AHFS Class:

• Glycylcyclines 8:12.24.12

Generic Name(s):

• Tigecycline

Chemical Name:

• (4 S ,4a S ,5a R ,12a S )-4,7-bis(dimethylamino)-9-[[[(1,1-dimethylethyl)amino]acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,112,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

Molecular Formula:

• C₂₉H₃₉N₅O₈

Tigecycline, a synthetic derivative of minocycline, is a glycylcycline antibiotic.1,2

Tigecycline is used for the treatment of complicated intra-abdominal infections, community-acquired pneumonia, and complicated skin and skin structure infections caused by certain susceptible gram-positive and gram-negative bacteria.1

Because a higher incidence of all-cause mortality has been reported in patients receiving tigecycline compared with those receiving comparator anti-infectives, tigecycline should be reserved for use in situations when alternative anti-infectives are not suitable.1,17 (See Increased Mortality under Warnings/Precautions: Warnings, in Cautions.)

Prior to initiation of tigecycline, appropriate specimens should be obtained for identification of the causative organism and in vitro susceptibility testing.1 Tigecycline may be initiated as empiric monotherapy pending results of these tests.1

Intra-abdominal Infections

Tigecycline is used for the treatment of complicated intra-abdominal infections caused by Citrobacter freundii , Enterobacter cloacae , Escherichia coli , Klebsiella oxytoca , K. pneumoniae , Enterococcus faecalis (vancomycin-susceptible strains only), Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA; also known as oxacillin-resistant S. aureus or ORSA]), Streptococcus anginosus group ( S. anginosus , S. intermedius , S. constellatus ), Bacteroides fragilis , B. thetaiotaomicron , B. uniformis , B. vulgatus , Clostridium perfringens , or Peptostreptococcus micros .1

For initial empiric treatment of mild to moderate community-acquired, extrabiliary, complicated intra-abdominal infections in adults (e.g., perforated or abscessed appendicitis), the Infectious Diseases Society of America (IDSA) recommends either monotherapy with cefoxitin, ertapenem, moxifloxacin, tigecycline, or the fixed combination of ticarcillin and clavulanic acid, or a combination regimen that includes either a cephalosporin (cefazolin, ceftriaxone, cefotaxime, cefuroxime) or fluoroquinolone (ciprofloxacin, levofloxacin) in conjunction with metronidazole.39

For additional information regarding management of intra-abdominal infections, the current IDSA clinical practice guidelines available at [Web] should be consulted.39

Clinical Experience

Safety and efficacy of tigecycline were established in 2 randomized, double-blind, active-controlled phase 3 studies in adults with complicated intra-abdominal infections, including appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, intestinal perforation, and peritonitis.1,3,7 In these studies, patients were randomized to receive tigecycline (100 mg IV initially, followed by 50 mg IV every 12 hours) or imipenem and cilastatin sodium (500 mg of imipenem IV every 6 hours) for 5-14 days.1,3,7 In a pooled analysis of both studies, the clinical cure rate in the clinically evaluable population was similar in patients treated with tigecycline (87%) and in those treated with imipenem and cilastatin (87%).7 In the subset of microbiologically evaluable patients from these clinical studies and 2 additional resistant-pathogen studies, the clinical cure rate in those who received tigecycline ranged from 71-95%, depending on the pathogen.1 When stratified according to causative organism, the clinical cure rate was 85% in infections caused by E. coli , 85% in infections caused by S. anginosus , 89% in infections caused by K. pneumoniae , and 77% in infections caused by the B. fragilis group.1

