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

• Oxytetracycline: pale yellow to tan crystalline powder, amphoteric. (B135.44.w44, B263)

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

183 - 185°C. (W324)

• Oxytetracycline hydrochloride: more soluble than oxytetracycline. (B135.44.w44); freely soluble. (B263)

• Oxytetracycline: sparingly soluble in alcohol. (B263)
• Oxytetracycline HCl: sparingly soluble in alcohol. (B263)

• Oxytetracycline hydrochloride solution: acidic. (B135.44.w44)

• 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)

• Store in tight containers preferably at room temperature (15-30°C), avoid freezing and temperatures above 40°C (104°F), protect from light. (B263)

Associated Techniques

• Active against many Gram-positive and Gram-negative bacteria (including some anaerobes). (B135.44.w44)
  • Active against the Gram-positive organisms: Actinomyces spp., Bacillus anthracis, Clostridium perfringens, Clostridium tetani, Listeria monocytogenes, Nocardia spp. (B263)
  • Active against some strains of staphylococci (Staphylococcus spp.) and streptococci (Streptococcus spp.) (resistance is increasing). (B263)
  • Active against the Gram-negative bacteria: Bordetella spp., Brucella spp., Bartonella spp., Haemophilus spp., Pasteurella multocida, Shigella, Yersinia pestis. (B263)
  • Little useful activity against Escherichia coli, Salmonella spp., Proteus spp., Pseudomonas spp. (B201.1.w1)
• Active against rickettsiae, chlamydiae (Chlamydia spp.), mycoplasmas (Mycoplasma spp.), L-forms.(B201.1.w1, B135.44.w44)
• Active against spirochetes. (B263)
• Active against some protozoa (Proctista) such as amoebas. (B135.44.w44)

• 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)

• 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)

• 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 µg/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)

• Tetracyclines are 40-80% protein-bound. (B135.44.w44)
• Oxytetracycline plasma protein-binding about 10-40%. (B263)

• 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)

• Renal clearance oxytetracycline (Human): 90 ml/minute. (B135.44.w44)

• 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)

• Depot preparations maintain effective plasma concentration for 72-96 hours. (B201.1.w1)

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 t_{1/2 β} varied by about 14-fold across the size range and gave an allometric equation: t_{1/2 β = 160} W^0.20 for this drug or across eutherian mammals only, t_{1/2 β = 160} W^0.22 . 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 t_{1/2 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):

Dogs:

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

Bears:

• In general: "Domestic dog drugs and dosages are used to treat bears." (B336.51.w51)
• Avoid using tetracyclines in young growing cubs. (V.w93)
• For Salmon Poisoning in Bears (Bacterial Disease Summary) or Elokomin Fluke Fever in Bears (Bacterial Disease Summary): 7 mg/kg intravenously every 12 hours until oral dosing is tolerated. (D251.9.w10)

• 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

• Adult Pan troglodytes - Chimpanzee: 250 - 300 mg/day intramuscularly or orally, divided between one to three doses daily. (W768.Jun2012.w1)
• Gorilla gorilla - Gorilla: 1,500 mg/kg per day intravenously by constant rate infusion. In the treatment of Balantidium coli Infection. (D425.3.15.w3o)

• 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)

• 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)

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