Tigecycline

Tigecycline

Systematic (IUPAC) name
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
Clinical data
Pronunciation
Trade names	Tygacil
AHFS/Drugs.com
Pregnancy category	AU: D US: D (Evidence of risk)
Legal status	AU: Prescription Only (S4) US: ℞-only
Routes of administration	IV only
Pharmacokinetic data
Bioavailability	NA
Protein binding	71-89%
Metabolism	not metabolised
Biological half-life	42.4 hours
Excretion	59% biliary, 33% renal
Identifiers
CAS Registry Number	Y
ATC code	J01
PubChem	CID:
DrugBank	Y
ChemSpider	Y
UNII	Y
KEGG	Y
ChEBI	Y
ChEMBL	Y
Synonyms	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
Chemical data
Formula	C29H39N5O8
Molecular mass	585.65 g/mol
SMILES 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 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 Y Key:FPZLLRFZJZRHSY-HJYUBDRYSA-N Y
Y

Tigecycline (INN) is a glycylcycline antibiotic^[1][2] 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. It was developed in response to the growing prevalence of antibiotic resistance in bacteria such as Staphylococcus aureus and Acinetobacter baumannii. The New Delhi metallo-β-Lactamase multidrug-resistant Enterobacteriaceae has also shown susceptibility to tigecycline.^[3]

Medical uses

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 (cSSSI), and to intravenous imipenem and cilastatin to treat complicated intra-abdominal infections (cIAI).^[4] 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.

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

^[5]

Dosing

Tigecycline is given by slow intravenous infusion (30 to 60 minutes). 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.

Side effects

Tigecycline has similar side effects to the tetracyclines. The most common side effects of tigecycline are diarrhea, nausea and vomiting. Nausea and vomiting is mild or moderate and usually occurs during the first two days of therapy. Other side effects include pain at the injection site, swelling and irritation; increased or decreased heart rate and infections. Also avoid use in children and pregnancy, due to its effects on teeth and bone. As with other antibiotics, overgrowth of organisms that are not susceptible to tigecycline can occur.

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. 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.^[6]

There are clinical reports of tigecycline-induced acute pancreatitis, with particular relevance to patients also diagnosed with cystic fibrosis.^[7]

Other uses

It may have potential for use in acute myeloid leukemia.^[8]

Structure

This antibiotic is the first clinically available drug in a new class of antibiotics called the glycylcyclines. It is structurally similar to the tetracyclines in that it contains a central four-ring carbocyclic skeleton and is actually a derivative of minocycline. Tigecycline has a substitution at the D-9 position which is believed to confer broad spectrum activity.

Mechanism of action

In general, tigecycline is considered bacteriostatic and is a protein synthesis inhibitor by binding to the 30S ribosomal subunit of bacteria and thereby blocking entry of Aminoacyl-tRNA into the A site of the ribosome during prokaryotic translation.^[9] Tigecycline has demonstrated bactericidal activity against isolates of S. pneumoniae and L. pneumophila.^[10]

Synonyms

• GAR-936^[11]
• Tygacil

References

External links

• Tygacil ( tigecycline iv ): Antibiotic for Skin Infections