Chemicals / Complex Chemical Agents/ Chemical:

Oxytetracycline (with special reference to Hedgehogs, Elephants, Bears, Lagomorphs, Ferrets and Great Apes)

INFORMATION AVAILABLE

GENERAL CHEMICAL INFORMATION THERAPEUTIC INFORMATION [DOSE, FREQUENCY & ROUTE]

NUTRITIONAL INFORMATION

TOXICITY INFORMATION ENVIRONMENTAL INFORMATION
Information in this page has been entered to support the current volumes of Wildpro and further information will be added as new volumes are completed. This page is not intended to substitute for the manufacturer's data sheet and the information is not yet complete for all species, or for all contra-indications etc.

CAUTION: Before any pharmaceutical product is used, the manufacturer's data sheet, containing information on uses, dosage and administration, contra-indications, warnings etc., should always be consulted. It is important to remember that licensing of pharmaceutical products for use in a particular species/condition, as well as mandatory meat and milk withdrawal times for food-producing animals, varies between countries and changes with time. Withdrawal times also may vary between different pharmaceutical formulations and depending on route of administration. In the EU, the prescription cascade must be followed (see LCofC1.2H and W564.Apr05.w1); note that specific restrictions apply for food-producing animals. In the USA, FARAD may be consulted regarding residues and meat and milk withdrawal times.

General Chemical Information

Summary 
Broad-spectrum bacteriostatic tetracycline antibiotic. (B135.44.w44)

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Names and Formulae
Type Tetracycline derived from Streptomyces rimosus. (B135.44.w44)
Alternative Names "Oxytetracycline dihydrate; Oxytetracycline base; Terramycin,  4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,6,10,12,12a-hexahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide; Glomycin; Terrafungine; Riomitsin; Hydroxytetracycline; Berkmycen; Biostat; Engemycin; Oxacycline; Oxatets; Oxydon; Oxy-Dumocyclin; Oxymycin; Oxypan; Oxytetracid; Ryomycin; Stevacin; Terraject; Tetramel; Tetran; Vendarcin; Vendracin; OXY-TET 200; Bio-mycin200; Maxim 200; 5-Hydroxytetracycline; 2-Naphthacenecarboxamide, 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,6,10,12,12a-hexahydroxy-6-methyl-1,11-dioxo-, [4S-(4alpha,4aalpha,5alpha,5aalpha,6beta,12aalpha)]-; Biostat PA; Mycoshield; Naphthacenecarboxamide, 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,6,10,12,12a-hexahydroxy-6-methyl-1,11-dioxo-, (4S-(4alpha,4aalpha,5alpha,5aalpha,6beta,12aalpha))-;" (W324)
Chemical Formula C22H24N2O9. (W324)
Chemical Structure  
Molecular Weight 460.4396. (W324)
Related Chemicals Other tetracyclines: tetracycline, chlortetracycline, demeclocycline, methacycline, doxycycline. minocycline. (B135.44.w44)

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Physical Properties / Chemistry
Appearance
  • Oxytetracycline: pale yellow to tan crystalline powder, amphoteric. (B135.44.w44, B263)

  • Oxytetracycline hydrochloride (Oxytetracycline HCl): yellow crystalline powder, hygroscopic, bitter-tasting. (B263)

Melting point

183 - 185C. (W324)

Boiling point --
Density --
Water solubility
  • Oxytetracycline hydrochloride: more soluble than oxytetracycline. (B135.44.w44); freely soluble. (B263)
Other solubility
  • Oxytetracycline: sparingly soluble in alcohol. (B263)
  • Oxytetracycline HCl: sparingly soluble in alcohol. (B263)
Acid/Base
  • Oxytetracycline hydrochloride solution: acidic. (B135.44.w44)

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Pharmacology & General Information
Pharmacology
  • Tetracyclines enter microorganisms partially by passive diffusion, partly by energy-dependant active transport. Susceptible cells concentrate the drug. (B135.44.w44)
  • With the cell, tetracyclines bind reversibly to receptors on the 30S ribosomal subunit, blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex and thus effectively preventing addition of new amino acids to the peptide chain, therefore inhibiting protein synthesis. (B135.44.w44, B263)
  • Tetracyclines are also believed to bid reversibly to 50S subunit of ribosomes and additionally alter cytoplasmic membrane permeability in susceptible organisms. (B263)
  • In high concentration, tetracyclines can inhibit protein synthesis in mammalian cells. (B263)
Storage / Stability
  • Store in tight containers preferably at room temperature (15-30C), avoid freezing and temperatures above 40C (104F), protect from light. (B263)
Legal Category (In UK) --

