.  
Isoniazid
 * Adverse Effect Noted

The Elephant Formulary
2003-06 Susan K. Mikota DVM and Donald C. Plumb, Pharm.D.
Published by Elephant Care International -
www.elephantcare.org


Elephant specific information, if available, is in blue.

Technical information to be added.

 

Elephants:

 

Note: Detailed guidelines for the treatment of tuberculosis in elephants have been developed in the U.S.A. by the National Tuberculosis Working Group for Zoo and Wildlife Species. The drugs and dosages recommended are based on human treatment protocols and information obtained from pharmacokinetic studies in elephants (unpublished data). The reader is advised to consult the current Guidelines available at the following websites:

 

http://www.elephantcare.org\protodoc_files\new03\Guidelines For The Control Of Tuberculosis In Elephants 2003.pdf 

 

http://www.aphis.usda.gov/ac/ElephTBGuidelines2003.html

 

a) Isoniazid 5 mg/kg by oral or rectal administration (Natl. TB Working Group, 2003).

b) Adverse effects:

- In one elephant under treatment for tuberculosis, isoniazid (INH) administered orally together with rifampin (8 mg/kg), pyrazinamide (35mg/kg) and vitamin B6 caused partial anorexia.  Rifampin was discontinued after the first 6 months of treatment due to failure to achieve therapeutic levels.  Rectally administered INH at a dose of 11.5 mg/kg resulted in anorexia, lethargy, and pica.  Yellow brown urine was observed and serum AST, total bilirubin, GGT, and bile acids were elevated. Signs resolved within 2-3 days after treatment was stopped.  Daily treatment with INH (3.75 mg/kg per rectum) had no adverse effects but symptoms resumed if the dose was increased to 5 mg/kg or greater.  When INH and pyrazinamide were administered rectally 4 times weekly, a low grade anemia was observed. The anemia resolved when the INH dose was decreased from 3.75 to 2.5 mg/kg and the PZA dose was decreased from 35 to 25 mg/kg.

- Four elephants receiving daily direct oral administration of  isoniazid (7.5 mg/kg) and rifampin (9.9 mg/kg) developed inappetance, lethargy, and pica. Symptoms resolved when the INH dose was reduced to 5.6 mg/kg and the rifampin dose was reduced to 7.5 mg/kg.

- One elephant showed a decreased white blood cell count (from 13,000 / l to 1,900 / l) which resolved when INH was discontinued.

-  One elephant given INH (10 mg/kg) rectally as the only drug developed lethargy, inappetance and an elevated LDH within 3 weeks.  Treatment was discontinued for one month then reinstated at 5 mg/kg. Pyrazinamide (25 mg/kg/day) was added and both drugs were given rectally. Periodic episodes of lethargy on this regimen responded to 1-2 weeks rest (no drugs) then reinstating INH at a half-dose and increasing to a full dose over a period of several weeks. (Mikota, et.al. 2001).

c) 5 mg/kg orally (Devine et.al. 1983).

d) 7.5 mg/kg (if using pre-mixed solution) or 4 mg /kg (if administered immediately following suspension of powder form) as a starting dose based on PK data; PO or rectally; monitor serum blood levels and adjust dose as needed (Maslow, 2005)

Elephant References:

 

a) The National Tuberculosis Working Group for Zoo and Wildlife Species. 2003. Guidelines for the Control of Tuberculosis in Elephants. Internet links above.

