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Doxycycline Hyclate

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Last Update: January 17, 2023.

Continuing Education Activity

Doxycycline hyclate is a medication used in the management and treatment of a variety of infections. It is in the tetracyclines class of drugs. This activity outlines the indications, action, and contraindications for doxycycline hyclate as a valuable agent in treating and managing skin, dental, respiratory, and urinary tract infections.


  • Identify the mechanism of action and administration of doxycycline hyclate.
  • Describe the adverse effects and contraindications of doxycycline hyclate.
  • Review cases of doxycycline hyclate toxicity and describe the appropriate monitoring process.
  • Explain the importance of improving care coordination amongst the interprofessional team to enhance the delivery of care for patients with doxycycline hyclate toxicity.
Access free multiple choice questions on this topic.


Doxycycline hyclate is a water-soluble tetracycline antibiotic that kills and prevents the growth of a wide range of gram-positive and -negative bacteria. It plays a role in managing and treating acne, malaria (for prophylaxis and treatment), skin infections, sexually transmitted infections (i.e., chlamydia, syphilis, gonorrhea, pelvic inflammatory disease) Lyme disease. Doxycycline hyclate is also effective for treating outbreaks such as cholera, mycoplasma, tularemia, typhus, and Rickettsia infections.[1] 

Several studies have also proven that tetracyclines, especially doxycycline, contain immunomodulating properties and can be used to control inflammation in diseases such as rheumatoid arthritis.[2] Tetracyclines, such as doxycycline, have shown effectiveness in treating acne vulgaris, rosacea, bullous dermatoses, granulomatous disease, and livedo vasculitis.[3]

Doxycycline hyclate has a specific indication for adult periodontal disease for its anti-collagenase and anti-matrix metalloproteinase activity in the gingival crevicular fluid. There is no evidence of changes or antibiotic susceptibility to normal periodontal flora or opportunistic pathogens.[4]

Mechanism of Action

Doxycycline hyclate works systemically in various tissues. Compared to other tetracyclines, its high lipophilicity allows doxycycline to cross multiple membranes to reach target molecules. Tetracyclines act as cationic coordination complexes to cross the OmpF and OmpC porin channels in gram-negative bacteria. Similarly, in gram-positive bacteria, the electroneutral, lipophilic form traverses the cytoplasmic membrane. Uptake across the cytoplasmic membrane is energy-dependent and driven by the proton motive force.[5] 

The bacteriostatic action of tetracyclines, like doxycycline hyclate, is intended to stop the growth of bacteria by allosterically binding to the 30S prokaryotic ribosomal unit during protein synthesis.[5] Doxycycline hyclate prevents the association of the charged aminoacyl-tRNA (aa-tRNA) with the ribosomal A site to stall the elongation phase, yielding an unproductive cycle of protein synthesis. Doxycycline affects the binding rate of the ternary complex (comprised of elongation factor Tu (EF-Tu), GTP, and aa-tRNA) to the ribosome.[6] The ternary complex attempts to bind the aa-tRNA to the A site but fails to do so.[7] This process halts the translation of the growing polypeptide chain, impeding the production of essential proteins and eventually killing the bacteria.  

Tetracyclines, such as doxycycline hyclate, present immunomodulating properties that inhibit leukocyte movement during inflammation by preventing calcium-dependent microtubular assembly and lymphocytic proliferation.[4] Doxycycline initiates anti-inflammatory actions in diseases such as osteoarthritis by inhibition of nitric acid synthase.[8]  

Bacterial ribosomal protection proteins Tet(O) and Tet(M) employ a variety of resistance mechanisms that include efflux, enzymatic degradation, and rRNA mutations. Tet(O) prevents tetracyclines from attaching to the primary binding site. Tet(O) and Tet(M) displace tetracyclines from the ribosome and increases the disassociation constant, Kd, and allow the aa-tRNA to bind to the A site so protein synthesis can resume.[7]


Administration of Doxycycline Hyclate: 

Bacterial Infections

  • For mild to moderate infections, Doxycycline hyclate should be taken in doses of 100 mg every 12 hours on the first day and then 100 mg/day onwards. For pelvic infections, the dose is 100 mg twice a day for one week.  
  • The maximum dosage is 300 mg/day, except in the case of acute gonorrheal infection, which is often treated with 600 mg/day for five days. 
  • The drug is best on an empty stomach at least 1 hour before or 2 hours after eating. Take medication with at least 8 ounces of water.  
  • For optimal gastrointestinal absorption, the medication should be taken 2 to 3 hours before or after consuming any supplements or drugs with magnesium, zinc, calcium, aluminum, iron, or sodium bicarbonate.  


  • Doxycycline hyclate can be taken at sub-acute doses of 40 mg daily for anti-inflammatory effects. The anti-microbial mechanism will not be in action at this sub-antimicrobial dose, sparing healthy bacteria and maintaining the body's microbiome.  