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References

Associated Techniques

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ORGANISATIONS

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ELECTRONIC LIBRARY
(Further Reading)
Click image for full contents list of ELECTRONIC LIBRARY

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Authors Debra Bourne (V.w5)
Referees Suzanne I. Boardman (V.w6); Becki Lawson (V.w26)

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Therapeutic Information

Uses/Indications
Activity
Appropriate Use --
Limitations
  • Most populations of susceptible organisms contain small numbers of resistant organisms, lacking the active transport mechanism across the cell membrane, or lacking passive permeability to tetracyclines. (B135.44.w44)
  • Highly resistant types of Gram-negative bacteria such as Pseudomonas, Proteus spp. and coliforms have been selected, greatly reducing the usefulness of tetracyclines. (B135.44.w44)
  • Most strains of Escherichia coli, Klebsiella, Bacteroides, Enterobacter, Proteus, Pseudomonas aeruginosa are tetracycline resistant. 
  • Tetracycline resistance is generally plasmid-transmitted, and as the genes for tetracycline resistance are closely associated with those for resistance to other drugs such as aminoglycosides and sulphonamides, plasmids often transmit resistance to multiple drug groups. (B135.44.w44)
Notes --

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Pharmacokinetics and Drug Interactions
Absorption /Bioavailability
  • Irregular absorption from the gastro-intestinal tract: a percentage of orally-administered tetracycline will remain in the gut lumen, modify intestinal flora and be excreted in the faeces. (B201, B135.44.w44)
  • 60-80% of orally administered oxytetracycline is absorbed. (B135.44.w44, B263
  • Absorbed mainly from the upper small intestine. (B135.44.w44)
  • Better absorption in the absence of food. (B135.44.w44, B263)
  • Absorption is impaired by chelation with divalent cations Ca2+, Mg2+, Fe2+ and with AL3+, particularly in milk or antacids.(B135.44.w44); reduction may be 50%. (B263)
  • Absorption is impaired by alkaline pH. (B135.44.w44)
  • Following intramuscular injection (not depot/long-acting), peak levels in 30 minutes to several hours, depending on site and volume of injection. (B263)
Distribution
  • Wide distribution in tissues and body fluids. (B135.44.w44): distributed to heart, kidney, lungs, muscle, pleural fluid, bronchial secretions, sputum, bile, saliva, urine, synovial fluid, ascitic fluid, ocular aqueous humour and vitreous humour. (B263)
  • Only low concentrations in CSF. (B135.44.w44, B263)
  • Human: oral administration of 500 mg every six hours results in peak blood levels of 4-6 g/ml. (B135.44.w44)
  • Cross the placenta. (B263)
  • Distributed into milk. (B263)
  • Deposited in developing teeth; in puppies kittens, following direct dosing or dosing of the mother in late pregnancy, may result in discoloured teeth and enamel defects in the temporary teeth. (B201.1.w1)

Volume of distribution:

  • Small animals: approximately 2.1 L/kg (B263)
  • Horses: 1.4 L/kg (B263)
  • Cattle: 0.8 L/kg (B263)
Plasma Protein binding / Storage
  • Tetracyclines are 40-80% protein-bound. (B135.44.w44)
  • Oxytetracycline plasma protein-binding about 10-40%. (B263)
Elimination Route
  • Mainly eliminated in bile and urine. (B135.44.w44, B201.1.w1)
  • Ten times higher concentration in bile than in serum, partial reabsorption (enterohepatic circulation). (B135.44.w44)
  • 10-50% of tetracyclines are excreted, primarily by glomerular filtration, in urine. (B135.44.w44)
  • 10-40% excreted in faeces. (B135.44.w44)
  • Elimination half-life may be prolonged in individuals with renal impairment, leading to drug accumulation with repeated dosing. (B263)

Elimination half-life:

