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Tetracycline

Pronunciation

Pronunciation

(tet ra SYE kleen)

Index Terms

  • Achromycin
  • TCN
  • Tetracycline HCl
  • Tetracycline Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral, as hydrochloride:

Generic: 250 mg, 500 mg

Pharmacologic Category

  • Antibiotic, Tetracycline Derivative

Pharmacology

Inhibits bacterial protein synthesis by binding with the 30S and possibly the 50S ribosomal subunit(s) of susceptible bacteria; may also cause alterations in the cytoplasmic membrane

Absorption

Oral: 77% to 88% (Agwuh 2006); IM: Poor, with less than 60% of dose absorbed

Distribution

Widely distributed to most body fluids and tissues including ascitic, synovial and pleural fluids; bronchial secretions; poor penetration into CSF

Excretion

Urine (30%); feces (20% to 60%) (Agwuh 2006)

Time to Peak

Serum: Oral: 2 to 4 hours (Agwuh 2006)

Half-Life Elimination

6 to 11 hours (Agwuh 2006)

Protein Binding

55% to 64% (Agwuh 2006)

Special Populations: Renal Function Impairment

Because renal Cl is by glomerular filtration, excretion is significantly affected by the state of renal function.

Use: Labeled Indications

Acute intestinal amebiasis: Adjunctive therapy in acute intestinal amebiasis caused by Entamoeba histolytica.

Acne: Adjunctive therapy for the treatment of severe acne.

Actinomycosis: Treatment of actinomycosis caused by Actinomyces species when penicillin is contraindicated.

Anthrax: Treatment of anthrax due to Bacillus anthracis when penicillin is contraindicated.

Campylobacter: Treatment of infections caused by Campylobacter fetus.

Cholera: Treatment of cholera caused by Vibrio cholerae.

Clostridium: Treatment of infections caused by Clostridium spp. when penicillin is contraindicated.

Gram-negative infections: Treatment of infections caused by Escherichia coli, Enterobacter aerogenes, Shigella spp., Acinetobacter spp., Klebsiella spp., and Bacteroides spp.

Listeriosis: Treatment of listeriosis due to Listeria monocytogenes when penicillin is contraindicated.

Ophthalmic infections: Treatment of inclusion conjunctivitis or trachoma caused by Chlamydia trachomatis.

Relapsing fever: Treatment of relapsing fever due to Borrelia spp.

Respiratory tract infection: Treatment of respiratory tract infections caused by Haemophilus influenzae (upper respiratory tract only), Klebsiella spp. (lower respiratory tract only), Mycoplasma pneumoniae (lower respiratory tract only), Streptococcus pneumoniae, or Streptococcus pyogenes.

Rickettsial infections: Treatment of Rocky Mountain spotted fever, typhus group infections, Q fever, and rickettsialpox caused by Rickettsiae.

Sexually transmitted diseases: Treatment of lymphogranuloma venereum or uncomplicated urethral, endocervical, or rectal infections caused by C. trachomatis; chancroid caused by Haemophilus ducreyi; granuloma inguinale (donovanosis) caused by Klebsiella granulomatis; syphilis caused by Treponema pallidum, when penicillin is contraindicated.

Limitations of use: Tetracycline is not a recommended alternative for uncomplicated gonorrhea according to the Centers for Disease Control and Prevention (CDC) sexually transmitted diseases guidelines (CDC [Workowski 2015]).

Skin and skin structure infections: Treatment of skin and skin structure infections caused by Staphylococcus aureus or S. pyogenes.

Urinary tract infections: Treatment of urinary tract infections caused by susceptible gram-negative organisms (eg, E. coli, Klebsiella spp.).

Vincent infection: Treatment of Vincent infection caused by Fusobacterium fusiforme when penicillin is contraindicated.

Yaws: Treatment of yaws caused by Treponema pertenue when penicillin is contraindicated.

Zoonotic infections: Treatment of psittacosis (ornithosis) due to Chlamydophila psittaci; plague due to Yersinia pestis; tularemia due to Francisella tularensis; brucellosis due to Brucella spp. (in conjunction with an aminoglycoside); bartonellosis due to Bartonella bacilliformis.