In 2 randomized, open-label, multicenter, phase 3b/4 studies, tigecycline was compared with a combination regimen of ceftriaxone in conjunction with metronidazole for the treatment of complicated intra-abdominal infections in adults.19,27 In both studies, patients were randomized to receive either tigecycline (100 mg IV initially, followed by 50 mg IV every 12 hours) or a 2-drug regimen of ceftriaxone (2 g IV once daily) and metronidazole (1-2 g daily in divided doses) for 4-14 days.19,27 In the first open-label study, demographic characteristics were balanced between groups (mean age 48 years, 64.7% male, 65.3% Caucasian, 52% with primary diagnosis of complicated appendicitis).27 Clinical cure rate in the clinically evaluable population (376 patients) was 70% in the tigecycline group compared with 74% in the ceftriaxone and metronidazole group.27 In the subset of microbiologically evaluable patients (275 patients), the clinical cure rate in those who received tigecycline was 66% compared with 70% in the ceftriaxone and metronidazole group.27 When stratified according to causative organism, the clinical cure rate in the tigecycline group was 70% for infections caused by E. coli , 79% for infections caused by S. anginosus , 40% for infections caused by Klebsiella , and 64% for infections caused by the B. fragilis group.27

In the second open-label study, demographic characteristics were balanced between groups (mean age 47-49 years, 66-69% male, 38-47% with primary diagnosis of complicated appendicitis).19 The mean Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II score was 6-7 and the mean duration of treatment was 7 days in both groups.19 Clinical cure rate in the clinically evaluable population (387 patients) was 82% in the tigecycline group compared with 79% in the ceftriaxone and metronidazole group.19 In the subset of microbiologically evaluable patients (227 patients), the clinical cure rate in those who received tigecycline was 82% compared with 80% in the ceftriaxone and metronidazole group.19 When stratified according to causative organism, the clinical cure rate in the tigecycline group was 83% for infections caused by E. coli , 94% for infections caused by the S. anginosus group, 77% for infections caused by K. pneumoniae , and 67% for infections caused by the B. fragilis group.19

Respiratory Tract Infections

Community-acquired Pneumonia

Tigecycline is used for the treatment of community-acquired pneumonia caused by S. pneumoniae (penicillin-susceptible strains only), including cases with concurrent bacteremia, or caused by Haemophilus influenzae (β-lactamase-negative strains only) or Legionella pneumophila .1

Clinical Experience

Safety and efficacy of tigecycline were established in 2 randomized, double-blind, active-controlled studies in adults with community-acquired pneumonia requiring hospitalization.1,8,9 Patients were randomized to receive tigecycline (100 mg IV initially, followed by 50 mg IV every 12 hours) or levofloxacin (500 mg IV every 12 or 24 hours) for 7-14 days.1,8,9 Clinical cure rates in the clinically evaluable population from the first study were similar in tigecycline-treated patients (89%) and levofloxacin-treated patients (85%).1,9 In the second study, patients in both treatment arms could be switched to oral levofloxacin (500 mg daily) after at least 3 days of IV treatment, and the clinical cure rates in the clinically evaluable population were 91% for tigecycline-treated patients and 87% for levofloxacin-treated patients.1,8 In the subset of microbiologically evaluable patients from both studies, the clinical cure rate in patients who received tigecycline was 96% in infections caused by S. pneumoniae (penicillin-susceptible strains only), 82% in infections caused by H. influenzae , and 100% in infections caused by L. pneumophila .1

Hospital-acquired Pneumonia

Tigecycline has not been shown to be effective and is not labeled by the US Food and Drug Administration (FDA) for the treatment of hospital-acquired pneumonia†, including ventilator-associated pneumonia†.1,10 Results of a randomized, comparator-controlled trial evaluating tigecycline in patients with hospital-acquired pneumonia† failed to show efficacy.1 The subgroup of patients with ventilator-associated pneumonia† who received tigecycline demonstrated lower cure rates (47.9% in those treated with tigecycline versus 70.1% in those treated with a comparator anti-infective) and a higher incidence of death (19.1% in those treated with tigecycline versus 12.3% in those treated with a comparator anti-infective).1 (See Increased Mortality under Warnings/Precautions: Warnings, in Cautions.)

