GI Effects
The most frequent adverse reactions to tetracyclines are dose-related GI effects including nausea, vomiting, diarrhea, bulky loose stools, anorexia, flatulence, abdominal discomfort, and epigastric burning and distress. Stomatitis, glossitis, dysphagia, sore throat, hoarseness, black hairy tongue, pancreatitis, and inflammatory lesions in the anogenital region with candidal overgrowth have also been reported occasionally.
GI effects occur most frequently when tetracyclines are administered orally, but may also occur when the drugs are administered IM or IV. In clinical trials in which combined therapy with tetracycline hydrochloride, metronidazole, and bismuth subsalicylate was used for the treatment of H. pylori infection and associated duodenal ulcer, adverse effects generally were related to the GI tract, were reversible, and infrequently led to discontinuance of therapy.
Adverse GI effects reported in at least 1% of patients receiving combined therapy with tetracycline hydrochloride, metronidazole, and bismuth subsalicylate (generally in conjunction with acid-suppression therapy) were nausea (10.2%), diarrhea (5.1%), abdominal pain (3%), melena (2.5%), anal discomfort (1.5%), anorexia (1.5%), vomiting (1.5%), and constipation (1%). Adverse GI effects reported in less than 1% of patients receiving combined therapy with tetracycline hydrochloride-metronidazole-bismuth subsalicylate in clinical trials were dry mouth, dyspepsia, dysphagia, flatulence, GI hemorrhage, glossitis, and stomatitis.
Rarely, doxycycline hyclate, minocycline hydrochloride, and tetracycline hydrochloride capsules or tablets have caused esophagitis and esophageal ulceration which were local in origin. In most reported cases, capsules of the drugs had been administered at bedtime, with insufficient quantities of fluid, or to patients with hiatal hernia. Oral candidiasis occurs occasionally during oral, IM, or IV tetracycline therapy and is presumably the result of alterations in the normal microbial flora caused by the anti-infectives.
Candidal suprainfections have been reported more frequently with tetracyclines than with penicillins, and occur most frequently during prolonged therapy and/or in debilitated patients. Clostridium difficile-associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis), caused by overgrowth of toxin-producing clostridia, has been reported rarely with oral or parenteral tetracycline therapy.
Staphylococcal enterocolitis with severe, fulminating diarrhea, dehydration, and circulatory collapse has also been reported rarely with oral or parenteral tetracycline therapy and is presumably caused by tetracycline- and penicillin-resistant Staphylococcus aureus. Although doxycycline and minocycline produce fewer alterations in the intestinal flora than do other tetracyclines following oral administration, there is no evidence that these 2 drugs produce fewer GI-related adverse effects.
Sensitivity Reactions
Hypersensitivity reactions have been reported rarely with tetracyclines and include maculopapular, morbilliform, or erythematous rash; exfoliative dermatitis; erythema multiforme; Stevens-Johnson syndrome; pruritus; urticaria; angioedema; pulmonary infiltrates and/or eosinophilia; asthma; anaphylaxis; anaphylactoid purpura; fixed drug eruptions of the genitalia (including balanitis) and other areas; pericarditis; exacerbation of systemic lupus erythematosus; and serum sickness-like reactions with fever, rash, headache, and arthralgia. Patients hypersensitive to one tetracycline derivative are likely to be hypersensitive to all tetracyclines.
Dermatologic Effects
Photosensitivity, manifested as an exaggerated sunburn reaction on sun-exposed areas of the body, has occurred with tetracyclines. Photosensitivity reactions occur most frequently and are most severe with demeclocycline; occur less frequently with doxycycline, oxytetracycline, and tetracycline; and very rarely occur with minocycline.
Photosensitivity reactions, if they occur, develop within a few minutes to several hours after sun exposure and usually persist 1-2 days after discontinuance of the tetracycline. Although in most cases photosensitivity reactions appear to result from accumulation of the drugs in skin and are phototoxic in nature, photoallergic reactions may also occur. Paresthesia, consisting mainly of tingling and burning of the hands, feet, and nose, may be an early indication of photosensitivity.
