Tetracycline

Clinical data
Pronunciation	/ˌtɛtrəˈsaɪkliːn/
Trade names	Sumycin, others
AHFS/Drugs.com	Monograph
MedlinePlus	a682098
License data	US FDA: Tetracycline
Pregnancy category	AU: D US: D (Evidence of risk)
Routes of administration	By mouth
ATC code	A01AB13 (WHO) D06AA04 (WHO) J01AA07 (WHO) S01AA09 (WHO) S02AA08 (WHO) S03AA02 (WHO) QG01AA90 (WHO) QG51AA02 (WHO) QJ51AA07 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	80%
Metabolism	Not metabolized
Elimination half-life	8–11 hours, 57–108 hours (kidney impairment)
Excretion	Urine (>60%), feces
Identifiers
CAS Number	60-54-8 Y 64-75-5 (hydrochloride)
PubChem CID	643969
DrugBank	DB00759 Y
ChemSpider	10257122 Y
UNII	F8VB5M810T
KEGG	D00201 Y
ChEBI	CHEBI:27902 Y
ChEMBL	ChEMBL1440 Y
PDB ligand	TAC (PDBe, RCSB PDB)
ECHA InfoCard	100.000.438
Chemical and physical data
Formula	C22H24N2O8
Molar mass	444.435 g/mol g·mol−1
3D model (JSmol)	Interactive image
SMILES C[C@]1(c2cccc(c2C(=O)C3=C([C@]4([C@@H](C[C@@H]31)[C@@H](C(=C(C4=O)C(=O)N)O)N(C)C)O)O)O)O
InChI InChI=1S/C22H24N2O8/c1-21(31)8-5-4-6-11(25)12(8)16(26)13-9(21)7-10-15(24(2)3)17(27)14(20(23)30)19(29)22(10,32)18(13)28/h4-6,9-10,15,25,27-28,31-32H,7H2,1-3H3,(H2,23,30)/t9-,10-,15-,21+,22-/m0/s1 Y Key:OFVLGDICTFRJMM-WESIUVDSSA-N Y
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Tetracycline, sold under the brand name Sumycin among others, is an antibiotic used to treat a number of infections.^[1] This includes acne, cholera, brucellosis, plague, malaria, and syphilis.^[1] It is taken by mouth.^[1]

Common side effects include vomiting, diarrhea, rash, and loss of appetite.^[1] Other side effects include poor tooth development if used by children less than eight years of age, kidney problems, and sunburning easily.^[1] Use during pregnancy may harm the baby.^[1] Tetracycline is in the tetracyclines family of medications.^[1] It works by blocking the ability of bacteria to make proteins.^[1]

Tetracycline was patented in 1953 and came into commercial use in 1978.^[2] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.^[3] Tetracycline is available as a generic medication.^[1] The wholesale cost in the developing world is about 0.35 to 1.78 USD for a course of treatment.^[4] In the United States a course of treatment typically costs less than 25 USD.^[5] Tetracycline was originally made from bacteria of the Streptomyces type.^[1]

Medical uses[edit]

It is first-line therapy for Rocky Mountain spotted fever (Rickettsia), Lyme disease (B. burgdorferi), Q fever (Coxiella), psittacosis, and Mycoplasma pneumoniae and to eradicate nasal carriage of meningococci. Tetracycline tablets were used in the plague outbreak in India in 1994.^[6]

Spectrum of bacterial susceptibility[edit]

Tetracyclines have a broad spectrum of antibiotic action. Originally, they possessed some level of bacteriostatic activity against almost all medically relevant aerobic and anaerobic bacterial genera, both Gram-positive and Gram-negative, with a few exceptions, such as Pseudomonas aeruginosa and Proteus spp., which display intrinsic resistance. However, acquired (as opposed to inherent) resistance has proliferated in many pathogenic organisms and greatly eroded the formerly vast versatility of this group of antibiotics. Resistance amongst Staphylococcus spp., Streptococcus spp., Neisseria gonorrhoeae, anaerobes, members of the Enterobacteriaceae, and several other previously sensitive organisms is now quite common. Tetracyclines remain especially useful in the management of infections by certain obligately intracellular bacterial pathogens such as Chlamydia, Mycoplasma, and Rickettsia. They are also of value in spirochaetal infections, such as syphilis, leptospirosis, and Lyme disease. Certain rare or exotic infections, including anthrax, plague and brucellosis, are also susceptible to tetracyclines. These agents also have activity against certain eukaryotic parasites, including those responsible for diseases such as malaria and balantidiasis. The following represents MIC susceptibility data for a few medically significant microorganisms:

• 
  Escherichia coli: 1 μg/mL – >128 μg/mL


• 
  Shigella spp.: 1 μg/mL – 128 μg/mL^[7]
  

Mechanisms of resistance[edit]

Bacteria usually acquire resistance to tetracycline from horizontal transfer of a gene that either encodes an efflux pump or a ribosomal protection protein. Efflux pumps actively eject tetracycline from the cell, preventing the buildup of an inhibitory concentration of tetracycline in the cytoplasm.^[8] Ribosomal protection proteins interact with the ribosome and dislodge tetracycline from the ribosome, allowing for translation to continue.^[9]

Precautions[edit]

Use of the tetracycline antibiotics group can:^[10]

• Discolor permanent teeth (yellow-gray-brown), from prenatal period through childhood and adulthood. Children receiving long- or short-term therapy with a tetracycline or glycylcycline may develop permanent brown discoloration of the teeth.


