CHLORAMPHENICOL

ANTIMICROBIAL SPECTRUM:
BROAD SPECTRUM ANTIBIOTIC:Active against nearly the same range of organisms (gram-positive and negative bacteria, rickettsiae, mycoplasma, chlamydia)
  • Gram-positive: Streptococcus sp., Staphylococcus sp., Enterococcus sp., Bacillus anthracis, Listeriamonocytogenes.
  • Gram- negative: H. influenzae, M. catarrhalis, N. meningitides, E. coli, P. mirabilis, Salmonella sp., Shigella sp., Stenotrophomonasmaltophilia.
  • Against anaerobes:Either bactericidal or (more commonly) bacteriostatic, depending on the organism.
  • Bactericidal against H. influenzae, Neisseria Meningitidis, and S. pneumoniae.
MOA:
  • Protein synthesis inhibitor in bacteria. Inhibits protein by binding irreversibly to the bacterial 50s ribosomal subunit.
  • It hinder the access of aminoacyl-tRNA to the acceptor site for amino acid incorporation by acting as a peptide analogue, it prevents formation of peptide bonds.
  • Thus inhibits protein synthesis at the peptidyl transferase reaction
RESISTANCE: i. Inactivation of the antimicrobial drug
  • This type of resistance is seen in members of Enterobacteriaceae, Acinetobacter Sp, Pseudomonas aeruginosa, S.aureus, Campylobacter Jejuni etc.
ii. Alteration of the antimicrobial target
  • Methylation of a single adenine in the bacterial 50s ribosome can lead to resistance against macrolides, lincosamides, and streptogramin B in S. aureus and S. pneumoniae.
 iii. Adaptation of alternative metabolic pathway
  • A mutational change in H. influenzae results in overproduction of dihydrofolate reductases, leading to trimethoprim resistance.
iv. Active efflux pumping out of the drug
  • This kind of resistance is seen to chloramphenicol (P.aeruginosa, K. pneumoniae, E. coli, S. typhimurium, V. cholerae), macrolides (Streptococcus pneumoniae, Enterococcus sps, Bacteroides sps, Pseudomonas sps and Enterobacteriaceae members), tetracyclines (S. aureus, E. coli, A. baumannii, S. typhimurium), aminoglycosides (E. coli, P.aeruginosa, A. baumannii) and beta-lactams (H. influenzae, P.aeruginosa, A. baumannii).
v. Decreased permeability of the drug
  • Some strains of P. aeruginosa and other gram-negative bacilli exhibit aminoglycoside resistance due to a transport defect or membrane permeabilization. Resistance to cefoxitin in E. coli and K. pneumoniae is due to mutations leading to narrowed outer membrane proteins.
PHARMACOKINETICS:
  • Administered either intravenously or orally.
  • Rapidly and completely absorbed via the oral route because of its lipophilic nature, and is widely distributed throughout the body.
  • 50-60% bound to plasma proteins and very widely distributed, volume of distribution 1 L/kg.
  • Freely penetrates serous cavities and blood-brain barrier: CSF concentration is nearly equal to that of unbound drug in plasma.
  • It crosses placenta and is secreted in bile and milk.
  • Hepatic metabolism to the inactive glucuronide is the major route of elimination. 
USES:
  • Treatment of serious rickettsial infections such as typhus and Rocky Mountain spotted fever.
  • Alternative to a b-lactam antibiotic for treatment of meningococcal meningitis occurring in patients who have major hypersensitivity reactions to penicillin or bacterial meningitis caused by penicillin-resistant strains of pneumococci.
  • Topically in the treatment of eye infections because of its broad spectrum and its penetration of ocular tissues and the aqueous humor. It is ineffective for chlamydial infections. Brucellosis: If tetracyclines are contraindicated, chloramphenicol is recommended.
  • Rare: Typhoid, when Third-generation cephalosporins and quinolones which are drugs of choice for the treatment of typhoid fever were contraindicated.
INTERACTIONS:
  • Inhibits the metabolism of such drugs as warfarin, phenytoin, tolbutamide, and chlorpropamide, thereby elevating their concentrations .
  • Concurrent administration of phenobarbital or rifampin, which potently induce CYPs, shortens chloramphenicol t1/2 and may result in sub therapeutic drug concentrations 
ADVERSE EFFECTS:
  • Anemia
  1. Hemolytic anemia –less glucose 6-phosphate dehydrogenase.
  2. Reversible anemia- side effect , dose related
  3. Aplastic anemia - rare - idiosyncratic - usually fatal
  • Hypersensitivity reaction
  1. Rashes,
  2. fever,
  3. atrophic glossitis
  4. angioedema
  • Gastrointestinal irritative effects
  1. Nausea
  2. vomiting
  3. diarrhoea
  • Gray baby syndrome
  1. Neonates have a low capacity to glucuronate the antibiotic, and they have underdeveloped renal function. 
  2. Therefore, neonates have a decreased ability to excrete the drug, which accumulates to levels that interfere with the function of mitochondrial ribosomes. 
  3. This leads to poor feeding,depressed breathing, cardiovascular collapse, cyanosis and death. 
  4. Adults who have received very high doses of the drug can also exhibit this toxicity.
Exam Question
  • A young male presents with meningococcal meningitis and allergy to penicillin can be treated with chloramphenicol
  • Chloramphenicol resistance in Pseudomonas aeruginosa is due to Active efflux pumping out of the drug
  • Gray baby syndrome is caused by Chloramphenicol
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