Tigecycline, sold under the brand name Tygacil, is a tetracycline antibiotic medication for a number of bacterial infections. It is a glycylcycline class drug that is administered intravenously. It was developed in response to the growing rate of antibiotic resistant bacteria such as ''

Staphylococcus aureus ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often posi ...

'', ''

Acinetobacter baumannii ''Acinetobacter baumannii'' is a typically short, almost round, rod-shaped (coccobacillus) Gram-negative bacterium. It is named after the bacteriologist Paul Baumann. It can be an opportunistic pathogen in humans, affecting people with compromis ...

'', and '' E. coli''. As a tetracycline derivative antibiotic, its structural modifications has expanded its therapeutic activity to include

Gram-positive In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. The Gram stain is ...

and

Gram-negative Gram-negative bacteria are bacteria that, unlike gram-positive bacteria, do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. Their defining characteristic is that their cell envelope consists ...

organisms, including those of multi-drug resistance. It was given a U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) fast-track approval and was approved on 17 June 2005. It was approved for medical use in the European Union in April 2006. It was removed from the World Health Organization's List of Essential Medicines in 2019. The World Health Organization classifies tigecycline as critically important for human medicine.

Medical uses

Antibacterial use

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 ''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Escherichia'' that is commonly fo ...

'', vancomycin-susceptible ''

Enterococcus faecalis ''Enterococcus faecalis'' – formerly classified as part of the group D '' Streptococcus,'' is a Gram-positive, commensal bacterium naturally inhabiting the gastrointestinal tracts of humans. Like other species in the genus '' Enterococcus'', ' ...

'', methicillin-resistant ''Staphylococcus aureus'' (MRSA), ''

Streptococcus agalactiae ''Streptococcus agalactiae'' (also known as group B streptococcus or GBS) is a gram-positive coccus (round bacterium) with a tendency to form chains (as reflected by the genus name ''Streptococcus''). It is a beta-hemolytic, catalase-negative, an ...

'', ''

Streptococcus anginosus ''Streptococcus anginosus'' is a species of ''Streptococcus''. This species, '' Streptococcus intermedius'', and '' Streptococcus constellatus'' constitute the ''anginosus'' group, which is sometimes also referred to as the ''milleri'' group af ...

'' grp., ''

Streptococcus pyogenes ''Streptococcus pyogenes'' is a species of Gram-positive, aerotolerant bacteria in the genus '' Streptococcus''. These bacteria are extracellular, and made up of non-motile and non-sporing cocci (round cells) that tend to link in chains. They ...

'', ''

Enterobacter cloacae ''Enterobacter cloacae'' is a clinically significant Gram-negative, facultatively-anaerobic, rod-shaped bacterium. Microbiology In microbiology laboratories, ''E. cloacae'' is frequently grown at 30 °C on nutrient agar or at 35 ...

'', ''

Klebsiella pneumoniae ''Klebsiella pneumoniae'' is a Gram-negative, non-motile, encapsulated, lactose- fermenting, facultative anaerobic, rod-shaped bacterium. It appears as a mucoid lactose fermenter on MacConkey agar. Although found in the normal flora of the mo ...

'', and ''

Bacteroides fragilis ''Bacteroides fragilis'' is an anaerobic, Gram-negative, pleomorphic to rod-shaped bacterium. It is part of the normal microbiota of the human colon and is generally commensal, but can cause infection if displaced into the bloodstream or surrou ...

''. * Tigecycline is indicated for the treatment of complicated intra-abdominal infections caused by: ''

Citrobacter freundii ''Citrobacter'' is a genus of Gram-negative, aerobic, rod-shaped coliform bacteria of the Enterobacteriaceae family. ''Citrobacter'' spp. cause opportunistic infections (including urinary tract infections, gastroenteritis, and bacteremia). ...

'', ''Enterobacter cloacae'', ''Escherichia coli'', ''

Klebsiella oxytoca ''Klebsiella oxytoca'' is a Gram-negative, rod-shaped bacterium that is closely related to '' K. pneumoniae'', from which it is distinguished by being indole-positive; it also has slightly different growth characteristics in that it is able to gr ...

'', ''Klebsiella pneumoniae'', vancomycin-susceptible ''Enterococcus faecalis'', methicillin-resistant ''Staphylococcus aureus'' (MRSA), ''Streptococcus anginosus'' grp., ''Bacteroides fragilis'', ''

Bacteroides thetaiotaomicron ''Bacteroides thetaiotaomicron'' is a Gram-negative, obligate anaerobic bacterium and a prominent member of the human gut microbiota, particularly within the large intestine. ''B. thetaiotaomicron'' belongs to the ''Bacteroides'' genus – a gro ...