Skin and Skin Structure Infections

Tigecycline is used for the treatment of complicated skin and skin structure infections caused by S. aureus (including MRSA), Streptococcus agalactiae (group B streptococci), S. anginosus group ( S. anginosus , S. intermedius , S. constellatus ), S. pyogenes (group A β-hemolytic streptococci), E. faecalis (vancomycin-susceptible strains only), E. cloacae , E. coli , K. pneumoniae , or B. fragilis .1

Tigecycline has not been shown to be effective and is not labeled by FDA for the treatment of diabetic foot infections†.1,21 In a phase 3, randomized, double-blind study that included 813 clinically evaluable adults with diabetic foot infection, tigecycline (150 mg IV once daily) did not meet the primary end point of noninferiority to ertapenem (1g IV once daily with or without vancomycin).21 In addition, a higher incidence of death has been observed in patients with diabetic foot infections receiving tigecycline (1.3%) compared with those receiving comparator anti-infectives (0.6%).1,10 (See Increased Mortality under Warnings/Precautions: Warnings, in Cautions.)

Clinical Experience

Safety and efficacy of tigecycline were established in 2 randomized, double-blind, active-controlled studies in adults with complicated deep soft tissue infections, including wound infections and cellulitis (10 cm or larger, requiring surgery or drainage, or with complicated underlying disease), major abscesses, infected ulcers, and burns.1,3,6 In these studies, patients were randomized to receive tigecycline (100 mg IV initially, followed by 50 mg IV every 12 hours) or a combination regimen of vancomycin (1 g IV every 12 hours) and aztreonam (2 g IV every 12 hours) for 5-14 days.1,3,6 In a pooled analysis of both studies, the clinical cure rate in the clinically evaluable population was 87% in patients treated with tigecycline and 89% in those treated with the 2-drug regimen of vancomycin and aztreonam.6 In the subset of microbiologically evaluable patients from these clinical studies and 2 additional resistant-pathogen studies, clinical cure rates ranged from 71-100%, depending on the pathogen.1,6 This included clinical cure rates of 91% in those with infections caused by methicillin-susceptible (oxacillin-susceptible) S. aureus , 83% in those with infections caused by MRSA, 97% in those with infections caused by S. pyogenes , and 81% in those with infections caused by E. coli .1

In a phase 3b/4 randomized, open-label, multicenter study, the safety and efficacy of tigecycline for the treatment of complicated skin and skin structure infections (e.g., deep soft tissue infection, major abscess, infected ulcers, burns covering less than 5% of body surface area) were evaluated in 405 adults.20 Patients were randomized to receive tigecycline (100 mg IV initially, followed by 50 mg IV every 12 hours) or a comparator anti-infective regimen (i.e., fixed combination of ampicillin and sulbactam [1.5-3 g IV every 6 hours] or fixed combination of amoxicillin and clavulanate [1.2 g IV every 6-8 hours]) for 4-14 days.20 Baseline characteristics were balanced between groups (mean age 51-52 years, 61-64% male, 53-56% white).20 Clinical cure was achieved in 77.5% of patients in the tigecycline group compared with 77.6% of patients in the comparator group.20 In the subset of microbiologically evaluable patients (219 patients), the eradication rate at the test-of-cure assessment was 79 and 77% in the tigecycline and comparator groups, respectively.20 When stratified according to causative organism, the clinical cure rate in the tigecycline group was 83% in those with infections caused by methicillin-susceptible (oxacillin-susceptible) S. aureus , 69% in those with infections caused by MRSA, 73% in those with infections caused by S. pyogenes , and 77% in those with infections caused by E. coli .20

Administration

Tigecycline is administered by IV infusion.1

Tigecycline may be administered through a dedicated line or through a Y-site.1 If the same IV line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of tigecycline with 0.9% sodium chloride, 5% dextrose, or lactated Ringer's injection.1 Tigecycline should not be administered simultaneously through the same Y-site with amphotericin B, amphotericin B lipid complex, diazepam, esomeprazole, or omeprazole.1

