Tigecycline

Tigecycline is an antibiotic agent belonging to the pharmacological class of Glycopeptide Antibiotics.

Tigecycline has been approved to relieve symptoms and also for the treatment and maintenance of Intra-abdominal infection,Pneumonia, community-acquired,Skin/skin structure infection, complicated.

After intravenous administration, tigecycline is rapidly absorbed with a mean peak plasma concentration (Cmax) of approximately 2.0 μg/mL. The time to reach the peak plasma concentration (Tmax) ranges from 1.5 to 3 hours. Tigecycline has a large volume of distribution, indicating extensive distribution into body tissues. It is highly protein-bound (approximately 77%) to plasma proteins, primarily albumin. Tigecycline is primarily eliminated through non-renal routes, with approximately 59% of the dose recovered in the feces and 33% in the urine. The mean elimination half-life of tigecycline ranges from 27 to 43 hours, allowing for once-daily or twice-daily dosing.

The common side effects involved in using Tigecycline are Nausea, Vomiting, Diarrhea, Abdominal pain, Gastrointestinal discomfort, Skin rash, Injection site pain, Injection site redness, Injection site swelling, Taste Disturbances.

Tigecycline is available in the form of Powder for injection.

Tigecycline is approved in Germany, Japan, Malaysia, India, the U.K., the U.S., and China.

Tigecycline belongs to the pharmacological class of Glycopeptide Antibiotics

Tigecycline, a type of glycylcycline, works by inhibiting protein synthesis at the bacterial ribosome. It achieves this by blocking the binding of amino-acyl tRNA to the A site of the ribosome. Tigecycline exhibits antibacterial activity against a wide range of pathogens both in vivo and in vitro . It effectively targets bacterial strains that possess conventional tetracycline-resistant genes responsible for either ribosomal protection or tetracycline efflux pumps. Various resistance mechanisms related to efflux have been identified, which can result in reduced activity or no activity against certain bacteria such as Proteus spp., Providencia spp., and Morganella spp.

Tigecycline has been approved to relieve symptoms and also for the treatment and maintenance of Intra-abdominal infection,Pneumonia, community-acquired,Skin/skin structure infection, complicated.

In a study conducted on healthy subjects, the Cmax of tigecycline was found to be approximately 2.0 μg/mL, with a Tmax of 1.5 to 3 hours after intravenous In terms of duration of action, tigecycline has a relatively long half-life of approximately 27 to 43 hours, allowing for sustained antibacterial activity. administration.

Tigecycline is found to be available in the form of Powder for injection.

Tigecycline can be used in the following treatment:

• Intra-abdominal infection
• Pneumonia, community-acquired
• Skin/skin structure infection, complicated

Tigecycline can help to relieve symptoms and also for the treatment and maintenance of Intra-abdominal infection, Pneumonia, community-acquired, Skin/skin structure infection, complicated.

Tigecycline is approved for use in the following clinical indications:

• Intra-abdominal infection
• Pneumonia, community-acquired
• Skin/skin structure infection, complicated

Intra-abdominal Infection (Alternative Agent):

Note: Not recommended for routine empirical use. Reserved for patients with or at risk for specific multidrug-resistant organisms (e.g., K. pneumoniae carbapenemase-producing Enterobacteriaceae, Acinetobacter baumannii) (Reference).

• Intravenous (IV): Initially 100 mg, followed by 50 mg every 12 hours. Some experts suggest an initial dose of 200 mg, followed by 100 mg every 12 hours for complicated infections involving abscess or the peritoneum. (Reference). In certain cases with resistant organisms, it may be used as part of an appropriate combination regimen. (Reference). The total duration of therapy, including transition to oral antibiotics, is 4 to 5 days after adequate source control. (Reference).

Community-Acquired Pneumonia (Alternative Agent):

For patients unable to tolerate beta-lactams or fluoroquinolones, inpatients without risk factors for Pseudomonas aeruginosa. Not recommended for routine empirical use. (Reference).

• IV: Single dose of 100 mg initially, followed by 50 mg every 12 hours. (Reference). The total duration, including oral step-down therapy, is a minimum of 5 days. Patients should exhibit clinical stability with normal vital signs before discontinuing therapy. (Reference).

Complicated Skin/Skin Structure Infection:

• IV: Initial dose of 100 mg as a single dose, followed by a maintenance dose of 50 mg every 12 hours for 5 to 14 days.

Powder for injection :50 mg/vial.

Powder for injection.