'', ''Bacteroides uniformis'', ''

Bacteroides vulgatus ''Bacteroides'' is a genus of Gram-negative, obligate anaerobic bacteria. ''Bacteroides'' species are non endospore–forming bacilli, and may be either motile or nonmotile, depending on the species. The DNA base composition is 40–48% GC. Unu ...

'', ''

Clostridium perfringens ''Clostridium perfringens'' (formerly known as ''C. welchii'', or ''Bacillus welchii'') is a Gram-positive, bacillus (rod-shaped), anaerobic, spore-forming pathogenic bacterium of the genus '' Clostridium''. ''C. perfringens'' is ever-present ...

'', and ''

Peptostreptococcus ''Peptostreptococcus'' is a genus of anaerobic, Gram-positive, non-spore forming bacteria. The cells are small, spherical, and can occur in short chains, in pairs or individually. They typically move using cilia. ''Peptostreptococcus'' are slow- ...

micros''. * Tigecycline may be used for treatment of community-acquired bacterial pneumonia caused by: penicillin-susceptible ''

Streptococcus pneumoniae ''Streptococcus pneumoniae'', or pneumococcus, is a Gram-positive, spherical bacteria, hemolysis (microbiology), alpha-hemolytic member of the genus ''Streptococcus''. ''S. pneumoniae'' cells are usually found in pairs (diplococci) and do not f ...

'', ''

Haemophilus influenzae ''Haemophilus influenzae'' (formerly called Pfeiffer's bacillus or ''Bacillus influenzae'') is a Gram-negative, Motility, non-motile, Coccobacillus, coccobacillary, facultative anaerobic organism, facultatively anaerobic, Capnophile, capnophili ...

'' that does not produce

Beta-lactamase Beta-lactamases (β-lactamases) are enzymes () produced by bacteria that provide multi-resistance to beta-lactam antibiotics such as penicillins, cephalosporins, cephamycins, monobactams and carbapenems ( ertapenem), although carbapene ...

and ''

Legionella pneumophila ''Legionella pneumophila'', the primary causative agent for Legionnaires' disease, Legionnaire's disease, is an Aerobic organism, aerobic, pleomorphic, Flagellum, flagellated, non-spore-forming, Gram-negative bacteria, Gram-negative bacterium. ' ...

''. Tigecycline is given intravenously and has activity against a variety of

and

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 Vancomycin is a glycopeptide antibiotic medication used to treat certain bacterial infections. It is administered intravenously ( injection into a vein) to treat complicated skin infections, bloodstream infections, endocarditis, bone an ...

and

aztreonam Aztreonam, sold under the brand name Azactam among others, is an antibiotic used primarily to treat infections caused by gram-negative bacteria such as ''Pseudomonas aeruginosa''. This may include bone infections, endometritis, intra abdomi ...

to treat complicated skin and skin structure infections, and to intravenous

imipenem Imipenem (trade name Primaxin among others) is a synthetic beta-lactam, β-lactam antibiotic belonging to the carbapenems chemical class. developed by Merck scientists Burton Christensen, William Leanza, and Kenneth Wildonger in the mid-1970s. Car ...

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 '' Stenotrophomonas maltophilia'' is an aerobic, nonfermentative, Gram-negative bacterium. It is an uncommon bacterium and human infection is difficult to treat. Initially classified as ''Bacterium bookeri'', then renamed ''Pseudomonas maltoph ...

'', ''Haemophilus influenzae'', and ''

Neisseria gonorrhoeae ''Neisseria gonorrhoeae'', also known as ''gonococcus'' (singular) or ''gonococci'' (plural), is a species of Gram-negative diplococci bacteria first isolated by Albert Ludwig Sigesmund Neisser, Albert Neisser in 1879. An obligate human pathog ...

'' (with MIC values reported at 2 μg/mL) and multi-drug resistant strains of ''

''. It has no activity against ''

Pseudomonas ''Pseudomonas'' is a genus of Gram-negative bacteria belonging to the family Pseudomonadaceae in the class Gammaproteobacteria. The 348 members of the genus demonstrate a great deal of metabolic diversity and consequently are able to colonize a ...

'' spp. or ''

Proteus In Greek mythology, Proteus ( ; ) is an early prophetic sea god or god of rivers and oceanic bodies of water, one of several deities whom Homer calls the "Old Man of the Sea" (''hálios gérôn''). Some who ascribe a specific domain to Prote ...

