Doxycycline

Doxycycline
Clinical data
Pronunciation /ˌdɒksiˈsaɪklin/
Trade names Doryx, Doxyhexal, Doxylin among others
AHFS/Drugs.com Monograph
MedlinePlus a682063
License data
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Routes of
administration		 by mouth, intravenous[1]
ATC code J01AA02 (WHO) A01AB22 (WHO)
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Bioavailability 100%
Protein binding 90%
Metabolism Hepatic
Biological half-life 15–25 hours
Excretion Urine (40%)
Identifiers
CAS Number 564-25-0 YesY
PubChem (CID) 11256
DrugBank DB00254 YesY
ChemSpider 10482106 YesY
UNII 334895S862 YesY
KEGG D00307 N
ChEBI CHEBI:60648 YesY
ChEMBL CHEMBL1433 N
ECHA InfoCard 100.008.429
Chemical and physical data
Formula C22H24N2O8
Molar mass 444.43 g/mol
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

Doxycycline is an antibiotic that is used in the treatment of a number of types of infections caused by bacteria and protozoa. It is useful for bacterial pneumonia, acne, chlamydia infections, early Lyme disease, cholera and syphilis. It is also useful for the treatment of malaria when used with quinine and for the prevention of malaria. Doxycycline can be used either by mouth or intravenously.[1]

Common side effects include diarrhea, nausea, vomiting, a red rash, and an increased risk of a sunburn. If used during pregnancy or in young children may result in permanent problems with the teeth including changes in their color. Its use during breastfeeding is probably safe.[1] Doxycycline is a broad-spectrum antibiotic of the tetracycline class.[1] Like other agents of this class it kills bacteria and protozoa by inhibiting protein production.[1][2]

Doxycycline came into use in 1967.[3] It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[4] Doxycycline is available as a generic medicine and is generally inexpensive.[1][5] The wholesale cost in the developing world is between 0.01 and 0.04 USD per pill.[6] In the United States 10 days of treatment is about 14 USD, however some in 2014 were selling it for more than 3.00 to 10.00 USD per pill.[1][7]

Medical use

Generic 100 mg doxycycline capsules

In addition to the general indications for all members of the tetracycline antibiotics group, doxycycline is frequently used to treat Lyme disease, chronic prostatitis, sinusitis, pelvic inflammatory disease,[8][9] acne, rosacea,[10][11] and rickettsial infections.[12]

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.[13]

It can be used in a treatment plan in combination with other agents, such as quinine.[14]

Antibacterial

Moraxella catarrhalis, Brucella melitensis, Chlamydia pneumoniae, and Mycoplasma pneumoniae are generally susceptible to doxycycline, while some Haemophilus spp., Mycoplasma hominis, and Pseudomonas aeruginosa have developed resistance to varying degrees.[15]

It is used in the treatment and prophylaxis of anthrax (caused by Bacillus anthracis) and Leptospirosis.[16] It is also effective against Yersinia pestis (the infectious agent of bubonic plague), and is prescribed for the treatment of Lyme disease,[17][18][19][20] ehrlichiosis[21][22] 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, it is not indicated for use in children under the age of eight years.

Doxycycline is indicated for treatment of:[23][24]

When bacteriologic testing indicates appropriate susceptibility to the drug, doxycycline may be used to treat these infections caused by Gram-negative bacteria:[23][24]

Some Gram-positive bacteria have developed resistance to doxycycline. Up to 44% of Streptococcus pyogenes and up to 74% of S. faecalis specimens have developed resistance to the tetracycline group of antibiotics. When bacteriologic testing indicates appropriate susceptibility to the drug, doxycycline may be used to treat these infections caused by Gram-positive bacteria:[23][24]

Doxycycline package

When penicillin is contraindicated, doxycycline can be used to treat:[23][24]

Doxycycline may also be used as adjunctive therapy for severe acne.[23][24]

The first-line for treatment brucellosis is combination of doxycycline and streptomycin and the second-line is combination of Doxyxycline and rifampin (rifampicin).[28]

