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'''Tigecycline''' is an [[antibiotic]] used to treat a number of [[bacterial infections]].<ref name="Rose-Rybak">{{Cite journal|vauthors=Rose W, Rybak M |title = Tigecycline: first of a new class of antimicrobial agents.|journal = Pharmacotherapy|volume = 26|issue = 8|pages = 1099–110|year = 2006|pmid = 16863487|doi = 10.1592/phco.26.8.1099}}</ref><ref name="Kasbekar">{{Cite journal|author = Kasbekar N|title = Tigecycline: a new glycylcycline antimicrobial agent.|journal = Am J Health Syst Pharm|volume = 63|issue = 13|pages = 1235–43|year = 2006|pmid = 16790575|doi = 10.2146/ajhp050487}}</ref> It is a [[glycylcycline]] that is administered intravenously. It was developed in response to the growing rate of [[antibiotic resistance]] in bacteria such as ''[[Staphylococcus aureus]]'', ''[[Acinetobacter baumannii]]'', and ''[[Escherichia coli|E. coli]]''.<ref name="Rose-Rybak" /> 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.
'''Tigecycline''' is an [[antibiotic]] for a number of [[bacterial infections]].<ref name="Rose-Rybak">{{Cite journal|vauthors=Rose W, Rybak M |title = Tigecycline: first of a new class of antimicrobial agents.|journal = Pharmacotherapy|volume = 26|issue = 8|pages = 1099–110|year = 2006|pmid = 16863487|doi = 10.1592/phco.26.8.1099}}</ref><ref name="Kasbekar">{{Cite journal|author = Kasbekar N|title = Tigecycline: a new glycylcycline antimicrobial agent.|journal = Am J Health Syst Pharm|volume = 63|issue = 13|pages = 1235–43|year = 2006|pmid = 16790575|doi = 10.2146/ajhp050487}}</ref> 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 ''[[Escherichia coli|E. coli]]''.<ref name="Rose-Rybak" /> 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.


Tigecycline is marketed by [[Pfizer]] under the brand name '''Tygacil.''' It was given a U.S. [[Food and Drug Administration]] (FDA) fast-track approval and was approved on June 17, 2005.<ref name="Rose-Rybak" /><ref name="Kasbekar" />
Tigecycline is marketed by [[Pfizer]] under the brand name '''Tygacil.''' It was given a U.S. [[Food and Drug Administration]] (FDA) fast-track approval and was approved on June 17, 2005.<ref name="Rose-Rybak" /><ref name="Kasbekar" />

Revision as of 16:26, 2 August 2018

Tigecycline
Clinical data
Pronunciation/ˌtaɪɡəˈsaɪkliːn/
Trade namesTygacil
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: D
Routes of
administration		IV only
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding71–89%
MetabolismNot metabolized
Elimination half-life42.4 hours
Excretion59% biliary, 33% renal
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[1]
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 mass585.65 g/mol 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 is an antibiotic for a number of bacterial infections.[2][3] 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.[2] 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.

Tigecycline is marketed by Pfizer under the brand name Tygacil. It was given a U.S. Food and Drug Administration (FDA) fast-track approval and was approved on June 17, 2005.[2][3]

Medical uses

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. The spectrum of activity of tigecycline is discussed below.

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.[5] 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.[6]

Tigecycline can also be used in vulnerable populations such as immunocompromised patients or patients with cancer.[6] Tigecycline may also have potential for use in acute myeloid leukemia.[7]

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[8]

Tigecycline generally has poor activity against most strains of Pseudomonas.[9]

Dosing

Tigecycline is given by slow intravenous infusion (30 to 60 minutes) every 12 hours. People with impaired liver function need to be given a lower dose. No adjustment is needed for patients with impaired kidney function. It is not licensed for use in children. There is no oral form available.[4]

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.[4]

Tigecycline does not require dose changes in people with poor kidney function or having hemodialysis.[4]

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.[10]

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.[6]

Common side effects of tigecycline include nausea and vomiting.[11] Nausea (26%) and vomiting (18%) tend to be mild or moderate and usually occur during the first two days of therapy.[12]

Rare adverse effects (<2%) include: swelling, pain, and irritation at injection site, anorexia, jaundice, hepatic dysfunction, pruritus, acute pancreatitis, and increased prothrombin time.[12]

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.[4] 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.[12] 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.[13]

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.[12] 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.[14]

Black box warning

FDA issued a black box warning in September 2010 for tigecycline regarding an increased risk of death compared to other appropriate treatment.[12][15] 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.[4][15]

In 2010, the U.S. Food and Drug Administration (FDA) updated the warnings section of the drug label to include information regarding increased mortality risk (seen most clearly in people treated for hospital-acquired pneumonia, especially ventilator-associated pneumonia).