Malaria Prevention

  • Must be taken at 100 mg dose once daily for malaria prophylaxis. Highly recommended to be taken with an adequate amount of fluids and food. The first dose should be taken 1 to 2 days before traveling, and the regimen should continue while traveling in high-risk areas and four more weeks after returning. Doxycycline hyclate should be used in conjunction with chloroquine.[9]

The course of prescribed doxycycline hyclate should be finished in its entirety, even if symptoms disappear sooner.  

Adverse Effects

Common Reactions 

  • Mild diarrhea 
  • Photosensitivity  
  • Nausea  
  • Vomiting 
  • Skin rash/itching 
  • Headaches 
  • Tooth discoloration 

Doxycycline hyclate is a highly tolerated drug compared to its tetracycline counterparts and has limited evidence for causing serious adverse effects. The following are some of the rarely observed adverse events: 

Severe Adverse Effects

  • Bloody diarrhea 
  • Leukopenia
  • Migraines 
  • Hemolytic anemia 
  • Throat irritation or trouble swallowing 
  • Chest pain 
  • Exacerbation of systemic lupus erythematosus  
  • Shortness of breath 
  • Irregular or fast heart rate 
  • Dysuria  
  • Intracranial hypertension 
  • Esophagitis/esophageal ulcerations if taken without water 

Researchers described a Type I anaphylactic reaction with hypotension, bronchospasms, and urticaria in a patient who received intravenous doxycycline with a beta-blocker during general anesthesia.[10] They have also observed a unique case of fever, lymphadenopathy, nephritis, hepatitis, and severe pneumonitis with respiratory failure resulting from oral administration of doxycycline.[11]

In rare cases, Doxycycline hyclate has also reportedly caused Steven-Johnson Syndrome, potentially life-threatening mucocutaneous eruptions with a diffuse distribution of purpuric macules or targetoid lesions. Treatment usually entails hospitalization and supportive care for symptoms, with the administration of hydroxyzine hydrochloride, mupirocin ointment, and prednisone.[12]

Administration of doxycycline with warfarin has resulted in an enhanced anticoagulant effect due to the competitive interaction for albumin binding and potential inhibition of the cytochrome P-450 pathway.[13]


Absolute Contraindications

  • Pregnancy or breastfeeding due to teratogenicity and permanent teeth discoloration after in utero exposure 
  • Children under the age of 12 due to teeth discoloration 
  • Allergy to tetracycline antibiotics 
  • Use with penicillin or isotretinoin  

Relative Contraindications  

  • Liver disease due to rare fatal hepatotoxicity 
  • History of yeast infections 
  • Recent colitis caused by antibiotic use 
  • Kidney disease diarrhea from C. Dificile 
  • History of lupus (autoimmune) 
  • Porphyria (a blood disease) 
  • Myasthenia gravis 


Doxycycline hyclate has proven to have an effective therapeutic spectrum. Oral administration is most common, but delivery can also via an IV if necessary. An oral dose of 100 to 200 mg is absorbed rapidly. Data shows doxycycline was detectable in the blood as soon as 15 minutes after administration. It has a reported peak plasma concentration of 1.7 to 5.9 mg/mL after 2 to 3 hours and an elimination half-life of 15 to 30 hours.[14] Doxycycline hyclate metabolism mainly occurs in the duodenum.[15] Elimination primarily occurs through the gastrointestinal tract, but 30 to 40% occurs through renal excretion.[4] 

There are no standard routine tests to monitor the use of doxycycline. The most significant side effect is hepatic injury, which can be avoided by administering doxycycline hyclate at the recommended dosage and keeping contraindications and adverse effects in mind.  

Tetracyclines are contraindicated in pregnancy, lactation, and children under 12 due to proven human teratogenic effects, yet there is no evidence against doxycycline specifically.[1]


In rare instances, doxycycline has correlated with hepatic injury about 1 to 2 weeks after starting therapy. Hepatic injury can range from hepatocellular to cholestatic or mixed. There is often a quick onset with reported symptoms of DRESS syndrome, such as rash, fever, and eosinophilia.[16]

Acute doxycycline hepatitis was noted in a patient receiving treatment of pulmonary actinomycosis after 1.5 months of 200 mg/daily dose of doxycycline. Liver function tests showed markedly elevated ALT, AST, ALP, and GGT. Liver biopsy demonstrated centrilobular necrosis, indicative of toxic hepatitis.[17] A liver reaction with non-specific hepatitis appeared within 24 hours of oral doxycycline therapy in a patient with a suspected pneumonia infection. The diagnosis was confirmed with liver biopsy showing cholestasis and inflammation as well as increased liver enzymes (ALT, AST, ALP).[18] Rapid recovery is expected within 4 to 6 weeks after discontinuation of doxycycline hyclate and treatment with corticosteroids.[12]

