Sumycin (Tetracycline)

Overview

Tetracycline hydrochloride (Sumycin) is a tetracycline antibiotic. In our catalog, it is available as oral tablets in 250 mg and 500 mg strengths. Use only as directed by a licensed clinician, and complete the full course unless your prescriber tells you to stop.

Uses and Administration

Tetracyclines are bacteriostatic antibiotics with a broad range of activity and have been used to treat many infections caused by susceptible organisms. As bacterial resistance has increased and other antibiotics have become available, their use has become more limited.

Administration and dosage

For systemic infections, tetracyclines are usually taken by mouth. They should be taken with plenty of fluid while sitting or standing, and well before bedtime, to reduce the risk of esophageal ulceration.

Tetracycline (anhydrous) 231 mg is equivalent to about 250 mg of tetracycline hydrochloride. The usual adult oral dose of tetracycline hydrochloride is 250 or 500 mg every 6 hours, preferably 1 hour before or 2 hours after meals.

Administration in children

In Canada, tetracycline may be given to children over 8 years of age at the usual oral dose of 25 to 50 mg/kg/day in 4 divided doses.

Interactions

Absorption of tetracyclines is reduced by divalent and trivalent cations such as aluminum, bismuth, calcium, iron, magnesium, and zinc. Taking tetracyclines with antacids, iron supplements, some foods such as milk and dairy products, or other products containing these cations, whether as active ingredients or excipients, may lead to subtherapeutic blood levels of the antibiotic.

Sodium bicarbonate, colestipol, cholestyramine, and kaolin-pectin have also been reported to reduce tetracycline absorption, but any reduction caused by cimetidine or sucralfate is probably of little clinical importance. These interactions can be reduced by taking these products at least 1 to 3 hours apart from tetracyclines. Strontium ranelate should not be given with tetracyclines because complexes may form.

The nephrotoxic effects of tetracyclines may be worsened by diuretics, methoxyflurane, or other potentially nephrotoxic drugs. Potentially hepatotoxic drugs should be used with caution in patients taking tetracyclines. An increased rate of benign intracranial hypertension has been reported when retinoids and tetracyclines are used together, so this combination should be avoided.

Tetracyclines have been reported to increase concentrations of lithium, digoxin, halofantrine, and theophylline, although these interactions are not firmly established. The effects of oral anticoagulants have also been increased in a few patients. There have been occasional reports of tetracyclines increasing the toxic effects of ergot alkaloids and methotrexate. Tetracyclines may decrease plasma atovaquone concentrations.

Eye inflammation has occurred after the use of eye preparations preserved with thiomersal in some patients taking tetracyclines. Tetracyclines may reduce the effectiveness of oral contraceptives. Because tetracyclines are mainly bacteriostatic, they may interfere with the action of penicillins, so the two types of drug are generally not used together, especially when a rapid bactericidal effect is needed.

Precautions

Tetracyclines are contraindicated in patients with hypersensitivity to any antibacterial in this group, since cross-sensitivity may occur. Tetracyclines should not be used during pregnancy because of the risk of hepatotoxicity in the mother as well as effects on the developing fetus.

They should also be avoided during breastfeeding and in children up to 8 years of age or, according to the BNF, 12 years. Use during pregnancy, possibly during breastfeeding, or in childhood may lead to impaired bone growth and permanent tooth discoloration in the child. In general, tetracyclines, except doxycycline, should be used with caution in people with kidney impairment and, if they must be given, doses should be reduced. However, the BNF advises avoiding tetracyclines, except doxycycline and minocycline, even in mild impairment.

Caution is also needed if tetracyclines are given to patients with liver impairment, and high doses should be avoided. Patients who may be exposed to direct sunlight should be warned about the risk of photosensitivity.

Caution is advisable in patients with myasthenia gravis, who may be at risk of neuromuscular blockade. Tetracyclines should be avoided in people with SLE. Monitoring tetracycline blood levels may be helpful in patients with risk factors who need prolonged treatment: it has been suggested that serum concentrations of tetracycline should not exceed 15 micrograms/mL.

To reduce the risk of esophageal ulceration, oral tetracyclines (especially doxycycline) should be taken with plenty of fluid while sitting or standing, and well before bedtime. Tetracycline may interfere with some diagnostic tests, including tests for urinary catecholamines or glucose.

