Difference between revisions of "Doxycycline"
|Line 2:||Line 2:|
|Category=Cornea/External Disease, Oculoplastics/Orbit
|Article status=Up to Date
|Article status=Up to Date
Latest revision as of 20:39, April 19, 2021
Affordable pricing, excellent pharmacokinetics, and limited adverse effects with appropriate dosing make doxycycline practical. Patient education, such as adequate sun protection, can further attenuate side effects. Due to its various mechanisms of action, doxycycline treats many medical and ocular pathology.
The success of Penicillin during World War II inspired others in the pursuit of antimicrobials. Scientists at Cyanamid and Pfizer each discovered two broad-spectrum antibiotics: chlortetracycline from Streptomyces aureofaciens and oxytetracycline from Streptomyces rimosus. In 1953, a chemist named Robert Woodward analyzed that both antibiotics exhibited the same naphthacene core of four aromatic rings, hence the name tetracyclines. Pfizer’s Lloyd Conover modified chlortetracycline and produced the first semisynthetic antibiotic named tetracycline. Eventually, chemical modifications by Charlie Stephens led to a more stable, safe, and efficacious antibiotic called doxycycline, approved for use by the FDA in 1967.
Absorption: mainly in the duodenum; half-life of absorption: 0.85 +/- 0.41 hours; peak concentrations: 2-3 hours; bioavailability (oral): 95%; Food and cations decrease serum levels by ~20%; take 1 hour prior to or 2 hours after meals.3 Average AUCs for 200 mg/day oral dose: 40-123 mg·h/L
Distribution: protein binding: 82-93%; volume of distribution: 0.7 L/kg.
Metabolism: no significant metabolism.
Elimination: unchanged in its active form, renal: 35-60%; bile: 30-40%.
Elimination half-life: 12-25 hours.
Mechanism of Action
By binding to the 16S ribosomal RNA of the 30S ribosomal subunit, tetracyclines sterically block interaction of aminoacyl-tRNA with the A-site of ribosomes, ultimately halting protein synthesis. Tetracyclines are bacteriostatic hence they still require a functioning immune system to clear the infection. 
Mechanism of Resistance
Organisms acquire resistance through mobile genetic elements or from selective mutations. Tetracyclines have been shown to employ efflux, ribosome protection, and enzymatic inactivation.
Indications and Uses
Acinetobacter infection, Acne, Actinomycotic infection, Amebic infection, Anthrax, Bartonellosis, Brucellosis, Chancroid, Chlamydial infection, Cholera, Clostridial infection, Epididymitis, Gonorrhea – uncomplicated, Granuloma inguinale, Infection by Campylobacter fetus, Infection due to Enterobacteriaceae, Infection due to Escherichia coli, Infection of skin and/or subcutaneous tissue,
Inhalational anthrax, Late latent syphilis, or latent syphilis of unknown duration; Penicillin allergy, Listeriosis, Lymphogranuloma venereum, Malaria prophylaxis, Necrotizing ulcerative gingivitis – acute, Nongonococcal urethritis, Plague, Psittacosis, Q fever, Relapsing fever, Respiratory tract infection, Rocky Mountain spotted fever, Rosacea inflammatory lesions, Shigellosis, Spotted fevers, Staphylococcal infection of skin, Syphilis – primary, secondary, or early latent or Penicillin allergy, Trachomatous follicular conjunctivitis, Tularemia postexposure, Typhus group rickettsial disease, Urinary tract infectious disease, Yaws.
Non-FDA Labeled Indications
Glanders, Human anaplasmosis, Infective endocarditis, Infective proctitis, Leptospirosis, Lyme disease, Malaria adjunct, Neoplastic pleural effusion, Nongonococcal cervicitis, Ocular rosacea, Operative procedure on female genital system – post operative infection prophylaxis, Pelvic inflammatory disease, Relapsing fever prophylaxis, Scrub typhus.
General Medical Use
- Adults and children >45 kg: oral doxycycline 100 mg twice daily on the first day followed by a maintenance dose of 100 mg once daily. If infection is severe, then 100 mg twice daily for maintenance. 
- Children > 8 years of age and <45 kg: 4.4 mg/kg of body weight on the first day (divided into two doses) followed by a maintenance dose of 2.2 mg/kg of body weight once daily. If infection is severe, 4 mg/kg of body weight once daily for maintenance.