'' spp. The drug is licensed for the treatment of skin and soft tissue infections as well as intra-abdominal infections. "Tigecycline is also active against ''Clostridioides difficile'' strains. Most ''C. difficile'' isolates have MICs <0.25 for tigecycline The European Society of Clinical Microbiology and Infection recommends tigecycline as a potential salvage therapy for severe and/or complicated or refractory ''Clostridoides difficile'' infection. Tigecycline can also be used in vulnerable populations such as immunocompromised patients or patients with cancer.

Non-antibacterial use

It is well established that tigecycline works as an effective antibiotic; however, it may have other properties that are not yet fully understood.

Minocycline Minocycline, sold under the brand name Minocin among others, is a tetracycline antibiotic medication used to treat a number of bacterial infections such as some occurring in certain forms of pneumonia. It is generally (but not always) less pre ...

has been shown to have anti-inflammatory and anti-apoptotic activities, inhibition of

proteolysis Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Protein degradation is a major regulatory mechanism of gene expression and contributes substantially to shaping mammalian proteomes. Uncatalysed, the hydrolysis o ...

and suppression of

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...

and tumor metastasis. This is a feature not unique to minocycline, with many tetracyclines exhibiting non-antibiotic clinical benefits. Tigecycline has shown ''in vitro'' and ''in vivo'' activity against acute

myeloid leukemia Myeloid leukemia is a type of leukemia affecting myeloid tissue. Types include: * Acute myeloid leukemia: A cancer of the myeloid line of blood cells, characterized by the rapid growth of myeloblasts that build up in the bone marrow and blood and ...

. The antileukemic activity of tigecycline can be attributed to the inhibition of mitochondrial protein translation in eukaryotic cells. Leukemic cells have an increased dependence on mitochondrial function, causing a heightened sensitivity to tigecycline. Tigecycline has also shown anti-cancer properties against several other kinds of tumors, including non-small cell lung cancer, gastric cancer, hepatocellular carcinoma, and

glioblastoma Glioblastoma, previously known as glioblastoma multiforme (GBM), is the most aggressive and most common type of cancer that originates in the brain, and has a very poor prognosis for survival. Initial signs and symptoms of glioblastoma are nons ...

. It also shows good activity against the causative agent of

pythiosis Pythiosis is a rare and deadly tropical disease caused by the oomycete '' Pythium insidiosum''. Long regarded as being caused by a fungus, the causative agent was not discovered until 1987. It occurs most commonly in horses, dogs, and humans, wit ...

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 ''μ''g/mL — 4 ''μ''g/mL * ''Klebsiella pneumoniae'': 0.06 ''μ''g/mL — 16 ''μ''g/mL * ''Staphylococcus aureus'' (methicillin-resistant): 0.03 ''μ''g/mL — 2 ''μ''g/mL Tigecycline generally has poor activity against most strains of ''Pseudomonas''.

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 Hemodialysis, American and British English spelling differences#ae and oe, also spelled haemodialysis, or simply ''"'dialysis'"'', is a process of filtering the blood of a person whose kidneys are not working normally. This type of Kidney dialys ...

Resistance mechanisms

Bacterial resistance towards tigecycline in

Enterobacteriaceae Enterobacteriaceae is a large family (biology), family of Gram-negative bacteria. It includes over 30 genera and more than 100 species. Its classification above the level of Family (taxonomy), family is still a subject of debate, but one class ...

(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 In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually used ...

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 The pregnancy category of a medication is an assessment of the risk of Fetus, fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. It does ''not'' include any breastfeeding#Medication use, risks conferre ...

. 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 Acute pancreatitis (AP) is a sudden inflammation of the pancreas. Causes include a gallstone impacted in the common bile duct or the pancreatic duct, heavy alcohol use, systemic disease, trauma, elevated calcium levels, hypertriglyceridemia (w ...

, with particular relevance to patients also diagnosed with

cystic fibrosis Cystic fibrosis (CF) is a genetic disorder inherited in an autosomal recessive manner that impairs the normal clearance of Sputum, mucus from the lungs, which facilitates the colonization and infection of the lungs by bacteria, notably ''Staphy ...

. 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 thus prompted a

black box warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears near the beginning of the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administratio ...

by the FDA.

Black box warning

The FDA issued a

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. The FDA updated the black box warning in 2013.