Breast feeding

Canadian breastfeeding guidance generally indicates that, after tetracycline use by breastfeeding mothers, infant absorption is negligible, so tetracycline is usually considered compatible with breastfeeding. However, product monographs state that side effects, including permanent tooth discoloration and enamel hypoplasia, may occur in breastfed infants and that breastfeeding is contraindicated during treatment with tetracyclines.

Porphyria

Tetracyclines are generally considered probably safe in patients with porphyria, although the experimental evidence about porphyrinogenicity is conflicting. Doxycycline has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients, and results from animals or in-vitro systems suggest that oxytetracycline might be porphyrinogenic.

Adverse Effects

The side effects of tetracycline are common to all tetracyclines. Gastrointestinal effects, including nausea, vomiting, and diarrhea, are common, especially with high doses, and most are thought to be due to irritation of the mucosa. Esophageal ulceration has been reported with doxycycline, minocycline, and tetracycline, particularly after capsules or tablets are taken with too little water at bedtime.

Other reported effects include glossitis, stomatitis, and dysphagia.

Oral candidiasis, vulvovaginitis, and pruritus ani occur mainly because of overgrowth of Candida albicans, and resistant coliform organisms such as Pseudomonas spp. and Proteus spp. may also overgrow and cause diarrhea. More serious but occasional reports include enterocolitis due to superinfection with resistant staphylococci and pseudomembranous colitis due to Clostridium difficile. It has been suggested that disturbances in intestinal flora are more common with tetracycline than with better-absorbed derivatives such as doxycycline.

Kidney dysfunction has been reported with tetracyclines, particularly worsening of dysfunction in people with pre-existing kidney impairment. Usual therapeutic doses given to patients with kidney impairment increase the severity of uremia, with increased nitrogen excretion and loss of sodium, accompanied by acidosis and hyperphosphatemia, and may lead to excessive systemic accumulation of tetracycline and possible liver toxicity.

These effects are related to the dose and the severity of kidney impairment and are probably due to the anti-anabolic effects of tetracyclines. Acute kidney failure and interstitial nephritis have rarely occurred. Increases in liver enzyme values have been reported with tetracyclines. In some cases, severe and sometimes fatal hepatotoxicity, associated with fatty changes in the liver and pancreatitis, has occurred in pregnant women and in patients with kidney impairment or those given high doses.

However, hepatotoxicity has also occurred in patients without these predisposing factors, although it is rarely reported with doxycycline. Tetracyclines are deposited in both deciduous teeth (milk teeth; primary teeth) and permanent teeth during their formation, causing permanent discoloration and enamel hypoplasia. The darkening effect of tetracyclines on permanent teeth appears to be related to the total dose given.

Doxycycline binds less strongly to calcium than other tetracyclines, and these changes may occur less often.

Tetracyclines are also deposited in calcifying areas of bone and nails and interfere with bone growth when given in therapeutic doses to young infants or pregnant women.

Nail discoloration and onycholysis may occur. Abnormal pigmentation of the skin, conjunctiva, oral mucosa, tongue, and internal organs such as the thyroid has rarely occurred. Permanent discoloration of the cornea has been reported in infants born to mothers given high doses of tetracycline during pregnancy. Intracranial hypertension with headache, dizziness, tinnitus, visual disturbances, and papilledema has been reported. The use of tetracyclines in infants has been associated with a bulging fontanelle. If increased intracranial pressure occurs, tetracycline treatment should be stopped. Temporary myopia in patients taking tetracyclines may be due to changes in the refractive power of the lens.

Other side effects occasionally reported with tetracyclines include increased muscle weakness in patients with myasthenia gravis and worsening of SLE. Hypersensitivity to tetracyclines is much less common than with beta-lactams, but hypersensitivity reactions, including rashes, fixed drug eruptions, exfoliative dermatitis, toxic epidermal necrolysis, drug fever, pericarditis, angioedema, urticaria, and asthma, have been reported; anaphylaxis has occurred very rarely.

Photosensitivity, which has been reported with most tetracyclines, occurs most often with demeclocycline and other long-acting derivatives, less often with chlortetracycline, and very rarely with oxytetracycline and tetracycline. It appears to be phototoxic rather than photoallergic in nature. Paresthesia may be an early sign of impending phototoxicity. Local pain and irritation can occur when tetracyclines are given parenterally, and thrombophlebitis may follow intravenous injections.