Reconstitution and Dilution

Tigecycline powder for injection must be reconstituted and diluted before IV infusion.1 The final tigecycline solution should have a maximum concentration of 1 mg/mL.1

Tigecycline powder for injection should be reconstituted by adding 5.3 mL of 0.9% sodium chloride, 5% dextrose, or lactated Ringer's injection to the vial labeled as containing 50 mg of tigecycline to provide a solution containing 10 mg/mL.1 The vial should be swirled gently until the drug dissolves.1 The reconstituted solution should be yellow or orange in color; if not, the solution should be discarded.1

For preparation of a 50-mg dose, 5 mL of the reconstituted solution should be withdrawn from the vial and diluted in 100 mL of 0.9% sodium chloride or 5% dextrose injection.1 For preparation of a 100-mg dose, two 50-mg vials of tigecycline should be reconstituted, and 10 mL of the reconstituted solution should be diluted in 100 mL of 0.9% sodium chloride or 5% dextrose injection.1

Following reconstitution with 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer's injection, tigecycline solutions may be stored at room temperature (not to exceed 25°C) for up to a total of 24 hours (up to 6 hours in original vial, remaining time after dose is diluted in an IV bag containing 0.9% sodium chloride or 5% dextrose injection).1,16 If storage conditions after reconstitution exceed 25°C, tigecycline should be used immediately.1 Alternatively, if the dose of reconstituted tigecycline is immediately diluted in an IV bag containing 0.9% sodium chloride or 5% dextrose, the solution may be stored at 2-8°C for up to 48 hours.1,16

Parenteral tigecycline solutions should be inspected visually for particulate matter and discoloration (e.g., green, black) prior to administration.1

Rate of Administration

Tigecycline should be administered by IV infusion over approximately 30-60 minutes.1

Dosage

Adult Dosage

Intra-abdominal Infections

The recommended dosage of tigecycline for the treatment of complicated intra-abdominal infections in adults 18 years of age and older is an initial dose of 100 mg, followed by 50 mg every 12 hours.1 Duration of therapy should be guided by the severity and site of infection and the patient's clinical and bacteriologic progress; the usual duration of therapy is 5-14 days.1

Community-acquired Pneumonia

The recommended dosage of tigecycline for the treatment of community-acquired pneumonia in adults 18 years of age and older is an initial dose of 100 mg, followed by 50 mg every 12 hours.1 Duration of therapy should be guided by the severity and site of infection and the patient's clinical and bacteriologic progress; the usual duration of therapy is 7-14 days.1

Skin and Skin Structure Infections

The recommended dosage of tigecycline for the treatment of complicated skin and skin structure infections in adults 18 years of age and older is an initial dose of 100 mg, followed by 50 mg every 12 hours.1 Duration of therapy should be guided by the severity and site of infection and the patient's clinical and bacteriologic progress; the usual duration of therapy is 5-14 days.1

Pediatric Dosage

General Pediatric Dosage

Safety and efficacy of tigecycline have not been established in pediatric patients and the drug should not be used in patients younger than 18 years of age unless no alternative anti-infectives are available.1 If no alternative anti-infectives are available, the manufacturer recommends the following tigecycline dosage for patients 8 years of age or older based on pharmacokinetic studies that included limited numbers of pediatric patients.1 (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

When use of the drug is considered necessary, the manufacturer states that children 8-11 years of age can receive tigecycline in a dosage of 1.2 mg/kg IV every 12 hours (maximum 50 mg IV every 12 hours) and children and adolescents 12-17 years of age can receive a dosage of 50 mg IV every 12 hours.1

Special Populations

Dosage adjustments are not required in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).1 If tigecycline is used in adults with severe hepatic impairment (Child-Pugh class C), an initial dose of 100 mg should be given followed by a maintenance dosage of 25 mg every 12 hours.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Dosage adjustments are not necessary in patients with renal impairment or in those undergoing hemodialysis.1

Dosage adjustments based on age are not necessary in geriatric patients.1

Dosage adjustments based on gender or race are not necessary.1

Contraindications

Known hypersensitivity to tigecycline or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Increased Mortality

