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Oxytetracycline

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.

Chemistry - A tetracycline derivative obtained from Streptomyces rimosus, oxytetracy­cline base occurs as a pale yellow to tan, crystalline powder that is very slightly soluble in water and sparingly soluble in alcohol. Oxytetracycline HCl occurs as a bitter-tasting, hy­groscopic, yellow, crystalline powder that is freely soluble in water and sparingly soluble in alcohol. Commercially available 50 mg/ml and 100 mg/ml oxytetracycline HCl injec­tions are usually available in either propylene glycol or povidone based products.

 

Storage/Stability/Compatibility - Unless otherwise directed by the manufacturer, oxyte­tracycline HCl and oxytetracycline products should be stored in tight, light-resistant con­tainers at temperatures of less than 40°C (104°) and preferably at room temperature (15-30°C); avoid freezing.

 

Oxytetracycline HCl is generally considered to be compatible with most commonly used IV infusion solutions, including D5W, sodium chloride 0.9%, and lactated Ringer’s, but can become relatively unstable in solutions with a pH > 6, particularly in those containing calcium. This is apparently more of a problem with the veterinary injections that are propylene glycol based, rather than those that are povidone based. Other drugs that are re­ported to be compatible with oxytetracycline for injection include: colistimethate sodium, corticotropin, dimenhydrinate, insulin (regular), isoproterenol HCl, methyldopate HCl, norepinephrine bitartrate, polymyxin B sulfate, potassium chloride, tetracycline HCl, and vitamin B-complex with C.

 

Drugs that are reportedly incompatible with oxytetracycline, data conflicts, or compati­bility is concentration/time dependent, include: amikacin sulfate, 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, and sodium bicarbonate. Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used. It is suggested to consult specialized references for more specific information (e.g., Handbook on Injectable Drugs by Trissel; see bibliography).

 

Pharmacology - Tetracyclines generally act as bacteriostatic antibiotics and inhibit pro­tein synthesis by reversibly binding to 30S ribosomal subunits of susceptible organisms, thereby preventing binding to those ribosomes of aminoacyl transfer-RNA. Tetracyclines also are believed to reversibly bind to 50S ribosomes and additionally alter cytoplasmic membrane permeability in susceptible organisms. In high concentrations, tetracyclines can also inhibit protein synthesis by mammalian cells.

 

As a class, the tetracyclines have activity against most mycoplasma, spirochetes (including the Lyme disease organism), Chlamydia, and Rickettsia. Against gram positive bacteria, the tetracyclines have activity against some strains of staphylococcus and strep­tococci, but resistance of these organisms is increasing. Gram positive bacteria that are usually covered by tetracyclines, include Actinomyces sp., Bacillus anthracis, Clostridium perfringens and tetani, Listeria monocytogenes, and Nocardia. Among gram negative bacteria that tetracyclines usually have in vitro and in vivo activity against include Bordetella sp., Brucella, Bartonella, Haemophilus sp., Pasturella multocida, Shigella, and Yersinia pestis. Many or most strains of E. coli, Klebsiella, Bacteroides, Enterobacter, Proteus and Pseudomonas aeruginosa are resistant to the tetracyclines. While most strains of Pseudomonas aeruginosa show in vitro resistance to tetracyclines, those compounds at­taining high urine levels (e.g., tetracycline, oxytetracycline) have been associated with clinical cures in dogs with UTI secondary to this organism.

 

Oxytetracycline and tetracycline share nearly identical spectrums of activity and patterns of cross-resistance and a tetracycline susceptibility disk is usually used for in vitro testing for oxytetracycline susceptibility.

 

Uses/Indications - Oxytetracycline products are approved for use in dogs and cats (no known products are being marketed, however), calves, non-lactating dairy cattle, beef cat­tle, swine, fish, and poultry. For more information refer to the Doses section, below.

 

Pharmacokinetics - Both oxytetracycline and tetracycline are readily absorbed after oral administration to fasting animals. Bioavialabilities are approximately 60-80%. The pres­ence of food or dairy products can significantly reduce the amount of tetracycline ab­sorbed, with reductions of 50% or more possible. After IM administration of oxytetracy­cline (not long-acting), peak levels may occur in 30 minutes to several hours, depending on the volume and site of injection. The long-acting product (LA-200®) has significantly slower absorption after IM injection.

 

Tetracyclines as a class, are widely distributed in the body, including to the heart, kidney, lungs, muscle, pleural fluid, bronchial secretions, sputum, bile, saliva, urine, synovial fluid, ascitic fluid, and aqueous and vitreous humor. Only small quantities of tetracycline and oxytetracycline are distributed to the CSF and therapeutic levels may not be attain­able. While all tetracyclines distribute to the prostate and eye, doxycycline or minocycline penetrate better into these and most other tissues. Tetracyclines cross the placenta, enter fetal circulation and are distributed into milk. The volume of distribution of oxytetracy­cline is approximately 2.1 L/kg in small animals, 1.4 L/kg in horses, and 0.8 L/kg in cattle. The amount of plasma protein binding is about 10-40% for oxytetracycline.