Drug interactions

Tigecycline has been found to interact with medications, such as: *

Warfarin Warfarin, sold under the brand name Coumadin among others. It is used as an anticoagulant, anticoagulant medication. It is commonly used to prevent deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who ha ...

: 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 Oral contraceptives, abbreviated OCPs, also known as birth control pills, are medications taken by mouth for the purpose of birth control. The introduction of the birth control pill ("the Pill") in 1960 revolutionized the options for contraception, ...

: 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.

History

was a commonly used tetracycline synthesized in

Lederle Laboratories American Cyanamid Company was an American manufacturing conglomerate. It began as a fertilizer company and added many additional lines of business before merging with American Home Products in 1994. The combined company sold off most of its di ...

in 1970, but antibiotic resistance to the drug began growing in prevalence throughout the 1970s and 1980s. While the problem of antibiotic resistance was known to scientists during the 1980s, apathy led to little federal attention given to the emerging crisis. However, by the late 1980s the worldwide threat began to be treated more seriously, which led to the renewed funding of antibiotic research. In 1993, researchers in the same laboratories that first synthesized minocycline created a new generation of tetracycline antibacterial agents, known as the glycylcyclines. These antibiotics were the first new drugs of the tetracycline class to be reported since the discovery of minocycline in 1970. The glycylcyclines were found to be active against a broad spectrum of tetracycline susceptible and resistant Gram (-) and Gram (+) aerobic and anaerobic bacteria. This initial research resulted in numerous studies being done on the antibacterial activity of various glycylcyclines, with extra focus being put on N,N-dimethylglycyl-amino derivatives, due to their reported potency. The aforementioned research culminated in a 1999 paper describing the discovery of a compound known as GAR-936, which would later be known as Tigecycline.

Mechanism of action

Tigecycline is a

broad-spectrum antibiotic A broad-antimicrobial spectrum, spectrum antibiotic is an antibiotic that acts on the two major bacterial groups, Gram-positive and Gram-negative, or any antibiotic that acts against a wide range of disease-causing bacteria. These medications are ...

that acts as a

protein synthesis inhibitor A protein synthesis inhibitor is a compound that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins. While a broad interpretation of this definition could be used t ...

. It exhibits bacteriostatic activity by binding to the

30S ribosomal subunit 3 (three) is a number, numeral and digit. It is the natural number following 2 and preceding 4, and is the smallest odd prime number and the only prime preceding a square number. It has religious and cultural significance in many societies ...

of bacteria and thereby blocking the interaction of

aminoacyl-tRNA Aminoacyl-tRNA (also aa-tRNA or charged tRNA) is tRNA to which its cognate amino acid is chemically bonded (charged). The aa-tRNA, along with particular elongation factors, deliver the amino acid to the ribosome for incorporation into the polyp ...

with the A site of the ribosome. In addition, tigecycline has demonstrated bactericidal activity against isolates of '' S. pneumoniae'' and '' L. pneumophila.'' Studies have shown that tigecycline binds to the 70S ribosome with 5 fold and >100 fold greater affinity than minocycline and tetracycline, respectively . As previously mentioned, tigecycline still binds to the A site of the 30S ribosomal subunit, however the binding of the novel antibiotic involves substantial interactions with residues of helix H34 of that same subunit. These interactions are not observed in the binding of tetracycline. The findings indicate that tigecycline likely has a unique mechanism of action that prevents inhibition from ribosomal protection. It is a third-generation

tetracycline Tetracycline, sold under various brand names, is an antibiotic in the tetracyclines family of medications, used to treat a number of infections, including acne, cholera, brucellosis, plague, malaria, and syphilis. It is available in oral an ...

derivative within a class called

glycylcyclines Glycylcyclines are a 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 ...

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 Minocycline, sold under the brand name Minocin among others, is a tetracycline antibiotic medication used to treat a number of bacterial infections such as some occurring in certain forms of pneumonia. It is generally (but not always) less pre ...

, 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 Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gly ...

into glucuronide conjugates and a ''N''-acetyl-9-amino

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 The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Northwestern Europe, off the coast of European mainland, the continental mainland. It comprises England, Scotlan ...

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) * Tigilyn (Marketed by Real Value therapy pharmaceuticals company in Myanmar, Manufactured by Lyka) * TIGILITE (marketed in INDIA, Scutonix Lifesciences, Bombay)

References

{{Portal bar, Medicine Carboxamides Glycylcycline antibiotics Drugs developed by Wyeth Drugs developed by Pfizer Dimethylamino compounds