Doxycycline

Doxycycline

Systematic (IUPAC) name
(4S,4aR,5S,5aR,6R,12aS)-4-(dimethylamino)- 3,5,10,12,12a-pentahydroxy- 6-methyl- 1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene- 2-carboxamide
Clinical data
Trade names	Vibramycin
AHFS/Drugs.com	monograph
MedlinePlus	a682063
Licence data	US FDA:link
Pregnancy cat.	D(US)
Legal status	POM (UK) ℞-only (US)
Routes	oral, buccal, iv, im
Pharmacokinetic data
Bioavailability	100%
Metabolism	hepatic,minimally
Half-life	18-22 hours
Excretion	urine, feces
Identifiers
CAS number	564-25-0 Y
ATC code	J01AA02 A01AB22
PubChem	CID 11256
DrugBank	APRD00597
ChemSpider	10482106 Y
UNII	334895S862 Y
KEGG	D02129 N
ChEBI	CHEBI:60648 Y
ChEMBL	CHEMBL1433 N
Chemical data
Formula	C22H24N2O8
Mol. mass	444.435 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C22H24N2O8.H2O/c1-7-8-5-4-6-9(25)11(8)16(26)12-10(7)17(27)14-15(24(2)3)18(28)13(21(23)31)20(30)22(14,32)19(12)29;/h4-7,10,14-15,17,25,27-29,32H,1-3H3,(H2,23,31);1H2/t7-,10+,14+,15-,17-,22-;/m0./s1 Y Key:XQTWDDCIUJNLTR-CVHRZJFOSA-N Y
N(what is this?)  (verify)

Generic 100 mg doxycycline capsules

Doxycycline INN ( /ˌdɒksɨˈsaɪkliːn/ doks-i-sy-kleen) is a member of the tetracycline antibiotics group, and is commonly used to treat a variety of infections. Doxycycline is a semisynthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc.^{[citation needed]} and marketed under the brand name Vibramycin.^{[citation needed]} Vibramycin received U.S. Food and Drug Administration (FDA) approval in 1967,^{[citation needed]} becoming Pfizer's first once-a-day, broad-spectrum antibiotic.^{[citation needed]} Other brand names include Monodox, Microdox, Periostat, Vibra-Tabs, Oracea, Doryx, Vibrox, Adoxa, Doxyhexal, Doxylin, Doxoral,Doxy-1 and Atridox (topical doxycycline hyclate for periodontitis).

Indicated uses

Main article: Tetracycline antibiotics

Further information: Oxytetracycline

As well as the general indications for all members of the tetracycline antibiotics group, doxycycline is frequently used to treat chronic prostatitis, sinusitis, syphilis, chlamydia, pelvic inflammatory disease,^[1][2] acne, rosacea,^[3][4] and rickettsial infections.

Antiprotozoal

It is used in prophylaxis against malaria. It should not be used alone for initial treatment of malaria, even when the parasite is doxycycline-sensitive, because the antimalarial effect of doxycycline is delayed. This delay is related to its mechanism of action, which is to specifically impair the progeny of the apicoplast genes, resulting in their abnormal cell division.^[5]

It can be used in a treatment plan in combination with other agents, such as quinine.^[6]

Antibacterial

It is used in the treatment and prophylaxis of Bacillus anthracis (anthrax).

It is also effective against Yersinia pestis (the infectious agent of bubonic plague), and is prescribed for the treatment of Lyme disease,^{[7][8][9][10]} ehrlichiosis^[11][12] and Rocky Mountain spotted fever. In fact, because doxycycline is one of the few medications shown to be effective in treating Rocky Mountain spotted fever (with the next-best alternative being chloramphenicol), doxycycline is indicated even for use in children for this illness. Otherwise, doxycycline is not indicated for use in children under the age of eight years. Doxycycline, like other antibiotics, will not work for colds, influenza, or other viral infections.

Doxycycline package.