Meta-analyses of phase 3 and 4 clinical trials indicate that all-cause mortality was higher in patients treated with tigecycline than in those treated with comparator anti-infectives.1,17 Tigecycline should be reserved for use in situations when alternative treatments are not suitable.1,17

Based on meta-analyses of data from clinical trials, there was an increased risk of death when tigecycline was used for FDA-labeled or unlabeled uses.17 The reason for the increased mortality risk has not been established.1 In general, deaths resulted from worsening infections, complications of infection, or other underlying medical conditions.1,17

In a pooled analysis of over 7400 patients from 13 phase 3 and 4, active-controlled clinical trials evaluating tigecycline for the treatment of serious infections, the mortality rate was 4% in tigecycline-treated patients versus 3% in patients treated with comparator anti-infectives.1,10,17,18 Overall, the adjusted risk difference in all-cause mortality between patients receiving tigecycline and those receiving comparator anti-infectives was 0.6%.1,10,17,18

Data from 10 clinical trials evaluating tigecycline for FDA-labeled indications (i.e., complicated skin and skin structure infections, complicated intra-abdominal infections, community-acquired pneumonia) indicate an adjusted mortality rate of 2.5% for tigecycline-treated patients versus 1.8% for patients treated with comparator anti-infectives.1,17 The adjusted risk difference in mortality stratified by trial weight was 0.6%.1,17

Data indicate that the mortality risk has been greatest when tigecycline was used for the treatment of hospital-acquired pneumonia†, particularly ventilator-associated pneumonia†, a use not included in FDA-approved labeling.1,10,17,18 (See Patients with Hospital-acquired Pneumonia under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

Sensitivity Reactions

Hypersensitivity Reactions

Potentially life-threatening anaphylaxis/anaphylactoid reactions have been reported with tigecycline.1

There have been postmarketing reports of severe skin reactions, including Stevens-Johnson syndrome.1

Tigecycline should be used with caution in patients with known hypersensitivity to tetracyclines.1

Other Warnings/Precautions

Hepatic Effects

Elevated total bilirubin and aminotransferase concentrations and prolonged prothrombin time have been reported in tigecycline-treated patients.1 Clinically important hepatic dysfunction and hepatic failure have been reported rarely, and there have been postmarketing reports of hepatic cholestasis and jaundice in patients receiving tigecycline.1 Adverse hepatic effects may occur after the drug is discontinued.1

Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function, and the risks and benefits of continuing tigecycline treatment should be evaluated.1

Patients with Hospital-acquired Pneumonia

Tigecycline has not been shown to be effective and is not labeled by FDA for the treatment of hospital-acquired pneumonia†, including ventilator-associated pneumonia†.1,10

Results of a randomized, comparator-controlled trial evaluating tigecycline in patients with hospital-acquired pneumonia† failed to show efficacy.1 In the subgroup of patients with ventilator-associated pneumonia†, the mortality rate was 19.1% in those treated with tigecycline compared with 12.3% in those treated with comparator anti-infectives.1 Mortality was particularly high in tigecycline-treated patients with ventilator-associated pneumonia† who had bacteremia at baseline (mortality rate 50% in those treated with tigecycline versus 7.7% in those treated with a comparator anti-infective).1 (See Increased Mortality under Warnings/Precautions: Warnings, in Cautions.)