A Jarisch-Herxheimer reaction commonly occurs in patients with relapsing fever treated with tetracyclines. Although rare, agranulocytosis, aplastic anemia, hemolytic anemia, eosinophilia, neutropenia, and thrombocytopenia have been reported. Tetracyclines may cause hypoprothrombinemia.

They have also been associated with reduced serum vitamin B concentrations, including a case of folate deficiency with megaloblastic anemia. Using tetracyclines that are out of date or have deteriorated has been associated with the development of a reversible Fanconi-type syndrome characterized by polyuria and polydipsia, with nausea, glycosuria, aminoaciduria, hyperphosphaturia, hypokalemia, and hyperuricemia with acidosis and proteinuria. These effects have been attributed to degradation products, in particular anhydroepitetracycline.

Effects on intracranial pressure

Benign intracranial hypertension (pseudotumor cerebri) has been described in patients given tetracyclines. Tetracycline is most often implicated, usually in patients being treated for acne; it has also been associated with doxycycline and minocycline.

Symptoms such as headache, tinnitus, visual loss, diplopia, nausea, and vomiting usually develop from within 2 weeks to 1 year or more after starting a tetracycline. Most cases resolved when the drug was stopped, although some required symptom relief with diuretics (including acetazolamide), corticosteroids, and/or lumbar puncture. Nevertheless, permanent visual loss has been reported.

Mechanism of action

Tetracyclines are taken up into sensitive bacterial cells by an active transport process. Once inside the cell, they bind reversibly to the 30S subunit of the ribosome, preventing the binding of aminoacyl transfer RNA and inhibiting protein synthesis, and therefore cell growth. Although tetracyclines also inhibit protein synthesis in mammalian cells, they are not actively taken up, which allows selective activity against the infecting organism.

Antimicrobial Action

Tetracyclines are mainly bacteriostatic, with a broad spectrum of antimicrobial activity that includes Chlamydiaceae, Mycoplasma spp., Rickettsia spp., spirochetes, many aerobic and anaerobic Gram-positive and Gram-negative pathogenic bacteria, and some protozoa.

Spectrum of activity

The following pathogenic organisms are usually sensitive to tetracyclines: Gram-positive cocci, including some strains of Staphylococcus aureus and coagulase-negative staphylococci, and streptococci including Str. pneumoniae, Str. pyogenes (group A), and some viridans streptococci. Enterococci are essentially resistant.

Other sensitive Gram-positive bacteria include strains of Actinomyces israelii, Bacillus anthracis, Erysipelothrix rhusiopathiae, Listeria monocytogenes, and, among the anaerobes, some Clostridium spp. Nocardia spp. are generally much less susceptible, although some are sensitive to minocycline. Propionibacterium acnes is susceptible, although the action of tetracyclines in acne is complex and benefit may be seen even at subinhibitory concentrations.

Gram-negative cocci include Neisseria meningitidis (meningococci) and N. gonorrhoeae (gonococci), although some strains are resistant, and Moraxella catarrhalis (Branhamella catarrhalis). Acinetobacter spp. may be resistant to tetracycline, but most strains are susceptible to doxycycline and minocycline.

Other sensitive Gram-negative aerobes include Bordetella pertussis, Brucella spp., Klebsiella granulomatis, Campylobacter spp., Eikenella corrodens, Francisella tularensis, Haemophilus influenzae and some strains of H. ducreyi, Legionella spp., Pasteurella multocida, Streptobacillus moniliformis, and various members of the Vibrionaceae including Aeromonas hydrophila, Plesiomonas shigelloides, Vibrio cholerae and V. parahaemolyticus.

Although many of the Enterobacteriaceae, including Salmonella, Shigella, and Yersinia spp., are susceptible, resistant strains are common. Proteus and Providencia spp. are not susceptible. Pseudomonas aeruginosa is also not susceptible, although some other species formerly classified as Pseudomonas do respond, including Burkholderia mallei, B. pseudomallei, and Stenotrophomonas maltophilia (Xanthomonas maltophilia).

