third-generation cephalosporin

**Mechanism:** Bind penicillin-binding proteins (PBPs) and inhibit transpeptidase cross-linking of peptidoglycan, which blocks cell wall synthesis. They are bactericidal and time-dependent killers. Their bulky side chains make them resistant to many (but not all) beta-lactamases.

**Spectrum (generational trend: gram-positive activity decreases, gram-negative increases):** - Excellent gram-negative coverage: Enterobacterales (E. coli, Klebsiella, Proteus), Neisseria (gonorrhoeae and meningitidis), H. influenzae, Serratia, and Borrelia burgdorferi (ceftriaxone for disseminated Lyme disease, including neuroborreliosis). - Gram-positive: good activity against penicillin-susceptible and many penicillin-resistant S. pneumoniae (ceftriaxone, cefotaxime) and viridans streptococci. Activity against MSSA is modest. Ceftazidime is weak against gram-positives. - **Pseudomonas:** ceftazidime (and cefoperazone) are active. Ceftriaxone and cefotaxime are not. - **Not covered ("LAME"):** Listeria, Atypicals (Mycoplasma, Chlamydia, Legionella), MRSA, and Enterococci. Also not reliably covered: Bacteroides fragilis and C. difficile, which is also promoted by these drugs.

**Key agents and notes:** - **Ceftriaxone:** Mostly biliary excretion, so no renal dose adjustment. Long half-life allows once-daily dosing. Can cause biliary sludging/pseudolithiasis. It is contraindicated in neonates (especially with IV calcium) because it displaces bilirubin (risk of kernicterus) and forms calcium precipitates. Avoid in hyperbilirubinemic neonates. - **Cefotaxime:** Preferred over ceftriaxone in neonates. - **Ceftazidime:** Antipseudomonal. Used for febrile neutropenia and Pseudomonas infections. Also available combined with avibactam (a beta-lactamase inhibitor) for resistant gram-negatives such as KPC-producing organisms. - **Oral agents (cefixime, cefdinir, cefpodoxime):** Used for otitis media, UTI, and step-down therapy.

**Clinical uses (high-yield):** - Bacterial meningitis: ceftriaxone or cefotaxime plus vancomycin (to cover resistant pneumococci), plus ampicillin if age <1 month or >50 years or immunocompromised (for Listeria). - Gonorrhea: IM ceftriaxone (give for presumed co-infection with chlamydia using doxycycline, if chlamydia is not excluded). - Community-acquired pneumonia (inpatient, with a macrolide or doxycycline for atypicals). - Spontaneous bacterial peritonitis, and prophylaxis in variceal bleeding in cirrhosis. - Pyelonephritis, complicated UTI, and sepsis. - Lyme disease (disseminated or neurologic).

**Resistance:** Extended-spectrum beta-lactamases (ESBLs) in Enterobacterales (e.g., E. coli, Klebsiella) hydrolyze third-generation cephalosporins, so use carbapenems. AmpC-producing organisms (Enterobacter, Citrobacter, Serratia) can develop resistance on therapy. Altered PBPs (e.g., PBP2a in MRSA) confer resistance.

**Adverse effects:** - Hypersensitivity (IgE-mediated reactions). Cross-reactivity with penicillin is low (~1–2%) and depends largely on similar R1 side chains, and third-generation agents have dissimilar side chains. - Disulfiram-like reaction (mainly with agents containing a methylthiotetrazole side chain, e.g., cefotetan, cefoperazone, and cefamandole). Also hypoprothrombinemia/bleeding from the same side chain (vitamin K antagonism). - Superinfection and C. difficile colitis. - Coombs-positive hemolytic anemia (rare). - Nephrotoxicity is enhanced with aminoglycosides. - Biliary sludging (ceftriaxone).

**Board pearl:** "Ceftriaxone for meningitis, gonorrhea, and Lyme; ceftazidime for Pseudomonas; no coverage for LAME organisms." In neonates, avoid ceftriaxone (kernicterus, calcium precipitation) and use cefotaxime.