Although it has been suggested that sunscreen agents containing benzophenone derivatives may protect against these photosensitivity reactions, most clinicians agree that these sunscreens provide, at most, only limited protection in patients susceptible to these reactions. The manufacturers state that severe photosensitivity reactions may require treatment with antihistamines and corticosteroids.
Onycholysis and discoloration of the nails, alone or associated with photosensitivity reactions, have been reported during tetracycline therapy. Maculopapular and erythematous rash and, rarely, exfoliative dermatitis, also have been reported in patients receiving tetracyclines.
Photosensitivity reaction or rash was reported in less than 1% of patients receiving combined therapy with tetracycline hydrochloride, metronidazole, and bismuth subsalicylate (generally in conjunction with acid-suppression therapy) in clinical trials. Blue-gray pigmentation at areas of cutaneous inflammation has been reported in a few patients receiving oral minocycline. The pigmentation is presumably caused by a minocycline degradation product or a drug-hemosiderin complex.
A generalized muddy-brown pigmentation of the skin, accentuated in sun-exposed areas of the skin, has also been reported in a few patients receiving oral minocycline for the treatment of acne vulgaris. Rarely, long-term therapy of inflammatory acne with oral tetracycline hydrochloride has resulted in gram-negative folliculitis caused by tetracycline-resistant organisms.
Renal Effects
Increased urinary excretion of nitrogen and increased BUN concentrations, with or without increased serum creatinine concentrations, have been reported rarely during tetracycline therapy. These effects are not usually clinically important in patients with normal renal function or in patients with impaired renal function receiving usual dosages of doxycycline or minocycline.
However, if the usual dosage of demeclocycline, oxytetracycline, or tetracycline is used in patients with impaired renal function, progressive azotemia, hyperphosphatemia, and acidosis may occur. Administration of outdated or deteriorated tetracyclines has caused a reversible Fanconi-like syndrome characterized by nausea, vomiting, lethargy, polydipsia, polyuria, glycosuria, aminoaciduria, phosphaturia, proteinuria, acidosis, and hypokalemia. In most cases, the outdated tetracycline preparation administered contained citric acid (an excipient no longer used in tetracycline preparations) which accelerated deterioration of the antibiotic during storage.
Therefore, this reaction is unlikely with currently available tetracycline preparations. In at least 1 patient, use of outdated tetracycline hydrochloride resulted in lactic acidosis in addition to the Fanconi-like syndrome. Demeclocycline has caused a reversible, dose-related diabetes insipidus syndrome (polyuria, polydipsia, weakness) in some patients who received long-term therapy with the drug.
This syndrome has been shown to be nephrogenic, dose-dependent, and reversible when demeclocycline is discontinued. When demeclocycline is used in dosages of 600 mg to 1.2 g daily, this effect reportedly occurs within 5 days after initiation of therapy and reverses within 2-6 days after discontinuance of the drug. This diabetes insipidus syndrome has not been reported with other currently available tetracyclines.
Hepatic Effects
Hepatotoxicity, characterized histologically as fatty metamorphosis of the liver without necrosis or inflammatory reactions and sometimes associated with pancreatitis, has been reported rarely with tetracyclines.
Elevations in liver function test results also have been reported. Fatalities have occurred because of irreversible deterioration of pancreatic, hepatic, and renal function. Liver toxicity has been reported most frequently following IV administration of large doses (more than 2 g daily) of tetracycline hydrochloride (no longer commercially available as a parenteral formulation in the US) to pregnant women with pyelonephritis but has also occurred following oral administration of large doses of the drugs to nonpregnant individuals. Liver toxicity is most likely to occur in patients receiving other hepatotoxic drugs or in patients with preexisting hepatic or renal impairment.
A syndrome consisting of a severe exfoliative dermatitis followed by acute hepatitis, which progressed to hepatic coma and death in at least one patient, has been reported rarely with minocycline therapy.
Hematologic Effects
Leukocytosis, neutropenia, leukopenia, atypical lymphocytes, toxic granulation of granulocytes, hemolytic anemia, thrombocytopenia, and thrombocytopenic purpura have occurred rarely with long-term tetracycline therapy. Increased urinary excretion of ascorbic acid and decreased leukocyte ascorbic acid concentrations have been reported during tetracycline therapy; although the clinical importance of these effects is unclear, they presumably may interfere with leukocyte migration and phagocytic activity.