Use: Unlabeled

Treatment of periodontitis associated with presence of Actinobacillus actinomycetemcomitans (AA); treatment of malaria

Contraindications

Hypersensitivity to any of the tetracyclines or any component of the formulation.

Dosing: Adult

Usual dosage range: Oral: 250 to 500 mg every 6 to 12 hours

Acne: Oral: Initial dose: 1 g daily in divided doses; reduce gradually to 125 to 500 mg/day once improvement is noted (alternate day or intermittent therapy may be adequate in some patients).

Helicobacter pylori eradication (off-label use): 500 mg 4 times daily for 10 to 14 days, in combination with bismuth subsalicylate, metronidazole, and either ranitidine or a proton pump inhibitor (Chey 2007)

Malaria, severe, treatment (off-label use): Oral: 250 mg 4 times daily for 7 days with quinidine gluconate. Note: Quinidine gluconate duration is region specific; consult CDC for current recommendations (CDC 2013).

Malaria, uncomplicated, treatment (off-label use): Oral: 250 mg 4 times daily for 7 days with quinine sulfate. Note: Quinine sulfate duration is region specific; consult CDC for current recommendations (CDC 2013).

Periodontitis (off-label use): Oral: 250 mg every 6 hours until improvement (usually 10 days)

Syphilis, penicillin-allergic patients: Note: Data to support the use of alternatives to penicillin are limited in primary and secondary syphilis and are not well documented in the treatment of latent syphilis (CDC [Workowski 2015])

Early syphilis (primary or secondary infection): 500 mg 4 times daily for 14 days.

Latent syphilis (late or of unknown duration): 500 mg 4 times daily for 28 days.

Tularemia (mild to moderate): Oral: 500 mg 4 times daily for at least 14 days (IDSA [Stevens 2014])

Vibrio cholerae: Oral: 500 mg 4 times daily for 3 days (Seas 1996)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Usual dosage range: Children >8 years and Adolescents: Oral: 25 to 50 mg/kg/day in divided doses every 6 hours

Malaria, severe, treatment (off-label use): Children ≥8 years and Adolescents: Oral: 25 mg/kg/day in divided doses every 6 hours (maximum dose: 250 mg every 6 hours) for 7 days with quinidine gluconate. Note: Quinidine gluconate duration is region specific; consult CDC for current recommendations (CDC 2013).

Malaria, uncomplicated, treatment (off-label use): Children ≥8 years and Adolescents: Oral: 25 mg/kg/day in divided doses every 6 hours (maximum dose: 250 mg every 6 hours) for 7 days with quinine sulfate. Note: Quinine sulfate duration is region specific; consult CDC for current recommendations (CDC 2013).

Dosing: Renal Impairment

Adults:

Manufacturer’s labeling: There are dosage adjustments provided in the manufacturer’s labeling; decrease dose and/or extend dosing interval.

Alternative dosing (Aronoff 2007): Note: Renally adjusted dose recommendations are based on doses of 250 mg to 500 mg twice daily to 4 times daily.

GFR >50 mL/minute: Administer recommended dose based on indication every 8 to 12 hours.

GFR 10 to 50 mL/minute: Administer recommended dose based on indication every 12 to 24 hours.

GFR <10 mL/minute: Administer recommended dose based on indication every 24 hours.

Children >8 years and Adolescents: There are dosage adjustments provided in the manufacturer’s labeling; decrease dose and/or extend dosing interval.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Extemporaneously Prepared

A 25 mg/mL oral suspension may be made using capsules. Empty the contents of six 500 mg capsules into mortar. Add a small amount (~20 mL) of a 1:1 mixture of Ora-Sweet® and Ora-Plus® and mix to a uniform paste; mix while adding the vehicle in geometric proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label "shake well" and "refrigerate". Stable 28 days refrigerated.

Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.

Administration

Administer on an empty stomach (ie, 1 hour prior to, or 2 hours after meals) to increase total absorption and with adequate amount of fluid to reduce risk of esophageal irritation and ulceration. Administer at least 1 to 2 hours prior to, or 4 hours after antacid because aluminum and magnesium cations may chelate with tetracycline and reduce its total absorption.

Dietary Considerations

Take on an empty stomach (ie, 1 hour prior to, or 2 hours after meals). Take at least 1-2 hours prior to, or 4 hours after antacid.

