Cephalosporins

Cephalosporins are a group of bactericidal beta-lactam antibiotics (similar to penicillins) that exert their effects by preventing bacteria from producing their cell walls, ultimately leading to cell death. Cephalosporins are categorized by generation and all drug names begin with “cef-” or “ceph-.” Cephalosporins have expanded antimicrobial activity compared with most penicillins, and are more effective against Enterobacteriaceae; some drugs are active against Pseudomonas and/or anaerobic species as well. Cephalosporins are often used to treat skin, soft tissue, bone, lung, urinary tract, intraabdominal, and pelvic infections caused by susceptible organisms.

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Chemistry

Cephalosporin structure

Cephalosporins are members of the beta-lactam drug family and consist of:

  • A beta-lactam ring: a 4-membered ring containing 2 carbons (α and β carbons), a nitrogen, and a carbonyl group (a carbon double-bonded to oxygen)
    • The group in the compound responsible for antibacterial activity
    • Can be hydrolyzed (i.e., broken down) by beta-lactamases, which are produced by certain resistant bacteria
    • If the beta-lactam ring is broken, the drug loses its antibacterial properties.
    • All beta-lactams contain a beta-lactam ring.
  • Side chain (R group): 
    • Bound to the α-carbon in the beta-lactam ring
    • Differentiates cephalosporins from each other
    • Responsible for their unique pharmacokinetics and spectra of activity
    • Certain structures can sterically inhibit the hydrolysis of the beta-lactam ring by beta-lactamases. 
  • A 6-membered ring containing both sulfur and nitrogen with a 2nd R group
Structure of beta-lactams

Structure of beta-lactams:
All beta-lactam antibiotics contain the same core 4-membered “beta-lactam” ring (highlighted in red). This ring is responsible for the antibacterial properties of the drug because it is the region that binds to and inhibits the penicillin-binding proteins (PBPs). The PBPs catalyze the formation of the cell wall by generating crosslinks between the peptide chains in the peptidoglycan molecules; PBPs form these crosslinks between acyl-D-Ala-D-Ala peptides, which have a structure similar to the beta-lactam ring.

Image by Lecturio. License: CC BY-NC-SA 4.0

Mechanisms of Action and Resistance

All beta-lactams, including cephalosporins, exert their effects by inhibiting bacterial cell wall synthesis.

Background: understanding cell walls

  • Bacterial cell walls contain peptidoglycan chains (large, thick layers in gram-positive organisms, and relatively smaller/thinner layers in gram-negative organisms).
  • Peptidoglycan chains are composed of:
    • A sugar backbone with 2 alternating sugars: 
      • N-acetylmuramic acid (NAM) 
      • N-acetylglucosamine (NAG)
    • Short, peptide side chains branching off the NAM sugars
  • The short peptides form crosslinked bridges between the adjacent peptidoglycan chains and create a fishnet structure.
    • Crosslinked bridges are necessary for the peptidoglycan (and thus cell wall) structure.
    • Penicillin-binding proteins (PBPs) are enzymes that create these crosslinked bridges.
Structure of bacterial cell walls Cephalosporins

Structure of bacterial cell walls

Image by Lecturio. License: CC BY-NC-SA 4.0

Mechanism of action

All beta-lactams work by irreversibly binding to and inhibiting the PBPs → beta-lactam antibiotics inhibit cell wall synthesis.

Bactericidal activity

Beta-lactams, including cephalosporins, have a bactericidal (rather than bacteriostatic) effect. 

  • Bacterial cell wall is necessary for survival → if lacking, cell death is initiated
  • When bacteria attempt to replicate, they shed their cell walls.
  • In the presence of beta-lactams, however, bacteria are unable to form a new cell wall.
  • Bacteria are unable to effectively divide, and the remaining cell autocatalyzes and dies.
Bacteria attempting to divide in the presence of penicillin

Bacterium attempting to divide in the presence of penicillin:
The bacterium sheds its wall and becomes a spheroplast. The spheroplast is unable to survive and autocatalyzes (dies).

Image by Lecturio. License: CC BY-NC-SA 4.0

Mechanisms of resistance

Bacteria use 3 primary mechanisms to resist cephalosporins:

  • Beta-lactamase resistance (cephalosporins are ineffective): 
    • Beta-lactamase is an enzyme that cleaves the beta-lactam ring and inactivates the antibiotic.
    • Cephalosporinases are involved in the case of cephalosporin resistance.
    • Can be produced by both gram-positive and gram-negative organisms
    • Usually secreted
    • May only be secreted in the presence of a beta-lactam antibiotic
    • Most common type of resistance
    • Most gram-negative bacilli possess a beta-lactamase gene.
  • PBP-mediated resistance (↓ cephalosporin binding to PBPs)
    • Mutations in PBPs → ↓ affinity of cephalosporins to PBP 
    • Despite the mutations, these PBPs can produce a cell wall.
  • Porin-mediated resistance (↓ cephalosporin uptake): 
    • Cephalosporins enter bacteria through channels called porins in the cell walls.
    • Bacteria can ↓ production of porins → ↓ antibiotic within the cell → antibiotic resistance
    • Common mechanism of resistance in Pseudomonas aeruginosa