Pancreatitis

Acute pancreatitis, including fatalities, has been reported in patients receiving tigecycline.1,22 Some cases have been reported in patients with no known risk factors for pancreatitis.1 Improvement usually occurs after the drug is discontinued.1

A diagnosis of pancreatitis should be considered in any patient receiving tigecycline who develops symptoms, signs, or laboratory abnormalities suggestive of acute pancreatitis.1 In suspected cases of pancreatitis, consideration should be given to discontinuing tigecycline.1

Fetal/Neonatal Morbidity and Mortality

Tigecycline may cause fetal harm; teratogenicity and embryolethality have been demonstrated in animals.1 Pregnancy should be avoided during tigecycline therapy.3 If a patient becomes pregnant while receiving tigecycline, she should be apprised of the potential fetal hazard.1

Superinfection/Clostridium difficile-associated Diarrhea and Colitis (CDAD)

Use of tigecycline may result in emergence and overgrowth of nonsusceptible bacteria or fungi.1 The patient should be carefully monitored and appropriate therapy instituted if a superinfection occurs.1

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile .1,12,14,15 C. difficile infection (CDI) and C. difficile -associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) have been reported with nearly all anti-infectives, including tigecycline, and may range in severity from mild diarrhea to fatal colitis.1,12,14,15 C. difficile produces toxins A and B which contribute to development of CDAD;1,12 hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since these infections may be refractory to anti-infectives and colectomy may be required.1

CDAD should be considered in the differential diagnosis of patients who develop diarrhea during or after anti-infective therapy.1,12,14,15 Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.1

If CDAD is suspected or confirmed, anti-infective therapy not directed against C. difficile should be discontinued whenever possible.1,12 Patients should be managed with appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.1,12,14,15

Patients with Intestinal Perforation

Tigecycline should be used with caution in patients with complicated intra-abdominal infections secondary to clinically apparent intestinal perforation.1 Although a causal relationship has not been established, sepsis or septic shock has been reported in several patients who received tigecycline for the treatment of complicated intra-abdominal infections secondary to intestinal perforation.1

Tetracycline-class Effects

Because tigecycline is structurally related to conventional tetracyclines, adverse effects reported with tetracyclines (e.g., photosensitivity, pseudotumor cerebri, antianabolic activity that may result in increased BUN, azotemia, acidosis, and hypophosphatemia) may occur.1 (See Cautions in the Tetracyclines General Statement 8:12.24.) Pancreatitis has been associated with conventional tetracyclines and has been reported in patients receiving tigecycline.1 (See Pancreatitis under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

Endocrine Effects

Symptomatic hypoglycemia has been reported during postmarketing experience in patients with and without diabetes receiving tigecycline.1

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of tigecycline and other antibacterials, the drug should be used only for treatment of infections proven or strongly suspected to be caused by susceptible bacteria.1

When selecting or modifying anti-infective therapy, results of culture and in vitro susceptibility testing should be used.1 In the absence of such data, local epidemiology and susceptibility patterns should be considered when selecting anti-infectives for empiric therapy.1

Specific Populations

Pregnancy

Category D. 1 (See Users Guide.) Tigecycline crosses the placenta and is found in fetal tissues.1 (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

Use of tigecycline during tooth development (last half of pregnancy) may cause permanent discoloration (yellow-gray-brown) of the teeth.1 (See Cautions: Pediatric Precautions in the Tetracyclines General Statement 8:12.24.)

Lactation

Tigecycline is distributed into milk in rats.1 It is not known whether tigecycline is distributed into human milk; caution is advised if the drug is administered in nursing women.1

Pediatric Use

Safety and efficacy of tigecycline have not been established in patients younger than 18 years of age and use in this age group is not recommended.1 Because of the increased mortality observed in adults receiving tigecycline, clinical trials evaluating safety and efficacy of tigecycline in pediatric patients have not been conducted.1

For circumstances when there are no alternative anti-infectives, pediatric dosage has been proposed based on data from pharmacokinetic studies that included limited numbers of pediatric patients.1,23 For children 8-11 years of age, a pharmacokinetic simulation showed that a tigecycline dosage of 1.2 mg/kg in this age group would likely result in an area under the plasma concentration-time curve (AUC) similar to that reported in adults receiving the recommended adult dosage.1,23 For children and adolescents 12-16 years of age, a tigecycline dosage of 50 mg twice daily would likely result in exposures comparable to those observed in adults receiving the recommended adult dosage.1 (See Pediatric Dosage under Dosage and Administration: Dosage.)

