Cephalosporin

See Also

General

Spectrum changes from first to third generation
1. First Generation: Better Gram Positive Cocci coverage
2. Third Generation: Better Gram Negative Rod coverage

Contraindications

Drug allergy to other Cephalosporin
Type I Hypersensitivity Reaction to a Penicillin
1. Less than 10% of those who report Penicillin Allergy actually have a Penicillin Allergy
2. Cross reactivity was originally over-estimated as high as 10% in the 1960s
  1. Attributed to cross contamination from co-production of Cephalosporins and Penicillins in the same factory
3. Penicillin Allergy has only an overall 1-2% risk of cross-reactivity with Cephalosporins
  1. Herbert (2000) West J Med 172(5): 341 [PubMed]
4. Penicillin Anaphylaxis confers a 0.001% risk of Anaphylaxis to Cephalosporins
  1. Apter (2006) Am J Med 119(4):354.e11-9 [PubMed]
5. Cross reactivity appears primarily limited to First Generation Cephalosporins and Penicillins
  1. Third Generation Cephalosporins have minimal to no allergy cross reactivity
  2. Campagna (2012) J Emerg Med 42(5): 612-20 [PubMed]
6. Aminopenicillins (Amoxicillin and Ampicillin) allergy and allergy to first and Second Generation Cephalosporins: High
  1. R1-side chain of Aminopenicillins are similar to first and Second Generation Cephalosporins (esp. Cefprozil, Cefadroxil)
  2. Reaction rate is as high as 27% for Cefadroxil
  3. Campagna (2012) J Emerg Med 42(5): 612-20 [PubMed]

Mechanism
Beta Lactams

See Beta Lactam
Beta Lactam Structure
1. Penicillins, Cephalosporins, Carbapenems and Monobactams are all Beta Lactams
2. Beta Lactams share a 4-membered ring structure (3 Carbons, 1 Nitrogen)
Bacteria (Gram Positive and negative) have cell walls that contain peptidoglycans
1. Peptidoglycans are repeated Disaccharides cross-linked with Amino Acids
2. Transpeptidase cross-links peptidoglycan mesh in the synthesis of the Bacterial cell wall
Beta Lactams bind and inactivate Transpeptidase (also known as Penicillin Binding Protein)
1. Transpeptidase enzymes are located on the Bacteria's inner cytoplasmic membrane
2. Beta Lactams must traverse outer cell wall layers to bind Transpeptidase
3. Beta-Lactam's inhibition of Transpeptidase results in lysis and death of the Bacterial cell
Beta-Lactams are inactivated by the enzyme Beta-Lactamase (Penicillinase, Cephalosporinase)
1. Beta-Lactamase is produced by beta-lactam resistant Bacteria
2. Beta Lactamase cleaves a carbon-nitrogen bond in the 4 member Beta Lactam ring
3. Cephalosporins were developed with a side chain at the CN bond to block Penicillinases
  1. However Bacteria have since developed resistance via Cephalosporinases
  2. MRSA and Enterococcus are also Cephalosporin resistant
Other Beta Lactam Resistance Mechanisms
1. Altered Transpeptidase Structure
  1. Prevents binding by Beta Lactams
  2. Example: Methicillin Resistant Staphylococcus Aureus (MRSA)
2. Gram Negative Bacteria are protected by an additional lipid bilayer
  1. Molecules pass through this layer via porin channels (e.g. OmpF, OmpC) to access the cell wall
  2. Porin channels retrict larger molecules, and not all Beta Lactams can pass through porins
  3. Other Gram Negative Bacteria may down regulate porin channels to limit entry
3. Beta Lactam Efflux Pumps
  1. Some Bacteria are able to actively pump the Beta Lactam out before transpeptidase binding
  2. Examples: E. coli (AcrAB-TolC) and Pseudomonas Aeruginosa (MexAB-OprM)
Beta-Lactamase inhibitors have been developed to counter Beta Lactam resistance
1. Amoxicillin-clavulanic acid (Augmentin)
2. Ampicillin-Sulbactam (Unasyn)
3. Ceftazidime-Avibactam

