Oxytetracycline

Overview

Oxytetracycline (Engemycin®, Oxycare®) is a tetracycline antimicrobial used in dogs and cats for the treatment of infections caused by susceptible organisms. It is a time-dependent, bacteriostatic antimicrobial with activity against a broad range of bacteria and other microorganisms.

Oxytetracycline is active against many Gram-positive and Gram-negative bacteria, rickettsiae, mycoplasmas, chlamydiae, spirochaetes, and other susceptible microbes. Resistance to tetracyclines is widespread and should be considered when selecting therapy.

Mechanism of Action (MOA): Oxytetracycline inhibits bacterial protein synthesis by binding reversibly to the 30S ribosomal subunit, preventing aminoacyl transfer-RNA from binding to the ribosome.

Indications

Oxytetracycline is used in dogs and cats for the treatment of infections caused by susceptible microorganisms.

• Bacterial infections: Treatment of susceptible Gram-positive and Gram-negative bacterial infections, including of the respiratory tract, urinary tract, soft tissues and skin; resistance is common among enteric Gram-negative bacilli and staphylococci.
• Rickettsial infections: Management of susceptible rickettsial diseases, including Rocky Mountain spotted fever; in small animals, however, doxycycline rather than oxytetracycline is generally used for Rickettsia and Ehrlichia infections.
• Mycoplasmal infections: Treatment of infections caused by susceptible Mycoplasma species.
• Spirochaetal infections: Treatment of susceptible spirochaetal organisms.
• Immune-mediated conditions (adjunctive use): Has been used historically, in combination with nicotinamide, for immune-mediated dermatoses including discoid lupus erythematosus, lupoid onychodystrophy and pemphigus foliaceus; long-term antibiotic use is not recommended, and no feline dosing information is published for the combination.
• Chlamydial infections: Treatment of susceptible chlamydial infection, including chlamydial conjunctivitis in cats.
• Salmon poisoning disease: Adjunctive treatment of salmon poisoning disease caused by Neorickettsia helminthoeca in dogs.
• Antibiotic-responsive diarrhoea: One of several antibacterial options for this condition; long-term use for the management of chronic enteropathy is not recommended.
• Superficial ocular infections: Prophylaxis and local treatment of superficial ocular infections – conjunctivitis, keratitis, corneal ulcer and blepharitis – using the combination ointment with polymyxin B.
• Tear staining: Has been used to address tear staining near the medial canthus, although using an antimicrobial for a non-antimicrobial effect is under increasing scrutiny and is difficult to justify against current antimicrobial stewardship advice.

Dosage (Reference)

Dog

The following extra-label dosages have been reported for susceptible systemic infections and selected rickettsial diseases.

Cat

The following extra-label dosages have been reported for susceptible systemic infections.

Warnings & Precautions

Oxytetracycline should be used cautiously because adverse effects may increase with prolonged therapy, dehydration, renal compromise, or inappropriate product selection.

