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Tigecycline

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Tigecycline
Clinical data
Pronunciation/ˌtaɪɡəˈsaɪkliːn/
Trade namesTygacil
AHFS/Drugs.comMonograph
MedlinePlusa614002
License data
Pregnancy
category
Routes of
administration		Intravenous (IV)
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding71–89%
MetabolismNot metabolized
Elimination half-life42.4 hours
Excretion59% Bile, 33% kidney
Identifiers
  • N-[(5aR,6aS,7S,9Z,10aS)-9-(amino-hydroxy-methylidene)-4,7-bis(dimethylamino)-1,10a,12-trihydroxy-8,10,11-trioxo-5a,6,6a,7-tetrahydro-5H-tetracen-2-yl]-2-(tert-butylamino) acetamide[4]
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.211.439 Edit this at Wikidata
Chemical and physical data
FormulaC29H39N5O8
Molar mass585.658 g·mol−1
3D model (JSmol)
  • CC(C)(C)NCC(=O)Nc1cc(c2C[C@H]3C[C@H]4[C@H](N(C)C)C(\O)=C(\C(N)=O)C(=O)[C@@]4(O)C(/O)=C3/C(=O)c2c1O)N(C)C
  • InChI=1S/C29H39N5O8/c1-28(2,3)31-11-17(35)32-15-10-16(33(4)5)13-8-12-9-14-21(34(6)7)24(38)20(27(30)41)26(40)29(14,42)25(39)18(12)23(37)19(13)22(15)36/h10,12,14,21,31,36,38-39,42H,8-9,11H2,1-7H3,(H2,30,41)(H,32,35)/t12-,14-,21-,29-/m0/s1 checkY
  • Key:FPZLLRFZJZRHSY-HJYUBDRYSA-N checkY
  (verify)

Tigecycline, sold under the brand name Tygacil, is an tetracycline antibiotic medication for a number of bacterial infections.[2][5][6] It is a glycylcycline administered intravenously. It was developed in response to the growing rate of antibiotic resistant bacteria such as Staphylococcus aureus, Acinetobacter baumannii, and E. coli.[5] As a tetracycline derivative antibiotic, its structural modifications has expanded its therapeutic activity to include Gram-positive and Gram-negative organisms, including those of multi-drug resistance.

It was given a U.S. Food and Drug Administration (FDA) fast-track approval and was approved on 17 June 2005.[5][6] It was approved for medical use in the European Union in April 2006.[3]

It was removed from the World Health Organization's List of Essential Medicines in 2019.[7][8] The World Health Organization classifies tigecycline as critically important for human medicine.[9]

Medical uses

Antibacterial use

Tigecycline is used to treat different kinds of bacterial infections, including complicated skin and structure infections, complicated intra-abdominal infections and community-acquired bacterial pneumonia. Tigecycline is a glycylcycline antibiotic that covers MRSA and Gram-negative organisms:

Tigecycline is given intravenously and has activity against a variety of Gram-positive and Gram-negative bacterial pathogens, many of which are resistant to existing antibiotics. Tigecycline successfully completed phase III trials in which it was at least equal to intravenous vancomycin and aztreonam to treat complicated skin and skin structure infections, and to intravenous imipenem and cilastatian to treat complicated intra-abdominal infections.[11] Tigecycline is active against many Gram-positive bacteria, Gram-negative bacteria and anaerobes – including activity against methicillin-resistant Staphylococcus aureus (MRSA), Stenotrophomonas maltophilia, Haemophilus influenzae, and Neisseria gonorrhoeae (with MIC values reported at 2 µg/mL) and multi-drug resistant strains of Acinetobacter baumannii. It has no activity against Pseudomonas spp. or Proteus spp. The drug is licensed for the treatment of skin and soft tissue infections as well as intra-abdominal infections.

The European Society of Clinical Microbiology and Infection recommends tigecycline as a potential salvage therapy for severe and/or complicated or refractory Clostridium difficile infection.[12]

Tigecycline can also be used in vulnerable populations such as immunocompromised patients or patients with cancer.[12] Tigecycline may also have potential for use in acute myeloid leukemia.[13]

Non-Antibacterial use

It is well established that tigecycline works as an effective antibiotic, however it may have other properties that are not yet fully understood.[14] Minocycline has been shown to have anti-inflammatory and anti-apoptotic activities, inhibition of proteolysis and suppression of angiogenesis and tumor metastasis.[14] This is a feature not unique to minocycline, with many tetracyclines exhibiting non-antibiotic clinical benefits.[15][16] Tigecycline has shown in vitro and in vivo activity against acute myeloid leukemia. The antileukemic activity of tigecycline can be attributed to the inhibition of mitochondrial protein translation in eukaryotic cells. Leukemic cells have an increased dependence on mitochondrial function, causing a heightened sensitivity to tigecycline.[17] Tigecycline has also shown anti-cancer properties against several other kinds of tumors, including non-small cell lung cancer, gastric cancer, hepatocellular carcinoma, and glioblastoma.[18]

Susceptibility data

Tigecycline targets both Gram-positive and Gram-negative bacteria including a few key multi-drug resistant pathogens. The following represents MIC susceptibility data for a few medically significant bacterial pathogens.

