Doxycycline (Doryx®)

Doxycycline in Brief
  • Generic name: Doxycycline Calcium, Doxycycline Hyclate, Doxycycline Monohydrate
  • Brand names: Doryx®, Periostat®, Vibramycin®
  • Therapeutic class: Antibiotic
  • Pharmacologic class: Tetracycline
  • FDA Approved: 1967
  • Pregnancy Category: D
  • Originally discovered: 1960s, Pfizer Inc., USA USA

Based on "Antibiotic and Chemotherapy"
written by Roger G. Finch


The first member of the tetracycline group - Chlortetracycline - was discovered in the late 1940s by Dr. Benjamin Duggar of Lederle Laboratories in New York. It was derived from the soil-dwelling bacterium Streptomyces aureofaciens. Oxytetracycline was isolated soon after from S. rimosus by scientists at Pfizer Laboratories in 1950. This was further developed to Doxycycline 37.

Doxycycline (6-Deoxy-5-hydroxytetracycline) is a semi-synthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand Vibramycin. This semi-synthetic tetracycline is manufactured by a 3-step synthesis with oxytetracycline as the starting material as described in U.S. Pat. No. 3,200,149 to Pfizer (1965).


Vibramycin received FDA approval in 1967, becoming Pfizer's first once-a-day broad-spectrum antibiotic.

FDA approved uses

  • Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae.
  • Respiratory tract infections caused by Mycoplasma pneumoniae.
  • Lymphogranuloma venereum caused by Chlamydia trachomatis.
  • Psittacosis (ornithosis) caused by Chlamydia psittaci.
  • Trachoma caused by Chlamydia trachomatis.
  • Inclusion conjunctivitis caused by Chlamydia trachomatis.
  • Uncomplicated urethral, endocervical or rectal infections in adults caused by Chlamydia trachomatis.
  • Nongonococcal urethritis caused by Ureaplasma urealyticum.
  • Relapsing fever due to Borrelia recurrentis.
  • Chancroid caused by Haemophilus ducreyi.
  • Plague due to Yersinia pestis (formerly Pasteurella pestis).
  • Tularemia due to Francisella tularensis (formerly Pasteurella tularensis).
  • Cholera caused by Vibrio cholerae (formerly Vibrio comma).
  • Campylobacter fetus infections caused by Campylobacter fetus (formerly Vibrio fetus).
  • Brucellosis due to Brucella species (in conjunction with streptomycin).
  • Bartonellosis due to Bartonella bacilliformis.
  • Granuloma Inguinale (donovanosis) caused by Calymmatobacterium granulomatis (preferred agent according to the CDC STD guidelines).
  • Lymphogranuloma venereum (preferred agent according to the CDC STD guidelines).
  • Anthrax due to Bacillus anthracis, including inhalational anthrax (post-exposure).
  • Uncomplicated gonorrhea caused by Neisseria gonorrhoeae.
  • Syphilis caused by Treponema pallidum.
  • Yaws caused by Treponema pertenue.
  • Listeriosis due to Listeria monocytogenes.
  • Vincent's infection caused by Fusobacterium fusiforme.
  • Actinomycosis caused by Actinomyces israelii.
  • Infections caused by Clostridium species.
  • Acute intestinal amebiasis.
  • Acne ( see Doxycycline dosage for acne)
  • Prophylaxis of malaria due to Plasmodium falciparum.
  • Periodontitis (Periostat®)
  • Rosacea (Oracea®)

When bacteriologic testing indicates appropriate susceptibility doxycycline, it may be used to treat:

  • Escherichia coli.
  • Enterobacter aerogenes (formerly Aerobacter aerogenes).
  • Shigella species.
  • Acinetobacter species (formerly Mima species and Herellea species).
  • Respiratory tract infections caused by Haemophilus influenzae.
  • Respiratory tract and urinary tract infections caused by Klebsiella species.
  • Upper respiratory infections caused by Streptococcus pneumoniae (formerly Diplococcus pneumoniae).

