first-generation cephalosporin

**Members:** Cefazolin (IV/IM), cephalexin (PO), cefadroxil (PO), cephalothin and cephapirin (historical). Mnemonic: first-generation names often start with "Cef-/Ceph-" with an "a" or "ex/adroxil" (cefazolin, cephalexin, cefadroxil).

**Mechanism:** Beta-lactam ring binds penicillin-binding proteins (transpeptidases) and inhibits peptidoglycan cross-linking in the bacterial cell wall. This is bactericidal against actively dividing cells. Cell lysis is mediated by autolysins. Resistance occurs through beta-lactamases, altered PBPs (e.g., PBP2a/mecA in MRSA), and reduced permeability. They are resistant to staphylococcal penicillinase but not to gram-negative beta-lactamases.

**Spectrum:** - Gram-positive cocci: MSSA, Streptococcus pyogenes (group A strep), viridans streptococci, and S. pneumoniae (penicillin-susceptible). - Gram-negatives (PEK): Proteus mirabilis, E. coli, Klebsiella pneumoniae. - NOT covered: MRSA, enterococci, Listeria, atypicals (Mycoplasma, Chlamydia, Legionella), anaerobes (Bacteroides fragilis), Pseudomonas, Serratia, Enterobacter, and Acinetobacter. - Gram-negative coverage increases and gram-positive coverage decreases from 1st to 3rd generation. 4th-generation (cefepime) and 5th-generation (ceftaroline) agents again cover gram-positives, and ceftaroline covers MRSA.

**Pharmacokinetics:** - Cefazolin is IV/IM. The oral agents are well absorbed. - Renal excretion by tubular secretion, so dose adjustment is needed in renal failure. Probenecid can prolong their half-life. - Poor CSF penetration, so they are not used for meningitis. Cefazolin is not used for CNS infections. Ceftriaxone, cefotaxime, and cefepime are used for meningitis.

**Clinical uses:** - **Surgical prophylaxis** (cefazolin): cardiac, orthopedic, and other procedures. Add vancomycin if MRSA risk. - Skin and soft tissue infections: cellulitis and erysipelas from strep or MSSA (cephalexin), and impetigo. - Uncomplicated UTI caused by PEK organisms. - MSSA bacteremia and endocarditis (cefazolin is an alternative to nafcillin or oxacillin). - Streptococcal pharyngitis in penicillin-allergic patients without a severe reaction. - Orthopedic and bone and joint infections and prophylaxis against infection in cesarean delivery. Cefazolin is used for intrapartum prophylaxis in penicillin-allergic patients with low anaphylaxis risk (GBS).

**Adverse effects:** - Hypersensitivity: rash, urticaria, rarely anaphylaxis. Cross-reactivity with penicillin is about 1-2%, mostly with similar R1 side chains (e.g., cephalexin and ampicillin/amoxicillin share similar side chains). Cefazolin has a unique side chain and low cross-reactivity, so it is generally safe in most penicillin-allergic patients, except those with a severe IgE-mediated reaction to cefazolin itself. - Positive Coombs test, and rarely hemolytic anemia. - Nephrotoxicity, especially with aminoglycosides (additive). - Vitamin K deficiency and bleeding (mostly with agents containing the N-methylthiotetrazole side chain such as cefotetan and cefoperazone, not 1st generation). - Disulfiram-like reaction with ethanol (cefotetan, cefoperazone, cefamandole, not classic first-generation). - C. difficile infection, as with any broad-spectrum antibiotic. - Seizure risk at high doses with renal impairment.

**Board pearls:** - "PEcK" or "PEK" organisms: Proteus, E. coli, Klebsiella are covered. - Cephalosporins do not cover "LAME": Listeria, Atypicals, MRSA, Enterococci. - Cefazolin = surgical prophylaxis for skin flora (S. aureus and strep). - Cephalexin: oral treatment for uncomplicated cellulitis, with MRSA coverage added if suspected (TMP-SMX, doxycycline, or clindamycin). - Cephalosporins are an alternative in penicillin-allergic patients only when the reaction was not severe (no history of SJS/TEN or anaphylaxis). - Cefazolin is safe in pregnancy (cephalosporins are Category B historically) and is used for GBS prophylaxis in penicillin-allergic patients at low risk for anaphylaxis.