  • Escherichia coli: 0.015 μg/mL — 4 μg/mL
  • Klebsiella pneumoniae: 0.06 μg/mL — 16 μg/mL
  • Staphylococcus aureus (methicillin-resistant): 0.03 μg/mL — 2 μg/mL[19]

Tigecycline generally has poor activity against most strains of Pseudomonas.[20]

Liver or kidney problems

Tigecycline does not require dose adjustment for people with mild to moderate liver problems. However, in people with severe liver problems dosing should be decreased and closely monitored.[10]

Tigecycline does not require dose changes in people with poor kidney function or having hemodialysis.[10]

Resistance mechanisms

Bacterial resistance towards tigecycline in Enterobacteriaceae (such as E. coli) is often caused by genetic mutations leading to an up-regulation of bacterial efflux pumps, such as the RND type efflux pump AcrAB. Some bacterial species such as Pseudomonas spp. can be naturally resistant to tigecycline through the constant over-expression of such efflux pumps. In some Enterobacteriaceae species, mutations in ribosomal genes such as rpsJ have been found to cause resistance to tigecycline.[21]

Side effects

As a tetracycline derivative, tigecycline exhibits similar side effects to the class of antibiotics. Gastrointestinal (GI) symptoms are the most common reported side effect.[12]

Common side effects of tigecycline include nausea and vomiting.[22] Nausea (26%) and vomiting (18%) tend to be mild or moderate and usually occur during the first two days of therapy.[2]

Rare adverse effects (<2%) include: swelling, pain, and irritation at injection site, anorexia, jaundice, hepatic dysfunction, pruritus, acute pancreatitis, and increased prothrombin time.[2]

Precautions

Precaution is needed when taken in individuals with tetracycline hypersensitivity, pregnant women, and children. It has been found to cause fetal harm when administered during pregnancy and therefore is classified as pregnancy category D.[10] In rats or rabbits, tigecycline crossed the placenta and was found in the fetal tissues, and is associated with slightly lower birth weights as well as slower bone ossification. Even though it was not considered teratogenic, tigecycline should be avoided unless benefits outweigh the risks.[2] In addition, its use during childhood can cause yellow-grey-brown discoloration of the teeth and should not be used unless necessary.

More so, there are clinical reports of tigecycline-induced acute pancreatitis, with particular relevance to patients also diagnosed with cystic fibrosis.[23]

Tigecycline showed an increased mortality in patients treated for hospital-acquired pneumonia, especially ventilator-associated pneumonia (a non-approved use), but also in patients with complicated skin and skin structure infections, complicated intra-abdominal infections and diabetic foot infection.[2] Increased mortality was in comparison to other treatment of the same types of infections. The difference was not statistically significant for any type, but mortality was numerically greater for every infection type with Tigecycline treatment, and prompted a black box warning by the FDA.[24][25]

Black box warning

The FDA issued a black box warning in September 2010, for tigecycline regarding an increased risk of death compared to other appropriate treatment.[24][2][26] As a result of increase in total death rate (cause is unknown) in individuals taking this drug, tigecycline is reserved for situations in which alternative treatment is not suitable.[10][26] The FDA updated the black box warning in 2013.[25]

Drug interactions

Tigecycline has been found to interact with medications, such as:

  • Warfarin: Since both tigecycline and warfarin bind to serum or plasma proteins, there is potential for protein-binding interactions, such that one drug will have more effect than the other. Although dose adjustment is not necessary, INR and prothrombin time should be monitored if given concurrently.[27]
  • Oral contraceptives: Effectiveness of oral contraceptives are decreased with concurrent use due to reduction in the concentration levels of oral contraceptives.

However, the mechanism behind these drug interactions have not been fully analyzed.[2]

History

Minocycline was a commonly used tetracycline synthesized in Lederle Laboratories in 1970, but antibiotic resistance to the drug began growing in prevalence throughout the 70's and 80's.[28][29] While the problem of antibiotic resistance was known to scientists during the 1980s, the conservative-era politics of both America and Great Britain led to little federal attention given to the emerging crisis. However, by the late 1980s the worldwide threat began to be treated more seriously, which led to the renewed funding of antibiotic research.[30]

In 1993, researchers in the same laboratories that first synthesized minocycline created a new generation of tetracycline antibacterial agents, known as the glycylcyclines. These antibiotics were the first new drugs of the tetracycline class to be reported since the discovery of minocycline in 1970.[31] The glycylcyclines were found to be active against a broad spectrum of tetracycline susceptible and resistant Gram (-) and Gram (+) aerobic and anaerobic bacteria. This initial research resulted in numerous studies being done on the antibacterial activity of various glycylcyclines, with extra focus being put on N,N-dimethylglycyl-amino derivatives, due to their reported potency.[32][33] The aforementioned research culminated in a 1999 paper describing the discovery of a compound known as GAR-936, which would later be known as Tigecycline.[34]

