Description: Demeclocycline is a tetracycline antibiotic. It is classified as intermediate in action duration between tetracycline and doxycycline, although this classification scheme is somewhat artificial since tetracycline can be dosed at longer intervals than usually occurs in clinical practice. Although demeclocycline has activity similar to the other tetracyclines, its main clinical use is to treat inappropriate secretion of ADH secondary to its ability to produce nephrogenic diabetes insipidus. Photosensitivity is more frequent and more severe with demeclocycline than with other tetracyclines. Demeclocycline was approved by the FDA in 1960. Mechanism of Action: Tetracyclines can be bacteriostatic or bactericidal depending on the concentration at the site of action or the organism being treated. In gram-negative bacteria, transportation of the tetracycline into the cell occurs both by passive diffusion and through an energy-dependent active transport system that pumps all tetracyclines through the inner cytoplasmic membrane. The latter system is also thought to exist in gram-positive bacteria. Binding of demeclocycline blocks the binding of aminoacyl transfer RNA (tRNA) to the messenger RNA (mRNA). Bacterial protein synthesis is inhibited, which ultimately accounts for the antibacterial action. In mammalian cells, high concentrations of antibiotic also can interfere with protein synthesis, but these cells lack the active transport systems found in bacteria. Resistance develops when the bacterial cell mutates and the cell wall becomes less permeable. With the exception of minocycline, there is almost complete cross-resistance among the tetracyclines. The activity spectrum of the tetracyclines include gram-positive and gram-negative organisms. Tetracyclines should not be routinely used for gram-positive bacteria because many of these organisms exhibit resistance. Streptococcus pyogenes, S. pneumoniae, and alpha-hemolytic streptococci are usually sensitive, but the enterococcus group (Streptococcus faecalis and S. faecium) is universally resistant. Gram-negative coverage includes Neisseria meningitidis, H. ducreyi, Vibrio cholera, Bartonella bacilliformis, Yersinia pestis, and Brucella species. H. influenzae exhibits variable sensitivity to the tetracycline class. Other infectious organisms that are susceptible to tetracyclines are Rickettsiae, Chlamydia species, Mycoplasma pneumoniae, Bacillus anthracis, Propionbacterium acnes, Borrelia recurrentis, Treponema pallidum (syphilis), and Actinomyces species. The tetracyclines and erythromycin are considered to be drugs of choice in treating Mycoplasma pneumoniae infections. Tetracyclines are not effective against viruses or fungi. Demeclocycline is the only tetracycline that is used in the treatment of SIADH. Demeclocycline produces a nephrogenic diabetes insipidus. Diuresis is produced by inhibition of ADH-induced water reabsorption in the distal portion of the convoluted tubules and collecting ducts of the kidneys. These effects are seen within 5 days and are reversed within 2—6 days following cessation of therapy. Many clinicians prefer demeclocycline over lithium for this condition due to demeclocycline's lower risk of toxicity. Pharmacokinetics: Absorption of demeclocycline from the GI tract following oral dosing is about 60—80% in the fasting state. Most absorption takes place in the stomach and upper intestine. As the dosage is increased, the percentage absorbed decreases. Chelation with di- and trivalent ions in antacids and dairy products reduces oral absorption. Peak serum concentrations are achieved in 3—4 hours. Demeclocycline is distributed widely into body fluids, including slow accumulation in the CSF. All tetracyclines tend to concentrate in bone, liver, tumors, spleen, and teeth. They cross the placenta and are distributed into breast milk. Protein binding ranges from 65—90%. The drug undergoes enterohepatic circulation and is excreted in the feces by way of the bile. Some fecal excretion is due to incomplete gastrointestinal absorption and occurs even with parenteral administration because of enterohepatic circulation. The primary excretion route is the kidney. Serum half-life is estimated to be about 10—17 hours in adults with normal renal function and is increased to about 42—68 hours in patients with severe renal impairment. About 42% of a dose is excreted unchanged from either route.

