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Tigecycline

tigecycline antibiotic, tigecycline
Tigecycline is an antibiotic used to treat a number of bacterial infections 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 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 marketed by Pfizer under the brand name Tygacil It was given a US Food and Drug Administration FDA fast-track approval and was approved on June 17, 2005

Contents

  • 1 Medical uses
    • 11 Susceptibility data
    • 12 Dosing
    • 13 Liver or kidney problems
    • 14 Resistance mechanisms
  • 2 Side effects
    • 21 Precautions
    • 22 Black box warning
    • 23 Drug interactions
  • 3 Mechanism of action
  • 4 Pharmacokinetics
  • 5 Society and culture
    • 51 Approval
    • 52 Other names
  • 6 References

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

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:0015 μg/mL — 4 μg/mL
  • Klebsiella pneumoniae:006 μg/mL — 16 μg/mL
  • Staphylococcus aureus methicillin-resistant:003 μg/mL — 2 μg/mL

Tigecycline generally has poor activity against most strains of Pseudomonas

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

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

Tigecycline does not require dose changes in people with poor kidney function or having hemodialysis

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

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

Common side effects of tigecycline include nausea and vomiting Nausea 26% and vomiting 18% tend to be mild or moderate and usually occur during the first two days of therapy

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

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 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

More so, there are clinical reports of tigecycline-induced acute pancreatitis, with particular relevance to patients also diagnosed with cystic fibrosis

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 US 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
  • 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

Pharmacokinetics

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

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 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

Other names

  • GAR-936
  • 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:101592/phco2681099 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:102146/ajhp050487 PMID 16790575 
  4. ^ a b c d e f g h "TYGACIL US 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:101080/09546630510011810 PMID 16249141 
  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:101517/147403382015997206 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:101016/jccr201110015 
  8. ^ "Tigecycline :Susceptibility and Minimum Inhibitory Concentration MIC Data" PDF Toku-ecom Retrieved 2017-03-13 
  9. ^ TygacilPhiladelphia, 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:101016/jijantimicag201604017 
  11. ^ Muralidharan, Gopal January 2005 "Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects" Antimicrobial Agents and Chemotherapy 49:220–229 doi:101128/aac491220-2292005 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 US Food and Drug Administration US 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:101016/jjcf201507008 PMID 26282838 
  14. ^ "FDA Drug Safety Communication:Increased risk of death with Tygacil tigecycline compared to other antibiotics used to treat similar infections" Fdagov 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:101586/147872102014894882 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:101592/phco287895 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:101515/hsz-2013-0292 
  19. ^ a b c Hoffman, Matthew May 25, 2007 "Metabolism, Excretion, and Pharmacokinetics of Tigecycline, a First-In-Class Glycylcycline Antibiotic, after Intravenous Infusion to Healthy Male Subjects" Drug Metabolism and Disposition 35 9:1543–1553 doi:101124/dmd107015735 
  20. ^ "Tygacil 50mg powder for solution for infusion - Summary of Product Characteristics SPC - eMC" Medicinesorguk 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:101093/jac/dkf196 PMID 12407139 

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