When bacteriologic testing indicates appropriate susceptibility to the drug, doxycycline may be used to treat and prevent:

• Escherichia coli
• Chlamydia trachomatis
• Enterobacter aerogenes (formerly Aerobacter aerogenes)
• Lyme disease, aka Lyme borreliosis complex (B. burgdorferi)
• Rocky mountain spotted fever
• Folliculitis
• Acne and other inflammatory skin diseases, such as hidradenitis suppurativa
• Shigella species
• Acinetobacter species (formerly Mima species and Herellea species)
• Respiratory tract infections caused by Haemophilus influenzae
• Respiratory tract and urinary tract infections
• Upper respiratory infections caused by Streptococcus pneumoniae (formerly Diplococcus pneumoniae)
• Methicillin-resistant Staphylococcus aureus (MRSA) infections

Anthelmintic

Elephantiasis is the end-stage condition of lymphatic filariases caused by one of two genera of filarial nematodes (roundworms): Wuchereria or Brugia (primarily Wuchereria bancrofti). Elephantiasis is characterized by permanently swollen limbs or genitals and permanent damage to the lymph system (often accompanied by severe secondary fungal and bacterial infections). This results from blockage of lymph flow caused by immune response against dead or dying adult worms in the lymphatics. This condition affects over 120 million people worldwide, with 1 billion at risk.^[13] Previous antinematode treatments have been limited by poor levels of effectiveness, drug side effects and high costs. Doxycycline was shown in 2003 to kill the symbiotic Wolbachia bacteria in the filarial worms' reproductive tracts, rendering them sterile, thus reducing transmission of the disease.^[14] Field trials in 2005 showed doxycycline almost completely eliminates the release of microfilariae when given for an 8 week course.^[15][16] However, doxycycline only reduces transmission and the relatively light pathology associated with microfilaraemia; there is currently no cure for lymphatic filariasis.

Cautions and side effects

Cautions and side effects are similar to those of other members of the tetracycline antibiotic group. However, the risk of photosensitivity skin reactions is of particular importance for those intending long-term use for malaria prophylaxis, because it can cause permanent sensitive and thin skin.

Unlike some other members of the tetracycline group, it may be used in those with renal impairment.^[17]

Previously, doxycycline was believed to impair the effectiveness of many types of hormonal contraception due to CYP450 induction. Recent research has shown no significant loss of effectiveness in oral contraceptives while using most tetracycline antibiotics (including doxycycline), although many physicians still recommend the use of barrier contraception for people taking the drug to prevent unwanted pregnancy.^[18][19][20]

Food, including dairy products, does not interfere with the absorption of doxycycline, unlike most other tetracycline antibiotics.^[21]

Doxycycline, like all tetracyclines, is not approved for general use in children, but specific exceptions are made for potentially fatal illnesses where the benefits outweigh the risks and there are few or no other alternatives, such as with Rocky Mountain spotted fever and anthrax.

Expired tetracyclines or tetracyclines allowed to stand at a pH less than 2 are reported to be nephrotoxic due to the formation of a degradation product, anhydro-4-epitetracycline^[22][23] causing Fanconi syndrome.^[24] In the case of doxycycline, the absence of an hydroxyl group in C-6 prevent the formation of the nephrotoxic compound.^[23] Nevertheless, tetracyclines and doxycycline itself have to be taken with precaution in patients with kidney injury, as they can worsen azotemia due to catabolic effects.^[24]

Experimental applications

Tet-ON inducible shRNA system

At subantimicrobial doses, doxycycline is an inhibitor of matrix metalloproteases, and has been used in various experimental systems for this purpose, such as for recalcitrant recurrent corneal erosions.^[25] Doxycycline has been used successfully in the treatment of one patient with lymphangioleiomyomatosis, an otherwise progressive and fatal disease.^[26] Doxycycline has also been shown to attenuate cardiac hypertrophy (in mice), a deadly consequence of prolonged hypertension.^[27] In chronic obstructive pulmonary disease, doxycycline has shown to improve lung functions in patients with stable symptoms.^[28] Doxycycline is also used in "Tet-on" and "Tet-off" tetracycline controlled transcriptional activation to regulate transgene expression in organisms and cell cultures.

