OXYTETRACYCLINE, OXYTETRACYCLINE HCL
Chemistry - A tetracycline derivative obtained from Streptomyces rimosus, oxytetracycline baseoccurs as a pale yellow to tan, crystalline powder that is very slightly soluble in water and sparinglysoluble in alcohol. Oxytetracycline HCl occurs as a bitter-tasting, hygroscopic, yellow, crystallinepowder that is freely soluble in water and sparingly soluble in alcohol. Commercially available 50mg/ml and 100 mg/ml oxytetracycline HCl injections are usually available in either propyleneglycol or povidone based products.
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 becomerelatively unstable in solutions with a pH > 6, particularly in those containing calcium. This isapparently more of a problem with the veterinary injections that are propylene glycol based, ratherthan those that are povidone based. Other drugs that are reported to be compatible withoxytetracycline 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 isconcentration/time dependent, include: amikacin sulfate, aminophylline, amphotericin B, calciumchloride/gluconate, carbenicillin disodium, cephalothin sodium, cephapirin sodium, chloramphenicolsodium succinate, erythromycin gluceptate, heparin sodium, hydrocortisone sodium succinate, irondextran, methicillin sodium, methohexital sodium, oxacillin sodium, penicillin G potassium/sodium, pentobarbital sodium, phenobarbital sodium, and sodium bicarbonate. Compatibility is dependentupon factors such as pH, concentration, temperature and diluents used. It is suggested to consultspecialized references for more specific information (e.g., Handbook on Injectable Drugs by
Trissel; see bibliography).
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 ofthese 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 andin vivo activity against include Bordetella sp., Brucella, Bartonella, Haemophilus sp., Pasturellamultocida, Shigella, and Yersinia pestis. Many or most strains of E. coli, Klebsiella, Bacteroides,
Enterobacter, Proteus and Pseudomonas aeruginosa are resistant to the tetracyclines. While moststrains of Pseudomonas aeruginosa show in vitro resistance to tetracyclines, those compoundsattaining high urine levels (e.g., tetracycline, oxytetracycline) have been associated with clinicalcures 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.
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, andaqueous and vitreous humor. Only small quantities of tetracycline and oxytetracycline aredistributed to the CSF and therapeutic levels may not be attainable. While all tetracyclines distributeto the prostate and eye, doxycycline or minocycline penetrate better into these and most othertissues. Tetracyclines cross the placenta, enter fetal circulation and are distributed into milk. Thevolume of distribution of oxytetracycline is approximately 2.1 L/kg in small animals, 1.4 L/kg inhorses, and 0.8 L/kg in cattle. The amount of plasma protein binding is about 10-40% foroxytetracycline.
Both oxytetracycline and tetracycline are eliminated unchanged primarily via glomerular filtration.
Patients with impaired renal function can have prolonged elimination half-lives and may accumulatethe 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 fecalmaterials. 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.
In patients with renal insufficiency or hepatic impairment, oxytetracycline and tetracycline must beused cautiously. Lower than normal dosages are recommended with enhanced monitoring of renaland hepatic function. Avoid concurrent administration of other nephrotoxic or hepatotoxic drugs iftetracyclines are administered to these patients. Monitoring of serum levels should be considered iflong-term therapy is required.
Tetracyclines in high levels can exert an antianabolic effect which can cause an increase in BUNand/or hepatotoxicity, particularly in patients with preexisting renal dysfunction. As renal functiondeteriorates 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 intravascularhemolysis with resultant hemoglobinuria. Propylene glycol based products have also causedcardiodepressant 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 nottolerate 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 afterreceiving 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, hepatotoxicityor 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 notdemonstrate 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, fluidsand electrolytes should be monitored and replaced if necessary. Chronic overdoses may lead todrug accumulation and nephrotoxicity.
High oral doses given to ruminants, can cause ruminal microflora depression and ruminoreticularstasis. Rapid intravenous injection of undiluted propylene glycol-based products can causeintravascular hemolysis with resultant hemoglobinuria.
Rapid intravenous injection of tetracyclines has induced transient collapse and cardiac arrhythmiasin several species, presumably due to chelation with intravascular calcium ions. Overdose quantitiesof 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 calciumgluconate.
Oral iron products are also associated with decreased tetracycline absorption, and administrationof iron salts should preferably be given 3 hours before or 2 hours after the tetracycline dose. Oralsodium bicarbonate, kaolin, pectin, or bismuth subsalicylate may impair tetracyclineabsorption 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 regardingthe 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 ofthe 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 thenephrotoxic 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 theophyllineproducts.
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 elevatedvalues of urine catecholamines when using fluorometric methods of determination.
Tetracyclines reportedly can cause false-positive urine glucose results if using the cupric sulfatemethod of determination (Benedict's reagent, Clinitest®), but this may be the result of ascorbic acidwhich is found in some parenteral formulations of tetracyclines. Tetracyclines have also reportedlycaused false-negative results in determining urine glucose when using the glucose oxidase method(Clinistix®, Tes-Tape®).