Jarisch-Herxheimer Reaction
A Jarisch-Herxheimer reaction has occurred occasionally when tetracyclines were used to treat brucellosis or spirochetal infections, including louse-borne relapsing fever caused by Borrelia recurrentis, leptospirosis, and syphilis. This reaction also have been observed in patients with Lyme disease treated with tetracyclines or certain other antibiotics (e.g., penicillins, cephalosporins). The reaction, consisting of headache, fever, chills, malaise, muscular aches, exacerbation of cutaneous lesions, and leukocytosis, is presumably caused by the release of pyrogen and/or endotoxin from phagocytized organisms and generally occurs 12-24 hours after initiation of tetracycline therapy. If tetracyclines are used in the treatment of brucellosis or spirochetal infections, patients should be warned to expect the reaction and should be treated with bedrest and aspirin or other nonsteroidal anti-inflammatory agents (NSAIAs) if necessary.
Nervous System Effects
Adverse CNS effects including lightheadedness, dizziness, vertigo, ataxia, drowsiness, headache, and fatigue occur with minocycline and are often associated with nausea and vomiting. The true incidence of these adverse effects has not been determined. Although vestibular symptoms were previously reported to occur in up to 21% of patients treated with minocycline, these reactions may occur in 30-90% of patients treated with usual dosages of minocycline. Vestibular symptoms appear to be dose related and occur more frequently in women than in men. These symptoms may disappear during continued therapy with minocycline, and rapidly disappear when the drug is discontinued.
Tinnitus, hearing loss, and visual disturbances also have been reported with tetracycline therapy.
Dizziness or paresthesia was reported in 1.5% of patients receiving combined therapy with tetracycline hydrochloride, metronidazole, and bismuth subsalicylate (generally in conjunction with acid-suppression therapy) in clinical trials; asthenia or insomnia was reported in 1% of such patients.
Nervousness, malaise, or syncope was reported in less than 1% of patients receiving tetracycline hydrochloride-metronidazole-bismuth subsalicylate therapy in clinical trials. Increased intracranial pressure and bulging fontanels (pseudotumor cerebri; benign intracranial hypertension) have been reported rarely when tetracyclines were used in infants. Pseudotumor cerebri, usually manifested by headache and blurred vision, also has been reported rarely in adults receiving tetracyclines.
Although this condition and related symptoms usually resolve following discontinuance of the tetracycline, the possibility of permanent sequelae exists. Animal studies indicate that tetracyclines may potentiate neuromuscular blockade produced by neuromuscular blocking agents.
An increase in muscular weakness (myasthenic syndrome) has been reported in a few patients with myasthenia gravis following IV administration of oxytetracycline hydrochloride, but a causal relationship has not been established.
Local Effects
IV administration of tetracyclines frequently causes thrombophlebitis, especially when IV therapy is prolonged or when a single vein is used for repeated infusions. IM administration of tetracyclines is painful. Although commercially available oxytetracycline hydrochloride IM preparations contain a local anesthetic, local irritation may occur. To minimize pain associated with IM administration of the drug, injections should be given deeply into a relatively large muscle, inadvertent intraneural injection or injection into blood vessels or subcutaneous or fat layers should be avoided, and injection sites should be alternated. Pain and induration may be relieved by applying ice packs.
Other Adverse Effects
Prolonged administration of tetracyclines has produced a microscopic brown-black discoloration of the thyroid in animals and humans, and goiter accompanied by elevated radioactive iodine uptake and evidence of thyroid tumors has occurred in rats during long-term treatment with minocycline (See Cautions: Mutagenicity and Carcinogenicity.)
However, abnormalities in thyroid function studies have not been reported to date in humans.
Vaginal candidiasis occurs occasionally and systemic candidiasis occurs rarely following oral or parenteral use of tetracyclines. For further discussion of candidiasis,use of outdated tetracyclines has also caused a lupus erythematosus-like syndrome. While tooth discoloration has been reported most frequently in children with developing teeth (see Cautions: Pregnancy, Lactation, and Pediatric Precautions), such discoloration also has been reported rarely in adults receiving tetracyclines.
