Pharmacokinetics of Chloramphenicol in Healthy Horses (14-01)

Investigators

K. Gary Magdesian, DVM, Dipl. ACVIM, ACVECC, ACVCP

T Patel, Pharm D; K Estell DVM DACVIM, H Knych DVM PhD DACVCP, V Wiebe Pharm D and J Edman.

Brief Background of the Problem: Despite scarce and conflicting research on the pharmacokinetics of orally administered chloramphenicol in horses, it is commonly used in equine practice. Single dose administration has demonstrated variable oral absorption and a very short half life using older analytical methodology, questioning the validity of its use in horses at some of the published recommended doses (as low as 25-30 mg/kg).1-3 There is a need to evaluate the pharmacokinetics of chloramphenicol, including compounded formulations which are commonly used in equine practice, using modern analytical methodology (LC-MS), and to do so in multi-dose studies to evaluate for accumulation with subsequent steady state concentrations.  

Hypothesis Statement: We hypothesize that: 1.) chloramphenicol is orally bioavailable in horses at doses of 50mg/kg and result in steady state serum concentrations above the minimum inhibitory concentrations (MICs) of common equine pathogens when administered every 6 hours.  2.) Compounded chloramphenicol will not be effectively absorbed in adult horses.

Specific Objective(s) of the Study: Study objectives are to determine pharmacokinetics of chloramphenicol at steady state (after multi-dosing), to evaluate how well it is absorbed, and to determine therapeutic dosing protocols for horses. Another objective is to determine how well compounded chloramphenicol is absorbed in the horse.

Overview of Experimental Approach: 

1. Seven healthy horses will be administered chloramphenicol orally and i.v. in a cross-over design and at a dose of 50mg/kg once to determine the pharmacokinetics of chloramphenicol in horses. Single dose studies are required to determine oral bioavailability and terminal half-life. Time points of serum sample collection include:  (baseline: time 0), and 3, 6, 9, 12, 15, 30, and 45 minutes, 1,1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 20, and 24

2. The same horses will be administered a single dose of each of 2 compounded formulations of chloramphenicol in a randomized order, cross-over design with 1) above in order to evaluate the bioavailability of these compounded formulations. In addition, the concentration of chloramphenicol will be measured in the products to determine the actual vs company-provided concentration in the product. 

3. The same seven healthy horses will be administered chloramphenicol for 2 days (8 doses) in order to determine multi-dose steady state concentrations.  The oral pharmacokinetics will be repeated after the last oral dose to determine the effects of multi-dose administration on the bioavailability and clearance (and half-life) of chloramphenicol. Urine and fecal concentrations will also be measured to determine risk of exposure to barn cleaning crew and clients, since chloramphenicol has been associated with both reversible and irreversible aplastic anemia in humans.

Anticipated Benefits to the Equine Industry: Despite variable and conflicting pharmacokinetic data from the 1950’s-1990’s, chloramphenicol is commonly used today as a broad spectrum oral antibiotic in horses in a wide range of doses (25-50 mg/kg orally, three to four times a day).4,5  The results of this proposed study will be to utilize modern analytical techniques (LC-MS) to accurately determine the pharmacologic disposition of chloramphenicol in horses after individual and repeated dosing, and will determine whether commonly used compounded formulations are absorbed well. This will be used to make accurate dosing recommendations for horses. 

Accomplishments/Results (in "bullet" form)

  • The single dose pharmacokinetics show a low peak concentration of chloramphenicol as compared to humans and dogs, indicating that horses do not absorb chloramphenicol as well.
  • The half life of chloramphenicol is very short in horses, indicating frequent administration is required
  • The absorption of two compounded formulations, a paste and a suspension, was equivalent to that of the tablets
  • The multiple dose study showed that chloramphenicol plasma levels reach steady state quickly 
  • On day 5, after four days of four times daily dosing, chloramphenicol levels were far those below of other species with similar dosing.  The serum concentrations were high enough to only target bacteria with low minimum inhibitory concentrations (MIC) (1-2 µg/mL) at a dose of 50 mg/kg administered every 6 hours. In contrast, in humans and dogs, bacteria with a MIC of 8 µg/mL can be targeted. 

Benefits to the Equine Industry (2 or 3 sentences)

 In contrast to its broad spectrum in human and canine medicine, chloramphenicol has a much narrowed predicted spectrum in horses because of a relatively poor absorption in horses.  Bacteria such as streptococci and nonenteric bacteria should be targeted.  

Final comments to RDVMs:  Because of the relative poor absorption of chloramphenicol in horses, and the low steady state plasma concentrations, chloramphenicol should only be used based on MIC susceptibility data rather than empirically.  It should be used only for treating bacteria with MIC values of ≤ 2 µg/mL, with dosing at 50 mg/kg q 6 hours.