• Sign Up

Doxycycline Hyclate


Doxycycline Hyclate

Article Author:
Reema Patel
Article Editor:
Mayur Parmar
Updated:
5/30/2020 8:56:39 PM
For CME on this topic:
Doxycycline Hyclate CME
PubMed Link:
Doxycycline Hyclate

Indications

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 the management and treatment of acne, malaria (for prophylaxis and treatment), skin infections, sexually transmitted infections (i.e., chlamydia, syphilis, gonorrhea, pelvic inflammatory disease), and 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. Its high lipophilicity, compared to other tetracyclines, allows it 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

Administration of Doxycycline Hyclate: 

For 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 infections 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 consumption of any supplements or drugs with magnesium, zinc, calcium, aluminum, iron, or sodium bicarbonate.  

For anti-inflammation:  

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

For 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 demonstrated to have an enhanced anticoagulant effect due to the competitive interaction for albumin binding and potential inhibition of the cytochrome P-450 pathway.[13]

Contraindications

Absolute contraindications for doxycycline hyclate include: 

  • 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 for doxycycline hyclate include: 

  • 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 

Monitoring

Doxycycline hyclate has proven to have an effective, yet inexpensive, 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. (Valentín, 2009) 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 a contraindication in pregnancy, lactation, and children under 12 due to proven human teratogenic effects, yet there is no evidence against doxycycline specifically.[1]

Toxicity

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 suspected of a 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 approach, with the physician, 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.  


References

[1] 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]
[2] Sapadin AN,Fleischmajer R, Tetracyclines: nonantibiotic properties and their clinical implications. Journal of the American Academy of Dermatology. 2006 Feb;     [PubMed PMID: 16443056]
[3] Webster G,Del Rosso JQ, Anti-inflammatory activity of tetracyclines. Dermatologic clinics. 2007 Apr;     [PubMed PMID: 17430750]
[4] 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]
[5] 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]
[6] Brodersen DE,Clemons WM Jr,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;     [PubMed PMID: 11163189]
[7] Connell SR,Tracz DM,Nierhaus KH,Taylor DE, Ribosomal protection proteins and their mechanism of tetracycline resistance. Antimicrobial agents and chemotherapy. 2003 Dec;     [PubMed PMID: 14638464]
[8] Chukwudi CU, rRNA Binding Sites and the Molecular Mechanism of Action of the Tetracyclines. Antimicrobial agents and chemotherapy. 2016 Aug;     [PubMed PMID: 27246781]
[9] Tan KR,Magill AJ,Parise ME,Arguin PM, Doxycycline for malaria chemoprophylaxis and treatment: report from the CDC expert meeting on malaria chemoprophylaxis. The American journal of tropical medicine and hygiene. 2011 Apr;     [PubMed PMID: 21460003]
[10] Hamilton LA,Guarascio AJ, Tetracycline Allergy. Pharmacy (Basel, Switzerland). 2019 Aug 3;     [PubMed PMID: 31382572]
[11] 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 (Basel, Switzerland). 2008;     [PubMed PMID: 18332631]
[12] Cac NN,Messingham MJ,Sniezek PJ,Walling HW, Stevens-Johnson syndrome induced by doxycycline. Cutis. 2007 Feb;     [PubMed PMID: 17388211]
[13] Hasan SA, Interaction of doxycycline and warfarin: an enhanced anticoagulant effect. Cornea. 2007 Jul;     [PubMed PMID: 17592328]
[14] 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. The Journal of pharmacology and experimental therapeutics. 2019 Jan;     [PubMed PMID: 30396916]
[15] Sloan B,Scheinfeld N, The use and safety of doxycycline hyclate and other second-generation tetracyclines. Expert opinion on drug safety. 2008 Sep;     [PubMed PMID: 18759709]
[16] Mailhol C,Tremeau-Martinage C,Paul C,Godel A,Lamant L,Giordano-Labadie F, [Severe drug hypersensitivity reaction (DRESS syndrome) to doxycycline]. Annales de dermatologie et de venereologie. 2010 Jan;     [PubMed PMID: 20110067]
[17] Chavant F,Lafay-Chebassier C,Beauchant M,Perault-Pochat MC, [Doxycycline induced hepatitis]. Gastroenterologie clinique et biologique. 2008 Oct;     [PubMed PMID: 18823729]
[18] Björnsson E,Lindberg J,Olsson R, Liver reactions to oral low-dose tetracyclines. Scandinavian journal of gastroenterology. 1997 Apr;     [PubMed PMID: 9140164]