Pain or upper respiratory infection was reported in 1% of patients receiving combined therapy with tetracycline hydrochloride, metronidazole, and bismuth subsalicylate (generally in conjunction with acid-suppression therapy) in clinical trials, while hypertension, myocardial infarction, or rheumatoid arthritis was reported in less than 1% of such patients.
Precautions and Contraindications
When the commercially available combination preparation containing tetracycline hydrochloride, metronidazole, and bismuth subsalicylate (Helidac® Therapy) is used for the treatment of Helicobacter pylori infection and associated duodenal ulcer disease, the cautions, precautions, and contraindications associated with metronidazole and bismuth subsalicylate must be considered in addition to those associated with tetracycline hydrochloride.
Use of tetracyclines may result in overgrowth of nonsusceptible organisms, including fungi. If suprainfection or superinfection occurs, tetracyclines should be discontinued and appropriate therapy instituted.
Capsules or tablets containing tetracyclines should be given with adequate amounts of fluid and probably should not be given at bedtime or to patients with esophageal obstruction or compression.
The manufacturers state that patients receiving tetracyclines who are apt to be exposed to direct sunlight or ultraviolet light (e.g., sun lamps) should be advised that photosensitivity may occur, and the drugs should be discontinued at the first sign of erythema.
Renal, hepatic, and hematologic systems should be evaluated periodically during prolonged therapy with tetracyclines. The manufacturers state that if tetracyclines are indicated in patients with preexisting hepatic or renal impairment, lower than usual dosage should be used, liver and renal function tests should be performed prior to and during therapy, and other potentially hepatotoxic drugs should not be administered concomitantly. In addition, if tetracyclines are used in these patients, serum concentrations of the drugs should be monitored if therapy is prolonged; serum concentrations of tetracycline hydrochloride should not exceed 15 mcg/mL.
Patients who experience CNS symptoms while receiving minocycline should be cautioned about driving vehicles or operating hazardous machinery during therapy. Dizziness, headache, and vertigo have also been reported rarely with other tetracycline derivatives. Some commercially available tetracycline preparations (e.g., doxycycline, minocycline oral suspension, oxytetracycline, tetracycline) contain sulfites that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals.
The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals. Some commercially available preparations of tetracycline hydrochloride (e.g., Panmycin® capsules) contain the dye tartrazine (FD&C yellow No. 5) which may cause allergic reactions including bronchial asthma in certain susceptible individuals. Although the incidence of tartrazine sensitivity is low, it frequently occurs in individuals who are sensitive to aspirin.
Although a causal relationship has not been definitely established, an increase in muscular weakness has been reported in a few patients with myasthenia gravis following IV administration of oxytetracycline hydrochloride. Therefore, parenteral tetracyclines probably should be used with caution in patients with this condition. Tetracyclines are contraindicated in patients hypersensitive to any of the tetracyclines.
Pediatric Precautions
Tetracyclines should not be used in children younger than 8 years of age unless other appropriate drugs are ineffective or are contraindicated. The American Academy of Pediatrics recommends that tetracyclines be used only in children who are 8 years of age or older, except under unusual circumstances.
Because the benefits outweigh the risks, doxycycline may be used in infants and children for the initial treatment of anthrax or for initial postexposure prophylaxis following exposure to anthrax spores. Doxycycline is considered a drug of choice for treatment or prophylaxis of anthrax following exposure to anthrax spores in the context of biologic warfare or bioterrorism.
However, because of potential adverse effects from prolonged use of doxycycline in infants and children, amoxicillin is an option in those with inhalational or cutaneous anthrax to complete the remaining 60 days of therapy after an initial 14-21 or 7-14 days of doxycycline, respectively, when susceptibility to penicillin is known; amoxicillin is not recommended for initial therapy. In addition, if exposure has been confirmed and in vitro tests indicate that the organism is susceptible to penicillin, the doxycycline postexposure prophylaxis regimen in children 8 years of age or younger may be switched to oral amoxicillin or oral penicillin V.
