Which should be avoided by patients taking tetracycline because of a resulting decrease in the absorption of the tetracyclines?

Continuing Education Activity

Tetracyclines (tetracycline, doxycycline, minocycline, tigecycline) are a class of medication used to manage and treat various bacterial infections. Tetracyclines classify as protein synthesis inhibitor antibiotics and are considered to be broad-spectrum. This activity reviews the indications, action, and contraindications for tetracyclines as a valuable agent in treating bacterial infections. This activity will highlight the mechanism of action, adverse event profile, and relevant interactions pertinent for members of the healthcare team involved in patient care of these infections.

Objectives:

• Summarize the mechanism of action of tetracyclines.

• Review the potential adverse effects of tetracyclines.

• Describe appropriate monitoring necessary for patients receiving tetracyclines.

• Outline interprofessional team strategies for improving care coordination and communication to advance tetracycline use and improve outcomes.

Access free multiple choice questions on this topic.

Indications

Tetracyclines are a class of broad-spectrum antibiotics used in the management and treatment of a variety of infectious diseases. Naturally occurring drugs in this class are tetracycline, chlortetracycline, oxytetracycline, and demeclocycline. Semi-synthetic tetracyclines are lymecycline, methacycline, minocycline, rolitetracycline, and doxycycline. There is one glycylcycline subclass agent named tigecycline. Lastly, there is a class of newer tetracyclines that includes ervacycline, sarecycline, and omadacycline. 

These drugs can treat rickettsial infections, ehrlichiosis, anaplasmosis, leptospirosis, amebiasis, actinomycosis, nocardiosis, brucellosis, melioidosis, tularemia, chlamydial infections, pelvic inflammatory disease, syphilis, traveler's diarrhea, early Lyme disease, acne, legionnaire's disease, and Whipple disease. They cover Borrelia recurrentis, Mycobacterium marinum, Mycoplasma pneumoniae, Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA]), Vibrio vulnificus, and vancomycin-resistant enterococcus (VRE) (susceptible strains). Meningococcal prophylaxis is also achievable. 

Other indications of tetracyclines include rosacea, bullous dermatoses, sarcoidosis, Kaposi sarcoma, pyoderma gangrenosum, hidradenitis suppurativa, Sweet syndrome, a1-antitrypsin deficiency, panniculitis, pityriasis lichenoides chronica, rheumatoid arthritis, scleroderma, cancer, and cardiovascular diseases (abdominal aortic aneurysm and acute myocardial infarction).[1]

Off-label usage of tetracyclines includes Helicobacter pylori eradication, malaria, and periodontitis.[2][3][1][4]

Mechanism of Action

Protein synthesis is an essential requirement of any cell. It involves the use of ribosomes, whose job is to translate an mRNA code into functioning proteins. In eukaryotes, this occurs on ribosomes with the 40S and 60S subunits. In prokaryotes, such as bacteria, protein synthesis occurs using ribosomes with the 30S and 50S subunits. At these sites, the ribosome transfer RNA (tRNA), which is charged with an amino acid, binds to the mRNA template. The subsequent binding of each tRNA charged with an amino acid contributes to the formation and elongation of cellular proteins. Tetracyclines specifically inhibit the 30S ribosomal subunit, hindering the binding of the aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex. When this process halts, a cell can no longer maintain proper functioning and will be unable to grow or further replicate. This type of impairment by the tetracyclines makes them “bacteriostatic.”  

There is a growing concern over bacterial strains that are resistant to tetracycline antibiotics. Bacterial genes that are resistant to tetracyclines are often encoded on plasmids or transferable elements like transposons. There are two well-documented mechanisms of resistance, which include alteration in ribosomal protection proteins or efflux pumps. The former mechanism allows the ribosomes to proceed with protein synthesis regardless of the high intracellular levels of the drug. The latter mechanism consists of various subtypes of transmembrane pumps that drive out solutes, in this instance, antimicrobials, out of the cell to prevent cell death. There is documentation of a third, less studied mechanism of resistance, which is that of tetracycline modification. All of these mechanisms reduce the efficacy of tetracyclines, calling for increased diligence when clinicians prescribe these drugs.[5][6][7][8]

Administration

The administration of most tetracyclines is via the oral route; however, topical, intramuscular (IM), and intravenous (IV) forms of the medication do exist. Only oxytetracycline and tetracycline administration can be via IM injection. Oral tetracycline absorption occurs primarily in the stomach, duodenum, and small intestine. They distribute well in tissues, ascitic fluid, synovial fluid, pleural fluid, and bronchial secretions. Tetracyclines have poor penetration into the cerebral spinal fluid. The absorption of all tetracyclines decreases when administered with multivalent cations such as aluminum, calcium, iron, or magnesium. Cations cause chelation of the tetracyclines, thus impairing their absorption in the gut, leading to excretion of the drug in the urine and feces.[9][10]