Indications...Dosage The following organisms are generally considered susceptible to demeclocycline in vitro: Actinomyces israelii; Bacillus anthracis; Bartonella bacilliformis; Bordetella pertussis; Borrelia burgdorferi; Borrelia recurrentis; Brucella sp.; Burkholderia mallei; Burkholderia pseudomallei; Calymmatobacterium granulomatis; Campylobacter fetus; Chlamydia psittaci; Chlamydia trachomatis; Clostridium perfringens; Clostridium tetani; Coxiella burnetii; Francisella tularensis; Fusobacterium fusiforme; Haemophilus ducreyi; Haemophilus influenzae (beta-lactamase negative); Haemophilus influenzae (beta-lactamase positive); Legionella pneumophila; Leptospira sp.; Leptotrichia buccalis; Listeria monocytogenes; Mycoplasma hominis; Mycoplasma pneumoniae; Neisseria gonorrhoeae; Neisseria meningitidis; Nocardia sp.; Pasteurella multocida; Propionibacterium acnes; Propionibacterium propionicum;Rickettsia akari; Rickettsia prowazekii; Rickettsia rickettsii; Rickettsia tsutsugamushi; Shigella sp.; Spirillum minus; Streptobacillus moniliformis; Treponema pallidum; Ureaplasma urealyticum; Vibrio cholerae; Vibrio parahaemolyticus; Yersinia enterocolitica; Yersinia pestis. For the treatment of syphilis caused by Treponema pallidum: Oral dosage: Adults: 150 mg PO every 6 hours, or 300 mg PO every 12 hours. Children > 8 years: 7—13 mg/kg PO per day in 2—4 divided doses. For the treatment of upper respiratory tract infections (e.g. sinusitis, pharyngitis, otitis media) and lower respiratory tract infections (e.g. pneumonia, bronchitis): Oral dosage: Adults: 150 mg PO every 6 hours, or 300 mg PO every 12 hours. Children > 8 years: 7—13 mg/kg PO per day in 2—4 divided doses. For the treatment of urinary tract infection (UTI): Oral dosage: Adults: 150 mg PO every 6 hours, or 300 mg PO every 12 hours. Children > 8 years: 7—13 mg/kg PO per day in 2—4 divided doses. For the treatment of acne vulgaris: Oral dosage: Adults: 150 mg PO every 6 hours, or 300 mg PO every 12 hours. Children > 8 years: 7—13 mg/kg PO per day in 2—4 divided doses. For the treatment of uncomplicated gonorrhea: Oral dosage: Adults: Current CDC guidelines state that tetracyclines used alone are not adequate therapy for the treatment of gonorrhea. Tetracyclines can be used, however, in conjunction with gonococcal regimens for the presumptive treatment of coexisting chlamydial infections. The manufacturer of demeclocycline states that uncomplicated gonorrhea may be treated with 600 mg PO, followed by 300 mg PO every 12 hours for 4 days for a total dose of 3 g. For the treatment of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH†): Oral dosage: Adults: 600—1200 mg PO per day given in 3—4 divided doses. Patients with renal impairment: Dosage should be modified depending on clinical response and degree of renal impairment, but no quantitative recommendations are available. †non-FDA-approved indication

Administration Administration •Demeclocycline is administered orally. •Food and/or milk interferes with absorption of demeclocycline. Take on an empty stomach (i.e., at least one hour prior to or two hours after a meal and/or milk) with plenty of fluids. •Divalent and trivalent cations significantly affect demeclocycline absorption. Do not administer sucralfate (contains aluminum), oral iron supplements, or aluminum-, magnesium- or calcium-containing antacids with or within 4 hours of oral demeclocycline. Multivitamins containing manganese or zinc salts will also decrease absorption of demeclocycline. •To reduce the risk of esophageal irritation or ulceration, demeclocycline should not be administered at bedtime or to patients with esophageal obstruction or compression.