Among Gram-negative anaerobes, Bacteroides fragilis may sometimes be susceptible, although wild strains are often resistant, and Fusobacterium may also be sensitive. Other organisms usually sensitive to tetracyclines include Helicobacter pylori, Chlamydiaceae, Rickettsia and Coxiella spp., many spirochetes including Borrelia burgdorferi, Leptospira spp., and Treponema pallidum, atypical mycobacteria such as Mycobacterium marinum, and mycoplasmas including Mycoplasma pneumoniae and Ureaplasma urealyticum. In addition, tetracyclines are active against some protozoa, including Plasmodium falciparum and Entamoeba histolytica. Fungi, yeasts, and viruses are generally resistant.

Resistance

Resistance to tetracyclines is usually plasmid-mediated and transferable. It is often inducible and appears to be associated with the ability to prevent accumulation of the antibiotic within the bacterial cell, both by decreasing active transport of the drug into the cell and by increasing tetracycline efflux. Given the widespread use of tetracyclines, including as components of animal feed, although this is now banned in some countries, resistant strains of most sensitive species have now been reported.

Resistance has increased particularly among Enterobacteriaceae such as Escherichia coli, Enterobacter, Salmonella, and Shigella spp., especially in hospital isolates, and multiple resistance is common.

Staphylococci are commonly resistant, although doxycycline or minocycline are occasionally effective against tetracycline-resistant strains. Resistance is now also common among group A streptococci, and even more so among group B streptococci. There is also resistance among pneumococci, which often show multiple drug resistance.

Pharmacokinetics

Most tetracyclines are incompletely absorbed from the gastrointestinal tract, with about 60 to 80% of a dose usually becoming available. The degree of absorption is reduced by the presence of divalent and trivalent metal ions and also by certain drugs, with which tetracyclines form stable insoluble complexes, and to a variable degree by milk or food (see Interactions above). However, the more lipophilic derivatives doxycycline and minocycline are almost completely absorbed (more than 90%), and they are little affected by food. Formulation with phosphate may enhance tetracycline absorption.

Tetracycline 500 mg orally every 6 hours generally produces steady-state plasma concentrations of 4 to 5 micrograms/mL, whereas with doxycycline a dose of 200 mg is enough to produce peak concentrations of about 3 micrograms/mL.

Peak plasma concentrations occur about 1 to 3 hours after oral use.

Stability and compatibility (professional information)

Tetracycline undergoes reversible epimerization in solution to the less active 4-epitetracycline; the degree of epimerization depends on pH. Intravenous solutions of tetracycline hydrochloride with a pH between 3 and 5 have been reported to be stable for 6 hours, but to lose about 8 to 12% of their potency in 24 hours at room temperature. In contrast, suspensions of tetracycline hydrochloride with a pH between 4 and 7 are stable for at least 3 months.

The stability of solid dosage forms and powder at various temperatures and humidities has also been studied. Tetracycline hydrochloride was fairly stable when stored at 37°C (98.6°F) and 66% humidity for 2 months, with about a 10% loss of potency, but the phosphate was somewhat less stable, with potency losses of 25 to 40% and the formation of potentially toxic degradation products.

Other routes

Although topical use carries a risk of sensitization and may contribute to resistance, tetracycline hydrochloride has been used as a 3% ointment. A 0.2% solution has been used for acne, but systemic treatment appears to give better results. A 1% eye ointment or eye drops have been used to treat eye infections caused by susceptible organisms.

For the treatment of pleural effusions, 500 mg of tetracycline hydrochloride has been dissolved in 30 to 50 mL of sodium chloride 0.9% and instilled into the pleural space.

Skin disorders

Acne treatment notes

Tetracycline antibiotics may be used for acne for their antibacterial and anti-inflammatory effects against Cutibacterium acnes (formerly Propionibacterium acnes).

Topical antibiotics are usually not used on their own because this can increase antibiotic resistance. They are typically combined with benzoyl peroxide, and often a topical retinoid, especially for inflammatory acne.

For moderate to severe inflammatory acne, a Canadian prescriber may prescribe an oral tetracycline antibiotic, commonly doxycycline or minocycline, as part of a combination regimen rather than on its own.

Oral antibiotics are generally used for the shortest time possible. A common target is about 3 to 4 months with periodic reassessment. After improvement, ongoing control is usually maintained with non-antibiotic topical therapy, for example, a retinoid with or without benzoyl peroxide, rather than continuing antibiotics long term.

Storage

Store at 20°C to 25°C. Dispense in a tight, light-resistant container with a child-resistant closure, where required.