- Maximum recommended daily dose: 300 mg.
- Adult chlamydial ophthalmia: doxycycline 100 mg p.o. daily for two weeks.
- Blepharitis/meibomian gland dysfunction: low dose doxycycline 20 mg p.o. twice daily; compared to high dose doxycycline (200 mg p.o. twice daily), low dose has similar efficacy with fewer side effects.
- Ocular rosacea: slow release doxycycline (Oracea) 40 mg p.o. once daily.
- Recalcitrant recurrent corneal erosions: doxycycline 50 mg p.o. twice daily for two months in addition to 1% topical methylprednisolone three times daily for 2-3 weeks.
Nausea, vomiting, diarrhea, and epigastric irritation are common. Esophagitis can be reduced with enteric-coated preparations, sufficient fluid intake, and remaining upright for 30 minutes after ingestion. Other adverse effects include dental staining, inhibition of bone growth, photosensitivity, photo-onycholysis, intracranial hypertension, hypersensitivity reactions, oropharyngeal and vaginal candidiasis, hepatoxicity, and Clostridium difficile-associated diarrhea.  
Contraindications include history of hypersensitivity to tetracyclines, pregnancy, breastfeeding women, and children < 8 years of age.
Absorption can be impaired by antacids containing iron, aluminum, calcium, or bismuth subsalicylate; avoid coadministration with doxycycline by a few hours. Cytochrome P450 3A4 inducers, such as barbiturates and certain antiepileptics, increase hepatic metabolism of doxycycline. Tetracyclines can decrease plasma prothrombin activity, so anticoagulation reduction may be necessary. Coadministration of methoxyflurane anesthesia and tetracycline can lead to renal failure. Concurrent use with topical retinoids may increase risk of pseudotumor cerebri. Hydrolysis of oral contraceptives (OCPs) by small intestinal bacteria is important for absorption. By reducing the bacterial population, tetracyclines interrupt this process and reduce the effectiveness of OCPs. Doxycycline can displace methotrexate from its binding site and lead to increased methotrexate levels.
Doxycycline for Ophthalmic Conditions
Separate from its antimicrobial properties, tetracyclines exhibit unique characteristics. By inhibiting pro-inflammatory cytokines and enzymes such as IL-1β, TNF-α, and matrix metalloproteinases, doxycycline is a potent anti-inflammatory agent.  Also, tetracyclines inhibit ocular flora lipase production, which lowers toxic byproducts such as free fatty acids. These features make tetracyclines useful in many ocular pathologies including chronic meibomian gland dysfunction, ocular rosacea, and recurrent corneal erosion.   Other investigations are listed: doxycycline cosmetically improved lower eyelid festoons and malar edema, ameliorated benzalkonium chloride induced dry eye in mice, reduced ocular adnexal MALT lymphoma, attenuated sulfur mustard ocular injuries in rabbits, and decreased inflammation in endotoxin induced uveitis in rats.    This staple drug will continue to be relevant in ocular conditions with development of current preliminary investigations.
Additional Resources and Patient Assistance
- Nelson ML, Levy SB. The history of the tetracyclines. Annals of the New York Academy of Sciences. 2011;1241:17-32.
- Agwuh KN, MacGowan A. Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines. In. Vol 582006:256-265.
- Holmes NE, Charles PGP. Safety and Efficacy Review of Doxycycline. Clinical Medicine Therapeutics. 2009;1:CMT.S2035.
- Nguyen F, Starosta AL, Arenz S, Sohmen D, Dönhöfer A, Wilson DN. Tetracycline antibiotics and resistance mechanisms. 2014;395(5):559.
- Loree J, Lappin SL. Bacteriostatic Antibiotics. In: StatPearls. Treasure Island (FL)2020.
- Grossman TH. Tetracycline Antibiotics and Resistance. Cold Spring Harb Perspect Med. 2016;6(4):a025387-a025387.
- IBM Micromedex Drug Reference, doxycycline.
- FDA. Doxycycline Hyclate: Highlights of Prescription Information 2008.
- Viswalingam ND, Darougar S, Yearsley P. Oral doxycycline in the treatment of adult chlamydial ophthalmia. Br J Ophthalmol. 1986;70(4):301-304.
- Yoo S-E, Lee D-C, Chang M-H. The Effect of Low-Dose Doxycycline Therapy in Chronic Meibomian Gland Dysfunction. Korean Journal of Ophthalmology. 2005;19(4):258-263.
