Chloramphenicol

Chloramphenicol, the only clinically relevant drug in the amphenicol class, is a potent inhibitor of bacterial protein synthesis by binding to the 50S ribosomal subunit and preventing peptide bond formation. Chloramphenicol is a broad-spectrum antibiotic with wide distribution; however, due to its toxicity, its use is limited to severe infections where another alternative antibiotic is not available (usually due to resistance issues). Adverse effects include optic neuritis, aplastic anemia, and gray baby syndrome.

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Pharmacodynamics and Pharmacokinetics

Chemical structure

  • Chloramphenicol is the only drug in its class.
  • Crystalline compound
  • Soluble in alcohol

Mechanism of action

  • Inhibits bacterial protein synthesis
    • Reversibly binds to the bacterial 50S ribosomal subunit of the 70S ribosome
    • Inhibits peptidyl transferase → prevents peptide bond formation (prevents transpeptidation)
  • Limits bacterial growth → bacteriostatic
Site of action for chloramphenicol on the 50S ribosomal subunit

Site of action for chloramphenicol on the 50S ribosomal subunit:
This prevents linkage of amino acids to the peptide chain, resulting in inhibition of protein synthesis.
tRNA: transfer RNA

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

Pharmacokinetics

  • Absorption: readily absorbed from the GI tract
  • Distribution:
    • 60% protein bound
    • Lipid soluble
    • Widely distributed
    • Crosses the blood-brain barrier
  • Metabolism: inactivated by hepatic glucuronyltransferase
  • Excretion: urine

Indications

Antimicrobial coverage

  • Gram-positive cocci and bacilli:
    • Streptococcus (particularly S. pneumoniae)
    • Staphylococcus
    • Enterococcus
    • Bacillus
    • Listeria
  • Gram-negative cocci and bacilli:
    • Haemophilus influenzae
    • Neisseria meningitidis
    • Moraxella catarrhalis
    • Escherichia coli
    • Yersinia pestis
    • Salmonella
    • Shigella
  • Atypical bacteria:
    • Rickettsia
    • Mycoplasma

Types of infections

Because of chloramphenicol’s side effects, use is generally limited to severe infections where resistance has developed against alternative agents:

  • Bacterial meningitis
  • Bacterial conjunctivitis and endophthalmitis
  • Otitis externa
  • Rocky Mountain spotted fever
  • Typhoid fever
  • Anthrax
  • Plague

Adverse Effects and Contraindications

Adverse effects

  • GI upset
  • Optic neuritis
  • Ototoxicity (with ear drops)
  • Bone marrow suppression
    • Mild anemia, thrombocytopenia, and neutropenia
    • Aplastic anemia
  • Gray baby syndrome
    • Due to immature glucuronidation from ↓ glucuronosyltransferase enzyme in neonates → chloramphenicol accumulation
    • Signs and symptoms:
      • Cyanosis appearing (gray color)
      • Hypothermia
      • Abdominal distention
      • Flaccidity
      • Cardiovascular collapse 

Contraindications

  • Should not be used if alternative antibiotic therapy is available
  • Avoid in pregnant or breastfeeding patients.

Drug interactions

  • Clozapine: ↑ risk of myelosuppression
  • May ↑ serum concentrations of:
    • Barbiturates
    • Cyclosporine
    • Fosphenytoin and phenytoin
    • Sulfonylureas
    • Tacrolimus

Mechanisms of Resistance

Resistance mechanisms to chloramphenicol in bacteria include:

  • Enzymatic inactivation by acetylation via
    • Chloramphenicol acetyltransferase (most common)
    • Chloramphenicol phosphotransferases 
  • Efflux pumps
  • Permeability barriers
  • Mutation of the target site on 50S subunit

Comparison of Medications

Table: Comparison of several classes of bacterial protein synthesis inhibitor antibiotics
Drug classMechanism of actionCoverageAdverse effects
Amphenicols
  • Bind to the 50S subunit
  • Prevent transpeptidation
  • Gram positives
  • Gram negatives
  • Atypicals
  • GI upset
  • Optic neuritis
  • Aplastic anemia
  • Gray baby syndrome
Lincosamides
  • Bind to the 50S subunit
  • Prevent transpeptidation
  • Gram-positive cocci:
    • MSSA
    • MRSA
    • Streptococcus
  • Anaerobes
  • GI upset
  • Allergic reactions
  • Pseudomembranous colitis
Macrolides
  • Bind to the 50S subunit
  • Prevent transpeptidation
  • Gram positives
  • Gram negatives
  • Atypicals
  • Mycobacterium avium complex
  • GI upset
  • QT prolongation
  • Hepatotoxicity
  • Myasthenia gravis exacerbation
Oxazolidinones
  • Bind to the 23S rRNA of the 50S subunit
  • Prevent initiation complex formation
Gram-positive cocci:
  • MSSA
  • MRSA
  • VRE
  • Streptococcus
  • Myelosuppression
  • Neuropathy
  • Lactic acidosis
  • Serotonin syndrome
rRNA: ribosomal RNA
VRE: vancomycin-resistant Enterococcus
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. PubChem. (20216). Chloramphenicol. Archived from the original on November 15, 2016, from https://web.archive.org/web/20161115131903/https://pubchem.ncbi.nlm.nih.gov/compound/5959#section=Top
  2. The American Society of Health-System Pharmacists. (2015). Chloramphenicol. Archived from the original on June 24, 2015, from https://web.archive.org/web/20150624080341/http://www.drugs.com/monograph/chloramphenicol.html
  3. Deck, D.H., and Winston, L.G. (2012). Tetracyclines, macrolides, clindamycin, chloramphenicol, streptogramins, & oxazolidinones. In Katzung, B.G., et al (Eds.), Basic & Clinical Pharmacology (12th edition, pp. 809–819). https://pharmacomedicale.org/images/cnpm/CNPM_2016/katzung-pharmacology.pdf
  4. Oong, G.C., and Tadi, P. (2021). Chloramphenicol. [online] StatPearls. Retrieved June 28, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK555966/
  5. Werth, B.J. (2020). Chloramphenicol. [online] MSD Manual Professional Version. Retrieved June 28, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-drugs/chloramphenicol

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