Enhancing Healthcare Team Outcomes

Clinicians need to be more diligent when prescribing doxycycline to avoid a dangerous drug-resistant infection. Doxycycline hyclate therapy requires an interprofessional team approach, with clinicians, nurses, and pharmacists all collaborating to achieve optimal patient results. Since adverse effects are rare and varied in symptoms, it is crucial for those involved in the care of patients undergoing doxycycline hyclate therapy to understand the mechanism of action, dosing protocols, and signs of toxicity. If toxicity occurs, normal liver function should be confirmed with liver enzyme tests and biopsy, if required. The clinician and pharmacist are responsible for medication reconciliation to prevent drug-drug interactions. After the patient stabilizes, the healthcare team should determine the reason for toxicity and potentially report any new findings. Interprofessional care will result in better patient outcomes and fewer adverse events with doxycycline. [Level 5]

Review Questions


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]
Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad Dermatol. 2006 Feb;54(2):258-65. [PubMed: 16443056]
Webster G, Del Rosso JQ. Anti-inflammatory activity of tetracyclines. Dermatol Clin. 2007 Apr;25(2):133-5, v. [PubMed: 17430750]
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]
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]
Brodersen DE, Clemons WM, Carter AP, Morgan-Warren RJ, Wimberly BT, Ramakrishnan V. The structural basis for the action of the antibiotics tetracycline, pactamycin, and hygromycin B on the 30S ribosomal subunit. Cell. 2000 Dec 22;103(7):1143-54. [PubMed: 11163189]
Connell SR, Tracz DM, Nierhaus KH, Taylor DE. Ribosomal protection proteins and their mechanism of tetracycline resistance. Antimicrob Agents Chemother. 2003 Dec;47(12):3675-81. [PMC free article: PMC296194] [PubMed: 14638464]
Chukwudi CU. rRNA Binding Sites and the Molecular Mechanism of Action of the Tetracyclines. Antimicrob Agents Chemother. 2016 Aug;60(8):4433-41. [PMC free article: PMC4958212] [PubMed: 27246781]
Tan KR, Magill AJ, Parise ME, Arguin PM., Centers for Disease Control and Prevention. Doxycycline for malaria chemoprophylaxis and treatment: report from the CDC expert meeting on malaria chemoprophylaxis. Am J Trop Med Hyg. 2011 Apr;84(4):517-31. [PMC free article: PMC3062442] [PubMed: 21460003]
Hamilton LA, Guarascio AJ. Tetracycline Allergy. Pharmacy (Basel). 2019 Aug 03;7(3) [PMC free article: PMC6789857] [PubMed: 31382572]
Robles DT, Leonard JL, Compton N, Waghmare A, McDonough KA, George E, Wolgamot G, Fleckman P. Severe drug hypersensitivity reaction in a young woman treated with doxycycline. Dermatology. 2008;217(1):23-6. [PubMed: 18332631]
Cac NN, Messingham MJ, Sniezek PJ, Walling HW. Stevens-Johnson syndrome induced by doxycycline. Cutis. 2007 Feb;79(2):119-22. [PubMed: 17388211]
Hasan SA. Interaction of doxycycline and warfarin: an enhanced anticoagulant effect. Cornea. 2007 Jul;26(6):742-3. [PubMed: 17592328]
Lucchetti J, Fracasso C, Balducci C, Passoni A, Forloni G, Salmona M, Gobbi M. Plasma and Brain Concentrations of Doxycycline after Single and Repeated Doses in Wild-Type and APP23 Mice. J Pharmacol Exp Ther. 2019 Jan;368(1):32-40. [PubMed: 30396916]
Sloan B, Scheinfeld N. The use and safety of doxycycline hyclate and other second-generation tetracyclines. Expert Opin Drug Saf. 2008 Sep;7(5):571-7. [PubMed: 18759709]
Mailhol C, Tremeau-Martinage C, Paul C, Godel A, Lamant L, Giordano-Labadie F. [Severe drug hypersensitivity reaction (DRESS syndrome) to doxycycline]. Ann Dermatol Venereol. 2010 Jan;137(1):40-3. [PubMed: 20110067]
Chavant F, Lafay-Chebassier C, Beauchant M, Perault-Pochat MC. [Doxycycline induced hepatitis]. Gastroenterol Clin Biol. 2008 Oct;32(10):825-7. [PubMed: 18823729]
Björnsson E, Lindberg J, Olsson R. Liver reactions to oral low-dose tetracyclines. Scand J Gastroenterol. 1997 Apr;32(4):390-5. [PubMed: 9140164]
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Bookshelf ID: NBK555888PMID: 32310348


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