Use of cephalosporin
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Cephalosporins - Clinical Uses
Cephalosporins are beta-lactam antibiotics that inhibit bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs). They are classified into five generations based on their spectrum of activity. Each successive generation generally has broader gram-negative coverage but sometimes reduced gram-positive potency.
Mechanism of Action
All cephalosporins share the 7-aminocephalosporanic acid nucleus and work by inhibiting the transpeptidase step of peptidoglycan crosslinking - the final step in bacterial cell wall synthesis. They are bactericidal and time-dependent antibiotics (efficacy depends on time above MIC).
Classification & Uses by Generation
First-Generation Cephalosporins
Drugs: Cefazolin (IV/IM), Cephalexin (oral), Cefadroxil (oral)
Spectrum: Excellent gram-positive activity (staphylococci, streptococci); limited gram-negative coverage (E. coli, K. pneumoniae, P. mirabilis). NOT active against MRSA, Enterococcus, Pseudomonas, B. fragilis.
| Clinical Use | Drug of Choice |
|---|---|
| Surgical prophylaxis (skin/soft tissue/orthopedic) | Cefazolin |
| Cellulitis, soft tissue abscess (oral) | Cephalexin |
| Staphylococcal/streptococcal bacteremia | Cefazolin |
| UTI (susceptible E. coli, Klebsiella) | Cephalexin or Cefazolin |
| Mild penicillin allergy (non-IgE-mediated) | Cefazolin |
Note: Cefazolin does NOT penetrate the CNS - cannot be used for meningitis.
- Katzung's Basic and Clinical Pharmacology, 16th Edition, p. 1247-1248
Second-Generation Cephalosporins
Drugs: Cefuroxime (oral/IV), Cefaclor, Cefprozil (oral); Cefoxitin, Cefotetan (IV - "cephamycins")
Spectrum: Broader gram-negative coverage than first-generation, including H. influenzae, Moraxella catarrhalis, and Klebsiella. Cefoxitin/Cefotetan also cover anaerobes including many B. fragilis strains. NOT active against Enterococcus or Pseudomonas.
| Clinical Use | Drug |
|---|---|
| Sinusitis, otitis media, lower RTI | Cefuroxime, Cefaclor |
| Community-acquired pneumonia | Cefuroxime |
| Peritonitis, diverticulitis (mixed anaerobic) | Cefoxitin or Cefotetan |
| Pelvic inflammatory disease (PID) | Cefoxitin or Cefotetan |
| H. influenzae/Moraxella infections | Cefuroxime |
Note: Cefuroxime crosses the blood-brain barrier but is less effective than ceftriaxone for meningitis and should not be used for it.
- Katzung's Basic and Clinical Pharmacology, 16th Edition, p. 1249-1250
Third-Generation Cephalosporins
Drugs: Ceftriaxone (IV/IM), Cefotaxime (IV), Ceftazidime (IV), Cefixime (oral), Cefdinir (oral), Cefpodoxime (oral)
Spectrum: Greatly expanded gram-negative coverage; penetrates the CNS well. Active against Citrobacter, Serratia, Providencia, beta-lactamase-producing Haemophilus and Neisseria. Ceftazidime is the only third-generation agent with useful activity against Pseudomonas aeruginosa.
| Clinical Use | Drug |
|---|---|
| Bacterial meningitis | Ceftriaxone or Cefotaxime |
| Community-acquired pneumonia (hospitalized) | Ceftriaxone |
| Gonorrhea | Ceftriaxone IM (single dose) |
| Typhoid fever / Salmonella | Ceftriaxone |
| Lyme disease (disseminated/neurologic) | Ceftriaxone |
| Intra-abdominal infections | Cefotaxime |
| Pseudomonal infections | Ceftazidime |
| Otitis media, sinusitis, pharyngitis (mild) | Cefdinir, Cefixime, Cefpodoxime |
| Prophylaxis in febrile neutropenia | Ceftazidime |
Ceftriaxone has a half-life of 7-8 hours and can be dosed once daily (1-2 g/day), making it very convenient for outpatient IV therapy.