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.[16]
  • 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.[12]

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.[17] In addition, tigecycline has demonstrated bactericidal activity against isolates of S. pneumoniae and L. pneumophila.[12]

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.[18] 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.[18]

Pharmacokinetics

Tigecycline is metabolized through glucuronidation into glucuronid conjugates and N-acetyl-9-aminominocycline metabolite.[19] Therefore, dose adjustments are needed for patients with severe hepatic impairment.[12] More so, it is primarily eliminated unchanged in the feces and secondarily eliminated by the kidneys.[19] 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.[2][3][19][12] 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.[20]

Other names

  • GAR-936[21]
  • Tygacil
  • Tigeplug (marketed by Biocon, India)

References

  1. ^ "EP2181330". European Patent Office. Retrieved 29 September 2017.
  2. ^ 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.
  3. ^ a b c Kasbekar N (2006). "Tigecycline: a new glycylcycline antimicrobial agent". Am J Health Syst Pharm. 63 (13): 1235–43. doi:10.2146/ajhp050487. PMID 16790575.
  4. ^ a b c d e f g h "TYGACIL U.S. Physician Prescribing Information". Pfizer. Retrieved 2015-10-31.
  5. ^ 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. {{cite journal}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  6. ^ a b c Kaewpoowat, Quanhathai; Ostrosky-Zeichner, Luis (2015-02-01). "Tigecycline: a critical safety review". Expert Opinion on Drug Safety. 14 (2): 335–342. doi:10.1517/14740338.2015.997206. ISSN 1474-0338. PMID 25539800.
  7. ^ Skrtić, M; Sriskanthadevan, S; Jhas, B; Gebbia, M; Wang, X; Wang, Z; Hurren, R; Jitkova, Y; Gronda, M; Maclean, N; Lai, CK; Eberhard, Y; Bartoszko, J; Spagnuolo, P; Rutledge, AC; Datti, A; Ketela, T; Moffat, J; Robinson, BH; Cameron, JH; Wrana, J; Eaves, CJ; Minden, MD; Wang, JC; Dick, JE; Humphries, K; Nislow, C; Giaever, G; Schimmer, AD (2011). "Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia". Cancer Cell. 20 (5): 674–688. doi:10.1016/j.ccr.2011.10.015.
  8. ^ "Tigecycline : Susceptibility and Minimum Inhibitory Concentration (MIC) Data" (PDF). Toku-e.com. Retrieved 2017-03-13.
  9. ^ Tygacil [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals; 2005. Updated July 2010.
  10. ^ Pournaras, Spyros; Koumaki, Vasiliki; Spanakis, Nicholas; Gennimata, Vasiliki; Tsakris, Athanassios. "Current perspectives on tigecycline resistance in Enterobacteriaceae: susceptibility testing issues and mechanisms of resistance". International Journal of Antimicrobial Agents. 48 (1): 11–18. doi:10.1016/j.ijantimicag.2016.04.017.
  11. ^ Muralidharan, Gopal (January 2005). "Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects". Antimicrobial Agents and Chemotherapy. 49: 220–229. doi:10.1128/aac.49.1.220-229.2005. PMC 538906. PMID 15616299.
  12. ^ a b c d e f g h i Wyeth Pharmaceuticals Inc. "Food and Drug Administration, TYGACIL® (tigecycline) FOR INJECTION for intravenous use Prescribing Information" (PDF). FDA U.S. Food and Drug Administration. U.S. Department of Health & Human Services. p. 16.
  13. ^ Hemphill MT, Jones KR (2015). "Tigecycline-induced acute pancreatitis in a cystic fibrosis patient: A case report and literature review". J Cyst Fibros. 15 (1): e9–11. doi:10.1016/j.jcf.2015.07.008. PMID 26282838.
  14. ^ "FDA Drug Safety Communication: Increased risk of death with Tygacil (tigecycline) compared to other antibiotics used to treat similar infections". Fda.gov. 2013-09-27. Retrieved 2017-03-13.
  15. ^ a b Dixit, Deepali (March 6, 2014). "The role of tigecycline in the treatment of infections in light of the new black box warning". Expert Review of Anti-infective Therapy. 12 (4): 397–400. doi:10.1586/14787210.2014.894882. PMID 24597542.
  16. ^ Zimmerman, James J.; Raible, Donald G.; Harper, Dawn M.; Matschke, Kyle; Speth, John L. (2008-07-01). "Evaluation of a Potential Tigecycline-Warfarin Drug Interaction". Pharmacotherapy: the Journal of Human Pharmacology and Drug Therapy. 28 (7): 895–905. doi:10.1592/phco.28.7.895. ISSN 1875-9114.
  17. ^ Tigecycline: A Novel Broad-Spectrum Antimicrobial: Pharmacology and Mechanism of Action Christine M. Slover, PharmD, Infectious Diseases Fellow, Keith A. Rodvold, PharmD and Larry H. Danziger, PharmD, Professor, Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, IL
  18. ^ a b Nguyen, Fabian (May 2014). "Tetracycline antibiotics and resistance mechanisms". Biol Chem. 395 (5). doi:10.1515/hsz-2013-0292.
  19. ^ a b c Hoffman, Matthew (May 25, 2007). "Metabolism, Excretion, and Pharmacokinetics of [14C]Tigecycline, a First-In-Class Glycylcycline Antibiotic, after Intravenous Infusion to Healthy Male Subjects". Drug Metabolism and Disposition. 35 (9): 1543–1553. doi:10.1124/dmd.107.015735.
  20. ^ "Tygacil 50mg powder for solution for infusion - Summary of Product Characteristics (SPC) - (eMC)". Medicines.org.uk. Retrieved 2017-03-13.
  21. ^ Betriu C, Rodríguez-Avial I, Sánchez BA, Gómez M, Picazo JJ (2002). "Comparative in vitro activities of tigecycline (GAR-936) and other antimicrobial agents against Stenotrophomonas maltophilia". J Antimicrob Chemother. 50 (5): 758–59. doi:10.1093/jac/dkf196. PMID 12407139.
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