 

Both oxytetracycline and tetracycline are eliminated unchanged primarily via glomerular filtration. Patients with impaired renal function can have prolonged elimination half-lives and may accumulate the drug with repeated dosing. These drugs apparently are not me­tabolized, but are excreted into the GI tract via both biliary and nonbiliary routes and may become inactive after chelation with fecal materials. The elimination half-life of oxytetra­cycline is approximately 4-6 hours in dogs and cats, 4.3 - 9.7 hours in cattle, 10.5 hours in horses, 6.7 hours in swine, and 3.6 hours in sheep.

 

Contraindications/Precautions/Reproductive Safety - Oxytetracycline is contraindi­cated in patients hypersensitive to it or other tetracyclines. Because tetracyclines can retard fetal skeletal development and discolor deciduous teeth, they should only be used in the last half of pregnancy when the benefits outweigh the fetal risks. Oxytetracycline and tetracycline are considered to be more likely to cause these abnormalities than either doxycycline or minocycline.

 

In patients with renal insufficiency or hepatic impairment, oxytetracycline and tetracy­cline must be used cautiously. Lower than normal dosages are recommended with en­hanced monitoring of renal and hepatic function. Avoid concurrent administration of other nephrotoxic or hepatotoxic drugs if tetracyclines are administered to these patients. Monitoring of serum levels should be considered if long-term therapy is required.

 

Adverse Effects/Warnings - Oxytetracycline and tetracycline given to young animals can cause discoloration of bones and teeth to a yellow, brown, or gray color. High dosages or chronic administration may delay bone growth and healing.

 

Tetracyclines in high levels can exert an antianabolic effect which can cause an increase in BUN and/or hepatotoxicity, particularly in patients with preexisting renal dysfunction. As renal function deteriorates secondary to drug accumulation, this effect may be exacer­bated.

 

In ruminants, high oral doses can cause ruminal microflora depression and ruminoreticu­lar stasis. Rapid intravenous injection of undiluted propylene glycol-based products can cause intravascular hemolysis with resultant hemoglobinuria. Propylene glycol based products have also caused cardiodepressant effects when administered to calves. When administered IM, local reactions, yellow staining and necrosis may be seen at the injection site.

 

In small animals, tetracyclines can cause nausea, vomiting, anorexia and diarrhea. Cats do not tolerate oral tetracycline or oxytetracycline very well, and may also present with symptoms of colic, fever, hair loss and depression.

 

Horses who are stressed by surgery, anesthesia, trauma, etc., may break with severe diar­rheas after receiving tetracyclines (especially with oral administration).

 

Tetracycline therapy (especially long-term) may result in overgrowth (superinfections) of non-susceptible bacteria or fungi. Tetracyclines have also been associated with photosensitivity reactions and, rarely, hepa­totoxicity or blood dyscrasias.

 

Overdosage/Acute Toxicity - Tetracyclines are generally well tolerated after acute over­doses. Dogs given more than 400 mg/kg/day orally or 100 mg/kg/day IM of oxytetracy­cline did not demonstrate any toxicity. Oral overdoses would most likely be associated with GI disturbances (vomiting, anorexia, and/or diarrhea). Should the patient develop se­vere emesis or diarrhea, fluids and electrolytes should be monitored and replaced if neces­sary. Chronic overdoses may lead to drug accumulation and nephrotoxicity.

 

High oral doses given to ruminants, can cause ruminal microflora depression and rumi­noreticular stasis. Rapid intravenous injection of undiluted propylene glycol-based prod­ucts can cause intravascular hemolysis with resultant hemoglobinuria.

 

Rapid intravenous injection of tetracyclines has induced transient collapse and cardiac ar­rhythmias in several species, presumably due to chelation with intravascular calcium ions. Overdose quantities of drug could exacerbate this effect if given too rapidly IV. If the drug must be given rapidly IV (less than 5 minutes), some clinicians recommend pre-treating the animal with intravenous calcium gluconate.

 

Drug Interactions - When orally administered, tetracyclines can chelate divalent or trivalent cations which can decrease the absorption of the tetracycline or the other drug if it contains these cations. Oral antacids, saline cathartics or other GI products containing aluminum, calcium, magnesium, zinc or bismuth cations are most commonly associated with this interaction. It is recommended that all oral tetracyclines be given at least 1-2 hours before or after the cation-containing product. Oral iron products are also associated with decreased tetracycline absorption, and ad­ministration of iron salts should preferably be given 3 hours before or 2 hours after the tetracycline dose. Oral sodium bicarbonate, kaolin, pectin, or bismuth subsalicylate may impair tetracycline absorption when given together orally. 
 