Storage

Store at 20°C to 25°C (68°F to 77°F); protect from light. Use of outdated tetracyclines has caused a Fanconi-like syndrome (nausea, vomiting, acidosis, proteinuria, glycosuria, aminoaciduria, polydipsia, polyuria, hypokalemia).

Drug Interactions

Aminolevulinic Acid: Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid. Monitor therapy

Antacids: May decrease the absorption of Tetracycline Derivatives. Consider therapy modification

Atovaquone: Tetracycline may decrease the serum concentration of Atovaquone. Monitor therapy

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Bile Acid Sequestrants: May decrease the absorption of Tetracycline Derivatives. Consider therapy modification

Bismuth Subcitrate: May decrease the serum concentration of Tetracycline Derivatives. Management: Avoid administration of oral tetracyclines within 30 minutes of bismuth subcitrate administration. This is of questionable significance for at least some regimens intended to treat H. pylori infections. Consider therapy modification

Bismuth Subsalicylate: May decrease the serum concentration of Tetracycline Derivatives. Management: Consider dosing tetracyclines 2 hours before or 6 hours after bismuth. The need to separate doses during Helicobacter pylori eradication regimens is questionable. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Calcium Salts: May decrease the serum concentration of Tetracycline Derivatives. Management: If coadministration of oral calcium with oral tetracyclines can not be avoided, consider separating administration of each agent by several hours. Consider therapy modification

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Iron Salts: Tetracycline Derivatives may decrease the absorption of Iron Salts. Iron Salts may decrease the serum concentration of Tetracycline Derivatives. Exceptions: Ferric Carboxymaltose; Ferric Gluconate; Ferric Hydroxide Polymaltose Complex; Ferric Pyrophosphate Citrate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Consider therapy modification

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

Lanthanum: May decrease the serum concentration of Tetracycline Derivatives. Management: Administer oral tetracycline antibiotics at least two hours before or after lanthanum. Consider therapy modification

Magnesium Dimecrotate: May interact via an unknown mechanism with Tetracycline Derivatives. Monitor therapy

Magnesium Salts: May decrease the absorption of Tetracycline Derivatives. Only applicable to oral preparations of each agent. Consider therapy modification

Mecamylamine: Tetracycline Derivatives may enhance the neuromuscular-blocking effect of Mecamylamine. Avoid combination

Mipomersen: Tetracycline Derivatives may enhance the hepatotoxic effect of Mipomersen. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Tetracycline Derivatives. Management: If coadministration of a polyvalent cation-containing multivitamin with oral tetracyclines can not be avoided, separate administration of each agent by several hours. Consider therapy modification

Multivitamins/Minerals (with AE, No Iron): May decrease the serum concentration of Tetracycline Derivatives. Management: If coadministration of a polyvalent cation-containing multivitamin with oral tetracyclines can not be avoided, separate administration of each agent by several hours. Consider therapy modification

Neuromuscular-Blocking Agents: Tetracycline Derivatives may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

Penicillins: Tetracycline Derivatives may diminish the therapeutic effect of Penicillins. Consider therapy modification

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Quinapril: May decrease the serum concentration of Tetracycline Derivatives. Management: Separate doses of quinapril and oral tetracycline derivatives by at least 2 hours in order to reduce the risk of interaction. Monitor for reduced efficacy of the tetracycline if these products are used concomitantly. Consider therapy modification

QuiNINE: Tetracycline may increase the serum concentration of QuiNINE. Monitor therapy

Retinoic Acid Derivatives: Tetracycline Derivatives may enhance the adverse/toxic effect of Retinoic Acid Derivatives. The development of pseudotumor cerebri is of particular concern. Exceptions: Adapalene; Bexarotene (Topical); Tretinoin (Topical). Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Strontium Ranelate: May decrease the serum concentration of Tetracycline Derivatives. Management: In order to minimize any potential impact of strontium ranelate on tetracycline antibiotic concentrations, it is recommended that strontium ranelate treatment be interrupted during tetracycline therapy. Avoid combination

Sucralfate: May decrease the absorption of Tetracycline Derivatives. Management: Administer the tetracycline derivative at least 2 hours prior to sucralfate in order to minimize the impact of this interaction. Consider therapy modification