Use of tetracyclines in infants has resulted in retardation of bone growth. Because tetracyclines localize in the dentin and enamel of developing teeth, use of the drugs during tooth development may cause enamel hypoplasia and permanent yellow-gray to brown discoloration of the teeth. Use of tetracyclines may result in discoloration of the deciduous teeth of children if the drugs are used during pregnancy or in children up to 4-6 months of age.
Discoloration of the permanent teeth may result if the drugs are used in children 4 months to 8 years of age. Discoloration of the permanent teeth has also occurred in older children and young adults in whom minocycline had been used. These effects are most common following long-term use of tetracyclines but have occurred following repeated short-term use of the drugs.
Mutagenicity and Carcinogenicity
Some tetracycline antibiotics (tetracycline, oxytetracycline) reportedly have demonstrated mutagenic potential in in vitro mammalian cell (e.g., mouse lymphoma, Chinese hamster lung cell) assays. Administration of certain tetracycline antibiotics reportedly has been associated with tumor production in animals. Long-term dietary administration of minocycline has resulted in evidence of thyroid tumors in rats, and adrenal and pituitary tumors have been reported in rats receiving oxytetracycline. However, in studies conducted in mice and rats, tetracycline hydrochloride did not demonstrate evidence of carcinogenicity.
Pregnancy, Fertitlity and Lactation
Tetracyclines can cause fetal toxicity when administered to pregnant women, but potential benefits from use of the drugs may be acceptable in certain conditions despite the possible risks to the fetus. The US Centers for Disease Control and Prevention (CDC) states that, although tetracyclines are not usually recommended for use during pregnancy, their use may be indicated for life-threatening illness.
Because the benefits of doxycycline outweigh the risks in the treatment of inhalational anthrax, the CDC and other experts (e.g., US Working Group on Civilian Biodefense) state that recommendations for use of doxycycline in pregnant women with anthrax are the same as those for women who are not pregnant. Since adverse effects on developing teeth and bones are dose-related, the CDC suggests that doxycycline might be used for a short period (7-14 days) before 6 months of gestation when necessary. If doxycycline is used in pregnant women, some clinicians recommend that periodic liver function testing be performed. Results of studies in animals indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (e.g., retardation of skeletal development). Evidence of embryotoxicity also has been found in animals treated with these drugs early in pregnancy.
When tetracyclines are administered during pregnancy or if the patient becomes pregnant while receiving a tetracycline, the patient should be informed of the potential hazard to the fetus. Liver toxicity has occurred following IV administration of tetracyclines to pregnant women. Reproduction studies in male rats have demonstrated that minocycline impairs fertility.
Tetracycline hydrochloride had no effect on fertility when administered in the diet to male and female rats at a daily intake of 25 times the human dosage. Tetracyclines are distributed into milk. Some manufacturers state that because of the potential for serious adverse reactions from tetracyclines in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
However, available limited data suggest that absorption of tetracycline by a nursing infant is negligible because of inhibition of the drug’s absorption by calcium in milk and that a short course of tetracycline therapy (e.g., 7-10 days) may be used in nursing women. Some clinicians recommend that tetracyclines not be used in nursing women, if possible, because of the potential for dental staining in the infant.
The AAP considers tetracyclines to be usually compatible with breast-feeding since the amount of the drugs potentially absorbed by nursing infants would be small and no observable change in infants associated with such exposure has been reported to date.
Because the long-term safety of prolonged exposure of nursing infants (e.g., during a 60-day regimen for anthrax) to breast milk from doxycycline-treated women currently is not known, the CDC recommends that lactating women who are concerned about the use of doxycycline during anthrax prophylaxis consider expressing and then discarding their breast milk so that breast-feeding can be resumed once anti-infective prophylaxis is complete.
Decisions about anti-infective choice and continuation of breast-feeding should be made by the woman and her and the infant’s clinicians, taking into consideration the efficacy of the anti-infective, safety for the infant, and benefits of breast-feeding. Minocycline-induced black pigmentation of milk has been reported in a woman with phenothiazine-induced galactorrhea.