Dosage Adjustments in Kidney Patients:

US Labeling:

• For patients with a creatinine clearance (CrCl) greater than 50 mL/minute, no dosage adjustment is necessary.
• For patients with a CrCl between 30 and 50 mL/minute, the recommended dosage is 7.5 mg/kg administered every 24 hours.
• For patients with a CrCl between 10 and less than 30 mL/minute, the recommended dosage is 10 mg/kg administered every 48 hours.
• No dosage adjustment is provided for patients with a CrCl less than 10 mL/minute or for patients with end-stage renal disease (ESRD) or undergoing hemodialysis, as these populations have not been studied.

Canadian Labeling:

• For patients with a CrCl greater than 50 mL/minute, no dosage adjustment is necessary.
• For patients with a CrCl between 30 and 50 mL/minute, the recommended dosage is 7.5 mg/kg administered every 24 hours.
• Tigecycline is not recommended for patients with a CrCl less than 30 mL/minute.

● Tigecycline is also not recommended for patients with end-stage renal disease (ESRD) or undergoing hemodialysis.

Dosage Adjustments in Pediatric Patients:

Infants and Children <8 years:

Dosing for pediatric patients (age range: 36 days to 15 years) is based on limited studies and case series. It should only be considered if the potential benefits outweigh the risks of uncertain dosing and impact on tooth development. (Reference)

• Loading dose (optional): Intravenous (IV) administration of 1.5 to 3 mg/kg once.
• Maintenance dose: IV administration of 1 to 2 mg/kg/dose every 12 hours, with a maximum dose of 50 mg/dose. If no loading dose is given, a maintenance dose of 2 mg/kg every 12 hours has been used.

Children ≥8 years and Adolescents:

Dosing is based on data from pharmacokinetic trials (Purdy 2012) as well as limited studies and case series in pediatric patients (age range: 36 days to 15 years). (Reference)

• Age 8 to 11 years: IV administration of 1.2 to 2 mg/kg/dose every 12 hours, with a maximum dose of 50 mg/dose.

● Age ≥12 years: IV administration of 50 mg every 12 hours.

There are no specific dietary restrictions related to the use of Tigecycline mentioned in the available information. However, it is always advisable to follow a healthy and balanced diet while undergoing any medical treatment.

Tigecycline may be contraindicated under the following conditions:

Tigecycline should not be used in patients who have a known hypersensitivity to Tigecycline.

All-Cause Mortality:

• Increased risk of all-cause mortality observed in clinical trials.
• Death occurred in a higher percentage of patients receiving Tigecycline compared to comparator drugs.
• The cause of the mortality difference has not been established, but it is often related to worsening infection, complications of infection, or the underlying co-morbidities.

Mortality Imbalance as well as Lower Cure Rates in Hospital-Acquired Pneumonia:

• In patients with hospital-acquired pneumonia, including ventilator-associated pneumonia, Tigecycline may have lower cure rates compared to the comparator.
• Greater mortality had been seen in patients with ventilator-associated pneumonia who received Tigecycline.

Anaphylaxis/Anaphylactoid Reactions:

• Anaphylaxis or anaphylactoid reactions have been reported with Tigecycline and may be life-threatening.
• Caution is to be exercised in patients with known hypersensitivity to tetracycline-class antibiotics.

Hepatic Effects:

• Tigecycline treatment may lead to increases in total bilirubin concentration, prothrombin time, and transaminases.
• Cases of a significant hepatic dysfunction as well as hepatic failure have been reported, particularly in patients receiving multiple concomitant medications.
• Monitoring of liver function tests is recommended during Tigecycline therapy.

Pancreatitis:

• Acute pancreatitis, including fatal cases, has been associated with Tigecycline treatment.
• Patients taking the drug Tigecycline who develop clinical symptoms, signs, or laboratory abnormalities suggestive of pancreatitis should be evaluated, and treatment with Tigecycline should be considered for discontinuation.

Use During Pregnancy:

• Tigecycline might cause fetal harm when administered to pregnant women.
• Animal studies have shown decreased fetal weights and other adverse effects with Tigecycline use during pregnancy.

Tooth Development:

• Use of Tigecycline during tooth development (last half of pregnancy, infancy, and childhood up to 8 years of age) might cause permanent discoloration of the teeth.
• Bone discoloration has been observed in animal studies.

Clostridium difficile Associated Diarrhea:

• Use of Tigecycline may lead to Clostridium difficile-associated diarrhea, ranging from mild to severe colitis.
• CDAD should be considered in patients presenting with diarrhea following Tigecycline use.
• For patients with complicated intra-abdominal infections (cIAI) resulting from intestinal perforation

Development of Drug-Resistant Bacteria:

• Prescribing Tigecycline without a proven or strongly suspected bacterial infection is not recommended, as it may contribute to the development of drug-resistant bacteria.