Because use of tigecycline during tooth development (i.e., in infants and children younger than 8 years of age) may cause permanent discoloration (yellow-gray-brown) of the teeth, the drug should not be used in this age group unless other anti-infectives cannot be used.1 (See Cautions: Pediatric Precautions in the Tetracyclines General Statement 8:12.24.)

Geriatric Use

There are no substantial differences in safety and efficacy in patients 65 years of age or older relative to younger adults, but increased sensitivity cannot be ruled out.1

Hepatic Impairment

Tigecycline should be used with caution and at a reduced dosage in patients with severe hepatic impairment (Child-Pugh class C); such patients should be monitored for treatment response.1 (See Dosage and Administration: Special Populations.)

In adults with mild hepatic impairment (Child-Pugh class A), tigecycline pharmacokinetics were similar to those in healthy adults.24 In those with moderate hepatic impairment (Child-Pugh class B), systemic clearance of tigecycline was reduced by 25%, AUC was increased by 50%, and half-life was prolonged by 23%.1,24 In those with severe hepatic impairment (Child-Pugh class C), systemic clearance was reduced by 55%, AUC was increased by 105%, and half-life was prolonged by 43%.1,24

Renal Impairment

In a small study, the pharmacokinetic profile of tigecycline in adults with severe renal impairment (creatinine clearance less than 30 mL/minute) or end-stage renal impairment was not substantially altered.1,25 Tigecycline is not removed by hemodialysis.1 Dosage adjustments are not necessary in patients with renal impairment or in those undergoing hemodialysis.1,25

Obese Patients

In otherwise healthy adults with class III obesity (body mass index [BMI] 40 kg/m² or higher), a single 100-mg IV dose of tigecycline resulted in serum and urine concentrations of the drug that were similar to concentrations in healthy adults with normal weight (BMI 18.5-24.99 kg/m²).26

Common Adverse Effects

Nausea, vomiting, and diarrhea are the most common adverse effects reported with tigecycline and have been reported in up to 35% of patients in clinical studies.1

Adverse effects reported in 2-8% of patients receiving tigecycline include abdominal pain, abnormal healing, abscess, anemia, asthenia, bilirubinemia, dizziness, dyspepsia, headache, hypoproteinemia, increased ALT or AST concentrations, increased alkaline phosphatase concentrations, increased amylase concentrations, increased BUN, infection, phlebitis, and rash.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions are unlikely with drugs metabolized by or affecting cytochrome P-450 (CYP) isoenzymes 1A2, 2C8, 2C9, 2C19, 2D6, or 3A4.1 Tigecycline is not metabolized by these CYP isoenzymes and does not inhibit these isoenzymes in vitro.1

Antibacterials

Although the clinical importance is unknown, in vitro studies indicate that tigecycline and colistin (commercially available as colistimethate sodium) are synergistic against some strains of Escherichia coli , Klebsiella pneumoniae , Enterobacter , and Acinetobacter baumannii , including some carbapenem-resistant strains; however, indifference or only an additive effect has also been reported.28,29,30 There also is some evidence of in vitro synergism between tigecycline and levofloxacin, amikacin, or imipenem against some multidrug-resistant (MDR) A. baumanii .30

Although in vitro antagonism between tigecycline and colistin against Serratia marcescens was reported in one study,28 in vitro antagonism between tigecycline and other commonly used anti-infectives has not been confirmed.1

Digoxin

Potential pharmacokinetic interaction (slight decrease in peak plasma concentrations of digoxin, but no change in area under the concentration time curve [AUC]); no effect on digoxin pharmacodynamics (as measured by changes in ECG parameters).1 No effect on tigecycline pharmacokinetics.1 Dosage adjustment are not needed for either drug.1

Oral Contraceptives

Potential pharmacologic interaction (decreased effectiveness of oral contraceptives).1

