Sumycin (Tetracycline)

Overview

Tetracycline hydrochloride (Sumycin) is a tetracycline-class 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

The tetracyclines are bacteriostatic antibacterials with a wide spectrum of activity and have been used in the treatment of a large number of infections caused by susceptible organisms. With the emergence of bacterial resistance and the development of other antibacterials their use has become more restricted.

Administration and dosage

In the treatment of systemic infections the tetracyclines are usually given orally. They should be taken with plenty of fluid while sitting or standing, and well before going to bed, to avoid the risk of oesophageal ulceration.

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

Administration in children

In the USA, tetracycline may be given to those over 8 years old in usual doses of 25 to 50 mg/kg daily by mouth in 4 divided doses.

Interactions

The absorption of the tetracyclines is reduced by divalent and trivalent cations such as aluminium, bismuth, calcium, iron, magnesium, and zinc, and therefore use of tetracyclines with antacids, iron preparations, some foods such as milk and dairy products, or other preparations containing such cations, whether as active ingredients or excipients, may result in subtherapeutic serum concentrations of the antibacterial.

Sodium bicarbonate, colestipol, colestyramine, and kaolin-pectin are also reported to reduce tetracycline absorption, but potential reductions due to cimetidine or sucralfate are probably of little clinical significance. These interactions can be minimised by giving such products at least 1 to 3 hours apart from tetracyclines. Strontium ranelate should not be given with tetracyclines because of possible complex formation.

The nephrotoxic effects of tetracyclines may be exacerbated by diuretics, methoxyflurane, or other potentially nephrotoxic drugs. Potentially hepatotoxic drugs should be used with caution in patients receiving tetracyclines. An increased incidence of benign intracranial hypertension has been reported when retinoids and tetracyclines are given together; such use should be avoided.

Tetracyclines have been reported to produce increased concentrations of lithium, digoxin, halofantrine, and theophylline (although these interactions are not strongly 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.

Ocular inflammation has occurred after the use of ocular preparations preserved with thiomersal in some patients receiving tetracyclines. Tetracyclines may decrease the effectiveness of oral contraceptives. Because of possible antagonism of the action of the penicillins by the mainly bacteriostatic tetracyclines it has been recommended that the two types of drug should not be used together, especially when a rapid bactericidal action is necessary.

Precautions

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

They should also be avoided during breast feeding and in children up to the age of 8, or according to the BNF, 12 years. Use in pregnancy, potentially during breast feeding, or in childhood, may result in impaired bone growth and permanent discoloration of the child's teeth. In general the tetracyclines, with the exception of doxycycline, should be used with caution in those with renal 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.

Care should also be taken if tetracyclines are given to patients with hepatic impairment and high doses should be avoided. Patients who may be exposed to direct sunlight should be warned of the risk of photosensitivity.

Care is advisable in patients with myasthenia gravis, who may be at risk of neuromuscular blockade. Tetracyclines should be avoided in those with SLE. Serum monitoring of tetracyclines may be helpful in patients with risk factors given prolonged therapy: it has been suggested that serum concentrations of tetracycline should not exceed 15 micrograms/mL.

To avoid the risk of oesophageal ulceration oral tetracyclines (notably doxycycline) should be taken with plenty of fluid while sitting or standing, and well before going to bed. Tetracycline may interfere with some diagnostic tests including determination of urinary catecholamines or glucose.

Breast feeding

The American Academy of Pediatrics states that, after use of tetracycline by breast-feeding mothers, there is negligible absorption by the infant and that tetracycline is therefore usually compatible with breast feeding. However, licensed product information states that adverse effects including permanent tooth discoloration and enamel hypoplasia may occur in breast-fed infants and that breast feeding is contraindicated during treatment with tetracyclines.

Porphyria

Tetracyclines are considered to be probably safe in patients with porphyria, although there is conflicting experimental evidence of porphyrinogenicity. 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 adverse effects of tetracycline are common to all tetracyclines. Gastrointestinal effects including nausea, vomiting, and diarrhoea are common especially with high doses and most are attributed to irritation of the mucosa. Oesophageal ulceration has been reported with doxycycline, minocycline, and tetracycline, particularly after ingestion of capsules or tablets with insufficient water at bedtime.

Other effects that have been reported include glossitis, stomatitis, and dysphagia.

Oral candidiasis, vulvovaginitis, and pruritus ani occur, mainly due to overgrowth with Candida albicans, and there may be overgrowth of resistant coliform organisms, such as Pseudomonas spp. and Proteus spp., causing diarrhoea. More seriously, enterocolitis due to superinfection with resistant staphylococci and pseudomembranous colitis due to Clostridium difficile have occasionally been reported. It has been suggested that disturbances in the intestinal flora are more common with tetracycline than with better absorbed derivatives such as doxycycline.

Renal dysfunction has been reported with tetracyclines, particularly exacerbation of dysfunction in those with pre-existing renal impairment. Usual therapeutic doses given to patients with renal impairment increase the severity of uraemia with increased excretion of nitrogen and loss of sodium, accompanied by acidosis and hyperphosphataemia, and may lead to excessive systemic accumulation of the tetracycline and possible liver toxicity.

