|Elimination half-life||42.4 hours|
|Excretion||59% biliary, 33% renal|
|Chemical and physical data|
|Molar mass||585.65 g/mol|
|3D model (JSmol)|
Tigecycline is an antibiotic for a number of bacterial infections. 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. 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 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 can treat complicated skin and structure infections caused by; Escherichia coli, vancomycin-susceptible Enterococcus faecalis, methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus agalactiae, Streptococcus anginosus grp., Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis.
- 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.
- Tigecycline may be used for treatment of community-acquired bacterial pneumonia caused by; penicillin susceptible Streptococcus pneumoniae, Haemophilus influenzae that does not produce Beta-lactamase and Legionella pneumophila.
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. 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.
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
Tigecycline generally has poor activity against most strains of Pseudomonas.
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.
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.
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.
Rare adverse effects (<2%) include: swelling, pain, and irritation at injection site, anorexia, jaundice, hepatic dysfunction, pruritus, acute pancreatitis, and increased prothrombin time.
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. 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. In addition, its use during childhood can cause yellow-grey-brown discoloration of the teeth and should not be used unless necessary.
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.
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. 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.
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).
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.
- 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.
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. In addition, tigecycline has demonstrated bactericidal activity against isolates of S. pneumoniae and L. pneumophila.
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. 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.
Tigecycline is metabolized through glucuronidation into glucuronid conjugates and N-acetyl-9-aminominocycline metabolite. Therefore, dose adjustments are needed for patients with severe hepatic impairment. More so, it is primarily eliminated unchanged in the feces and secondarily eliminated by the kidneys. No renal adjustments are necessary.
Society and culture
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. 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.
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