Antihelminthic

Doxycycline kills the symbiotic Wolbachia bacteria in the reproductive tracts of parasitic filarial nematodes, making the nematodes sterile, and thus reducing transmission of diseases such as onchocerciasis and elephantiasis.[29] Field trials in 2005 showed an eight-week course of doxycycline almost completely eliminates the release of microfilariae.[30]

Spectrum of susceptibility

Doxycycline has been used successfully to treat sexually transmitted, respiratory, and ophthalmic infections. Representative pathogenic genera include Chlamydia, Streptococcus, Ureaplasma, Mycoplasma, and others. The following represents MIC susceptibility data for a few medically significant microorganisms.

Adverse effects

Cautions and side effects are similar to those of other members of the tetracycline antibiotic group.

An erythematous rash in sun-exposed parts of the body has been reported to occur in 7.3–21.2% of persons taking doxycycline for malaria prophylaxis. One study examined the tolerability of various malaria prophylactic regimens and found doxycycline did not cause a significantly higher percentage of all skin events (photosensitivity not specified) when compared with other antimalarials. The rash resolves upon discontinuation of the drug.[32]

Unlike some other members of the tetracycline group, it may be used in those with renal impairment.[33] Doxycycline is contraindicated in the pediatric treatment of acute bacterial rhinosinusitis.

Interactions

The combination of doxycycline with dairy, antacids, calcium supplements, iron products, and laxatives containing magnesium is not inherently dangerous, but any of these foods and supplements may decrease doxycycline's effectiveness.[34]

Breakfast was observed to reduce doxycycline absorption significantly. Absorption of tetracycline occurs in the stomach and the upper small intestine. Absorption of tetracyclines has been reported to be impaired by milk products, aluminum hydroxide gels, sodium bicarbonate, calcium and magnesium salts, laxatives containing magnesium and iron preparations. The mechanisms responsible for decreased absorption appear to be chelation and an increase in gastric pH. ... In view of these results, it is advisable to instruct the patients to take doxycycline on an empty stomach.[35]

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.[36][37][38]

Pregnancy and lactation

Doxycycline is categorized by the FDA as a class D drug in pregnancy. As with all tetracycline antibiotics, it is contraindicated in pregnancy through infancy and childhood up to eight years of age, due to the potential for disrupting bone and tooth development.[39] Therefore, doxycycline should not be administered to children under the age of eight except in the treatment of anthrax, or where other medications are contraindicated or ineffective.[23]

Doxycycline crosses into breastmilk. The adverse effects on teeth and long bones of children directly administered tetracycline antibiotics is documented, but these effects have not been recorded in infants exposed through breastmilk. Although the dose an infant would receive through breastfeeding would likely be minimal, a theoretical risk exists.[40]

Pharmacokinetics

Doxycycline–metal ion complexes are unstable at acid pH, therefore more doxycycline enters the duodenum for absorption than the earlier tetracycline compounds. In addition, food has less effect on absorption than on absorption of earlier drugs with doxycycline serum concentrations being reduced by about 20% by test meals compared with 50% for tetracycline.[41]

Chemistry

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[42][43] causing Fanconi syndrome.[44] In the case of doxycycline, the absence of a hydroxyl group in C-6 prevents the formation of the nephrotoxic compound.[43] 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.[44]

History

After penicillin revolutionized the treatment of bacterial infections in WWII, many chemical companies moved into the field of discovering antibiotics by bioprospecting. American Cyanamid was one of these, and in the late 1940s chemists there discovered chlortetracycline, the first member of the tetracycline class of antibiotics.[45] Shortly thereafter, scientists at Pfizer discovered terramycin and it was brought to market. Both compounds, like penicillin, were natural products and it was commonly believed that nature had perfected them, and further chemical changes could only degrade their effectiveness. Scientists at Pfizer led by Lloyd Conover modified these compounds, which led to the invention of tetracycline itself, the first semi-synthetic antibiotic. Charlie Stephens at Pfizer worked on further analogs and created one with greatly improved stability and pharmacological efficacy: doxycycline. It was clinically developed in the early 1960s and approved by the FDA in 1967.[45]

