Elephant specific information, if available, is in blue.

Chemistry – A semi-synthetic zwitterion derivative of rifamycin B, rifampin occurs as a red-brown, crystalline powder with a pKa of 7.9. It is very slightly soluble in water and slightly soluble in alcohol.

 

Storage/Stability/Compatibility – Rifampin capsules should be stored in tight, light-resis­tant containers, preferably at room temperature (15-30°C).

 

Pharmacology – Rifampin may act as either a bactericidal or bacteriostatic antimicrobial dependent upon the susceptibility of the organism and the concentration of the drug. Rifampin acts by inhibiting DNA-dependent RNA polymerase in susceptible organisms, thereby suppressing the initiation of chain formation for RNA synthesis. It does not inhibit the mammalian enzyme.

 

Rifampin is active against a variety of mycobacterium species and Staphylococcus au­reus, Neisseria, Haemophilus, and Rhodococcus equi (C. equi). At very high levels, ri­fampin also has activity against poxviruses, adenoviruses, and Chlamydia trachomatis. Rifampin also has antifungal activity when combined with other antifungal agents.

 

Uses/Indications – At the present time, the principle use of rifampin in veterinary medicine is in the treatment of Rhodococcus equi (Corynebacterium equi) infections (usually with erythromycin estolate) in young horses.

 

In small animals, the drug is sometimes used in combination with other antifungal agents (amphotericin B and 5-FC) in the treatment of histoplasmosis or aspergillosis with CNS involvement.

 

Pharmacokinetics – After oral administration, rifampin is relatively well absorbed from the GI tract. Oral bioavailability is reportedly about 40-70% in horses and 37% in adult sheep. If food is given concurrently, peak plasma levels may be delayed and slightly re­duced.
 

Rifampin is very lipophilic and penetrates most body tissues (including bone and prostate), cells and fluids (including CSF) well. It also penetrates abscesses and caseous material. Rifampin is 70-90% bound to serum proteins and is distributed into milk and crosses the placenta. Mean volume of distribution is approximately 0.9 L/kg in horses, and 1.3 L/kg in sheep.

 

Rifampin is metabolized in the liver to a deacetylated form which also has antibacterial activity. Both this metabolite and unchanged drug are excreted primarily in the bile, but up to 30% may be excreted in the urine. The parent drug is substantially reabsorbed in the gut, but the metabolite is not. Reported elimination half-lives for various species are: 6-8 hours (horses), 8 hours (dogs), 3-5 hours (sheep). Because rifampin can induce hepatic microsomal enzymes, elimination rates may increase with time.

 

Contraindications/Precautions/Reproductive Safety – Rifampin is contraindicated in patients hypersensitive to it or other rifamycins. It should be used with caution in patients with preexisting hepatic dysfunction.

 

Rodents given high doses of rifampin 150 – 250 mg/kg/day resulted in some congenital malformations in offspring, but the drug has been used in pregnant women with no re­ported increases in teratogenicity.

 

Adverse Effects/Warnings – Rifampin can cause red-orange colored urine, tears, sweat and saliva. There are no harmful consequences from this effect. In some species (e.g., hu­mans), rashes, GI distress, and increases in liver enzymes may occur, particularly with long-term use.
 

Adverse effects in horses are apparently rare when rifampin is given orally. Although not commercially available, intravenous rifampin has caused CNS depression, sweating, hemolysis and anorexia in horses.

 

Overdosage/Acute Toxicity – Symptoms associated with overdosage of oral rifampin generally are extensions of the adverse effects outlined above (GI, orange-red coloring of fluids, and skin), but massive overdoses may cause hepatotoxicity. Should a massive oral overdosage occur, the gut should be emptied following standard protocols. Liver enzymes should be monitored and supportive treatment initiated if necessary.

 

Drug Interactions – Because rifampin has been documented to induce hepatic microsomal enzymes, drugs that are metabolized by these enzymes may have their elimination half-lives shortened and serum levels decreased Drugs that may be affected by this process in­clude propranolol, quinidine, dapsone, chloramphenicol, corticosteroids, oral antico­agulants (e.g., warfarin), benzodiazepines (e.g., diazepam), and barbiturates (e.g., phenobarbital).  Rifampin may cause decreased serum concentrations of ketoconazole if administered concurrently.

 

Drug/Laboratory Interactions – Microbiologic methods of assaying serum folate and vitamin B12 are interfered with by rifampin. Rifampin can cause false-positive BSP (bromosulfophthalein, sulfobromophthalein) test results, by inhibiting the hepatic uptake of the drug.

 

Doses –

Horses:

For treatment of C. equi infections in foals:

a)   Rifampin 5 mg/kg PO tid with erythromycin estolate or ethylsuccinate 25 mg/kg PO tid. May cause urine to become red. Use a continuous course of rifampin as intermittent use may be associated with allergic reactions. Treat until chest ra­diographs and plasma fibrinogen levels return to normal. (Hillidge and Zertuche 1987)

 

For susceptible infections in foals:

a)   5 mg/kg PO q12h (dose extrapolated from adult horses). Used in combination with erythromycin for C. equi infections (see above), but could be used with other agents (e.g., penicillins) to treat other gram positive infections. Should be used with other antimicrobial agents to minimize the potential for bacterial re­sistance development. (Caprile and Short 1987)

 

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) Rifampin 10 mg/kg orally only.  Therapeutic levels have not been achieved with 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.  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 also showed a decreased white blood cell count (from 13,000/µl to 1,900/µl) which resolved when INH was discontinued. (Mikota, et.al. 2001)

c) 10 mg/kg PO as a starting dose for the treatment of tuberculosis; monitor serum drug levels and adjust dose as needed. Adequate serum drug levels have not been achieved with rectal administration (Peloquin, 2006).

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) Peloquin,C.A., Maslow,J.N., Mikota,S.K., Forrest,A., Dunker,F., Isaza,R., Peddie,L.R., Peddie,J., and Zhu,M. 2006. Dose selection and pharmacokinetics of rifampin in elephants fro the treatment of tuberculosis. J Vet Pharmacol Ther. 29:1-6.

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

Monitoring Parameters –

1) Clinical efficacy

a)   For monitoring C. equi infections in foals and response to ri­fampin/erythromycin: Chest radiographs and plasma fibrinogen levels have been suggested as prognostic indicators when done after 1 week of therapy. (Hillidge and Zertuche 1987)

2)   Adverse effects; may consider liver function monitoring with long-term therapy

 

Client Information – Rifampin may cause urine and other secretions (tears, saliva, etc.) to turn red-orange in color. This is not abnormal.

 

Dosage Forms/Preparations/FDA Approval Status/Withholding Times –

 

Veterinary-Approved Products:      None

 

Human-Approved Products:

Rifampin Capsules 150 mg, 300 mg; Rifadin®  (Hoechst Marion Roussel);  Rimactane ® (Ciba); (Rx)

Rifampin Powder for Injection:  600 mg; Rifadin® (Hoechst Marion Roussel) (Rx)