Off-label & Investigational uses

  • Vancomycin-resistant enterococci (VRE) (although it is not active against non-VRE enterococci) 21
  • Infected animal bite wounds (Pasteurella multocida, Pasteurella pneumotropica) 22
  • Lyme disease, prevention and treatment 23, 25, 26
  • Rosacea 27, 28
  • Rheumatoid arthritis 29, 30, 31
  • Pelvic inflammatory disease 33
  • Chronic inflammatory lung diseases (panbronchiolitis, asthma, cystic fibrosis, bronchitis) 18, 32
  • Human ehrlichiosis 35
  • Legionella infections 38, 16
  • Toxoplasmosis
  • Mediterranean spotted fever 8
  • Sarcoidosis 39, 40
  • Leptospirosis 34


Doxycycline "pros" and "cons"


  • excellent safety record
  • among currently available tetracyclines, doxycycline has the least affinity for calcium
  • unlikely to cause tooth staining in children9
  • Suitable for patients with impaired kidney function. Unlike other tetracyclines, doxycycline is eliminated by nonrenal mechanisms and does not accumulate significantly in patients with renal insufficiency.
  • long half-life permits once- or twice-daily dosing
  • blood and tissue levels are equivalent whether doxycycline is administered orally or intravenously
  • highly effective against all of the common pathogens that cause upper respiratory tract infections
  • quite active against Streptococcus pneumoniae, the most important respiratory tract pathogen in otitis, sinusitis, bronchitis, and community-acquired pneumonia 17
  • active against penicillin-resistant pneumococci 12, 19
  • active against all common typical (Streptococcus pneumoniae, Haemophilus influenzae) and atypical (Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella species) pathogens that cause pneumonia 17, 38, 36, 24
  • anti-inflammatory effects 5, 9, 18
  • inhibition of metalloproteinases (enzymes that inhibit collagen and gelatin production) 20
  • can slow the progression of osteoarthritis 13, 14
  • can inhibit pathologic collagenolysis 15
  • intestinal flora is not affected by doxycycline due to it's almost complete absorption 42
  • inexpensive


  • Use during tooth development may cause permanent discoloration of the teeth and enamel hypoplasia in young children. This is because tetracyclines are readily bound to calcium and are deposited in calcifying areas in bone and teeth.
  • prolonged use may result in superinfection, including oral or vaginal candidiasis
  • photosensitivity reaction
  • absorption may be decreased by 20% when given with food or milk
  • not active against penicillinase-producing Neisseria gonorrhoeae
  • poorly active against Haemophilus influenzae (common pathogen causing pneumonia) 11, 17
  • risk of intracranial hypertension
  • risk of esophageal ulceration (if the capsules for some reason do not reach the stomach but remain in the esophagus)

Mode of action

Antibacterial action

Bacteria need to synthesize proteins in order to ensure their reproduction. This biological activity requires the capture of nutrients from the surrounding environment at the expense of the host. Among those nutrients are the amino acids, which are incorporated in the bacteria's ribosomes, the cell organites where protein synthesis takes place.

Doxycycline is generally bacteriostatic against a wide variety of organisms, both gram-positive and gram-negative. In gram-negative bacteria, transportation of the doxycycline into the cell occurs either by passive diffusion or through an energy-dependent active transport system. The latter system is also believed to exist in gram-positive bacteria. Doxycycline is more lipophilic than the other tetracyclines, which allows it to pass easily through the lipid bilayer of bacteria.

Doxycycline penetrates the bacterial cell and interferes with the protein biosynthesis, stopping the process of bacteria reproduction. Bacteria cannot reproduce and die or are killed by the defense mechanisms (white cells) of the host. Doxycycline can also alter the cytoplasmic membrane and this in turn causes leakage of nucleotides and other compounds out of the cell. This does not directly kill the bacteria but instead inhibit it.