Adverse Effects

Tetracyclines can commonly cause GI distress, including abdominal discomfort, epigastric pain, nausea, vomiting, and anorexia. While taking tetracyclines, discoloration of teeth and inhibition of bone growth in children may occur. Some patients experience photosensitivity, which can manifest as a red rash or skin blistering. Photosensitivity reactions can be lessened by avoiding direct sunlight and tanning equipment or wearing sunscreen and protective clothing when outdoors.[11] 

More rarely, tetracyclines can cause hepatotoxicity and might exacerbate preexisting renal failure. Further, there have been reports of esophageal ulceration and strictures from tetracycline use, which can typically be avoided by taking the drugs with adequate water and staying upright following usage. Further, intracranial hypertension (IH, pseudotumor cerebri) correlates with tetracycline use.

Lastly, all antibiotics have implications in the development of Clostridium difficile associated diarrhea, including the tetracycline class of antibiotics.[12]

Contraindications

Tetracyclines are contraindicated in pregnancy because of the risk of hepatotoxicity in the mother, the potential for permanent discoloration of teeth in the fetus (yellow or brown in appearance), as well as impairment of fetal long bone growth. Tetracycline usage is also associated with teeth discoloration in children under the age of eight. Thus it should be avoided in pediatric patients under that age.

Clinicians should also avoid tetracyclines in patients with renal failure due to the excretion of the drug being primarily by the kidneys. If tetracyclines must be used in this group of patients, either reduce the dosage and/or increase the interval between doses should be prolonged.[13][14][15]

Tetracyclines do cross into breastmilk; therefore, they are safe while breastfeeding. The significant amount of calcium in breastmilk chelates the drug and limits its availability to the infant.[16][17][18][19]

Monitoring

The dosing of tetracyclines is different in adults and children. Adults may receive 1g total of tetracyclines daily, which can be broken up into 500 mg twice a day or 250 mg four times a day. Higher doses may be given for more severe infections, such as 500 mg four times a day. Pediatric patients above eight years old can receive a daily dose of 25 mg/kg up to 50 mg/kg, divided into four equal doses.

Normal levels of tetracyclines achieved in the serum after oral dosing range from 2 to 5 mcg/ml. The majority of tetracyclines require dosing two to four times daily to maintain therapeutic concentrations in the serum. That said, doxycycline and minocycline have longer elimination half-lives and permit once or twice daily dosing.

Achieving adequate serum concentrations of tetracyclines may be impaired by antacids that contain aluminum, calcium, magnesium, iron, zinc, or sodium bicarbonate. Thus, certain foods high in these cations, as well as some dairy products, may interfere with absorption.

Tetracyclines may render oral contraceptive pills less effective. Therefore clinicians should strongly encourage the use of some form of barrier protection in sexually active females.[20][21]

Toxicity

In the case of overdose with tetracyclines, initiate supportive measures, and the medication discontinued immediately. High doses of tetracyclines can result in liver failure and death. Tetracyclines are not dialyzable.[21]

Enhancing Healthcare Team Outcomes

Appropriately managing patients inflicted with infectious diseases is of utmost importance to the entire healthcare team. As antimicrobial resistance is on the rise, ensuring the use of the proper antibiotic agent during the eradication of infection is essential. The interprofessional healthcare team needs to recognize the importance of targeted drug-susceptible therapy. The pharmacist should work collaboratively with the prescriber to ensure the tetracycline is the appropriate agent for the infection and verify dosing and duration. This approach will significantly benefit the patient and confer a societal benefit.

Along with the clinician and nursing, the pharmacist should provide patient counseling regarding the medication. Nursing will be the front-line contact for the patient and should instruct the patient on how to take the drug and what signs to watch for as it pertains to possible toxicity or adverse reactions. With this interprofessional cooperation, patient outcomes can be optimized while minimizing adverse events. [Level 5]

The entire community will benefit and be less at risk for developing a dangerous drug-resistant infection through adequately targeted treatment of those with infectious diseases.[22]

Review Questions

References

Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad Dermatol. 2006 Feb;54(2):258-65. [PubMed: 16443056]

Nelson ML, Levy SB. The history of the tetracyclines. Ann N Y Acad Sci. 2011 Dec;1241:17-32. [PubMed: 22191524]

Pallett AP, Smyth EG. Clinicians' guide to antibiotics. Tetracycline. Br J Hosp Med. 1988 Nov;40(5):385-90. [PubMed: 3069173]