Bacteriostatic drugs like the tetracyclines, may interfere with bactericidal activity of the penicillins, cephalosporins, and aminoglycosides. There is some amount of controversy regarding the actual clinical significance of this interaction, however.
 

Tetracyclines may increase the bioavailability of digoxin in a small percentage of pa­tients (human) and lead to digoxin toxicity. These effects may persist for months after dis­continuation of the tetracycline.

 

Tetracyclines may depress plasma prothrombin activity and patients on anticoagulant (e.g., warfarin) therapy may need dosage adjustment. Tetracyclines have been reported to increase the nephrotoxic effects of methoxyflurane and tetracycline HCl or oxytetracy­cline are not recommended to used with methoxyflurane. GI side effects may be increased if tetracyclines are administered concurrently with theophylline products. Tetracyclines have reportedly reduced insulin requirements in diabetic patients, but this interaction is yet to be confirmed with controlled studies.

 

Drug/Laboratory Interactions - Tetracyclines (not minocycline) may cause falsely ele­vated values of urine catecholamines when using fluorometric methods of determination.  Tetracyclines reportedly can cause false-positive urine glucose results if using the cupric sulfate method of determination (Benedict’s reagent, Clinitest®), but this may be the result of ascorbic acid which is found in some parenteral formulations of tetracyclines. Tetracyclines have also reportedly caused false-negative results in determining urine glu­cose when using the glucose oxidase method (Clinistix®, Tes-Tape®).

 

Doses -

Horses:

For susceptible infections:

a)   5 - 10 mg/kg IV bid (Robinson 1987)

b)   For respiratory tract infections: 5 mg/kg IV q12h; do not give too rapidly. (Beech 1987b)

c)   3 mg/kg IV q12h (Baggot and Prescott 1987)

d)   5 - 11 mg/kg IV q12h (Upson 1988)

 

 

Elephants:

a) 18mg/kg IM q 48 -72 h. The authors state that this dose does not achieve a serum concentration of > 4µg /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 elephant’s 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 µg /ml were achieved between 1 and 48 hours post-injection and were higher than the MIC reported for most susceptible pathogens (0.5 µg /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 µg/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 µg/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 µg /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 µg 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 µg /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 µg /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

 

 

Monitoring Parameters -

1)   Adverse effects

2)   Clinical efficacy

3)   Long-term use or in susceptible patients: periodic renal, hepatic, hematologic evaluations

 

Client Information - Avoid giving this drug orally within 1-2 hours of feeding, giving milk or dairy products.

 

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

 

Veterinary-Approved Products:

Oxytetracycline HCl 50 mg/ml, 100 mg/ml Injection. There are many approved oxyte­tracycline products marketed in these concentrations. Some are labeled for Rx (legend) use only, while some are over-the-counter (OTC). Depending on the actual product, this drug may be approved for use in swine, non-lactating dairy cattle, beef cattle, chickens or turkeys. Products may also be labeled for IV, IM, or SQ use. Withdrawal times vary with regard to individual products. Slaughter withdrawal times vary in cattle from 15-22 days, swine 20-26 days, and 5 days for chickens and turkeys. Refer to the actual labeled information for the product used for more information. Some trade names for these products include: Terramycin® , Liquamycin ®, Biomycin  (Bio-Ceutic), Medamycin®  (TechAmerica), Biocyl®  (Anthony), Oxyject®  (Fermenta), and Oxytet®  (BI).

 

Oxytetracycline base 200 mg/ml Injection in 100, 250, and 500 ml bottles; Liquamycin® LA-200®  (Pfizer); (OTC or Rx) Approved for use in swine, non-lactat­ing dairy cattle and beef cattle. Slaughter withdrawal = 28 days for swine and cattle.

 

Oxytetracycline Oral Tablets (Boluses) 250 mg tablet; Terramycin® Scours Tablets  (Pfizer); (OTC)  Approved for use in non-lactating dairy and beef cattle. Slaughter withdrawal = 7 days.

 

Oxytetracycline is also available in feed additive, premix, ophthalmic and intramam­mary products.

 

Established residue tolerances: Uncooked edible tissues of swine, cattle, salmonids, cat­fish and lobsters: 0.10 ppm. Uncooked kidneys of chickens or turkeys: 3 ppm. Uncooked muscle, liver, fat or skin of chickens or turkeys: 1 ppm.

 

Human-Approved Products:

Oxytetracycline Oral Capsules 250 mg; Terramycin®  (Pfizer); Uri-Tet®  (American Urologicals); generic; (Rx)

 

 

Oxytetracycline For Injection (IM only) 50 mg/ml or 125 mg/ml (both with 2% lido­caine) in 2 ml amps and 10 ml vials; Terramycin® I.M.  (Roerig); generic, (Rx)

 

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