Non-antibiotic properties

Antibiotics also have non-antibiotic properties, which are not well understood. These nonantibioitc properties include:

  • Anti-inflammatory effects
  • Inhibition of metalloproteinases (enzymes that inhibit collagen and gelatin production)
  • Reduction of new blood vessel formation (angiogenesis)
  • Reduction of programmed cell death (apoptosis)

At subantimicrobial doses, doxycycline reduces inflammation via anticollagenolytic, antimatrix-degrading metalloproteinase, and cytokine down-regulating properties 2.

In the treatment of periodontitis doxycycline works by inhibiting collagenase 15 which breaks down connective tissue and leads to the separation of the gum from the tooth.

Doxycycline inhibits the nitric oxide synthesis. This activity is another possible pathway by which tetracyclines may function as anti-inflammatory compounds 9. The data suggests that the direct inhibition of nitrate release is the main mechanism of the anti-inflammatory activity of doxycycline in septic shock 10.

Doxycycline may slow OA progression by inhibiting the degradation of type XI collagen, reducing levels of collagen-degrading enzymes, and inhibiting messenger RNA for nitric oxide synthesis, which results in secretion of matrix MMPs in the chondrocyte.

Time for Doxycycline to clear out of the system

The half-life is 18 to 22 hr. Approximately 40% excreted by the kidneys in 72 hr.