- Katzung's Basic and Clinical Pharmacology, 16th Edition, p. 1250-1252
Fourth-Generation Cephalosporins
Drug: Cefepime (IV)
Spectrum: Extends third-generation activity to include Pseudomonas aeruginosa AND better gram-positive coverage (including some MRSA? No - still not MRSA). More stable against AmpC beta-lactamases than third-generation agents.
| Clinical Use | Notes |
|---|---|
| Febrile neutropenia (empiric) | Broad gram-negative + Pseudomonas |
| Hospital-acquired pneumonia | Covers Pseudomonas, Enterobacterales |
| Complicated UTI | Gram-negative coverage |
| Meningitis (gram-negative) | CNS penetration |
| Infections due to Enterobacter sp. | More AmpC-stable than 3rd gen |
Fifth-Generation Cephalosporins
Drugs: Ceftaroline (IV), Ceftobiprole (IV)
Unique feature: These are the only cephalosporins active against MRSA (methicillin-resistant S. aureus), because they bind to PBP2a, the altered penicillin-binding protein in MRSA.
| Clinical Use | Notes |
|---|---|
| MRSA skin/soft tissue infections | Ceftaroline FDA-approved |
| Community-acquired pneumonia | Including drug-resistant S. pneumoniae |
| MRSA bacteremia | Off-label salvage use |
Siderophore Cephalosporin (Novel)
Drug: Cefiderocol - a catechol-substituted siderophore cephalosporin that exploits iron transport channels to penetrate gram-negative bacteria. Active against carbapenem-resistant Enterobacterales, Pseudomonas, and Acinetobacter.
- Katzung's Basic and Clinical Pharmacology, 16th Edition
Cephalosporin + Beta-Lactamase Inhibitor Combinations
These combinations extend the spectrum against multidrug-resistant (MDR) pathogens:
| Combination | Spectrum / Indication |
|---|---|
| Ceftolozane-tazobactam | MDR Pseudomonas aeruginosa, ESBL-producing Enterobacterales; complicated UTI, intra-abdominal infection |
| Ceftazidime-avibactam | KPC-producing CRE, MDR Pseudomonas; complicated UTI, intra-abdominal infection |
Both are reserved for infections due to multidrug-resistant pathogens, especially when carbapenem alternatives are needed.
- Lippincott Illustrated Reviews Pharmacology, p. 968
Adverse Effects
| Adverse Effect | Notes |
|---|---|
| Hypersensitivity reactions | Rash, urticaria, anaphylaxis (less common than penicillin) |
| Cross-reactivity with penicillin | ~1-2% true cross-reactivity; avoid in immediate penicillin hypersensitivity |
| Diarrhea / GI disturbance | Common with oral forms; C. difficile risk |
| Hypoprothrombinemia / bleeding | Seen with cefoperazone, cefotetan (methylthiotetrazole side chain) |
| Disulfiram-like reaction | Cefotetan, cefamandole (with alcohol) |
| Nephrotoxicity | Rare alone; increased when combined with aminoglycosides |
| Positive Coombs test | Hemolytic anemia (rare) |
Cephalosporins are generally well-tolerated. A patient allergic to penicillin can often receive cephalosporins (especially if the penicillin reaction was mild), but caution is warranted with immediate-type hypersensitivity. Patients most often tolerate cephalosporins with dissimilar R1 side chains.
- Red Book 2021, Report of the Committee on Infectious Diseases
Quick Reference Summary
| Generation | Key Gram (+) Coverage | Key Gram (-) Coverage | Clinical Niche |
|---|---|---|---|
| 1st | Excellent (Staph, Strep) | E. coli, Klebsiella, P. mirabilis | Surgical prophylaxis, skin infections |
| 2nd | Good | + H. influenzae, Moraxella; Cephamycins add anaerobes | RTI, sinusitis, otitis, PID |
| 3rd | Moderate | Broad (Citrobacter, Serratia); Ceftazidime adds Pseudomonas | Meningitis, pneumonia, gonorrhea |
| 4th | Good | Broad + Pseudomonas, AmpC-stable | Febrile neutropenia, HAP |
| 5th | MRSA activity | Moderate gram-negative | MRSA infections, CAP |
| Novel combos | Variable | MDR Pseudomonas, CRE | Last-resort MDR coverage |
Sources: Katzung's Basic and Clinical Pharmacology, 16th Edition | Lippincott Illustrated Reviews Pharmacology | Red Book 2021
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