Other experimental applications include:

• Vancomycin-resistant enterococcus (VRE)^[29]
• Infected animal bite wounds (Pasteurella multocida, Pasteurella pneumotropica)^[30]
• Rheumatoid arthritis^[31][32] and reactive arthritis
• Chronic inflammatory lung diseases (panbronchiolitis, asthma, cystic fibrosis, bronchitis)^[33][34]
• Sarcoidosis^[35][36]
• Prevention of aortic aneurysm in people with Marfan syndrome and Vascular Ehlers-Danlos syndrome^[37]
• Multiple sclerosis^[38]
• Meibomian gland dysfunction
• Treatment of filariasis and onchocerciasis due to filariae and onchocercae, in general, harbouring endosymbiotic Wolbachia bacteria, doxycycline kills the bacteria, and (by removal of the endosymbiotes) the nematodes.
• New daily persistent headache
• Idiopathic pulmonary fibrosis (IPF)^[39]

References

1. ^ Sweet RL, Schachter J, Landers DV, Ohm-Smith M, Robbie MO (1988). "Treatment of hospitalized patients with acute pelvic inflammatory disease: comparison of cefotetan plus doxycycline and ana doxycycline". Am. J. Obstet. Gynecol. 158 (3 Pt 2): 736–41. PMID 3162653. 
2. ^ Gjønnaess H, Holten E (1978). "Doxycycline (Vibramycin) in pelvic inflammatory disease". Acta Obstet Gynecol Scand 57 (2): 137–9. doi:10.3109/00016347809155893. PMID 345730. 
3. ^ Määttä M, Kari O, Tervahartiala T, et al. (2006). "Tear fluid levels of MMP-8 are elevated in ocular rosacea--treatment effect of oral doxycycline". Graefes Arch. Clin. Exp. Ophthalmol. 244 (8): 957–62. doi:10.1007/s00417-005-0212-3. PMID 16411105. 
4. ^ Quarterman MJ, Johnson DW, Abele DC, Lesher JL, Hull DS, Davis LS (1997). "Ocular rosacea. Signs, symptoms, and tear studies before and after treatment with doxycycline". Arch Dermatol 133 (1): 49–54. doi:10.1001/archderm.133.1.49. PMID 9006372. 
5. ^ Dahl EL, Shock JL, Shenai BR, Gut J, DeRisi JL, Rosenthal PJ (2006). "Tetracyclines specifically target the apicoplast of the malaria parasite Plasmodium falciparum". Antimicrob. Agents Chemother. 50 (9): 3124–31. doi:10.1128/AAC.00394-06. PMC 1563505. PMID 16940111. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1563505. 
6. ^ Lalloo DG, Shingadia D, Pasvol G, et al. (February 2007). "UK malaria treatment guidelines". J. Infect. 54 (2): 111–21. doi:10.1016/j.jinf.2006.12.003. PMID 17215045. http://linkinghub.elsevier.com/retrieve/pii/S0163-4453(06)00416-6. 
7. ^ Nadelman RB, Luger SW, Frank E, Wisniewski M, Collins JJ, Wormser GP (1992). "Comparison of cefuroxime axetil and doxycycline in the treatment of early Lyme disease". Ann. Intern. Med. 117 (4): 273–80. PMID 1637021. 
8. ^ Luger SW, Paparone P, Wormser GP, et al. (March 1995). "Comparison of cefuroxime axetil and doxycycline in treatment of patients with early Lyme disease associated with erythema migrans". Antimicrob. Agents Chemother. 39 (3): 661–7. PMC 162601. PMID 7793869. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=162601. 
9. ^ Nadelman RB, Nowakowski J, Fish D, et al. (2001). "Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite". N. Engl. J. Med. 345 (2): 79–84. doi:10.1056/NEJM200107123450201. PMID 11450675. http://content.nejm.org/cgi/content/full/345/2/79. 
10. ^ Karlsson M, Hammers-Berggren S, Lindquist L, Stiernstedt G, Svenungsson B (1994). "Comparison of intravenous penicillin G and oral doxycycline for treatment of Lyme neuroborreliosis". Neurologe 44 (7): 1203–7. PMID 8035916. 