While there is no specific food interaction between Tigecycline and alcohol, it's generally recommended to avoid alcohol when taking any antibiotic medication. Alcohol can interfere with the effectiveness of the medication and may also exacerbate certain side effects.

Findings from animal studies using 14C-labeled tigecycline suggest that tigecycline can be eliminated through the milk of lactating rats. However, due to the limited oral bioavailability of tigecycline, nursing pups do not experience significant systemic exposure to tigecycline through maternal milk.

The excretion of tigecycline in human milk is currently unknown. Considering that many drugs are excreted in human milk, caution should be exercised when administering Tigecycline to a nursing woman.

Pregnancy Category D

Tigecycline did not exhibit teratogenic effects in rats or rabbits. During preclinical safety studies, 14C-labeled tigecycline was able to cross the placenta and reach fetal tissues, including fetal bony structures. Administration of tigecycline led to reductions in fetal weights and an increased occurrence of skeletal anomalies (specifically delays in bone ossification) in rats and rabbits at exposures equivalent to 5 times and 1 times the human daily dose based on AUC, respectively (28 mcg·hr/mL and 6 mcg·hr/mL at 12 and 4 mg/kg/day). In rabbits, an increased rate of fetal loss was observed at maternotoxic doses equivalent to the human dose.

There are no sufficient and well-controlled studies on the use of tigecycline in pregnant women. Tigecycline should only be used during pregnancy if the potential benefits outweigh the potential risks to the fetus.

There are no specific food warnings associated with the use of tigecycline. However, it is generally recommended to take tigecycline on an empty stomach or at least 1 hour before or 2 hours after a meal, as food may affect its absorption.

The adverse reactions related to Tigecycline can be categorized as follows:

Common:

1. Nausea
2. Vomiting
3. Diarrhea
4. Abdominal pain
5. Headache
6. Dizziness
7. Fever
8. Rash or itching
9. Increased liver enzymes (transaminases)
10. Injection site reactions (e.g., pain, redness, swelling)

Less common:

1. Changes in taste
2. Decreased appetite
3. Constipation
4. Difficulty sleeping (insomnia)
5. Joint pain
6. Muscle pain
7. Yeast infection (candidiasis)
8. Prolonged QT interval on an electrocardiogram (ECG)
9. Low platelet count (thrombocytopenia)
10. Allergic reactions (e.g., hives, itching, swelling, difficulty breathing)

Rare:

1. Severe allergic reactions (e.g., anaphylaxis)
2. Stevens-Johnson syndrome (a severe skin reaction)
3. Clostridium difficile-associated diarrhea (a severe form of diarrhea caused by a bacterial infection)
4. Liver toxicity or damage
5. Pancreatitis (inflammation of the pancreas)
6. Hemolytic anemia (destruction of red blood cells)
7. Photosensitivity (increased sensitivity to sunlight)
8. Tooth discoloration (mostly seen with long-term use in children)

Warfarin:

If tigecycline is used alongside warfarin, it is important to monitor prothrombin time or another appropriate anticoagulation test.

Oral Contraceptives :

The simultaneous use of antibacterial drugs and oral contraceptives may potentially reduce the effectiveness of oral contraceptives.

The following are the side effects involving Tigecycline:

• Nausea
• Vomiting
• Diarrhea
• Abdominal pain
• Headache
• Dizziness
• Fever
• Rash or itching
• Increased liver enzymes (transaminases)
• Injection site reactions (e.g., pain, redness, swelling)

Pregnancy:

Pregnancy Category D

Tigecycline did not exhibit teratogenic effects in rats or rabbits. During preclinical safety studies, 14C-labeled tigecycline was able to cross the placenta and reach fetal tissues, including fetal bony structures. Administration of tigecycline led to reductions in fetal weights and an increased occurrence of skeletal anomalies (specifically delays in bone ossification) in rats and rabbits at exposures equivalent to 5 times and 1 times the human daily dose based on AUC, respectively (28 mcg·hr/mL and 6 mcg·hr/mL at 12 and 4 mg/kg/day). In rabbits, an increased rate of fetal loss was observed at maternotoxic doses equivalent to the human dose.

There are no sufficient and well-controlled studies on the use of tigecycline in pregnant women. Tigecycline should only be used during pregnancy if the potential benefits outweigh the potential risks to the fetus.

Lactation:

Findings from animal studies using 14C-labeled tigecycline suggest that tigecycline can be eliminated through the milk of lactating rats. However, due to the limited oral bioavailability of tigecycline, nursing pups do not experience significant systemic exposure to tigecycline through maternal milk.