Storage, Stability, Compatibility
Unless otherwise directed by the manufacturer, oxytetracycline HCl and oxytetracycline products should be stored in tight, light-resistant containers attemperatures of less than 40°C (104°) and preferably at room temperature (15-30°C); avoidfreezing.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 becomerelatively unstable in solutions with a pH > 6, particularly in those containing calcium. This isapparently more of a problem with the veterinary injections that are propylene glycol based, ratherthan those that are povidone based. Other drugs that are reported to be compatible withoxytetracycline 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 isconcentration/time dependent, include: amikacin sulfate, aminophylline, amphotericin B, calciumchloride/gluconate, carbenicillin disodium, cephalothin sodium, cephapirin sodium, chloramphenicolsodium succinate, erythromycin gluceptate, heparin sodium, hydrocortisone sodium succinate, irondextran, methicillin sodium, methohexital sodium, oxacillin sodium, penicillin G potassium/sodium, pentobarbital sodium, phenobarbital sodium, and sodium bicarbonate. Compatibility is dependentupon factors such as pH, concentration, temperature and diluents used. It is suggested to consultspecialized references for more specific information (e.g., Handbook on Injectable Drugs by
Trissel; see bibliography).
Pharmacology - OXYTETRACYCLINE, OXYTETRACYCLINE HCL
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 insusceptible organisms. In high concentrations, tetracyclines can also inhibit protein synthesis bymammalian 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 ofthese 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 andin vivo activity against include Bordetella sp., Brucella, Bartonella, Haemophilus sp., Pasturellamultocida, Shigella, and Yersinia pestis. Many or most strains of E. coli, Klebsiella, Bacteroides,
Enterobacter, Proteus and Pseudomonas aeruginosa are resistant to the tetracyclines. While moststrains of Pseudomonas aeruginosa show in vitro resistance to tetracyclines, those compoundsattaining high urine levels (e.g., tetracycline, oxytetracycline) have been associated with clinicalcures 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 knownproducts are being marketed, however), calves, non-lactating dairy cattle, beef cattle, swine, fish, andpoultry. For more information refer to the Doses section, below.Pharmacokinetics - OXYTETRACYCLINE, OXYTETRACYCLINE HCL
Both oxytetracycline and tetracycline are readily absorbed after oral administration to fasting animals. Bioavialabilities are approximately 60-80%. The presence of food ordairy 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 mayoccur in 30 minutes to several hours, depending on the volume and site of injection. The long-actingproduct (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, andaqueous and vitreous humor. Only small quantities of tetracycline and oxytetracycline aredistributed to the CSF and therapeutic levels may not be attainable. While all tetracyclines distributeto the prostate and eye, doxycycline or minocycline penetrate better into these and most othertissues. Tetracyclines cross the placenta, enter fetal circulation and are distributed into milk. Thevolume of distribution of oxytetracycline is approximately 2.1 L/kg in small animals, 1.4 L/kg inhorses, and 0.8 L/kg in cattle. The amount of plasma protein binding is about 10-40% foroxytetracycline.
Both oxytetracycline and tetracycline are eliminated unchanged primarily via glomerular filtration.
Patients with impaired renal function can have prolonged elimination half-lives and may accumulatethe 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 fecalmaterials. 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 inpatients hypersensitive to it or other tetracyclines. Because tetracyclines can retard fetal skeletaldevelopment and discolor deciduous teeth, they should only be used in the last half of pregnancywhen the benefits outweigh the fetal risks. Oxytetracycline and tetracycline are considered to bemore likely to cause these abnormalities than either doxycycline or minocycline.In patients with renal insufficiency or hepatic impairment, oxytetracycline and tetracycline must beused cautiously. Lower than normal dosages are recommended with enhanced monitoring of renaland hepatic function. Avoid concurrent administration of other nephrotoxic or hepatotoxic drugs iftetracyclines are administered to these patients. Monitoring of serum levels should be considered iflong-term therapy is required.
Adverse Effects, Warnings
Oxytetracycline and tetracycline given to young animals can causediscoloration 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 BUNand/or hepatotoxicity, particularly in patients with preexisting renal dysfunction. As renal functiondeteriorates 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 intravascularhemolysis with resultant hemoglobinuria. Propylene glycol based products have also causedcardiodepressant 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 nottolerate 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 afterreceiving 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, hepatotoxicityor 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 notdemonstrate 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, fluidsand electrolytes should be monitored and replaced if necessary. Chronic overdoses may lead todrug accumulation and nephrotoxicity.
High oral doses given to ruminants, can cause ruminal microflora depression and ruminoreticularstasis. Rapid intravenous injection of undiluted propylene glycol-based products can causeintravascular hemolysis with resultant hemoglobinuria.
Rapid intravenous injection of tetracyclines has induced transient collapse and cardiac arrhythmiasin several species, presumably due to chelation with intravascular calcium ions. Overdose quantitiesof 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 calciumgluconate.
Drug Interactions
When orally administered, tetracyclines can chelate divalent or trivalentcations which can decrease the absorption of the tetracycline or the other drug if it contains thesecations. Oral antacids, saline cathartics or other GI products containing aluminum, calcium, magnesium, zinc or bismuth cations are most commonly associated with this interaction. It isrecommended 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 administrationof iron salts should preferably be given 3 hours before or 2 hours after the tetracycline dose. Oralsodium bicarbonate, kaolin, pectin, or bismuth subsalicylate may impair tetracyclineabsorption 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 regardingthe 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 ofthe 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 thenephrotoxic 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 theophyllineproducts.
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 elevatedvalues of urine catecholamines when using fluorometric methods of determination.
Tetracyclines reportedly can cause false-positive urine glucose results if using the cupric sulfatemethod of determination (Benedict's reagent, Clinitest®), but this may be the result of ascorbic acidwhich is found in some parenteral formulations of tetracyclines. Tetracyclines have also reportedlycaused false-negative results in determining urine glucose when using the glucose oxidase method(Clinistix®, Tes-Tape®).