As its patent grew near to expiring in the early 1970s, the patent became the subject of lawsuit between Pfizer and International Rectifier[46] that wasn't resolved until 1983; at the time it was the largest litigated patent case in US history.[47] Instead of a cash payment for infringement, Pfizer took the veterinary and feed-additive businesses of International Rectifier's subsidiary, Rachelle Laboratories.[47]

In January 2013, the FDA reported shortages of some, but not all, forms of doxycyline "caused by increased demand and manufacturing issues".[48] Companies involved included an unnamed major generics manufacturer that ceased production in February 2013, Teva (which ceased production in May 2013), Mylan, Actavis, and Hikma Pharmaceuticals.[49][50] The shortage came at a particularly bad time, since there were also shortages of an alternative antibiotic, tetracycline, at the same time.[51] The market price for doxycycline dramatically increased in the United States in 2013 and early 2014 (from $20 to over $1800 for a bottle of 500 tablets),[52][53][54] before decreasing again.[55][56]

Society and culture

Doxycycline is available worldwide under many brand names.[57] Doxycycline is available as a generic medicine and is inexpensive.[1][5] The wholesale cost is between 0.01 and 0.04 USD per pill.[6]

Research

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.[58] Doxycycline has been demonstrated to reduce the in vitro growth of human cancer cells (breast and prostate), possibly through G1 phase cell cycle arrest.[59][60] Doxycycline and other tetracyclines are also highly osteotropic, and in animal models of breast cancer bone metastases, doxycycline treatments have reduced the growth of breast cancer tumours in the bone.[61]

Doxycycline has been used successfully in the treatment of one patient with lymphangioleiomyomatosis, an otherwise progressive and fatal disease.[62] It has also been shown to attenuate cardiac hypertrophy (in mice), a deadly consequence of prolonged hypertension.[63] In chronic obstructive pulmonary disease, doxycycline has been shown to improve lung functions in patients with stable symptoms.[64]

Doxycycline is also used in "tet-on" (gene expression activated by doxycycline) and "tet-off" (gene expression inactivated by doxycycline) tetracycline-controlled transcriptional activation to regulate transgene expression in organisms and cell cultures.[65] Doxycycline is more stable than tetracycline for this purpose.[65]

Other experimental applications include treating:

Research reagent

Doxycycline and other member of the tetracycline class of antibiotics are often used as research reagents in in vitro and in vivo biomedical research experiments involving bacteria as well in experiments in eukaryotic cells and organisms with inducible protein expression systems using tetracycline-controlled transcriptional activation. The mechanism of action for the antibacterial effect of tetracyclines relies on disrupting protein translation in bacteria, thereby damaging the ability of microbes to grow and repair; however protein translation is also disrupted in eukaryotic mitochondria impairing metabolism and leading to effects that can confound experimental results.[78][79]

References

  1. 1 2 3 4 5 6 7 8 "Doxycycline calcium". The American Society of Health-System Pharmacists. Retrieved Aug 18, 2015.
  2. ↑ Nelson, ML; Levy, SB (December 2011). "The history of the tetracyclines.". Annals of the New York Academy of Sciences. 1241: 17–32. doi:10.1111/j.1749-6632.2011.06354.x. PMID 22191524.
  3. ↑ Corey, E.J. (2013). Drug discovery practices, processes, and perspectives. Hoboken, N.J.: John Wiley & Sons. p. 406. ISBN 9781118354469.
  4. ↑ "WHO Model List of Essential Medicines" (PDF). World Health Organization. April 2015. Retrieved 2 June 2015.
  5. 1 2 Hamilton, Richard J. (2011). Tarascon pharmacopoeia (2011 library ed., 2011 ed., 12th ed.). Sudbury, MA: Jones & Bartlett Learning. p. 79. ISBN 9781449600679.
  6. 1 2 "Doxycycline". International Drug Price Indicator Guide. Retrieved 18 August 2015.
  7. ↑ "Officials Question the Rising Costs of Generic Drugs". New York Times. Oct 7, 2014. Retrieved 22 September 2015.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
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