes (*Bacteroides*). - 3rd (ceftriaxone, cefotaxime, ceftazidime): better gram-negative coverage and CNS penetration. Ceftriaxone is used for meningitis, gonorrhea, and Lyme disease. Ceftazidime covers *Pseudomonas*. - 4th (cefepime): broad spectrum with *Pseudomonas* coverage and AmpC stability. - 5th (ceftaroline): covers MRSA and *Enterococcus faecalis*, with some gram-negative coverage but no *Pseudomonas*.

**Clinical uses:** - Empiric therapy for febrile neutropenia - Hospital-acquired and ventilator-associated pneumonia - Complicated UTI and intra-abdominal infection (with metronidazole) - Pseudomonal infections - Nosocomial meningitis (good CSF penetration)

**Adverse effects:** - Hypersensitivity: Cross-reactivity with penicillins is low (about 1–2%) and depends mostly on side-chain similarity. - **Cefepime-induced neurotoxicity:** This includes encephalopathy, myoclonus, and nonconvulsive status epilepticus. The risk is highest in renal impairment when the dose is not adjusted, because the drug is renally cleared. - *C. difficile* infection - Possible positive Coombs test or hemolytic anemia - Other cephalosporin effects: The disulfiram-like reaction and hypoprothrombinemia (vitamin K–related) are classic for cephalosporins with an N-methylthiotetrazole side chain, such as cefotetan. Cefepime does not have this side chain.

**Pharmacokinetics:** Eliminated renally, so adjust the dose in CKD. It is not metabolized significantly.

**Resistance:** ESBLs and carbapenemases hydrolyze it. Altered PBPs (as in MRSA) also cause resistance. Efflux pumps and porin loss cause resistance in *Pseudomonas*.

**Boards pearls:** - "4th gen = *Pseudomonas* + gram-positives + AmpC stability" and the drug is cefepime. - Cephalosporins do not cover **LAME**: *Listeria*, Atypicals (*Mycoplasma*, *Chlamydia*), MRSA, and Enterococci. (Ceftaroline covers MRSA.) - Add vancomycin for MRSA coverage, and add ampicillin for *Listeria* in meningitis.