Mechanism of action

Tigecycline is broad-spectrum antibiotic that acts as a protein synthesis inhibitor. It exhibits bacteriostatic activity by binding to the 30S ribosomal subunit of bacteria and thereby blocking the interaction of aminoacyl-tRNA with the A site of the ribosome.[35] In addition, tigecycline has demonstrated bactericidal activity against isolates of S. pneumoniae and L. pneumophila.[2]

Studies have shown that tigecycline binds to the 70S ribosome with 5 fold and >100 fold greater affinity than minocycline and tetracycline, respectively .[36] As previously mentioned, tigecycline still binds to the A site of the 30S ribosomal subunit, however the binding of the novel antibiotic involves substantial interactions with residues of helix H34 of that same subunit. These interactions are not observed in the binding of tetracycline.[37] The findings indicate that tigecycline likely has a unique mechanism of action that prevents inhibition from ribosomal protection.[36]

It is a third-generation tetracycline derivative within a class called glycylcyclines which carry a N,N-dimethyglycylamido (DMG) moiety attached to the 9-position of tetracycline ring D.[38] With structural modifications as a 9-DMG derivative of minocycline, tigecycline has been found to improve minimal inhibitory concentrations against Gram-negative and Gram-positive organisms, when compared to tetracyclines.[38]

Pharmacokinetics

Tigecycline is metabolized through glucuronidation into glucuronide conjugates and N-acetyl-9-aminominocycline metabolite.[39] Therefore, dose adjustments are needed for patients with severe hepatic impairment.[2] More so, it is primarily eliminated unchanged in the feces and secondarily eliminated by the kidneys.[39] No renal adjustments are necessary.

Society and culture

Approval

It is approved to treat complicated skin and soft tissue infections (cSSTI), complicated intra-abdominal infections (cIAI), and community-acquired bacterial pneumonia (CAP) in individuals 18 years and older.[5][6][39][2] In the United Kingdom it is approved in adults and in children from the age of eight years for the treatment of complicated skin and soft tissue infections (excluding diabetic foot infections) and complicated intra-abdominal infections in situations where other alternative antibiotics are not suitable.[40]

Other names

  • GAR-936[41]
  • Tygacil
  • Tigeplug (marketed by Biocon, India)
  • Tigilyn (Marketed by Real Value therapy pharmaceuticals company in Myanmar, Manufactured by Lyka)
  • TIGILITE (marketed in INDIA, Scutonix Lifesciences, Bombay)

References

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  2. ^ a b c d e f g h i j k "Tygacil- tigecycline injection, powder, lyophilized, for solution". DailyMed. 20 July 2020. Retrieved 26 September 2020.
  3. ^ a b "Tygacil EPAR". European Medicines Agency (EMA) (in Aragonese). Retrieved 26 September 2020.
  4. ^ "EP2181330". European Patent Office. Retrieved 29 September 2017.
  5. ^ a b c d Rose W, Rybak M (2006). "Tigecycline: first of a new class of antimicrobial agents". Pharmacotherapy. 26 (8): 1099–110. doi:10.1592/phco.26.8.1099. PMID 16863487. S2CID 29714610.
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  7. ^ World Health Organization (2019). Executive summary: the selection and use of essential medicines 2019: report of the 22nd WHO Expert Committee on the selection and use of essential medicines. Geneva: World Health Organization. hdl:10665/325773. WHO/MVP/EMP/IAU/2019.05. License: CC BY-NC-SA 3.0 IGO.
  8. ^ World Health Organization (2019). The selection and use of essential medicines: report of the WHO Expert Committee on Selection and Use of Essential Medicines, 2019 (including the 21st WHO Model List of Essential Medicines and the 7th WHO Model List of Essential Medicines for Children). Geneva: World Health Organization. hdl:10665/330668. ISBN 9789241210300. ISSN 0512-3054. WHO technical report series;1021.
  9. ^ World Health Organization (2019). Critically important antimicrobials for human medicine (6th revision ed.). Geneva: World Health Organization. hdl:10665/312266. ISBN 9789241515528.
  10. ^ a b c d e f g "TYGACIL U.S. Physician Prescribing Information". Pfizer. Retrieved 31 October 2015.
  11. ^ Scheinfeld N (2005). "Tigecycline: a review of a new glycylcycline antibiotic". Journal of Dermatological Treatment. 16 (4): 207–12. doi:10.1080/09546630510011810. PMID 16249141. S2CID 28869637.
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  • "Tigecycline". Drug Information Portal. U.S. National Library of Medicine.
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