CHLORAMPHENICOL
Outline

Overview

• Nearly perfect antibacterial
• Major flaw
  • Aplastic anemia
  • Other blood dyscrasias
• Bacteriostatic
• Broad spectrum
• Near uniform distribution in body
• Specifically DISALLOWED in food animals

Structure and chemical characteristics

• Contains nitrobenzene ring
  • pontential for carcinogenesis
• High lipid solubility
• Low water solubility

Mechanism of action

• Binds to peptidyl transferase enzyme
• Inhibits transfer of growing peptide chain to "Acceptor" site aminoacyl-tRNA
• Reversible binding -- bacteriostatic

Resistance

• Increasing
• Due to altered molecule
• Plasmid borne

Pharmacokinetics

• Many routes
• Rapidly absorbed
• Well distributed
  • CSF in inflammation 89% of plasma
  • Eye
• 90% Eliminated by glucuronyl transferase
  • Conjugation with glucuronic acid
  • Poorly developed newborn

Adverse Effects

Allergic

• Typical allergies -- not major
• May be allergic component to idiosyncratic blood dyscrasias

Biological effects

• Superinfection typical of broad spectrum
• Less GI effect than others because of pharmacokinetics
• Anorexia in dolphins, whales, California sea lions
  • After 1-2 days Rx of drug in fish for food
  • Difficult to get animals eating
  • ref: Former student / Mystic Aquarium

Direct toxicity

Reversible, dose-related anemia

• Humans
  • normocytic anemia
  • plasma conc >25 mcg/mL (Soldin et. al)
  • slightly higher than normal dose will produce
  • Rx 2 wks or more increase risk
• Dogs
  • 50 mg/kg q6h, indefinitely
  • Well tolerated
• Cats
  • 50 mg/kg IM, q12h x 7 d
    • Severe depression
    • Leucopenia
    • bone marrow depression
  • Cats -- poor glucurnide formation

Idiosyncratic blood dyscrasias

• Major liability
• High probability of death
• Aplastic anemia in humans: 1:11,000 to 1:40,000 patients
• Leuopenia: 1:30,000 patients
• Those that recover have high incidence of leukemia
• Increased risk --
  • Some genetic tendency
  • Mulitple exposures
  • Long ezposures

Teratogenesis

• Avoid in pregnant patients

Gray Baby Syndrome

• Improper dosage in nenonates (< 1 mo)
• Poor glucuronidation capability
• Cardiovascular collapse
• 40% die by 5th day
• Assoc. with conc. >40 mcg/mL

Drug interaction

• Depresses hepatic biotransformation of other drugs
• Bacteriostatic

Clinical applications

• Resembles tetracyclines, except
  • NO in FOOD PRODUCING ANIMALS
  • More serious hazard so limit use
• NO protozoans
• More likely for CNS than tetracyclines
• Universally active vs
  • anaerobic bacteria
  • rickettsiae
  • chlamydia
  • mycoplasma

References

• Feldman,W.E. 1978. Effect of ampicillin and chloramphenicol against Haemophilus influenzae. Pediatrics 61:406-9.
• Feldman, W.E., and T. Sweighaft. 1979. Effect of ampicillin and chloramphenicol against Streptococcus pneumoniae and Neisseria meningitidis. Antimicrobial Agents and Chemotherapy 15:240-2.
• KAGAN3rd. Chapter 10, pp 127-136.
• Sisodia, Chatur. 1980. Pharmacotherapeutics of chloramphenicol in veterinary medicine. JAVMA 176(10, part 2):1069-1071.
• Soldin, S.J., et.al., The high performance liquid chromatographic measurement of chloramphenicol and its succinate esters in serum. Journal?, Vol?, pp. 171-177, Yr?,

Study Questions

1. Note the low water solubilitiy of chloramphenicol base and it high lipid solubility. Given that protein binding is moderate (meaning not much of a factor), predict its bioavailability after oral administration (assuming no biotransformation) and the relation between its plasma and intracellular concentrations (CSF, too).
2. Why must chloramphenicol not be used in food producing animals?
3. How does the antimicrobial (As opposed to antibacterial) spectrum of chloramphenicol differ from that of the tetracyclines?
4. How does the mechanism of action of chloramphenicol compare to that of the aminoglycosides and beta-lactams?
5. What is the major route of elimination of chloramphenicol? How do poor renal function and poorly developed biotransforming enzymes and elimination\lr<120> systems affect chloramphenicol toxicity? Name a condition in neonates that stems from these deficiencies and failure to properly adjust dosage.
6. What is the major adverse effects of chloramphenicol that limits its use?

   ---

   | Drug Groups | | top |
   Gordon L. Coppoc, DVM, PhD
   Professor of Veterinary Pharmacology
   Head, Department of Basic Medical Sciences
   School of Veterinary Medicine
   Purdue University
   West Lafayette, IN 47907-1246
   Tel: 317-494-8633Fax: 317-494-0781
   Email: coppoc@vet.purdue.edu
   
   Last modified
   9:56 PM on 4/15/96
   GLC