Sucroferric Oxyhydroxide: May decrease the serum concentration of Tetracycline Derivatives. Management: Administer oral/enteral doxycycline at least 1 h before sucroferric oxyhydroxide. Specific dose separation guidelines for other tetracyclines are not presently available. No interaction is anticipated with parenteral administration of tetracyclines. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Tetracycline Derivatives may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Zinc Salts: May decrease the absorption of Tetracycline Derivatives. Only a concern when both products are administered orally. Management: Consider doxycycline as a noninteracting tetracycline derivative. Separate dose administration of oral tetracycline derivative and oral zinc salts by at least 2 hours to minimize interaction. Exceptions: Zinc Chloride. Consider therapy modification

Adverse Reactions

Frequency not defined.

Cardiovascular: Pericarditis

Central nervous system: Bulging fontanels in infants, increased intracranial pressure, paresthesia, pseudotumor cerebri

Dermatologic: Exfoliative dermatitis, photosensitivity, pigmentation of nails, pruritus

Gastrointestinal: Abdominal cramps, anorexia, antibiotic-associated pseudomembranous colitis, diarrhea, discoloration of teeth and enamel hypoplasia (young children), esophagitis, nausea, pancreatitis, staphylococcal enterocolitis, vomiting

Hematologic: Thrombophlebitis

Hepatic: Hepatotoxicity

Renal: Acute renal failure, azotemia, renal damage

Miscellaneous: Anaphylaxis, candidal superinfection, hypersensitivity reactions, superinfection

Warnings/Precautions

Concerns related to adverse effects:

• Increased BUN: May be associated with increases in serum urea nitrogen (BUN) secondary to antianabolic effects; use caution in patients with renal impairment.

• Intracranial hypertension (eg, pseudotumor cerebri): Intracranial hypertension (headache, blurred vision, diplopia, vision loss, and/or papilledema) has been associated with use. Women of childbearing age who are overweight or have a history of intracranial hypertension are at greater risk. Concomitant use of isotretinoin (known to cause pseudotumor cerebri [PTC]) and tetracycline should be avoided. Intracranial hypertension typically resolves after discontinuation of treatment; however, permanent visual loss is possible. If visual symptoms develop during treatment, prompt ophthalmologic evaluation is warranted. Intracranial pressure can remain elevated for weeks after drug discontinuation; monitor patients until they stabilize.

• Photosensitivity: May cause photosensitivity; discontinue if skin erythema occurs. Use skin protection and avoid prolonged exposure to sunlight; do not use tanning equipment.

• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including Clostridium difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Hepatic impairment: Hepatotoxicity has been reported rarely; risk may be increased in patients with preexisting hepatic or renal impairment.

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment recommended.

Special populations:

• Pediatric: May cause tissue hyperpigmentation, enamel hypoplasia, or permanent tooth discoloration; use of tetracyclines should be avoided during tooth development (children <8 years of age) unless other drugs are not likely to be effective or are contraindicated.

• Pregnancy: Do not use during pregnancy. In addition to affecting tooth development, tetracycline use has been associated with retardation of skeletal development and reduced bone growth.

Monitoring Parameters

Renal, hepatic, and hematologic function test, temperature, WBC, cultures and sensitivity, appetite, mental status

Pregnancy Risk Factor

D

Pregnancy Considerations

Tetracyclines cross the placenta and accumulate in developing teeth and long tubular bones. Tetracyclines may discolor fetal teeth following maternal use during pregnancy; the specific teeth involved and the portion of the tooth affected depends on the timing and duration of exposure relative to tooth calcification. The pharmacokinetics of tetracycline are not altered in pregnant patients with normal renal function. Hepatic toxicity during pregnancy, potentially associated with tetracycline use, has been widely reported in the literature. As a class, tetracyclines are generally considered second-line antibiotics in pregnant women and their use should be avoided (Mylonas 2011; Whalley 1966; Whalley 1970).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience lack of appetite or diarrhea. Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), chills, pharyngitis, dysphagia, bruising, bleeding, severe loss of strength and energy, severe headache, severe nausea, severe vomiting, joint pain, vaginitis, blindness, blurred vision, double vision, or signs of Clostridium difficile (C. diff)-associated diarrhea (stomach pain or cramps, very loose or watery stools, or bloody stools) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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