11. ^ Weinstein RS (1996). "Human ehrlichiosis". Am Fam Physician 54 (6): 1971–6. PMID 8900357. 
12. ^ Karlsson U, Bjöersdorff A, Massung RF, Christensson B (2001). "Human granulocytic ehrlichiosis--a clinical case in Scandinavia". Scand. J. Infect. Dis. 33 (1): 73–4. doi:10.1080/003655401750064130. PMID 11234985. 
13. ^ Watkins BM (November 2003). "Drugs for the control of parasitic diseases: current status and development". Trends Parasitol 19 (11): 477–8. doi:10.1016/j.pt.2003.09.010. PMID 14580957. 
14. ^ Hoerauf A, Mand S, Fischer K, et al. (2003). "Doxycycline as a novel strategy against bancroftian filariasis-depletion of Wolbachia endosymbionts from Wuchereria bancrofti and stop of microfilaria production". Med. Microbiol. Immunol. 192 (4): 211–6. doi:10.1007/s00430-002-0174-6. PMID 12684759. 
15. ^ Taylor MJ, Makunde WH, McGarry HF, Turner JD, Mand S, Hoerauf A (2005). "Macrofilaricidal activity after doxycycline treatment of Wuchereria bancrofti: a double-blind, randomised placebo-controlled trial". Lancet 365 (9477): 2116–21. doi:10.1016/S0140-6736(05)66591-9. PMID 15964448. 
16. ^ Outland, Katrina (24 June 2005). "New Treatment for Elephantitis: Antibiotics". 13. The Journal of Young Investigators. http://www.jyi.org/news/nb.php?id=361. 
17. ^ Center for Drug Evaluation and Research (November–December 2004). "European recommendations on the use of oral antibiotics for acne". Food and Drug Administration. http://www.jle.com/en/revues/medecine/ejd/e-docs/00/04/07/1B/article.md?type=text.html. Retrieved 2008-01-31. ^{[verification needed]}
18. ^ Archer JS, Archer DF (2002). "Oral contraceptive efficacy and antibiotic interaction: a myth debunked". J. Am. Acad. Dermatol. 46 (6): 917–23. doi:10.1067/mjd.2002.120448. PMID 12063491. 
19. ^ Dréno B, Bettoli V, Ochsendorf F, Layton A, Mobacken H, Degreef H (November–December 2004). "European recommendations on the use of oral antibiotics for acne". Eur J Dermatol 14 (6): 391–9. PMID 15564203. http://www.jle.com/e-docs/00/04/07/1B/vers_alt/VersionPDF.pdf. 
20. ^ DeRossi SS, Hersh EV (2002). "Antibiotics and oral contraceptives". Dent. Clin. North Am. 46 (4): 653–64. doi:10.1016/S0011-8532(02)00017-4. PMID 12436822. 
21. ^ Pharmacological Basis of Therapeutics; Editors: A. G. Gilman, L. S. Goodman, T. W. Rall and F. Murad, 7th edition, MacMillan Publishing Co., New York, 1985, pp. 1170-1198
22. ^ "Principles and methods for the assessment of nephrotoxicity associated with exposure to chemicals". Environmental health criteria: 119. World Health Organization (WHO). ISBN 92 4 157119 5. ISSN 0250-863X. 1991.
23. ^ ^{a b} Foye's Principles of Medicinal Chemistry; David A. Williams; William O. Foye, Thomas L. Lemke
24. ^ ^{a b} Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12ed, Laurence L. Brunton, Bruce A. Chabner, Björn C. Knollmann
25. ^ Dursun D, Kim MC, Solomon A, Pflugfelder SC (2001). "Treatment of recalcitrant recurrent corneal erosions with inhibitors of matrix metalloproteinase-9, doxycycline and corticosteroids". Am. J. Ophthalmol. 132 (1): 8–13. doi:10.1016/S0002-9394(01)00913-8. PMID 11438047. 
