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Clinical data
Pronunciation/ˌtaɪɡəˈsaɪkliːn/
Trade namesTygacil
Other namesN-[(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
AHFS/Drugs.comMonograph
Pregnancy
category
  • AU: D
Routes of
administration		IV only
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityNA
Protein binding71-89%
Metabolismnot metabolised
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-5,5a,6,6a,7,8,9,10,10a,11-decahydrotetracen-2-yl]-2-(tert-butylamino)acetamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
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 (INN) is a first in class glycylcycline antibiotic[1][2] that is adminstered intravenously. It was developed in response to the growing prevalence of antibiotic resistance in bacteria such as Staphylococcus aureus, Acinetobacter baumannii, and E. coli.[1] 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 is approved to treat complicated skin and skin structure infections (cSSTI), complicated intra-abdominal infections (cIAI), and community-acquired bacterial pneumonia (CAP) in individuals 18 years and older.[1] [2][3][4]

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.[1][2]

Medical uses edit

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 (cSSTI), and to intravenous imipenem and cilastatin to treat complicated intra-abdominal infections (cIAI).[6] 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.[7]

Tigecycline can also be used in vulnerable populations such as immunocompromised patients or patients with cancer.[7] Tigecycline may also have potential for use in acute myeloid leukemia.[8]

Susceptibility data edit

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

[9]

Dosing edit

Tigecycline is given by slow intravenous infusion (30 to 60 minutes) every 12 hours. Patients 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.[5]

Use in Patients with Hepatic Impairment edit

Tigecycline does not require dose adjustment for patients with mild to moderate hepatic impairment. However, based on the pharmacokinetic profile of tigecycline, patients with severe hepatic impairment, the initial dose dose of tigecycline should be 100 mg followed by a lower maintenance dose of 25 mg every 12 hours. Patients with severe hepatic dysfunction should be monitored closely and treated with caution.[5]

Use in Patients with Renal Impairment edit

Tigecycline does not require dose adjustment in patients with renal impairment or in patients undergoing hemodialysis. [5]

Adverse effects edit

As a tetracycline derivative, tigecycline exhibits similar side effects to the class of antibiotics. In human studies, gastrointestinal (GI) symptoms are the most common reported side effect.[7]

Common side effects of tigecycline include nausea and vomiting. [10] Nausea (26%) and vomiting (18%) tend to be mild or moderate and usually occur during the first two days of therapy.[4]

Rare adverse effects (<2%) include: swelling, pain, and irritation at injection site, anorexia, jaundice, hepatic dysfunction, pruritus, acute pancreatitis, and increased prothrombin time.[4]

Warnings and Precautions edit

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. [5] 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 [4] 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.[11]

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.[4] 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.[12]

Black Box Warning edit

FDA issued a black box warning in September 2010 for tigecycline stating an increased in all cause mortality in patients treated with tigecycline (4%) versus the comparator antibiotic (3%) with a risk difference of 0.6%.[13] As a result of the increase in all cause mortality, tigecycline is reserved for situations in which alternative treatment is not suitable[5].

Drug interactions edit

Tigecycline have been found to interact with medications, such as:[4]

  • 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.[14]
  • Oral Contraceptives: Effectiveness of oral contraceptives are decreased with concurrent use due to reduction in the concentration levels of oral contraceptives.

However, the mechanism of resistance is unknown.

Mechanism of action edit

Tigecycline is broad spectrum glycylcycline 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.[15] In addition, tigecycline has demonstrated bactericidal activity against isolates of S. pneumoniae and L. pneumophila.[4]

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. [16] 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.[16]

Pharmacokinetics edit

Tigecycline is metabolized through glucuronidation into glucuronid conjugates and N-acetyl-9-aminominocycline metabolite. [3] Therefore, dose adjustments are needed for patients with severe hepatic impairment. [4] More so, it is primarily eliminated unchanged in the feces and secondarily eliminated by the kidneys. [3] No renal adjustments are necessary.

Also known as edit

References edit

  1. ^ 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.
  2. ^ 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.
  3. ^ 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): 1543–53. doi:10.1124/dmd.107.015735. PMID 17537869. S2CID 5070076.
  4. ^ a b c d e f g h 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.
  5. ^ a b c d e f g h "TYGACIL U.S. Physician Prescribing Information". Pfizer. Retrieved 10/31/2015. {{cite web}}: Check date values in: |accessdate= (help)
  6. ^ 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.
  7. ^ 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. S2CID 43407481.
  8. ^ 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
  9. ^ http://www.toku-e.com/Assets/MIC/Tigecycline.pdf
  10. ^ Muralidharan, Gopal (January 2005). "Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects". Antimicrobial Agents and Chemotherapy. 49 (1): 220–9. doi:10.1128/AAC.49.1.220-229.2005. PMC 538906. PMID 15616299.
  11. ^ 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–e11. doi:10.1016/j.jcf.2015.07.008. PMID 26282838.
  12. ^ http://www.fda.gov/Drugs/DrugSafety/ucm224370.htm
  13. ^ 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. S2CID 36614422.
  14. ^ 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. PMID 18576904. S2CID 3474652.
  15. ^ 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
  16. ^ a b Nguyen, Fabian (May 2014). "Tetracycline antibiotics and resistance mechanisms". Biol Chem. 395 (5): 559–75. doi:10.1515/hsz-2013-0292. PMID 24497223. S2CID 12668198. Retrieved November 2, 2015.
  17. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)

External links edit

Category:Glycylcycline antibiotics Category:Amides

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