  • Dogs, cats: approximately 4-6 hours. (B263)
  • Horses: approximately 10.5 hours. (B263)
  • Cattle: approximately 4.3-9.7 hours. (B263)
  • Sheep: approximately 3.6 hours.(B263)
  • Pigs: approximately 6.7 hours. (B263)
Elimination half-life / Clearance Rate
  • Renal clearance oxytetracycline (Human): 90 ml/minute. (B135.44.w44)
Drug Interactions
  • Orally administered tetracyclines may chelate divalent or trivalent cations: absorption of the tetracycline/other preparation may be decreased: oral administration should be separated by at least one to two hours. (B263). 
  • Decreased adsorption of orally administered tetracyclines in the presence of oral iron products: give iron salts at least three hours before or two hours after the tetracycline. (B263)
  • Decreased absorption of orally administered tetracyclines may occur if given together with oral sodium bicarbonate, kaolin, pectin or bismuth subsalicylate. (B263)
  • Tetracyclines, being bacteriostatic, may interfere with the bactericidal effect of beta-lactam antibiotics (penicillins and cephalosporins) and aminoglycosides (some controversy regarding the clinical significance). (B263)
  • Tetracyclines may, in a small proportion of human patients, increase digoxin bioavailability, leading to digoxin toxicity: this effect may persist for months after the tetracycline administration is discontinued. (B263).
  • Tetracyclines may depress the activity of plasma prothrombin: individuals receiving anticoagulants such as warfarin may require adjustment of their anticoagulant dose. (B263)
  • Reportedly (not yet confirmed by controlled studies), tetracyclines may reduce the insulin requirements of diabetic individuals. (B263)
  • May increase the nephrotoxic effects of methoxyflurane. (B263)
  • Concurrent use with theophylline may lead to increased gastro-intestinal side effects. (B263)

Physical incompatibility recorded, or data is conflicting, or compatibility is dependent on time or concentration: amikacin sulphate, aminophylline, amphotericin B, calcium chloride/gluconate, carbenicillin disodium, cephalothin sodium, cephapirin sodium, chloramphenicol sodium succinate, erythromycin gluceptate, heparin sodium, hydrocortisone sodium succinate, iron dextran, methicillin sodium, methohexital sodium, oxacillin sodium, penicillin G potassium/sodium, pentobarbital sodium, phenobarbital sodium, sodium bicarbonate. (B263)

Physical compatibility with: most common intravenous infusion solutions (D5W, sodium chloride 0.9%, lactated Ringers), colistimethate sodium, corticotropin, dimenhydrinate, insulin (regular), isoproterenol HCl, methyldopate HCl, norepinephrine bitartrate, polymyxin B sulphate, potassium chloride, tetracycline HCl, vitamin B-complex with C. (B263)

May become relatively unstable in intravenous infusion solutions with pH greater than 6.0, particularly in those fluids containing calcium. This appears to be less of a problem with povidone based veterinary oxytetracycline injections than with propylene glycol based products. (B263)

Compatibility is affected by factors including pH, concentration, temperature and diluents used. (B263)

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Administration
Formulations available Many formulations available. (B266)
  • Depot preparations maintain effective plasma concentration for 72-96 hours. (B201.1.w1)
Doses / Administration Routes / Frequencies

Use of Drugs (Medication):

  • Before administration of any pharmaceutical product the manufacturer's datasheet must be consulted regarding operator safety, relevant withdrawal times etc.
  • Many drugs are not registered for use in particular species and additional care should be taken in their use, with proper regard for possible toxic effects. 
  • Consideration should be given to relevant legislation regarding the use of drugs.
  • In the UK, guidelines regarding the use of drugs are set out in the Royal College of Veterinary Surgeons' Guide to Professional Conduct 2000: (See: LCofC1 - RCVS Guide to Professional Conduct 2000 - Choice of Medicinal Products).

Erinaceus europaeus - West European Hedgehog:

  • 50 mg/kg orally every 24 hours for five days. For pneumonia involving Bordetella bronchiseptica; may administer in food. (B117.w2, B267)
  • 15 mg/kg orally twice daily. Broad spectrum. (B22.27.w3)
  • 50-100 mg/kg once daily for five days subcutaneously. (D107)
  • 50 mg/kg once daily for five days subcutaneously or intramuscularly. (D107)

Atelerix albiventris - Four-toed hedgehog:

  • 50 mg/kg daily orally. Administer in food for 5-7 days. Broad spectrum. (J204.59.w1)

Elephants:

  • A study comparing the plasma half-life of oxytetracycline in mammal and bird species of different sizes following intravenous administration, found that t1/2 β varied by about 14-fold across the size range and gave an allometric equation: t1/2 β = 160 W0.20 for this drug or across eutherian mammals only, t1/2 β = 160 W0.22 . However, it was also noted that bodyweight only accounted for 36% of total variation in half-life between species. The equation suggested a predicted elimination half-life for elephants of 878 minutes [Editor's note: it should be noted that the studies in horses, with assumed bodyweights of 500 kg, gave t1/2 β varying from 482 - 942 minutes]. (J21.48.w1)

The following information is taken with permission directly from the Elephant Care International website (W580.Aug2005.w25):