• Use in cats: Only use in cats when no other suitable antimicrobial agent is available.
• Depot formulations: Concentrated injectable depot formulations intended for cattle and sheep should never be administered to small animals.
• Renal effects: Tetracyclines may cause dose-related functional changes in renal tubules, particularly in susceptible patients; some references regard the class as contraindicated in renal insufficiency, doxycycline excepted, and others advise reduced doses with monitoring of renal function.
• Dehydration and nephrotoxic drugs: Renal adverse effects may be exacerbated by dehydration, haemoglobinuria, myoglobinuria, or concurrent administration of nephrotoxic medications.
• Outdated or improperly stored products: Severe tubular damage has been associated with degradation products formed in outdated or improperly stored tetracycline preparations, although one reference regards this as historical and attributable to an ingredient no longer used. Do not use out-of-date or improperly stored product.
• Young animals: Tetracyclines chelate calcium and are deposited irreversibly in growing bone and in the dentine and enamel of unerupted teeth, causing yellow to brown discolouration; this is documented in dogs. High doses or long-term administration may also delay bone growth and healing. Do not use oral tetracycline in puppies or kittens, and it is prudent to restrict the use of tetracyclines in all young animals.
• Long-term therapy: Prolonged administration may result in the development of superinfections.
• Hypersensitivity: Systemic oxytetracycline is contraindicated in animals that are hypersensitive to oxytetracycline or to any other tetracycline. The ophthalmic combination is contraindicated in patients hypersensitive to oxytetracycline, to polymyxin B, to drugs in either class, or to any component of the formulation.
• Pregnancy: Tetracyclines cross the placenta and are embryotoxic early in pregnancy, retarding foetal skeletal growth and permanently discolouring teeth. Use with extreme caution and only in the last half of pregnancy where the benefit outweighs the foetal risk; oxytetracycline is considered more likely than doxycycline or minocycline to cause these abnormalities.
• Lactation: Tetracyclines are excreted in maternal milk, with milk-to-plasma ratios between 0.25 and 1.5. Safety in nursing animals has not been established, so use only where the benefit to the dam outweighs the risk to the offspring.
• Reduced organ function: In renal insufficiency or hepatic impairment use lower than usual doses with enhanced monitoring of renal and hepatic function, avoid other nephrotoxic or hepatotoxic drugs, and consider monitoring serum concentrations if long-term treatment is required.
• Rate of administration: Rapid intravenous injection has caused hypotension, transient collapse and cardiac arrhythmia, attributed to chelation of ionised calcium and to the propylene glycol vehicle, and undiluted propylene-glycol-based products can also cause intravascular haemolysis. Give intravenous doses over at least 5 minutes. If a dose must be given in less than 5 minutes, some clinicians pretreat with intravenous calcium gluconate.
• Neuromuscular junction disease: Tetracyclines have neuromuscular blocking effects and are contraindicated in diseases of the neuromuscular junction, such as botulism.
• Sun exposure while treated: Tetracyclines have been associated with photosensitivity reactions. Keep treated animals out of direct sun or apply a veterinary-approved sunblock to hairless areas such as the nose and around the eyelids and ears, and report any reddening of the skin.
• Topical ophthalmic use in cats: Serious, life-threatening anaphylactic reactions have been reported in some cats after ophthalmic antibiotic preparations. Facial swelling, itching, weakness, vomiting or difficulty breathing within 4 hours of application means stopping treatment immediately.
• Empirical use: Resistance and the bacteriostatic nature of the tetracyclines make empirical use a poor default in dogs and cats; base treatment on culture and susceptibility wherever possible. Oxytetracycline has been associated with a high incidence of bacterial transfer of resistance genes.

Drug Interactions

Several clinically important interactions may occur with oxytetracycline, particularly those affecting antimicrobial activity, drug absorption, or renal toxicity.

• Penicillins: Tetracyclines may interfere with the bactericidal activity of penicillins, cephalosporins and aminoglycosides, although the clinical significance of this interaction is uncertain.
• Antacids containing Mg²⁺, Ca²⁺, or AL³⁺: Aluminium, bismuth, calcium, iron, magnesium and zinc chelate oxytetracycline and reduce absorption of either drug – in antacids, saline cathartics and sucralfate among other products. Give oral tetracyclines at least 1 to 2 hours before or after any such product.
• Food and milk products: Food, and especially dairy products, bind oxytetracycline and can reduce the amount absorbed by as much as 50% or more. Antacids, kaolin and iron preparations reduce absorption the same way; give oral doses on an empty stomach.
• Methoxyflurane: Oxytetracycline may increase the nephrotoxic effects of methoxyflurane.
• Theophylline products: Concurrent administration may increase gastrointestinal adverse effects.
• Digoxin: In human patients, tetracyclines may increase the bioavailability of digoxin and lead to digoxin toxicity, and the effect can persist for months after the tetracycline is discontinued. The interaction is reported or theoretical in humans or animals, and may be of significance in veterinary patients.
• Anticoagulants: Tetracyclines may depress plasma prothrombin activity, so animals on anticoagulant therapy may need their dosage adjusted.
• Diuretics: Concurrent furosemide increases the risk of acute kidney injury and renal failure, and tetracyclines given with a diuretic are often associated with a marked rise in blood urea nitrogen.
• Retinoids (acitretin, isotretinoin): Concurrent use may increase the risk of intracranial hypertension, and the combination is contraindicated.
• Binding agents: Cholestyramine and lanthanum may both decrease oxytetracycline absorption.
• Atovaquone: Tetracyclines have caused decreased atovaquone concentrations.
• Corticosteroid co-treatment: Combined use with glucocorticoids often leads to substantial weight loss, particularly in anorectic animals.
• Mixing with intravenous fluids: Do not mix with solutions containing iron, calcium, aluminium, or magnesium. Although physically compatible with many IV fluids, including lactated Ringer’s, stability decreases above pH 6, especially with calcium-containing solutions. Compatibility with many injectable drugs is uncertain or poor; check compatibility before mixing and administer separately when in doubt.