Contraindications Demeclocycline is classified as pregnancy category D. All tetracyclines have a detrimental effect on the skeletal development and bone growth of the fetus or child. They should not be used in the second half of pregnancy unless benefits from treatment outweigh the risks to the fetus, and their use should be considered only with extreme caution. Tetracyclines also have a serious effect on the dentin and enamel of developing teeth, causing permanent yellow or brown discoloration and enamel hypoplasia. Except when other therapy is ineffective, use in children under age 8 should be avoided, or the permanent teeth and bone development can be affected. Tetracyclines are distributed into breast milk, although tetracyclines can form nonabsorbable complexes with the calcium in breast milk. In general, tetracycline antibiotics should not be used in breast-feeding mothers because there is still the risk of causing teeth discoloration, enamel hypoplasia, inhibition of linear skeletal growth, oral and vaginal thrush, or photosensitivity reactions in the nursing infant. Tetracyclines should not be used in patients who have severe renal impairment. The dose and/or frequency may need to be modified. Doxycycline is the preferred tetracycline in patients for whom this class of antibiotic is indicated. Demeclocycline can induce a reversible nephrogenic diabetes insipidus. It should be used with caution in patients with renal disease. Dose adjustment may be necessary when prescribing demeclocycline to patients with hepatic disease because hepatic metabolism may be delayed and elimination half-life extended. Any tetracycline can produce photosensitivity reactions from sunlight (UV) exposure, but this risk is greatest with demeclocycline. Photosensitivity reactions are believed to be caused by accumulation of the drug in the skin and are mostly phototoxic in nature, but photoallergic reactions also can occur. Reactions can develop from within a few minutes to up to several hours after exposure and will last for 1—2 days after discontinuation of the drug. It is generally agreed that sunscreens provide limited protection for this reaction. Demeclocycline should be discontinued at the first sign of erythema.

Interactions Divalent or trivalent cations readily chelate with tetracycline antibiotics, forming insoluble compounds. The oral absorption of these antibiotics will be significantly reduced by other orally administered compounds that contain aluminum salts, calcium salts, iron salts, magnesium salts, and/or zinc salts, particularly if the time of administration is within 60 minutes of each other. Examples of compounds that may interfere with the bioavailability of tetracycline antibiotics include antacids; sucralfate; magnesium salicylate; polysaccharide-iron complex; quinapril (tablets contain magnesium); and multivitamins that contain iron, calcium, manganese, or zinc. Laxative preparations containing magnesium are also contraindicated. Didanosine, ddI, may also decrease tetracycline antibiotic bioavailability due to the buffering agents in didanosine tablets or powder. Delayed-release didanosine capsules do not contain a buffering agent and would not be expected to interact with tetracycline antibiotics. Some antidiarrheals also contain cations that will form chelated compounds. Calcium salts and magnesium salts that are present in foods and dairy products can form chelates with tetracyclines and impair absorption. Clinicians should warn patients about all dairy products and other high calcium- and iron-containing foods while taking tetracyclines. To reduce this effect, the administration of tetracyclines and foods, especially dairy products, should be staggered by several hours. Sevelamer could potentially interfere with the absorption of antibiotics such as the tetracyclines; however, no drug interaction data are available. Potential drug interactions can be minimized by administering antibiotics at least 1 hour before or 3 hours after sevelamer doses. The absorption of all tetracyclines is affected by pH of the gut. Sodium bicarbonate should not be used concurrently with demeclocycline because of increased gastric pH, unless administration of each agent can be separated by as much as 1—3 hours. Many texts warn not to use bacteriostatic and bactericidal antibiotics together because the bactericidal effects of, for example, a penicillin may be inhibited by the bacteriostatic agent. The clinical significance of this is debatable; however, because demeclocycline is a bacteriostatic agent, it should not be used concurrently with beta-lactam antibiotics such as penicillins and cephalosporins. Demeclocycline can increase the action of warfarin or other oral anticoagulants by either impairing prothrombin utilization or, possibly, decreasing production of vitamin K through its antiinfective action on gut bacteria. In approximately 10% of patients, digoxin is partially metabolized by bacteria in the large intestine. For digoxin-stabilized patients, an alteration in the enteric bacterial flora by an antiinfective agent, such as demeclocycline, can increase the bioavailability of digoxin. Patients should be monitored carefully for digoxin toxicity and the dose of digoxin reduced, if necessary. Colestipol has been shown to reduce tetracycline absorption by roughly 50%. It is likely this is enough to cause a clinically significant effect. Although no data are available for other tetracyclines, or for cholestyramine, it should be assumed that any tetracycline antibiotic may be affected similarly by either cholestyramine or colestipol. Staggering oral doses of each agent is recommended to minimize this pharmacokinetic interaction. Although evidence of a drug interaction is scanty, concomitant use of demeclocycline and oral contraceptives containing estrogen may reduce their protection and increase the incidence of breakthrough bleeding. It would be wise to use an alternative method of birth control during demeclocycline administration. Methoxyflurane can increase the potential for demeclocycline-induced nephrotoxicity. There have been reports of benign intracranial hypertension during concurrent use of tetracycline and vitamin A. This has not been reported with demeclocycline. The antidiuretic effect of desmopressin may be suppressed by use with demeclocycline. Demeclocycline appears to directly oppose the actions of ADH on the collecting duct. Tetracyclines, such as demeclocycline, may potentiate the neuromuscular effects of nondepolarizing neuromuscular blockers. Tetracyclines may increase the photosensitizing effects of griseofulvin, phenothiazines, sulfonamides, sulfonylureas, thiazide diuretics, retinoids, and photosensitizing agents used in photodynamic therapy. Bacteria in the intestine produce enzymes which hydrolyze the soy isoflavones to the active isoflavonoids genistein and daidzein. Some antibiotics significantly reduce the GI flora and could essentially prevent the formation of the active components of the soy isoflavones.