- Sobolewska B, Doycheva D, Deuter C, Pfeffer I, Schaller M, Zierhut M. Treatment of ocular rosacea with once-daily low-dose doxycycline. Cornea. 2014;33(3):257-260.
- Dursun D, Kim MC, Solomon A, Pflugfelder SC. Treatment of recalcitrant recurrent corneal erosions with inhibitors of matrix metalloproteinase-9, doxycycline and corticosteroids. American Journal of Ophthalmology. 2001;132(1):8-13.
- Digre KB. Not so benign intracranial hypertension. BMJ. 2003;326(7390):613-614.
- Carroll LA, Laumann AE. Doxycycline-induced photo-onycholysis. Journal of drugs in dermatology : JDD. 2003;2(6):662-663.
- Demers P, Fraser D, Goldbloom RB, et al. Effects of tetracyclines on skeletal growth and dentition. A report by the Nutrition Committee of the Canadian Paediatric Society. Can Med Assoc J. 1968;99(17):849-854.
- Neuvonen PJ, Penttilä O. Interaction between doxycycline and barbiturates. Br Med J. 1974;1(5907):535-536.
- Hasan SA. Interaction of doxycycline and warfarin: an enhanced anticoagulant effect. Cornea. 2007;26(6):742-743.
- Kuzucu EY. Methoxyflurane, Tetracycline, and Renal Failure. JAMA. 1970;211(7):1162-1164.
- Tabibian JH, Gutierrez MA. Doxycycline-induced pseudotumor cerebri. South Med J. 2009;102(3):310-311.
- Zhanel GG, Siemens S, Slayter K, Mandell L. Antibiotic and oral contraceptive drug interactions: Is there a need for concern? Can J Infect Dis. 1999;10(6):429-433.
- Tortajada-Ituren JJ, Ordovás-Baines JP, Llopis-Salvia P, Jiménez-Torres NV. High-Dose Methotrexate–Doxycycline Interaction. Annals of Pharmacotherapy. 1999;33(7-8):804-808.
- Huang J, Su W, Chen X, et al. Doxycycline Attenuates Endotoxin-Induced Uveitis by Prostaglandin E2-EP4 Signaling. Investigative Ophthalmology & Visual Science. 2015;56(11):6686-6693.
- Nissinen L, Kähäri V-M. Matrix metalloproteinases in inflammation. BBA - General Subjects. 2014;1840(8):2571-2580.
- Dougherty JM, McCulley JP, Silvany RE, Meyer DR. The role of tetracycline in chronic blepharitis. Inhibition of lipase production in staphylococci. Investigative Ophthalmology & Visual Science. 1991;32(11):2970-2975.
- Yoo S-E, Lee D-C, Chang M-H. The effect of low-dose doxycycline therapy in chronic meibomian gland dysfunction. Korean J Ophthalmol. 2005;19(4):258-263.
- Frucht-Pery J, Sagi E, Hemo I, Ever-Hadani P. Efficacy of doxycycline and tetracycline in ocular rosacea. American journal of ophthalmology. 1993;116(1):88-92.
- Wang L, Tsang H, Coroneo M. Treatment of recurrent corneal erosion syndrome using the combination of oral doxycycline and topical corticosteroid. Clin Experiment Ophthalmol. 2008;36(1):8-12.
- Godfrey KJ, Kally P, Dunbar KE, et al. Doxycycline Injection for Sclerotherapy of Lower Eyelid Festoons and Malar Edema: Preliminary Results. Ophthalmic Plast Reconstr Surg. 2019;35(5):474-477.
- Zhang Z, Yang W-Z, Zhu Z-Z, et al. Therapeutic Effects of Topical Doxycycline in a Benzalkonium Chloride–Induced Mouse Dry Eye Model. Investigative Ophthalmology & Visual Science. 2014;55(5):2963-2974.
- Ferreri AJM, Ponzoni M, Guidoboni M, et al. Bacteria-Eradicating Therapy With Doxycycline in Ocular Adnexal MALT Lymphoma: A Multicenter Prospective Trial. JNCI: Journal of the National Cancer Institute. 2006;98(19):1375-1382.
- Gordon MK, Desantis A, Deshmukh M, et al. Doxycycline hydrogels as a potential therapy for ocular vesicant injury. J Ocul Pharmacol Ther. 2010;26(5):407-419