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).
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 often get 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. A third, less studied mechanism of resistance has been documented, which is that of tetracycline modification. All of these mechanisms reduce the efficacy of tetracyclines, calling for more diligent prescription of these drugs by physicians.
The administration of most tetracyclines is oral; however, topical, intramuscular (IM) and intravenous (IV) forms of the medication do exist. Only oxytetracycline and tetracycline administration can be via IM injection. Oral Tetracyclines are absorbed 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. They then get excreted in the urine and feces.
Tetracyclines can most commonly cause GI distress, such as 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 through avoidance of direct sunlight and tanning equipment or by wearing sunscreen and protective clothing when outdoors.
More rarely, tetracyclines can cause hepatotoxicity and might exacerbate preexisting renal failure. Besides, 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; and this does include the tetracycline class of antibiotics.
Tetracyclines are contraindicated in pregnancy as a result 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 long bone growth in the fetus. Tetracycline usage is also associated with teeth discoloration in children under the age of eight, thus should be avoided in the younger patient population.
Clinicians should also avoid tetracyclines in patients with renal failure due to being primarily excreted by kidneys. If tetracyclines must be used in this group of patients, reduce the dosage and/or increase the interval between doses should be prolonged.
Tetracyclines do cross into breastmilk; however, they are safe while breastfeeding. The significant amount of calcium in breastmilk chelates the drug and limits its availability to the infant.
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. For more severe infections, higher doses may be given, such as 500 mg four times a day. Pediatric patients above eight years old can receive a daily dose of 25mg/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 must be given 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.
Achievement of 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.
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.
Appropriately managing patients inflicted with infectious disease 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 healthcare team needs to recognize the importance of targeted drug-susceptible therapy. This approach will significantly benefit the patient and confer a societal benefit. The pharmacist should work collaboratively with the prescriber to ensure the tetracycline is the appropriate agent for the infection, and verify dosing and duration. 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 pertains to possible toxicity or adverse reactions. With this interprofessional cooperation, patient outcomes can be optimized while minimizing adverse events. [Level V]
The entire community, inside and outside of the healthcare realm, will be less at risk for developing a dangerous drug-resistant infection through adequately treating those with infectious disease.
|||Sapadin AN,Fleischmajer R, Tetracyclines: nonantibiotic properties and their clinical implications. Journal of the American Academy of Dermatology. 2006 Feb; [PubMed PMID: 16443056]|
|||Nelson ML,Levy SB, The history of the tetracyclines. Annals of the New York Academy of Sciences. 2011 Dec; [PubMed PMID: 22191524]|
|||Pallett AP,Smyth EG, Clinicians' guide to antibiotics. Tetracycline. British journal of hospital medicine. 1988 Nov; [PubMed PMID: 3069173]|
|||Valentín S,Morales A,Sánchez JL,Rivera A, Safety and efficacy of doxycycline in the treatment of rosacea. Clinical, cosmetic and investigational dermatology. 2009 Aug 12; [PubMed PMID: 21436975]|
|||Speer BS,Shoemaker NB,Salyers AA, Bacterial resistance to tetracycline: mechanisms, transfer, and clinical significance. Clinical microbiology reviews. 1992 Oct [PubMed PMID: 1423217]|
|||Yılmaz Ç,Özcengiz G, Antibiotics: Pharmacokinetics, toxicity, resistance and multidrug efflux pumps. Biochemical pharmacology. 2017 Jun 1; [PubMed PMID: 27765485]|
|||Arenz S,Wilson DN, Bacterial Protein Synthesis as a Target for Antibiotic Inhibition. Cold Spring Harbor perspectives in medicine. 2016 Sep 1; [PubMed PMID: 27481773]|
|||Chopra I,Roberts M, Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiology and molecular biology reviews : MMBR. 2001 Jun; [PubMed PMID: 11381101]|
|||Bernier C,Dréno B, [Minocycline]. Annales de dermatologie et de venereologie. 2001 May; [PubMed PMID: 11427798]|
|||Dougherty JA,Sucher AJ,Chahine EB,Shihadeh KC, Omadacycline: A New Tetracycline Antibiotic. The Annals of pharmacotherapy. 2019 May; [PubMed PMID: 30917674]|
|||Sánchez AR,Rogers RS 3rd,Sheridan PJ, Tetracycline and other tetracycline-derivative staining of the teeth and oral cavity. International journal of dermatology. 2004 Oct; [PubMed PMID: 15485524]|
|||Deboyser D,Goethals F,Krack G,Roberfroid M, Investigation into the mechanism of tetracycline-induced steatosis: study in isolated hepatocytes. Toxicology and applied pharmacology. 1989 Mar 1; [PubMed PMID: 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. Canadian Medical Association journal. 1968 Nov 2; [PubMed PMID: 4879536]|
|||SUKHORUKIKH SV, TETRACYCLINES IN PREGNANCY. British medical journal. 1965 Mar 20; [PubMed PMID: 14248441]|
|||Cross R,Ling C,Day NP,McGready R,Paris DH, Revisiting doxycycline in pregnancy and early childhood--time to rebuild its reputation? Expert opinion on drug safety. 2016; [PubMed PMID: 26680308]|
|||Heaton PC,Fenwick SR,Brewer DE, Association between tetracycline or doxycycline and hepatotoxicity: a population based case-control study. Journal of clinical pharmacy and therapeutics. 2007 Oct; [PubMed PMID: 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. Paediatric and perinatal epidemiology. 2009 Jan; [PubMed PMID: 19228311]|
|||Phillips ME,Eastwood JB,Curtis JR,Gower PC,De Wardener HE, Tetracycline poisoning in renal failure. British medical journal. 1974 Apr 20; [PubMed PMID: 4825113]|
|||Chung AM,Reed MD,Blumer JL, Antibiotics and breast-feeding: a critical review of the literature. Paediatric drugs. 2002; [PubMed PMID: 12431134]|
|||Agwuh KN,MacGowan A, Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines. The Journal of antimicrobial chemotherapy. 2006 Aug; [PubMed PMID: 16816396]|
|||Saivin S,Houin G, Clinical pharmacokinetics of doxycycline and minocycline. Clinical pharmacokinetics. 1988 Dec; [PubMed PMID: 3072140]|
|||Yacoby I,Benhar I, Targeted anti bacterial therapy. Infectious disorders drug targets. 2007 Sep; [PubMed PMID: 17897058]|