• Be inactivated by calcium ions, so are not to be taken with milk, yogurt, and other dairy products


• Be inactivated by aluminium, iron, and zinc ions, not to be taken at the same time as indigestion remedies (some common antacids and over-the-counter heartburn medicines)


• Cause skin photosensitivity, so exposure to the sun or intense light is not recommended


• Cause drug-induced lupus, and hepatitis
  


• Cause microvesicular fatty liver
  


• Cause tinnitus^{[citation needed]}
  


• Interfere with methotrexate by displacing it from the various protein-binding sites


• Cause breathing complications, as well as anaphylactic shock, in some individuals


• Affect bone growth of the fetus, so should be avoided during pregnancy
  


• 
  Fanconi syndrome may result from ingesting expired tetracyclines.

Caution should be exercised in long-term use when breastfeeding. Short-term use is safe; bioavailability in milk is low to nil.^[11] According to the U.S. Food and Drug Administration (FDA), cases of Stevens–Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme associated with doxycyline use have been reported, but a causative role has not been established.^[12]

Other uses[edit]

Tetracycline hydrochloride is available as yellow crystalline powder.

Since tetracycline is absorbed into bone, it is used as a marker of bone growth for biopsies in humans. Tetracycline labeling is used to determine the amount of bone growth within a certain period of time, usually a period around 21 days. Tetracycline is incorporated into mineralizing bone and can be detected by its fluorescence.^[13] In "double tetracycline labeling", a second dose is given 11–14 days after the first dose, and the amount of bone formed during that interval can be calculated by measuring the distance between the two fluorescent labels.^[14]

Tetracycline is also used as a biomarker in wildlife to detect consumption of medicine- or vaccine-containing baits.^[15]

In genetic engineering, tetracycline is used in transcriptional activation.
It is also one of a group of antibiotics which together may be used to treat peptic ulcers caused by bacterial infections. 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 leading to effects that may confound experimental results.^[16][17]

Tetracycline has been used as an engineered "control switch" in chronic myelogenous leukemia models in mice. Engineers were able to develop a retrovirus that induced a particular type of leukemia in mice, and could then "switch" the cancer on and off through tetracycline administration. This could be used to grow the cancer in mice and then halt it at a particular stage to allow for further experimentation or study.^[18]

A technique being developed for the control of the mosquito species Aedes aegypti uses a strain that is genetically modified to require tetracycline to develop beyond the larval stage. Modified males raised in a laboratory develop normally as they are supplied with this chemical and can be released into the wild. Their subsequent offspring inherit this trait, but find no tetracycline in their environments, so never develop into adults.^[19]

Mechanism of action[edit]

Tetracycline inhibits protein synthesis by blocking the attachment of charged aminoacyl-tRNA to the A site on the ribosome. Tetracycline binds to the 30S subunit of microbial ribosomes. Thus, it prevents introduction of new amino acids to the nascent peptide chain.^[20] The action is usually inhibitory and reversible upon withdrawal of the drug. Mammalian cells are less vulnerable to the effect of tetracyclines, despite the fact that tetracycline binds to the small ribosomal subunit of both prokaryotes and eukaryotes (30S and 40S, respectively). This is because bacteria actively pump tetracycline into their cytoplasm, even against a concentration gradient, whereas mammalian cells do not. This accounts for the relatively small off-site effect of tetracycline on human cells.^[21]

History[edit]

The tetracyclines, a large family of antibiotics, were discovered by Benjamin Minge Duggar in 1945 as natural products, and first prescribed in 1948.^[22] Benjamin Duggar, working under Yellapragada Subbarow at Lederle Laboratories, discovered the first tetracycline antibiotic, chlortetracycline (Aureomycin), in 1945.^[23]

In 1950, Harvard University professor R.B. Woodward determined the chemical structure of the related substance, oxytetracycline (Terramycin);^[24] the patent protection for its fermentation and production was also first issued in that year.^[25] Chemist Lloyd Conover, in a research team of eight scientists at Pfizer, collaborated with Woodward over a two-year period, leading to tetracycline's discovery.^[26][27][28]

Pfizer was of the view that it deserved the right to a patent on tetracycline and filed its Conover application in October 1952. Cyanamid filed its Boothe-Morton application for similar rights in March 1953, while Heyden Chemicals filed its Minieri application in September 1953, named after scientist P. Paul Minieri, to obtain a patent on tetracycline and its fermentation process.^{[29][full citation needed][non-primary source needed]} This resulted in tetracycline litigation in which the winner would have to prove beyond reasonable doubt of priority invention and tetracycline's natural state.^{[clarification needed][needs update][30]}

Evidence in antiquity[edit]

Nubian mummies studied in the 1990s were found to contain significant levels of tetracycline; the beer brewed at the time was conjectured to have been the source.^[31]

Society and culture[edit]

Price[edit]

According to data from EvaluatePharma and published in the Boston Globe, the price of tetracycline rose from $0.06 per 250-mg pill in 2013 to $4.06 a pill in 2015.^[32] The Globe described the "big price hikes of some generic drugs" as a "relatively new phenomenon" which has left most pharmacists "grappling" with large upswings" in the "costs of generics, with 'overnight' price changes sometimes exceeding 1,000%."^[32]

Names[edit]

It is marketed under the brand names Sumycin, Tetracyn, and Panmycin, among others. Actisite is a thread-like fiber formulation used in dental applications.

It is also used to produce several semisynthetic derivatives, which together are known as the tetracycline antibiotics. The term "tetracycline" is also used to denote the four-ring system of this compound; "tetracyclines" are related substances that contain the same four-ring system.

References[edit]