Further reading


  • 1. Physicians’ Desk Reference, 54th ed; Medical Economics, Thomson Healthcare: Montvale, NJ; 2000.
  • 2. Bikowski JB. Subantimicrobial dose doxycycline for acne and rosacea. Skinmed. 2003 Jul-Aug;2(4):234-45. PubMed
  • 5. Hoyt JC, Ballering J, Numanami H, Hayden JM, Robbins RA. Doxycycline modulates nitric oxide production in murine lung epithelial cells. J Immunol. 2006 Jan 1;176(1):567-72.
  • 6. Perez-Trallero E, Iglesias L. Enferm Infecc Microbiol Clin. 2003 Nov;21(9):520-8; quiz 529, 533. PubMed
  • 8. Ruiz Beltran R, Herrero Herrero JI. Evaluation of doxycycline in the treatment of Mediterranean spotted fever. Eur J Clin Microbiol Infect Dis. 1992 May PubMed
  • 9. Volovitz B, Shkap R, Amir J, Calderon S, Varsano I, Nussinovitch M. Absence of tooth staining with doxycycline treatment in young children. Clin Pediatr (Phila). 2007 Mar;46(2):121-6.
  • 10. D'Agostino P, La Rosa M, Barbera C, Arcoleo F, Di Bella G, Milano S, Cillari E. Doxycycline reduces mortality to lethal endotoxemia by reducing nitric oxide synthesis via an interleukin-10-independent mechanism. J Infect Dis. 1998 Feb;177(2):489-92. PubMed
  • 11. Maesen FP, Davies BI, van den Bergh JJ. J Antimicrob Chemother. 1989 Jan;23(1):123-9.
  • 12. Cullmann W, Schlunegger H. Sensitivity of penicillin-resistance pneumococci. Immun Infekt. 1993 Feb;21(1):9-12. PubMed
  • 13. Brandt KD, Mazzuca SA, Katz BP, Lane KA, Buckwalter KA, Yocum DE, Wolfe F, Schnitzer TJ, Moreland LW, Manzi S, Bradley JD, Sharma L, Oddis CV, Hugenberg ST, Heck LW. Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo-controlled, double-blind trial. Arthritis Rheum. 2005 Jul;52(7):2015-25. PubMed
  • 14. Yu LP, Burr DB, Brandt KD, O'Connor BL, Rubinow A, Albrecht M. Effects of oral doxycycline administration on histomorphometry and dynamics of subchondral bone in a canine model of osteoarthritis. J Rheumatol. 1996 Jan;23(1):137-42. PubMed
  • 15. Golub LM, McNamara TF, Ryan ME, Kohut B, Blieden T, Payonk G, Sipos T, Baron HJ. Adjunctive treatment with subantimicrobial doses of doxycycline: effects on gingival fluid collagenase activity and attachment loss in adult periodontitis. J Clin Periodontol. 2001 Feb;28(2):146-56.
  • 16. Yoshida S, Mizuguchi Y, Ohta H, Ogawa M. Effects of tetracyclines on experimental Legionella pneumophila infection in guinea-pigs. J Antimicrob Chemother. 1985 Aug;16(2):199-204.
  • 17. Jacobs MR, Bajaksouzian S, Windau A, Good CE, Lin G, Pankuch GA, Appelbaum PC. Susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis to 17 oral antimicrobial agents based on pharmacodynamic parameters: 1998-2001 U S Surveillance Study. Clin Lab Med. 2004 Jun;24(2):503-30. PubMed
  • 18. Raza M, Ballering JG, Hayden JM, Robbins RA, Hoyt JC. Doxycycline decreases monocyte chemoattractant protein-1 in human lung epithelial cells. Exp Lung Res. 2006 Jan-Feb;32(1-2):15-26. PubMed
  • 19. Cunha BA. Clinical relevance of penicillin-resistant Streptococcus pneumoniae. Semin Respir Infect. 2002 Sep;17(3):204-14. PubMed
  • 20. Walker SG, Carnu OI, Tu"ter G, Ryan ME. The immunoglobulin A1 proteinase from Streptococcus pneumoniae is inhibited by tetracycline compounds. FEMS Immunol Med Microbiol. 2006 Nov;48(2):218-22. PubMed
  • 21. Heintz BH, Halilovic J, Christensen CL. Vancomycin-resistant enterococcal urinary tract infections. Pharmacotherapy. 2010 Nov;30(11):1136-49 PubMed
  • 22. Dibb WL, Digranes A. Characteristics of 20 human Pasteurella isolates from animal bite wounds. Acta Pathol Microbiol Scand [B]. 1981 Jun;89(3):137-41. PubMed
  • 23. Nadelman RB, Nowakowski J, Fish D, Falco RC, Freeman K, McKenna D, Welch P, Marcus R, Aguero-Rosenfeld ME, Dennis DT, Wormser GP. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med. 2001 Jul 12;345(2):79-84.
  • 24. Ragnar Norrby S. Atypical pneumonia in the Nordic countries: aetiology and clinical results of a trial comparing fleroxacin and doxycycline. Nordic Atypical Pneumonia Study Group. J Antimicrob Chemother. 1997 Apr;39(4):499-508. PubMed
  • 25. Bremell D, Dotevall L. Oral doxycycline for Lyme neuroborreliosis with symptoms of encephalitis, myelitis, vasculitis or intracranial hypertension. Eur J Neurol. 2014 Mar 29.