Elephants:

a) 18mg/kg IM q 48 -72 h. The authors state that this dose does not achieve a serum concentration of > 4g /ml, as recommended by the National Committee for Clinical Laboratory Standards. They further suggest that the efficacy of oxytetracycline against specific pathogens isolated from elephants is important to determine because the susceptibility to tetracyclines varies greatly (Bush et.al. 2000).

b) 52 133 mg/cm IM q 48-72 h. Note that the weights of the African elephants in this study were estimated by using the sum of the elephants girth and length in cm and that the dose is expressed in mg/cm (Bush et.al. 1996).

c) 20 mg/kg IM q 48-72 h. Peak plasma levels of 1.09 2.87 g /ml were achieved between 1 and 48 hours post-injection and were higher than the MIC reported for most susceptible pathogens (0.5 g /ml OTC) for approximately 84 hours except for E. coli. The MIC for E.coli has been reported to be 4 ug/ml and this organism would probably be little affected by this IM dose (Limpoka et.al. 1987).

Elephant References:
a) Bush,M., Stoskopf,M.K., Raath,J.P., and Papich,M.G. 2000. Serum oxytetracycline concentrations in African elephant (Loxodonta africana) calves after long-acting formulation injection. Journal of Zoo and Wildlife Medicine 31:(1):41-46 Abstract: Serum oxytetracycline pharmacokinetics were studied in 18 African elephant calves. Each elephant received separate injections of oxytetracycline at approximately 18 mg/kg i.m. and 8 mg/kg i.v. in a cross-over study. Blood samples were drawn at 0, 24, 48, 72 and 96 h postinjection. An additional sample was drawn 110 h before the animals were reinjected in the cross-over study and a final blood sample was drawn 48 h after the second dose. No lameness or stiffness was observed following i.m. injections. Serum oxytetracycline concentrations >0.5 g/ml were present 48 h after initial dosing for all elephants (i.m., i.v., high or low dosage). Only elephants given the high i.m. dosage (18 mg/kg) maintained levels >0.5 g/ml 72 h postinjection. No significant difference in serum oxytetracycline concentration with time was observed between the groups given different i.v. dosages. These studies demonstrated that quantifiable serum oxytetracycline concentrations can be maintained in young African elephants with a low-dosage multidose i.m. regimen.

b) Bush,M., Raath,J.P., de Vos,V., and Stoskopf,M. 1996. Serum oxytetracycline levels in free-ranging male African elephants (Loxodonta africana) injected with a long-acting formulation. Journal of Zoo and Wildlife Medicine 27:(3):382-385 Abstract: Thirteen adult free-living male African elephants (Loxodonta africana) were anesthetized and given 20-100 g of a long-acting tetracycline (OTC) preparation either i.m. or i.v. Five dosages were established based on body measurements (the sum of the body length and the girth in centimeters) Serum concentrations of OTC were measured 48 hr after injection. Serum concentrations >/= 0.5 g /ml were measured in 11 of 12 elephants receiving OTC dosages of 52-133 mg/cm either i.v. or i.m. The i.m. administration route produced serum concentrations from 0.75-1.6 g g/ml in four of four elephants. A dosage of 60-80 mg/cm i.m. or i.v. should provide a therapeutic serum concentration of OTC for at least 48 hr. The use of an i.v. catheter avoids multiple i.m. injections of large drug volumes.

c) Limpoka,P., Chai Anan,S., Sirivejpandu,R., Kanchanomai,S., Rattanamonthianchai, and Puangkum,P. 1987. Plasma concentrations of oxytetracycline in elephants following intravenous and intramuscular administration of Terramycin/LA injectable solution. ACTA VET.BRNO 56:173-179 Abstract: The blood concentrations of oxytetracycline were studied in Asian elephants following the intravenous and intramuscular administration of Terramycin/LA solution. The drug was administered as 200 mg of oxytetracycline base/ml in aqueous 2-pyrrolidone at a dose of 20mg/kg body mass. The blood samples were collected from the ear veins of each animal. Plasma concentrations of oxytetracycline were analyzed by microbiological method and high pressure liquid chromatography. An average peak plasma concentration of 6.2 g /ml was obtained in one hour following intravenous administration in elephants No oxytetracycline was detected in plasma after the 60th post dosing hour. The average peak plasma concentration of 2.87 g /ml was found in two hours following intramuscular administration of the drug. Concentrations exceeding 1 ug/ml were maintained for 48 hours after intramuscular dose. The drug was shown to result in sustained oxytetracycline blood concentrations over a three-day period following a single intramuscular administration of the drug to elephants.