26. ^ Moses MA, Harper J, Folkman J (2006). "Doxycycline treatment for lymphangioleiomyomatosis with urinary monitoring for MMPs". N. Engl. J. Med. 354 (24): 2621–2. doi:10.1056/NEJMc053410. PMID 16775248. 
27. ^ Errami M, Galindo CL, Tassa AT, Dimaio JM, Hill JA, Garner HR (2007). "Doxycycline attenuates isoproterenol- and transverse aortic banding- induced cardiac hypertrophy in mice". J Pharmacol Exp Ther 324 (3): 1196–203. doi:10.1124/jpet.107.133975. PMID 18089841. 
28. ^ Dalvi PS, Singh A, Trivedi HR, et al. (2011). "Effect of doxycycline in patients of moderate to severe chronic obstructive pulmonary disease with stable symptoms". Ann Thorac Med 6 (4): 221-6. doi:10.4103/1817-1737.84777. http://www.thoracicmedicine.org/article.asp?issn=1817-1737;year=2011;volume=6;issue=4;spage=221;epage=226;aulast=Dalvi. 
29. ^ Saraiva IH, Jones RN, Erwin M, Sader HS (1997). "[Evaluation of antimicrobial sensitivity of 87 clinical isolates of vancomycin-resistant enterococci]" (in Portuguese). Rev Assoc Med Bras 43 (3): 217–22. doi:10.1590/S0104-42301997000300009. PMID 9497549. 
30. ^ Dibb WL, Digranes A (1981). "Characteristics of 20 human Pasteurella isolates from animal bite wounds". Acta Pathol Microbiol Scand [B] 89 (3): 137–41. PMID 7315339. 
31. ^ Sreekanth VR, Handa R, Wali JP, Aggarwal P, Dwivedi SN (2000). "Doxycycline in the treatment of rheumatoid arthritis--a pilot study". J Assoc Physicians India 48 (8): 804–7. PMID 11273473. 
32. ^ Nordström D, Lindy O, Lauhio A, Sorsa T, Santavirta S, Konttinen YT (1998). "Anti-collagenolytic mechanism of action of doxycycline treatment in rheumatoid arthritis". Rheumatol. Int. 17 (5): 175–80. doi:10.1007/s002960050030. PMID 9542777. 
33. ^ Raza M, Ballering JG, Hayden JM, Robbins RA, Hoyt JC (2006). "Doxycycline decreases monocyte chemoattractant protein-1 in human lung epithelial cells". Exp. Lung Res. 32 (1-2): 15–26. doi:10.1080/01902140600691399. PMID 16809218. 
34. ^ Chodosh S, Tuck J, Pizzuto D (1988). "Comparative trials of doxycycline versus amoxicillin, cephalexin and enoxacin in bacterial infections in chronic bronchitis and asthma". Scand J Infect Dis Suppl 53: 22–8. PMID 3047855. 
35. ^ Bachelez H, Senet P, Cadranel J, Kaoukhov A, Dubertret L (2001). "The use of tetracyclines for the treatment of sarcoidosis". Arch Dermatol 137 (1): 69–73. PMID 11176663. http://archderm.ama-assn.org/cgi/content/full/137/1/69. 
36. ^ El Sayed F, Dhaybi R, Ammoury A (2006). "Subcutaneous nodular sarcoidosis and systemic involvement successfully treated with doxycycline". J Med Liban 54 (1): 42–4. PMID 17044634. 
37. ^ Briest W, Cooper TK, Tae HJ, Krawczyk M, McDonnell NB, Talan MI (2011). "Doxycycline ameliorates the susceptibility to aortic lesions in a mouse model for the vascular type of ehlers-danlos syndrome". J Pharmacol Exp Ther 337 (3): 621–27. doi:10.1124/jpet.110.177782. PMID 21363928. 
38. ^ "Antibiotics 'could help slow MS'". BBC News. 2007-12-11. http://news.bbc.co.uk/2/hi/health/7136088.stm. Retrieved 2008-01-31. 
39. ^ Mishra GP, Mulani JD. "Doxycycline: An Old Drug With A New Role In Idiopathic Pulmonary Fibrosis". International Journal of Pharma and Bio Sciences. V1(2) 2010. ISSN 0975-6299.

External links

• Patient Information Leaflet
• Drugs.com Article on Doxycycline
• U.S. National Library of Medicine: Drug Information Portal - Doxycycline