Side Effects & Overdose

Side Effects

Adverse effects are primarily gastrointestinal, although hepatic, renal, and systemic reactions have also been reported.

• Gastrointestinal effects: Vomiting, diarrhoea, and other gastrointestinal disturbances may occur, particularly with oral administration.
• Anorexia: Reported in cats, as part of a wider intolerance picture with gastrointestinal distress, fever, hair loss and depression.
• Fever: Described in cats as a drug reaction, often accompanied by vomiting, diarrhoea, depression, inappetence and eosinophilia; the mechanism is unknown.
• Hypotension: May occur following intravenous administration, together with transient collapse and cardiac arrhythmia; it is attributed to chelation of ionised calcium and to the propylene glycol vehicle, and is avoided by infusing over more than 5 minutes.
• Hepatotoxicity: Rarely reported, along with blood dyscrasias; the online pharmacology literature reports hepatotoxic effects from large doses in pregnant animals with a high mortality rate.
• Superinfections: May develop with prolonged use.
• Teeth and bones: Yellow, brown or grey discoloration of teeth and bones in young growing animals, with inhibited calcification and hypoplastic dental enamel; high or long-term doses may delay bone growth and fracture healing.
• Uroliths: Long-term tetracycline use has been reported to cause urolith formation in dogs, although this is thought to occur very rarely.
• Photosensitivity: Increased skin sensitivity to sunlight, with a risk of sunburn on hairless areas such as the nose and around the eyelids and ears.
• Damage at the site: Injection may be painful and cause local reaction, yellow staining or necrosis at the site; perivascular leakage from an intravenous injection can cause severe swelling.
• Intravascular hemolysis: Rapid intravenous injection of undiluted propylene-glycol-based products can cause intravascular haemolysis with resulting haemoglobinuria.
• Rising blood urea nitrogen: In humans, tetracyclines in high concentrations exert an antianabolic effect that can increase blood urea nitrogen, and the veterinary significance is unclear. At high doses the azotaemia seen is attributed to inhibition of protein synthesis in mammalian cells rather than to a direct nephrotoxic effect.
• Colour change: Darkening of the urine may occur, sometimes shortly after the first dose. Contact the practice if this effect persists, or if there is blood in the urine.

Overdose

Tetracyclines are generally well tolerated after acute overdose. Excessive exposure may increase the likelihood and severity of the adverse effects listed above, particularly gastrointestinal and renal adverse reactions.

• Gastrointestinal toxicity: Increased risk of vomiting, diarrhoea, anorexia, and gastrointestinal irritation.
• Renal toxicity: Functional renal tubular changes may become more pronounced, especially in dehydrated patients or those receiving nephrotoxic drugs concurrently. At very high doses the drug may also cause metabolic acidosis, haemoglobinaemia or myoglobinaemia, with injury to the kidneys as a consequence. Chronic overdose leads to drug accumulation and nephrotoxicity, and impaired renal function prolongs the half-life so that the drug accumulates further with repeated dosing.
• Management: Discontinue treatment and provide supportive care based on clinical signs; where severe vomiting or diarrhoea develops, monitor fluid and electrolyte status and replace as necessary.
• Reported tolerance: Dogs given more than 400 mg/kg/day by mouth, or 100 mg/kg/day intramuscularly, did not demonstrate any toxicity.
• How fast to give it: Rapid intravenous injection has induced transient collapse and cardiac arrhythmia in several species, attributed to chelation of intravascular calcium and to the propylene glycol vehicle. Where a rapid dose is unavoidable, some clinicians pretreat with intravenous calcium gluconate.
• Where to get help: For a suspected or confirmed overdose, consult a 24-hour poison consultation centre that provides veterinary-specific information.