The excretion of tigecycline in human milk is currently unknown. Considering that many drugs are excreted in human milk, caution should be exercised when administering Tigecycline to a nursing woman.

Pediatric:

The use of tigecycline in pediatric patients aged 8 years and older have limited clinical experience. Therefore, its use in children should be limited to situations where no alternative antibacterial therapy is available.

Nausea and vomiting are common adverse reactions in children and adolescents. It is important to monitor for possible dehydration. For pediatric patients, it is preferable to administer tigecycline over a 60-minute infusion duration.

Abdominal pain, which is commonly experienced by both children and adults, may be a sign of pancreatitis. If pancreatitis occurs, treatment with tigecycline should be discontinued.

Before initiating tigecycline treatment and regularly during treatment, liver function tests, coagulation parameters, hematology parameters, amylase, and lipase should be monitored.

Tigecycline should not be used in children under 8 years of age due to insufficient safety and efficacy data in this age group. Additionally, tigecycline may cause permanent teeth discoloration.

Geriatric Use:

In Phase 3 clinical studies, out of the total number of subjects who received Tigecycline (n=2514), 664 were 65 years old and above, with 288 being 75 years old and above. There were no unexpected differences in terms of safety or effectiveness observed between these older subjects and the younger subjects. However, it is important to note that certain older individuals may exhibit increased sensitivity to adverse events, although this possibility cannot be ruled out.

Additionally, there was no significant disparity in tigecycline exposure between healthy elderly subjects and younger subjects after receiving a single 100 mg dose of tigecycline.

Physicians should be knowledgeable as well as vigilant about the treatment and identification of overdosage of Tigecycline.

Regarding overdosage, there is no specific information available on its treatment. However, it is worth noting that the intravenous administration of tigecycline at a single dose of 300 mg over 60 minutes in healthy volunteers led to a higher occurrence of nausea and vomiting. Furthermore, it is important to note that tigecycline is not substantially eliminated through hemodialysis.

Pharmacodynamics

Tigecycline belongs to the first clinically-available class of antibiotics known as glycylcyclines, which are derived from tetracycline. These antibiotics are specifically designed to overcome two common mechanisms of tetracycline resistance, namely acquired efflux pumps and ribosomal protection. Glycylcyclines and tetracyclines share a similar mechanism of action, as they both bind to the 30S ribosomal subunit, preventing the binding of amino-acyl tRNA to the A site of the ribosome. However, glycylcyclines demonstrate enhanced binding efficacy compared to tetracyclines.

Pharmacokinetics

Absorption

When administered intravenously, Tigecycline exhibits complete bioavailability i.e.100%.

Plasma Protein Binding and Distribution of Tigecycline

● In clinical studies, tigecycline's plasma protein binding ranges from 71% to 89% at concentrations from 0.1 to 1.0 mcg/mL

● . It has a steady-state volume of distribution averaging 500 to 700 L (7 to 9 L/kg), indicating widespread distribution beyond the plasma volume and into the tissues.

Distribution

● Administration of tigecycline to 33 healthy volunteers resulted in significant differences in drug concentration across different compartments.

● The level of AUC0-12h in alveolar cells was significantly higher (134 mcg·h/mL) compared to that found in serum.

● In epithelial lining fluid, the AUC0-12h was 32% higher (2.28 mcg·h/mL) than in serum, while in skin blister fluid, it was 26% lower (1.61 mcg·h/mL). 

● In a study where subjects were given a single dose of tigecycline 100 mg before surgery or medical procedures for tissue extraction, tissue concentrations were found to be higher four hours after administration.the gallbladder (38-fold), lung (3.7-fold), and colon (2.3-fold) compared to serum.

● Concentrations were lower in synovial fluid (0.58-fold) and bone (0.35-fold) relative to serum.

● Multiple-dose tissue concentrations have not been studied.

Metabolism

● Tigecycline undergoes minimal metabolism.

● In vitro studies using the human liver microsomes, liver slices, and hepatocytes showed only trace amounts of metabolites.

● In healthy male volunteers, tigecycline was the primary 14C-labeled material recovered in urine and feces, with minor amounts of a glucuronide, an N-acetyl metabolite, and a tigecycline epimer.

Elimination

● Following administration of 14C-tigecycline, approximately 59% of the dose is eliminated by biliary/fecal excretion, while 33% is excreted in urine.

● Around 22% of the total dose is excreted as unchanged tigecycline in urine.

● Biliary excretion of unchanged tigecycline and its metabolites is the primary route of elimination, while glucuronidation and renal excretion of unchanged tigecycline are secondary routes.

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