Adverse Reactions Benign intracranial hypertension (pseudotumor cerebri) can occur, which is usually reversible following discontinuation of the drug, but it may produce permanent sequelae. Diarrhea, nausea/vomiting, epigastric distress, and anorexia are all possible gastric side effects. They occur most often following oral administration and can be alleviated by taking the medication with a large glass of water and avoiding dosage at bedtime. Hepatotoxicity (e.g., elevated hepatic enzymes, hepatitis) should be considered.[61] Rare cases of esophagitis and esophageal ulceration have been reported in patients receiving capsule and tablet dosage forms of tetracycline antibiotics. Oral therapy can result in oral, rectal, or vaginal candidiasis due to changes in the normal balance of microbial flora. Candidal infections are more likely to occur in debilitated patients, those taking the drug over prolonged periods, and geriatric patients. The condition usually resolves upon discontinuation of the drug. Photosensitivity, if apparent, can appear within minutes of taking the drug if the patient is exposed to direct sunlight or UV light. Warning signs, including paresthesias (tingling and burning) in the hands, feet, and nose, can indicate latent photosensitivity. If the drug is discontinued, symptoms are usually alleviated within 1—2 days. Sunscreens seem to provide only limited protection, and severe response may necessitate treatment with corticosteroids or antihistamines. Rashes and discolored nails have been reported. Also, tetracyclines have been associated with erythema multiforme including Stevens-Johnson syndrome (aching joints and muscles; redness, blistering, peeling of the skin). Tooth discoloration has been seen in children who received a tetracycline antibiotic (see Contraindications), but this reaction has also been reported in adults. Enamel hypoplasia can result. Although this is not typically thought of as teratogenesis, some references include tetracyclines in lists of teratogenic drugs.[865] While isolated cases of major fetal malformations have been reported in offspring of mothers who received a tetracycline drug during pregnancy, analysis of the data does not support an association between these drugs and these major malformations (e.g., oral clefts, spina bifida, polydactyly). Limited data exist which support a possible risk of minor malformations (e.g., hypospadias, inguinal hernia). Hematologic effects, such as neutropenia and eosinophilia, are more likely to occur during long-term therapy. Patients should be evaluated regularly in these instances. Adverse renal effects are usually a problem only for patients with impaired renal function, in whom the half-life is increased. Lower doses may be necessary, and these patients' renal function should be monitored before and during treatment. Fanconi syndrome has been associated with use of outdated tetracycline therapy, so shelf-life dates should be strictly adhered to. This syndrome may be caused by accelerated deterioration of the antibiotic due to the inclusion of citric acid in the preparation. Patients on long-term therapy with tetracyclines can develop a vitamin B deficiency, possibly as a result of the antibiotic action on the gut flora. This deficiency could have potentially serious effects, especially in geriatric patients. Vitamin B supplements may be advisable for these patients. Polydipsia and polyuria can occur with demeclocycline therapy. These effects are indicative of nephrogenic diabetes insipidus, which is reversible and does not occur with other tetracyclines.

61. Carson JL, Strom BL, Duff A et al. Acute liver disease associated with erythromycins, sulfonamides, and tetracyclines. Ann Intern Med 1993;119:576—83.

865. Koren G, Pastuszak A, Ito S. Drugs in pregnancy. N Engl J Med 1998;338:1128—37.

Demeclocycline Declomycin®