These effects are related to the dose and the severity of renal impairment and are probably due to the anti-anabolic effects of tetracyclines. Acute renal failure and interstitial nephritis have occurred rarely. 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 renal impairment or those given high doses.

However, hepatotoxicity has also occurred in patients without these predisposing factors but is rarely reported with doxycycline. Tetracyclines are deposited both in deciduous teeth (milk teeth; primary teeth) and in 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 with calcium compared with other tetracyclines and these changes may occur less frequently.

Tetracyclines are also deposited in calcifying areas in bone and the 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 occurred rarely. Permanent discoloration of the cornea has been reported in infants born to mothers given tetracycline in high doses during pregnancy. Intracranial hypertension with headache, dizziness, tinnitus, visual disturbances, and papilloedema has been reported. The use of tetracyclines in infants has been associated with a bulging fontanelle. If raised intracranial pressure occurs tetracycline treatment should be stopped. Transient myopia in patients taking tetracyclines may be due to changes in refractive power of the lens.

Other adverse effects that have occasionally been reported with tetracyclines include increased muscle weakness in patients with myasthenia gravis and exacerbation of SLE. Hypersensitivity to the tetracyclines is much less common than to the 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 frequently with demeclocycline and other long-acting derivatives, less with chlortetracycline, and very rarely with oxytetracycline and tetracycline; it appears to be phototoxic rather than photoallergic in nature. Paraesthesia 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 occurs commonly in patients with relapsing fever treated with tetracyclines. Although rare, agranulocytosis, aplastic anaemia, haemolytic anaemia, eosinophilia, neutropenia, and thrombocytopenia have been reported. Tetracyclines may produce hypoprothrombinaemia.

They have also been associated with reductions in serum vitamin B concentrations, including a case of folate deficiency and concomitant megaloblastic anaemia. The use of tetracyclines that are out-of-date or which have deteriorated has been associated with the development of a reversible Fanconi-type syndrome characterised by polyuria and polydipsia with nausea, glycosuria, aminoaciduria, hyperphosphaturia, hypokalaemia, and hyperuricaemia with acidosis and proteinuria; these effects have been attributed to the presence of degradation products, in particular anhydroepitetracycline.

Effects on intracranial pressure

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

Presenting symptoms, such as headaches, tinnitus, visual loss, diplopia, nausea, and vomiting, usually develop from within 2 weeks to 1 year or more of starting a tetracycline. Most cases resolved when the drug was stopped although some required symptomatic treatment 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 within the cell they bind reversibly to the 30S subunit of the ribosome, preventing the binding of aminoacyl transfer RNA and inhibiting protein synthesis, and hence cell growth. Although tetracyclines also inhibit protein synthesis in mammalian cells they are not actively taken up, permitting selective activity against the infecting organism.

Antimicrobial Action

The tetracyclines are mainly bacteriostatic, with a broad spectrum of antimicrobial activity including Chlamydiaceae, Mycoplasma spp., Rickettsia spp., spirochaetes, 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 including 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 the tetracyclines in acne is complex and benefit may be seen even at subinhibitory concentrations.

Gram-negative cocci including 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 including 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 not susceptible either, although some other species formerly classified as Pseudomonas respond, including Burkholderia mallei, B. pseudomallei, and Stenotrophomonas maltophilia (Xanthomonas maltophilia).

Among the 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 spirochaetes including Borrelia burgdorferi, Leptospira spp., and Treponema pallidum, atypical mycobacteria such as Mycobacterium marinum, and mycoplasmas including Mycoplasma pneumoniae and Ureaplasma urealyticum. In addition the tetracyclines are active against some protozoa including Plasmodium falciparum and Entamoeba histolytica. Fungi, yeasts, and viruses are generally resistant.

Resistance

Resistance to the tetracyclines is usually plasmid-mediated and transferable. It is often inducible, and appears to be associated with the ability to prevent accumulation of the antibacterial within the bacterial cell, both by decreasing active transport of the drug into the cell and by increasing tetracycline efflux. Unsurprisingly, given the widespread use of the tetracyclines (including as components of animal feeds, although this is now banned in some countries), resistant strains of the majority of 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, about 60 to 80% of a dose of the drug usually being available. The degree of absorption is reduced by the presence of divalent and trivalent metal ions and also 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 the absorption of tetracycline.

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 sufficient 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 epimerisation in solution to the less active 4-epitetracycline; the degree of epimerisation is dependent 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 to the case in solution, 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 rather less stable, with potency losses of 25 to 40% and the formation of potentially toxic degradation products.

Other routes

Although topical application carries the risk of sensitisation and may contribute to the development of resistance, tetracycline hydrochloride has been used as a 3% ointment; a 0.2% solution has been used in acne but systemic treatment appears to produce better results. A 1% eye ointment or eye drops have been used in the treatment of ocular infections due to 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-class antibiotics may be used in acne for antibacterial and anti-inflammatory effects against Cutibacterium acnes (formerly Propionibacterium acnes).

Topical antibiotics are usually not used alone 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, an oral tetracycline-class antibiotic (commonly doxycycline or minocycline; sarecycline is another U.S.-approved option) may be prescribed as part of a combination regimen rather than as monotherapy.

Oral antibiotics are generally used for the shortest time possible. A common target is about 3–4 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 68° to 77°F (20° to 25°C). Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).