Key Notes

Practical clinical points for the use of oxytetracycline in dogs and cats:

• Broad antimicrobial spectrum: Active against many Gram-positive and Gram-negative bacteria, rickettsiae, mycoplasmas, chlamydiae and spirochaetes, with resistance common among enteric Gram-negative bacilli and staphylococci.
• When an in-vitro result misleads: Although most Pseudomonas aeruginosa strains are resistant in vitro, oxytetracycline reaches high concentrations in urine and has been associated with clinical cures in dogs with Pseudomonas urinary tract infection. Tetracyclines are less active in alkaline urine, and acidifying the urine can increase their antimicrobial efficacy.
• A property beyond the antibacterial one: Oxytetracycline appears to have immunomodulatory effects that may contribute to its clinical efficacy.
• Time-dependent activity: Clinical efficacy depends on maintaining drug concentrations above the minimum inhibitory concentration for an adequate duration. Oxytetracycline is bacteriostatic.
• Limited lipid solubility: Only small quantities reach the cerebrospinal fluid, where therapeutic concentrations may not be attainable, and doxycycline or minocycline penetrate the prostate, eye and most other tissues better.
• Elimination: Largely unchanged, mainly by glomerular filtration, with the remainder eliminated into the gastrointestinal tract by biliary and non-biliary routes, where it may be inactivated by chelation with faecal material.
• Immune-mediated disorders: Has been used historically in combination with nicotinamide for immune-mediated dermatoses including discoid lupus erythematosus, lupoid onychodystrophy and pemphigus foliaceus; the published dosing for the combination is canine only.
• Antimicrobial resistance: Resistance to tetracyclines is widespread and should be considered when selecting therapy.
• Oral administration: Give oral doses on an empty stomach, 1 to 2 hours before or after food, milk, dairy products or any mineral supplement. If the animal vomits or seems unwell on an empty stomach, a small amount of food may help; if vomiting continues, review the choice of drug.
• Oral absorption is poor and variable: Bioavailability is 60% to 80% in fasted animals, but oral absorption is poor and variable in dogs – one study found the amount absorbed too low to produce therapeutic effects – so an oral course should be judged on clinical response.
• Pharmacokinetics: The elimination half-life is 4 to 6 hours in dogs and cats. The volume of distribution is about 2.1 L/kg in small animals and plasma protein binding is 10% to 40%, although one reference gives 30% to 50%. Tissue concentrations are higher in diseased than in healthy lung.
• Susceptibility testing: Oxytetracycline and tetracycline share nearly identical spectra and cross-resistance patterns, and a tetracycline susceptibility disk is what laboratories normally use; a tetracycline-susceptible result indicates oxytetracycline susceptibility.
• Laboratory test interference: Tetracyclines may cause falsely elevated urine catecholamines, and both false positive and false negative urine glucose results depending on the method used. Amylase, blood urea nitrogen, bromsulphthalein, eosinophil count, AST and ALT may rise, while cholesterol, glucose, potassium and prothrombin time may fall.
• Antimicrobial stewardship: Classified as category D (Prudence) under the European antimicrobial categorisation, to be used as a first-line choice where possible and prudently, avoiding unnecessary use and long treatment periods.
• Where doxycycline is preferred: In small animals, doxycycline rather than oxytetracycline is used as a treatment for Rickettsia and Ehrlichia infection, and small-animal tetracycline use has relied primarily on doxycycline or minocycline. In renal insufficiency, tetracycline should not be used due to renal excretion; doxycycline may be given instead, being excreted via the gastrointestinal tract.
• Prolonged courses: In monogastric animals, prolonged treatment reduces gut-flora synthesis and availability of the B vitamins and vitamin K, and vitamin supplementation is a useful precaution on a long course.
• Storage: Store in airtight, light-resistant containers below 40 degrees Celsius and preferably at room temperature, 15 to 30 degrees Celsius; do not freeze. Refrigeration is not required. Some products specify discarding the vial after a set number of punctures or days. Discard a diluted injection solution if it is not used immediately. A solution may darken slightly without losing potency.
• Dosing the nicotinamide combination: Where the nicotinamide combination is used, the published nicotinamide dose is 250 mg per dog every 8 hours up to 25 kg bodyweight and 500 mg per dog every 8 hours above 25 kg, tapered to effect. No feline dosing information is published.