Tigecycline is the First Clinically-Available Drug in a new class of Antibiotics called the Glycylcyclines: A Review

Mr. Mayur S. Jain*, Dr. Shashikant D. Barhate

Shree Sureshadada Jain Institutes of Pharmaceutical Education and Research, Jammer, Maharashtra (India).

*Corresponding Author E-mail: mayurjain176@gmail.com

ABSTRACT:

Tigecycline is a glycylcycline antibiotic developed and marketed by Wyeth under the brand name Tygacil. It was developed in response to the growing prevalence of antibiotic resistance in bacteria such as Staphylococcus aureus. It was granted fast-track approval by the U.S. Food and Drug Administration (FDA) on June 17, 2005. Tigecycline is the first clinically-available drug in a new class of antibiotics called the glycylcyclines. Glycylcyclines are a new class of antibiotics derived from tetracycline. These tetracycline analogues are specifically designed to overcome two common mechanisms of tetracycline resistance, namely resistance mediated by acquired efflux pumps and/or ribosomal protection. Glycylcycline antibiotics have a similar mechanism of action as tetracycline antibiotics. Both classes of antibiotics bind to the 30S ribosomal subunit to prevent the amino-acyl tRNA from binding to the A site of the ribosome. However, the glycylcyclines appear to bind more effectively than the tetracyclines.

KEYWORDS: Tigecycline

INTRODUCTION:

Tigecycline is an antibiotic for a quantity 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 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 17 June 2005.[2][3]

It was removed from the World Health Organization's List of Essential Medicines in 2019.

Tigecycline, a glycylcycline, inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. This prevents incorporation of amino acid residues into elongating peptide chains. Tigecycline carries a glycylamido moiety attached to the 9-position of minocycline. The substitution pattern is not present in any naturally occurring or semisynthetic tetracycline and imparts certain microbiologic properties to tigecycline. Tigecycline is not affected by the two major tetracycline resistance mechanisms, ribosomal protection and efflux. Accordingly, tigecycline has demonstrated in vitro and in vivo activity against a broad spectrum of bacterial pathogens. There has been no cross resistance observed between tigecycline and other antibiotics. Tigecycline is not affected by resistance mechanisms such as beta-lactamases (including extended spectrum beta-lactamases), target site modifications, macrolide efflux pumps or enzyme target changes (e.g. gyrase/topoisomerase). In vitro studies have not demonstrated antagonism between tigecycline and other commonly used antibacterial drugs. In general, tigecycline is considered bacteriostatic. [3][4]

TYGACIL (tigecycline) is a tetracycline class antibacterial for intravenous infusion. The chemical name of tigecycline is (4S,4aS,5aR,12aS)-9-[2-(tert-butylamino) acetamido]-4,7bis (dimethylamino) -1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2naphthacenecarboxamide. The empirical formula is C29H39N5O8 and the molecular weight is 585.65. [2][3]

The following represents the chemical structure of tigecycline:

Figure 1: Structure of Tigecycline

TYGACIL is an orange lyophilized powder or cake. Each TYGACIL single-dose 5 mL or 10 mL vial contains 50 mg tigecycline lyophilized powder for reconstitution for intravenous infusion and 100 mg of lactose monohydrate. The pH is adjusted with hydrochloric acid, and if necessary sodium hydroxide. The product does not contain preservatives.

Chemical formula: C29H39N5O8

Weight: Average: 585.6487, Monoisotopic: 585.279863249.

IUPAC Name: (4S, 4aS, 5aR, 12aS)-9-[2-(tert-butylamino) acetamido]-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1, 4, 4a, 5, 5a, 6, 11, 12a-octahydrotetracene-2-carboxamide

Indication:

Complicated Skin and Skin Structure Infections

Tigecycline for injection is indicated in patients 18 years of age and older for the treatment of complicated skin and skin structure infections caused by susceptible isolates of Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis. [4][6]

Pharmacodynamics:

Tigecycline is the first clinically-available drug in a new class of antibiotics called the glycylcyclines. Glycylcyclines are a new class of antibiotics derived from tetracycline. These tetracycline analogues are specifically designed to overcome two common mechanisms of tetracycline resistance, namely resistance mediated by acquired efflux pumps and/or ribosomal protection. Glycylcycline antibiotics have a similar mechanism of action as tetracycline antibiotics. Both classes of antibiotics bind to the 30S ribosomal subunit to prevent the amino-acyl tRNA from binding to the A site of the ribosome. However, the glycylcyclines appear to bind more effectively than the tetracyclines. [1][3]

Mechanism of action:

Proteinbinding: 71% to 89%

Metabolism:

Tigecycline is not extensively metabolized. In vitro studies with tigecycline using human liver microsomes, liver slices, and hepatocytes led to the formation of only trace amounts of metabolites. A glucuronide, an N-acetyl metabolite, and a tigecycline epimer (each at no more than 10% of the administered dose) are the primary metabolites. [4][6]

Half life: 27-43 hours

Toxicity:

Since glycylcyclines are similar to tetracyclines, they share many of the same side effects and contraindications as tetracyclines. These side effects may include nausea/vomiting, headache, photosensitivity, discoloration of growing teeth, and fetal damage.

Usage:

To reduce the development of drug-resistant bacteria and maintain the effectiveness of TYGACIL and other antibacterial drugs, TYGACIL should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to tigecycline. TYGACIL may be initiated as empiric monotherapy before results of these tests are known.

Side Effects:

Nausea, vomiting, headache, dizziness, or pain/swelling at the injection site may occur. If any of these effects last or get worse, tell your doctor or pharmacist promptly.

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.[17]

· 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.

Synthesis:

CONCLUSION:

ACKNOWLEDGEMENT:

The authors would like to thanks Shree. Sureshadada Jain Institutes of Pharmaceutical Education and Research, Jamner Maharashtra (India) for supporting the fulfillment of this work.

CONFLICT OF INTEREST:

Declared none.

REFERENCES:

1. Www.drugbank.com

2. "EP2181330". European Patent Office. Retrieved 29 September 2017.

3. Jump up to: 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.

4. Jump up to: 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

5. Rose WE, Rybak MJ: Tigecycline: first of a new class of antimicrobial agents. Pharmacotherapy. 2006 Aug; 26(8):1099-110. [Pub Med:16863487]

6. Kasbekar N: Tigecycline: a new glycylcycline antimicrobial agent. Am J Health Syst Pharm. 2006 Jul 1;63(13):1235-43. [PubMed:16790575]

Received on 12.12.2019 Modified on 10.01.2020

Asian J. Pharm. Tech. 2020; 10(1):48-50.

DOI: 10.5958/2231-5713.2020.00010.0