Valentín S, Morales A, Sánchez JL, Rivera A. Safety and efficacy of doxycycline in the treatment of rosacea. Clin Cosmet Investig Dermatol. 2009 Aug 12;2:129-40. [PMC free article: PMC3047926] [PubMed: 21436975]

Speer BS, Shoemaker NB, Salyers AA. Bacterial resistance to tetracycline: mechanisms, transfer, and clinical significance. Clin Microbiol Rev. 1992 Oct;5(4):387-99. [PMC free article: PMC358256] [PubMed: 1423217]

Yılmaz Ç, Özcengiz G. Antibiotics: Pharmacokinetics, toxicity, resistance and multidrug efflux pumps. Biochem Pharmacol. 2017 Jun 01;133:43-62. [PubMed: 27765485]

Arenz S, Wilson DN. Bacterial Protein Synthesis as a Target for Antibiotic Inhibition. Cold Spring Harb Perspect Med. 2016 Sep 01;6(9) [PMC free article: PMC5008061] [PubMed: 27481773]

Chopra I, Roberts M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev. 2001 Jun;65(2):232-60 ; second page, table of contents. [PMC free article: PMC99026] [PubMed: 11381101]

Bernier C, Dréno B. [Minocycline]. Ann Dermatol Venereol. 2001 May;128(5):627-37. [PubMed: 11427798]

Dougherty JA, Sucher AJ, Chahine EB, Shihadeh KC. Omadacycline: A New Tetracycline Antibiotic. Ann Pharmacother. 2019 May;53(5):486-500. [PubMed: 30917674]

Sánchez AR, Rogers RS, Sheridan PJ. Tetracycline and other tetracycline-derivative staining of the teeth and oral cavity. Int J Dermatol. 2004 Oct;43(10):709-15. [PubMed: 15485524]

Deboyser D, Goethals F, Krack G, Roberfroid M. Investigation into the mechanism of tetracycline-induced steatosis: study in isolated hepatocytes. Toxicol Appl Pharmacol. 1989 Mar 01;97(3):473-9. [PubMed: 2609344]

Demers P, Fraser D, Goldbloom RB, Haworth JC, LaRochelle J, MacLean R, Murray TK. Effects of tetracyclines on skeletal growth and dentition. A report by the Nutrition Committee of the Canadian Paediatric Society. Can Med Assoc J. 1968 Nov 02;99(17):849-54. [PMC free article: PMC1945410] [PubMed: 4879536]

SUKHORUKIKH SV. TETRACYCLINES IN PREGNANCY. Br Med J. 1965 Mar 20;1(5437):743-4. [PMC free article: PMC2166172] [PubMed: 14248441]

Cross R, Ling C, Day NP, McGready R, Paris DH. Revisiting doxycycline in pregnancy and early childhood--time to rebuild its reputation? Expert Opin Drug Saf. 2016;15(3):367-82. [PMC free article: PMC4898140] [PubMed: 26680308]

Heaton PC, Fenwick SR, Brewer DE. Association between tetracycline or doxycycline and hepatotoxicity: a population based case-control study. J Clin Pharm Ther. 2007 Oct;32(5):483-7. [PubMed: 17875115]

Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer SM, Gideon PS, Hall KS, Kaltenbach LA, Ray WA. Antibiotics potentially used in response to bioterrorism and the risk of major congenital malformations. Paediatr Perinat Epidemiol. 2009 Jan;23(1):18-28. [PMC free article: PMC3381893] [PubMed: 19228311]

Phillips ME, Eastwood JB, Curtis JR, Gower PC, De Wardener HE. Tetracycline poisoning in renal failure. Br Med J. 1974 Apr 20;2(5911):149-51. [PMC free article: PMC1610351] [PubMed: 4825113]

Chung AM, Reed MD, Blumer JL. Antibiotics and breast-feeding: a critical review of the literature. Paediatr Drugs. 2002;4(12):817-37. [PubMed: 12431134]

Agwuh KN, MacGowan A. Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines. J Antimicrob Chemother. 2006 Aug;58(2):256-65. [PubMed: 16816396]

Saivin S, Houin G. Clinical pharmacokinetics of doxycycline and minocycline. Clin Pharmacokinet. 1988 Dec;15(6):355-66. [PubMed: 3072140]

Yacoby I, Benhar I. Targeted anti bacterial therapy. Infect Disord Drug Targets. 2007 Sep;7(3):221-9. [PubMed: 17897058]

What should be avoided when taking tetracycline?

What decreases the absorption of tetracycline?

What drugs interact with tetracycline?