b) Mikota,S.K., Peddie,L., Peddie,J., Isaza,R., Dunker,F., West,G., Lindsay,W., Larsen,R.S., Salman,M.D., Chatterjee,D., Payeur,J., Whipple,D., Thoen,C., Davis,D.S., Sedgwick,C., Montali,R.J., Ziccardi,M., and Maslow,J. 2001. Epidemiology and diagnosis of Mycobacterium tuberculosis in captive Asian elephants (Elephas maximus). Journal of Zoo and Wildlife Medicine 32:(1):1-16  Abstract: The deaths of two Asian elephants (Elephas maximus) in August 1996 led the United States Department of Agriculture to require the testing and treatment of elephants for tuberculosis. From August 1996 to September 1999, Mycobacterium tuberculosis infection was confirmed by culture in 12 of 118 elephants in six herds. Eight diagnoses were made antemortem on the basis of isolation of M. tuberculosis by culture of trunk wash samples; the remainder (including the initial two) were diagnosed postmortem. We present the case histories, epidemiologic characteristics, diagnostic test results and therapeutic plans from these six herds. The intradermal tuberculin test, enzyme-linked immunosorbent assay serology, the blood tuberculosis test and nucleic acid amplification and culture are compared as methods to diagnose M. tuberculosis infection in elephants.

c) Devine,J.E., Boever,W.J., and Miller,E. 1983. Isoniazid therapy in an Asiatic elephant (Elephas maximus). Journal of Zoo Animal Medicine 14:130-133.  Summary: A single Asian elephant (approx. 2300 kg) was given 10 g of isoniazid with food and blood levels evaluated at 1,2,3,4,6, and 7 hours after dosing.  Total INH concentrations ranged from 8.63 g/ml at 1 hour to 2.63 g/ml at 7 hours. The authors suggest that a dose of 5 mg/kg in elephants should be adequate to achieve blood levels found to be effective in humans.

d) Maslow, J.N., Mikota, S.K., Zhu, M., Isaza, R., Peddie, L.R., Dunker, F., Peddie, J., Riddle, H., and Peloquin, C.A. 2005. Population pharmacokinetics of isoniazid in the treatment of Mycobacterium tuberculosis among Asian and African elephants (Elephas maximus and Loxodonta africana). J Vet Pharmacol Ther. 28(1):21-7.

We recently described the clinical presentation and treatment of 18 elephants from six herds infected with TB. Treatment protocols and methods varied between herds to include both oral and rectal dosing using multiple drug doses and formulations. In this paper we present information regarding the pharmacokinetics (PK) of isoniazid (INH) in elephants and provide suggestions regarding initial treatment regimens. Forty-one elephants received INH daily by either oral or rectal administration with different formulations. Population PK analysis was performed using Non-linear Mixed Effect Modeling (NONMEM). Results of oral administration indicated that compared with premixed INH solution, the drug exposure was highest with a suspension prepared freshly with INH powder. When INH was concomitantly given as an admixture over food, Tmax was delayed and variability in drug absorption was significantly increased. Compared with oral administration, similar drug exposures were found when INH was dosed rectally. The data generated suggest that a starting dose of 7.5 mg/kg of INH is appropriate for initial TB treatment in elephants when premixed solution is administered directly into the oropharynx or rectal vault and 4 mg/kg are when INH is administered following immediate suspension from powdered form.
 

See also:

Mikota,S.K., Larsen,R.S., and Montali,R.J. 2000. Tuberculosis in Elephants in North America. Zoo Biology 19:393-403  Abstract: Within the past 4 years, TB has emerged as a disease of concern in elephants. The population of elephants in North America is declining (Weise,1997), and transmissible diseases such as TB may exacerbate this trend. Guidelines for all elephants for TB, were instituted in 1997 (USDA, 1997, 2000). Between August 1996 and May 2000, Mycobacterium tuberculosis was isolated form 18 of 539 elephants in North America, indicating an estimated prevalence of 3.3%. Isolation of the TB organism by culture is the currently recommended test to establish a diagnosis of TB; however, culture requires 8 weeks. Further research is essential to validate other diagnostic tests and treatment protocols.

Dunker,F.and Rudovsky,M.  1998. Management and treatment of a Mycobacterium tuberculosis positive elephant at the San Francisco Zoo.  Proceedings AAZV and AAWV Joint Conference. Pages: 122-123

 

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