  • 26. Dotevall L, Hagberg L. Successful oral doxycycline treatment of Lyme disease-associated facial palsy and meningitis. Clin Infect Dis. 1999 Mar;28(3):569-74. PubMed
  • 27. Maatta M, Kari O, Tervahartiala T, Peltonen S, Kari M, Saari M, Sorsa T. Tear fluid levels of MMP-8 are elevated in ocular rosacea--treatment effect of oral doxycycline. Graefes Arch Clin Exp Ophthalmol. 2006 Aug;244(8):957-62. PubMed
  • 28. Sobolewska B, Doycheva D, Deuter C, Pfeffer I, Schaller M, Zierhut M. Treatment of ocular rosacea with once-daily low-dose doxycycline. Cornea. 2014 Mar;33(3):257-60.
  • 29. Sreekanth VR, Handa R, Wali JP, Aggarwal P, Dwivedi SN. Doxycycline in the treatment of rheumatoid arthritis--a pilot study. J Assoc Physicians India. 2000 Aug;48(8):804-7. PubMed
  • 30. Nordstrom D, Lindy O, Lauhio A, Sorsa T, Santavirta S, Konttinen YT. Anti-collagenolytic mechanism of action of doxycycline treatment in rheumatoid arthritis. Rheumatol Int. 1998;17(5):175-80.
  • 31. van der Laan W, Molenaar E, Ronday K, Verheijen J, Breedveld F, Greenwald R, Dijkmans B, TeKoppele J. Lack of effect of doxycycline on disease activity and joint damage in patients with rheumatoid arthritis. A double blind, placebo controlled trial. J Rheumatol. 2001 Sep;28(9):1967-74
  • 32. Chodosh S, Tuck J, Pizzuto D. Comparative trials of doxycycline in bacterial infections in chronic bronchitis and asthma. Scand J Infect Dis Suppl. 1988;53:22-8. PubMed
  • 33. Sweet RL, Schachter J, Landers DV, Ohm-Smith M, Robbie MO. Treatment of hospitalized patients with acute pelvic inflammatory disease: comparison of cefotetan plus doxycycline and cefoxitin plus doxycycline. Am J Obstet Gynecol. 1988 Mar;158(3 Pt 2):736-41. PubMed
  • 34. Bhardwaj P, Kosambiya JK, Vikas KD, Karan J. Chemoprophylaxis with doxycycline in suspected epidemic of leptospirosis during floods: does this really work? Afr Health Sci. 2010 Jun
  • 35. McClure JC, Crothers ML, Schaefer JJ, Stanley PD, Needham GR, Ewing SA, Stich RW. Efficacy of a doxycycline treatment regimen initiated during three different phases of experimental ehrlichiosis. Antimicrob Agents Chemother. 2010 Dec;54(12):5012-20. PubMed
  • 36. Freidank HM, Losch P, Vogele H, Wiedmann-Al-Ahmad M. In vitro susceptibilities of Chlamydia pneumoniae isolates from German patients and synergistic activity of antibiotic combinations. Antimicrob Agents Chemother. 1999 Jul;43(7):1808-10.
  • 37. Synthesis of tetracyclines and analogues thereof.
  • 38. Havlichek D, Saravolatz L, Pohlod D. Effect of quinolones and other antimicrobial agents on cell-associated Legionella pneumophila. Antimicrob Agents Chemother. 1987 Oct;31(10):1529-34.
  • 39. Bachelez H, Senet P, Cadranel J, Kaoukhov A, Dubertret L. The use of tetracyclines for the treatment of sarcoidosis. Arch Dermatol. 2001 Jan;137(1):69-73.
  • 40. El Sayed F, Dhaybi R, Ammoury A. Subcutaneous nodular sarcoidosis and systemic involvement successfully treated with doxycycline. J Med Liban. 2006 Jan-Mar;54(1):42-4. PubMed
  • 42. Walker C, Preshaw PM, Novak J, Hefti AF, Bradshaw M, Powala C. Long-term treatment with sub-antimicrobial dose doxycycline has no antibacterial effect on intestinal flora. J Clin Periodontol. 2005 Nov;32(11):1163-9. PubMed

Published: March 31, 2008
Last updated: July 28, 2019

Interesting facts
Doxycycline molecule
  • Doxycycline is currently the most frequently used tetracycline in human medicine and it is included in the List of Essential Medicines of the World Health Organization.
  • Doxycycline is available in several different salts: monohydrate, hydrochloride (hyclate), carrageenate, calcium and phosphate (fosfatex).
  • Doxycycline is most commonly used under two chemical forms: monohydrate and hyclate. The monohydrate is the base molecule hydrated with one molecule of water and is used in the formulation of capsules and, in some markets, powder oral suspensions. The hyclate is a hydrochloric acid salt solvated with water and ethanol and is used in the formulation of capsules or tablets.

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