See also:
Kirkwood,J.K. and Widdowson,M.A. 1990. Interspecies variation in the plasma half-life of oxytetracycline in relation to body weight. Res.Vet Sci. 48:180-183

Dogs:

  • Dogs 25 mg/kg orally twice daily or 2-10 mg/kg daily by subcutaneous or intramuscular injection. (B373.1.w1)

Bears:

Lagomorphs - Oryctolagus cuniculus domesticus - Domestic rabbit:
  • 30 mg/kg orally twice daily. (B373.Guide.w41)
  • 15 mg/kg intramuscularly twice daily. (B373.Guide.w41)
  • 15 mg/kg intramuscularly every 12 hours. (B546)
  • 15 mg/kg intramuscularly every eight hours. (B548.w8)
  • 25 mg/kg subcutaneously every 24 hours. (B548.w8)
  • 50 mg/kg orally every 12 hours. (B548.w8, B603.5.w5)
  • 1 mg per mL of drinking water. (B548.w8)
  • 15 mg/kg subcutaneously or intramuscularly every 24 hours. (B600.4.w4, B601.15.w15)
  • 50 mg/kg orally. (B600.4.w4)
  • 100 - 125 mg per litre of drinking water, for 30 days. (B601.15.w15)
  • 10 mg per kg of food. (B601.15.w15)
  • 30 mg/kg of long-acting preparation intramuscularly every three days. (B603.5.w5)
  • 30 mg/kg of long-acting preparation (depot injection) subcutaneously every three days. (B600.4.w4, B601.15.w15) Treatment of choice for Tyzzer's Disease in Lagomorphs. (B601.15.w15)
  • Note: Tetracyclines are broad-spectrum, including activity against Pasteurella spp. and against many anaerobes, with good tissue penetration including of bones and teeth. If given in drinking water, water intake may be decreased and absorption is low. (B603.5.w5)

Ferrets - Mustela putorius furo - Ferret:

  • 20 mg/kg orally three times daily. "Can get renal disease in geriatric ferrets. Also teeth discolouration in neonatals." (B626.App.w22)
  • "Not for use in pregnant jills. (J213.3.w1)

Great Apes

Monitoring parameters --

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Withdrawal period / Withholding time
Notes Before the use of any pharmaceutical product in food-producing animals, the label instructions for the product should be consulted regarding withdrawal requirements.

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Toxic Information

Toxic effects of Pharmaceutical Products
Contraindications / Precautions
  • Caution in using in horses, as stressed horses given parenteral or oral tetracyclines may develop severe, sometimes fatal, enterocolitis. (B201)
  • Contra-indicated for use in individuals hypersensitive to tetracyclines. (B263)
  • Contra-indicated in the last half of pregnancy unless the benefits "outweigh the fetal risks", due to risk of discolouration of teeth and retardation of skeletal growth. (B263)
  • Use with caution in individuals with renal insufficiency or hepatic impairment and avoid concurrent administration of nephrotoxic or hepatotoxic drugs. (B263)
  • Consider monitoring of serum levels in long-term therapy. (B263)
  • Not recommended for use with methoxyflurane as tetracyclines may increase its nephrotoxic effects. (B263)
Adverse Effects / Side Effects / Warnings
  • Intramuscular administration may be irritant. (B201)
  • Oral administration may cause diarrhoea. (B201)
  • Rapid intravenous administration in cattle may cause cardiovascular collapse; this effect is apparently due to chelation of calcium. (B201)
  • Photodermatitis may occur if animals treated with tetracyclines are exposed to intense sunlight or ultraviolet light. (B201)
  • Tetracycline use has been reported to be associated with nephrotoxicity; this may be due to degradation products which accumulate in preparations used beyond the expiry date. (B201)
Operator Warnings Before the use of any pharmaceutical product the label instructions for the product should be consulted regarding operator safety/warnings.
Overdose / Acute Toxicity --

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Detailed Toxicological Information
Classification --
Acute Toxicity --
Chronic Toxicity --
Reproductive effects --
Teratogenic effects --
Mutagenic effects --
Carcinogenic effects

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Organ toxicity --
Bird Toxicity --
Aquatic organism activity --
Other organism toxicity --

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Nutrient Information

Nutritional Data
Sources --
Biological Use --
Recommended Daily Allowance / Recommended level in food --
Stability in food (Storage time) --
Interactions --

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External / Environmental Information

External / Environmental Uses
Use --
Formulation --
Application method --
Application Concentration --
Persistence of Effect / Frequency of Application --

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Effects on the Environment
Effects in the aquatic environment

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Effects on land --

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Persistence in the Environment
Breakdown in soil and groundwater

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Breakdown in water --
Breakdown in vegetation --

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