Class
First Generation Cephalosporins

Oral Agents
1. Cephalexin (Keflex)
2. Cephradine (Velosef)
3. Cefadroxil (Duricef)
Parenteral Agents
1. Cefazolin (Ancef)
Organisms covered
1. Gram Positive Cocci (Streptococcus and MSSA)
2. EKP Gram Negative Bacteria

Class
Second Generation Cephalosporins

Second Generation Broad-spectrum Cephalosporins
1. Oral Agents
  1. Loracarbef (Lorabid)
  2. Cefprozil (Cefzil)
  3. Cefuroxime (Ceftin, Zinacef)
  4. Cefaclor (Ceclor)
2. Organisms Covered
  1. Gram Positive Cocci
  2. EKP Gram Negative Bacteria (e.g. Streptococcus Pneumoniae)
  3. Gram Negative Coccobacilli (H. Influenzae) or Diplococci (M. catarrhalis)
Second Generation Anti-anaerobe Cephalosporins
1. Parenteral Agents
2. Organisms Covered
  1. Anaerobic coverage (differentiates from Second Generation Broad-spectrum Cephalosporins)
    1. Bacteroides fragilis
    2. Growing Anaerobe resistance
  2. Gram Positive Bacteria
    1. Less than Second Generation Broad-spectrum Cephalosporins (e.g. Cefuroxime)
  3. Gram Negative Bacteria

Class
Third Generation Cephalosporins

Third Generation Broad-Spectrum Cephalosporins
1. Oral agents
  1. Cefixime (Suprax)
    1. Only indication is for Gonorrhea
  2. Cefpodoxime (Vantin)
    1. Does not cover Enterobacter or Pseudomonas
  3. Cefdinir (Omnicef)
2. Parenteral agents
  1. Cefotaxime (Claforan)
  2. Ceftizoxime (Cefizox)
  3. Ceftriaxone (Rocephin)
3. Organisms Covered
  1. Gram Positive Cocci
  2. EKP Gram Negative Bacteria
  3. ESP Gram Negative Bacteria
  4. No Pseudomonas activity
Third Generation Anti-Pseudomonal Cephalosporins
1. Parenteral Agents
  1. Ceftazidime (Fortaz)
2. Organisms Covered
  1. Pseudomonas
  2. EKP Gram Negative Bacteria
  3. ESP Gram Negative Bacteria
  4. Poor Gram Positive Cocci coverage
  5. No Coccobacilli coverage

Class
Fourth Generation Cephalosporins

Parenteral Agents
1. Cefepime (Maxipime)
Organisms Covered
1. Broad spectrum Gram-positive and Gram-negative organisms building on third generation coverage
2. Beta-Lactamase resistant organisms
3. Pseudomonas coverage

Class
Fifth Generation Cephalosporins

Parenteral Agents
1. Ceftaroline
2. Ceftolozane and Tazobactam (Zerbaxa)
3. Ceftazidime and Avibactam (Avycaz)
Organisms Covered
1. Broad spectrum Gram-positive and Gram-negative organisms building on third generation coverage
2. Pseudomonas coverage
3. Methicillin Resistant Staphylococcus Aureus (MRSA)

Dosing
Adults

Almost all Cephalosporins
1. Typical Dose: 1-2 grams IV q8h
Exceptions
1. Ceftriaxone 1-2 grams IV q24 hours
2. Cefotetan 1-2 grams IV q12 hours

Dosing
Children

Almost all Cephalosporins
1. Typical dose: 100-200 mg/kg/day divided q8 hours
Exceptions
1. Ceftriaxone 75-100 mg/kg/day q24 hours

Prevention
Reducing Adverse Effects

Least Diarrhea
1. Loracarbef (Lorabid)
2. Cefprozil (Cefzil)
Best taste
1. Loracarbef (Lorabid)
2. Cefixime (Suprax)
3. Cefpodoxime (Vantin, taste applies to under age 2 years)

References

Pensa and Hayes in Swadron (2022) EM:Rap 22(9): 6-8