Cephalosporins

Chemistry

Mechanism of Action

1. Enter the bacterial cell and bind covalently to PBPs (transpeptidases, carboxypeptidases)
2. Inhibit cross-linking of peptidoglycan chains (transpeptidation step)
3. Trigger autolytic enzymes that degrade the cell wall
4. Cause cell lysis and death

Resistance Mechanisms

1. Beta-lactamase production - enzymes hydrolyze the beta-lactam ring, destroying activity. This is the most clinically important mechanism. Gram-positive bacteria secrete beta-lactamases extracellularly; gram-negative bacteria do so in the periplasmic space.
2. Altered PBPs - Modified PBPs with lower affinity for beta-lactams. Classic example: MRSA has mecA gene producing a modified PBP2a, conferring resistance to virtually all cephalosporins (except the newer 5th-generation agents).
3. Decreased permeability / efflux pumps - Reduced penetration through outer membrane porins (especially in gram-negatives like P. aeruginosa) or active efflux of drug.

Generations

First Generation

• Excellent gram-positive coverage: streptococci, MSSA (Methicillin-sensitive Staphylococcus aureus)
• Modest gram-negative: E. coli, K. pneumoniae, Proteus mirabilis (the "3 Keps")
• Gram-positive anaerobes (peptococci, peptostreptococci)
• NOT active against: MRSA, Pseudomonas, Enterobacter, Serratia, Bacteroides fragilis

• Cefazolin: Surgical prophylaxis (most common antibiotic used perioperatively), skin/soft tissue infections, MSSA bacteremia
• Cephalexin: Uncomplicated skin infections, UTIs

Second Generation

• Greater gram-negative activity than 1st generation: H. influenzae, Klebsiella spp., Moraxella catarrhalis, Proteus spp., E. coli
• Slightly weaker gram-positive coverage than 1st generation
• Cephamycins only (cefoxitin, cefotetan): Also cover anaerobes including B. fragilis - making them unique among cephalosporins. However, increasing resistance among B. fragilis limits their use.

• Cefuroxime: Community-acquired pneumonia, sinusitis
• Cefoxitin/cefotetan: Intra-abdominal infections, gynecologic infections, surgical prophylaxis for bowel surgery

Third Generation

• Markedly expanded gram-negative coverage including Serratia marcescens, Enterobacter aerogenes, and most Enterobacteriaceae
• Less potent against MSSA compared to 1st generation
• Ceftriaxone and cefotaxime: Excellent CNS penetration - drugs of choice for bacterial meningitis
• Ceftazidime: Unique anti-Pseudomonas activity among 3rd-gen agents

• Ceftriaxone: Bacterial meningitis (with vancomycin), community-acquired pneumonia, gonorrhea, Lyme disease, typhoid fever, sepsis
• Cefotaxime: Meningitis, serious gram-negative infections
• Ceftazidime: Pseudomonal infections

Fourth Generation

• Combines the gram-positive activity of 1st-gen with the gram-negative breadth of 3rd-gen
• Anti-Pseudomonas activity (like ceftazidime)
• Greater stability against beta-lactamases (AmpC) than 3rd generation
• Does NOT cover MRSA or anaerobes

Fifth Generation (Anti-MRSA Cephalosporins)

• Cover MRSA (by binding to the modified PBP2a) - the defining feature of this class
• Broad gram-negative coverage similar to 3rd generation
• Does NOT cover Pseudomonas

Siderophore Cephalosporin (Newest)

Summary of Coverage by Generation

Adverse Effects

1. Hypersensitivity reactions - Most common. About 1-2% of patients develop reactions. Cross-reactivity with penicillin is approximately 1-2% (much lower than the historically cited 10%, which was due to shared contaminants in early manufacturing). Patients with a history of severe penicillin anaphylaxis should avoid cephalosporins.
2. GI effects - Nausea, diarrhea, particularly with oral agents. Broad-spectrum agents can cause C. difficile colitis.
3. Nephrotoxicity - Rare with modern cephalosporins; risk increased when combined with aminoglycosides.
4. Disulfiram-like reaction - Cefotetan and cefoperazone contain a methylthiotetrazole (MTT) side chain that inhibits aldehyde dehydrogenase. Patients must avoid alcohol.
5. Hypoprothrombinemia / bleeding - Also due to MTT side chains (affect vitamin K metabolism). Monitor coagulation in at-risk patients.
6. Positive Coombs test - Cephalosporins can adsorb onto red blood cells, giving a false-positive direct Coombs without clinical hemolysis.

Key Clinical Pearls

• Surgical prophylaxis: Cefazolin is the gold-standard single-dose preoperative antibiotic for most clean and clean-contaminated procedures.
• Meningitis: 3rd-gen (ceftriaxone or cefotaxime) + vancomycin is standard empiric therapy for bacterial meningitis in immunocompetent adults.
• Renal dosing: Most cephalosporins require dose adjustment in renal impairment. Ceftriaxone is the notable exception - it is primarily biliary-excreted and does not need renal dose adjustment.
• Ceftriaxone and calcium: Avoid concomitant IV calcium in neonates (risk of precipitation in lungs and kidneys).
• ESBL-producing organisms: Extended-spectrum beta-lactamases (ESBLs) hydrolyze all cephalosporins. Carbapenems are the treatment of choice for serious ESBL infections.