Tigecycline
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| Systematic (IUPAC) name | |
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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
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| Pronunciation | /ˌtaɪɡəˈsaɪkliːn/ |
| Trade names | Tygacil |
| AHFS/Drugs.com | monograph |
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| 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 Number | 220620-09-7  |
| ATC code | J01AA12 (WHO) |
| PubChem | CID: 5282044 |
| DrugBank | DB00560 |
| ChemSpider | 10482314 |
| UNII | 70JE2N95KR |
| KEGG | D01079 |
| ChEBI | CHEBI:149836 |
| ChEMBL | CHEMBL376140 |
| 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 |
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Tigecycline (INN) is an antibiotic used to treat a number of bacterial infections.[1][2] It is a first in class 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 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 soft tissue 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]
Contents
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 can treat complicated skin and structure infections caused by; Escherichia coli, vancomycin-susceptible Enterococcus faecalis, methicillin-resistant Staphylococcus aureus , Streptococcus agalactiae, Streptococcus anginosus grp., Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis.[5]
- Tigecycline is indicated for treatment of complicated intra-abdominal infections caused by; Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, vancomycin-susceptible Enterococcus faecalis, methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus anginosus grp., Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.[5]
- Tigecycline may be used for treatment of community-acquired bacterial penumonia caused by; penicillin susceptible Streptococcus pneumoniae, Haemophilus influenzae that does not produce Beta-lactamase and Legionella pneumophila.[5]
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 cilastatin to treat complicated intra-abdominal infections.[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
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
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]
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.[5]
Tigecycline does not require dose changes in people with poor kidney function or having hemodialysis.[5]
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.[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.[11]
Rare adverse effects (<2%) include: swelling, pain, and irritation at injection site, anorexia, jaundice, hepatic dysfunction, pruritus, acute pancreatitis, and increased prothrombin time.[11]
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.[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.[11] 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.[12]
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.[11] 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.[13]
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.[4][14] 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.[5][14]
Drug interactions
Tigecycline have 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.[15]
- 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.[11]
Mechanism of action
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.[16] In addition, tigecycline has demonstrated bactericidal activity against isolates of S. pneumoniae and L. pneumophila.[17]
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.[3] Therefore, dose adjustments are needed for patients with severe hepatic impairment.[19] More so, it is primarily eliminated unchanged in the feces and secondarily eliminated by the kidneys.[3] No renal adjustments are necessary.
Other names
- GAR-936[20]
- Tygacil
References
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- ↑ http://www.toku-e.com/Assets/MIC/Tigecycline.pdf
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- ↑ http://www.fda.gov/Drugs/DrugSafety/ucm224370.htm
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- ↑ 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
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