Beta-lactamase-resistant medications

  • Some medications can overcome beta-lactamases by acting as beta-lactamase inhibitors.
  • Beta-lactamase inhibitors can be combined with beta-lactamase-sensitive cephalosporins to enhance their activity.
  • Beta-lactamase inhibitors include:
    • Tazobactam
    • Avibactam
    • Clavulanic acid (not available in combination with cephalosporins)
    • Sulbactam (not available in combination with cephalosporins)

Pharmacokinetics

Absorption and half-life

  • Oral cephalosporins are rapidly absorbed.
  • Half-lives tend to be short.
    • Most cephalosporins have a half-life < 1 hour and should be dosed every 4 hours in patients with normal renal function.
    • Cephalosporins with longer half-lives:
      • Ceftriaxone (dosed q24 hours)
      • Cefazolin (dosed q8 hours)

Distribution

  • All cephalosporins achieve therapeutic levels in:
    • Pleural fluid
    • Pericardial fluid
    • Peritoneal fluid
    • Synovial fluid
    • Urine
  • Penetration across the blood-brain barrier into the CSF:
    • 1st and 2nd generation: poor
    • 3rd generation (especially ceftriaxone, cefotaxime, and ceftazidime): good with meningeal irritation
  • Protein binding varies significantly between drugs:
    • < 20%: cefalexin, ceftazidime, cefepime, ceftolozane-tazobactam, ceftaroline
    • 20%‒80%: cefuroxime, cefoxitin
    • > 80%: cefazolin, cefotetan, ceftriaxone

Excretion

  • Primarily renal excretion
  • All cephalosporins except ceftriaxone require dose modification in renal failure.

Ceftriaxone precipitation

  • Ceftriaxone can precipitate in the presence of calcium, especially in the lungs and kidneys.

Thus, ceftriaxone should not be reconstituted/directly mixed with calcium-containing products such as lactated Ringers or total parenteral nutrition (TPN).

Classification

Cephalosporins are generally classified by generation, with the 1st generation drugs being the oldest in this class. Some of the most commonly used drugs are shown in the table below.

Table: Classification of cephalosporins
GenerationParental agentsOral agents
1st generationCefazolin (Ancef)Cephalexin (Keflex)
2nd generation
  • Cefuroxime
  • Cephamycins (subgroup):
    • Cefotetan
    • Cefoxitin
Cefaclor (Ceclor)
3rd generation
  • Ceftriaxone (Rocephin)
  • Cefotaxime
  • Ceftazidime
  • Cefdinir (Omnicef)
  • Cefixime (Suprax)
4th generationCefepimeNone
5th generation and advanced combinations
  • Ceftaroline
  • Ceftolozane
  • Ceftolozane-tazobactam
  • Ceftazidime-avibactam
None

Indications

Activity spectrum

Table: Spectrum of activity of cephalosporins
DrugsGram-positive cocciGram-negative bacilliGram-negative cocciAnaerobes
Streptococcus, MSSA
  • Escherichia coli
  • Klebsiella pneumoniae
  • Haemophilus influenzae
SPACE organismsPseudomonasNeisseriasppPeptostreptococcus
1st generation
  • Cephalexin
  • Cefazolin
XX*X
2nd generation
  • Cefuroxime
  • Cefaclor
  • Cefoxitin
  • Cefotetan
XXX**X+
3rd generation
  • Ceftriaxone
  • Cefotaxime
  • Ceftazidime
  • Cefdinir
  • Cefixime
XXX++XX
4th generation
  • Cefepime
XXXXX+
5th generation and combinations:
  • Ceftaroline
  • Ceftolozane-tazobactam
  • Ceftazidime-avibactam
XXXXX+

SPACE organisms: Serratia marcescens, Proteus mirabilis, Acinetobacter spp., Citrobacter spp., and Enterobacter spp.
*Only non-beta-lactamase-producing species
**Only cephamycins: cefoxitin and cefotetan
+Cefoxitin and ceftolozane-tazobactam are also active against “below the diaphragm anaerobes” Bacteroides
++Only ceftazidime

Clinical uses

Cephalosporins are used to treat infections caused by susceptible organisms, including:

  • Preoperative prophylaxis against surgical site infections (cefazolin)
  • Skin and soft tissue infections
  • Bone and joint infections
  • Respiratory infections caused by S. pneumoniae and S. pyogenes
    • Upper respiratory infections, including pharyngitis
    • Pneumonia
    • Cystic fibrosis exacerbations
  • Otitis media due to susceptible organisms
  • UTIs due to susceptible gram-negative organisms, especially Escherichia coli, Klebsiella, or Proteus spp.
  • Sepsis due to susceptible organisms
  • Bacterial meningitis due to Enterobacteriaceae: 3rd- and 4th-generation cephalosporins (therapy of choice)
  • “Below the diaphragm” infections: cephamycins and 3rd-generation cephalosporins
    • Pelvic inflammatory disease
    • Endometritis
    • Neisseria gonorrhoeae (note: cefoxitin is ineffective against Chlamydia trachomatis)

Adverse Effects and Contraindications

Adverse effects

Allergic reactions are the most common adverse effects.

  • IgE-mediated allergic reactions:
    • Present with pruritis, urticaria, angioedema, hypotension, and/or anaphylaxis
    • Patients with penicillin allergies are more likely to have cephalosporin allergies due to cross-reactivity
      • Most common with 1st- and 2nd-generation cephalosporins due to similarities in their R groups
      • 3rd- to 5th-generation cephalosporins show minimal cross-reactivity.
  • Dermatologic reactions:
    • Morbilliform rash: a maculopapular eruption due to a hypersensitivity reaction
    • Erythema multiforme: target lesions developing with acute onset
    • Stevens-Johnson syndrome: a desquamating skin condition involving mucosal surfaces
  • Neurologic reactions:
    • Seizures (cefepime, especially in the setting of renal impairment)
  • GI and hepatic reactions:
    • Clostridioides difficile colitis 
    • Suppression of gut flora leading to vitamin K deficiency
    • Formation of biliary sludge and pseudocholelithiasis (ceftriaxone, especially in children)
  • Renal reactions:
    • Cephalosporins can potentiate the renal toxicity of aminoglycosides.
    • Glomerulonephritis is seen in association with allergic reactions.
  • Hematologic reactions:
    • Hemolytic anemia
    • Neutropenia
    • Immune thrombocytopenia

Contraindications

  • All cephalosporins:
    • Hypersensitivity reactions
    • Anaphylactic reactions to penicillins
  • Ceftriaxone-specific contraindications:
    • Hyperbilirubinemia in neonates (especially if premature)
    • Infants < 28 days of age receiving any IV calcium-containing products
  • Use with caution:
    • Patients with elevated INR
    • Other penicillin allergies
    • Seizure disorders
    • Renal impairment

Comparison of Antibiotic Coverage

Comparison based on mechanisms of action

Antibiotics can be classified in several ways. One way is to classify them based on their mechanism of action:

Table: Antibiotics classified by primary mechanism of action
MechanismClasses of antibiotics
Bacterial cell wall synthesis inhibitors
  • Penicillins
  • Cephalosporins
  • Penems
  • Miscellaneous
Bacterial protein synthesis inhibitors
  • Tetracyclines
  • Macrolides
  • Ketolide
  • Lincosamides
  • Streptogramins
  • Linezolid
Agents acting against DNA and/or folate
  • Sulfonamides
  • Trimethoprim
  • Fluoroquinolones
Antimycobacterial agents
  • Anti-TB agents
  • Antileprosy agents
  • Atypical mycobacterial agents

Comparison based on coverage

Different antibiotics have varying degrees of activity against different bacteria. The table below outlines the antibiotics that are active against 3 important classes of bacteria, including gram-positive cocci, gram-negative bacilli, and anaerobes.

Antibiotic sensitivity chart

Antibiotic sensitivity:
Chart comparing the microbial coverage of different antibiotics for gram-positive cocci, gram-negative bacilli, and anaerobes.

Image by Lecturio. License: CC BY-NC-SA 4.0

References

  1. McCormack, J., Lalji, F. (2019). The “best” antibiotic sensitivity chart. Retrieved July 12, 2021, from https://therapeuticseducation.org/sites/therapeuticseducation.org/files/Antibiotic_Sensitivity_FINAL_Nov_2019.pdf 
  2. Letourneau, A.R. (2019). Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects. In Bloom, A. (Ed.), UpToDate. Retrieved May 20, 2021, from https://www.uptodate.com/contents/beta-lactam-antibiotics-mechanisms-of-action-and-resistance-and-adverse-effects
  3. Letourneau, A.R. (2019). Cephalosporins. In Bloom, A. (Ed.), UpToDate. Retrieved May 20, 2021, from https://www.uptodate.com/contents/cephalosporins 
  4. Bui, T., and Preuss, C.V. (2021). Cephalosporins. StatPearls. Retrieved July 12, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK551517/ 
  5. Lexicomp, Inc. (2021). Drug Information Sheets, UpToDate, Retrieved July 12, 2021, from:

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