Warfarin

Potential pharmacokinetic interaction (decreased clearance of warfarin, resulting in increased warfarin concentrations and AUC); pharmacologic interaction (altered international normalized ratio [INR]) unlikely.1 No effect on tigecycline pharmacokinetics.1 Monitor prothrombin time (PT) or other suitable coagulation tests if tigecycline is used concomitantly with warfarin.1

Description

Tigecycline, a synthetic derivative of minocycline, is a glycylcycline antibiotic.1,2 Tigecycline is structurally related to tetracyclines, differing mainly in the addition of a glycylamido moiety at position 9 of the tetracycline nucleus.1,2 Like tetracyclines, tigecycline inhibits protein synthesis in susceptible organisms mainly by reversibly binding to 30S ribosomal subunits, thereby inhibiting binding of aminoacyl transfer-RNA to those ribosomes.1

Tigecycline has a broad spectrum of antibacterial activity and usually is bacteriostatic in action.1,2 Tigecycline is active in vitro and in clinical infections against various gram-positive aerobic and facultatively aerobic bacteria, including Staphylococcus aureus (including methicillin-resistant [oxacillin-resistant] strains), Streptococcus agalactiae (group B streptococci), S. anginosus group ( S. anginosus , S. intermedius , S. constellatus ), S. pneumoniae (penicillin-susceptible strains), S. pyogenes (group A β-hemolytic streptococci), and Enterococcus faecalis (vancomycin-susceptible strains only).1 The drug also is active in vitro and in clinical infections against various gram-negative aerobic and facultatively aerobic bacteria, including Citrobacter freundii , Enterobacter cloacae , Escherichia coli , Haemophilus influenzae (β-lactamase-negative strains), Klebsiella oxytoca , K. pneumoniae , and Legionella pneumophila , and some anaerobic bacteria, including Bacteroides fragilis , B. thetaiotaomicron , B. uniformis , B. vulgatus , Clostridium perfringens , and Peptostreptococcus micros .1

Tigecycline may be active against some bacteria resistant to conventional tetracyclines since susceptibility to the drug is not affected by the 2 major tetracycline resistance mechanisms (i.e., ribosomal protection, efflux).1,2 In addition, susceptibility to tigecycline is not affected by many other common resistance mechanisms, including β-lactamases (e.g., extended-spectrum β-lactamases [ESBLs]), target site modifications, macrolide efflux pumps, or enzyme target (e.g., gyrase, topoisomerase) changes.1 Tigecycline resistance in some bacteria (e.g., Acinetobacter calcoaceticus-baumannii complex) is attributed to multidrug-resistant (MDR) efflux pumps.1 In vitro studies have demonstrated synergism between tigecycline and some other antibacterials (e.g., colistin) against some Enterobacteriaceae.28,29,30 (See Drug Interactions: Antibacterials.)

Tigecycline is extensively distributed into various tissues, including alveolar cells, epithelial lining fluid, skin blister fluid, gall bladder, lung, colon, synovial fluid, and bone.1,4 Tigecycline concentrations in certain tissues (i.e., alveolar cells, gallbladder, lung, colon, epithelial fluid) are substantially higher than concentrations in serum.1 Animal studies indicate that tigecycline crosses the placenta and is found in fetal tissues.1 The drug is approximately 71-89% bound to plasma proteins.1,4 Tigecycline is not extensively metabolized; each of the recovered metabolites (a glucuronide, an N -acetyl metabolite, and a tigecycline epimer) constitutes less than 10% of the administered dose.1 The half-life of tigecycline is 27.1 or 42.4 hours following single or multiple dosing, respectively.1 Tigecycline is principally eliminated by biliary and fecal excretion as unchanged tigecycline and metabolites.1 About 59% of a dose is eliminated by biliary and fecal excretion; 33% is eliminated in urine (22% as unchanged drug).1

Advice to Patients

Advise patients that antibacterials (including tigecycline) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).1

Importance of completing full course of therapy, even if feeling better after a few days.1

Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with tigecycline or other antibacterials in the future.1

Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued.1 Importance of contacting a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise pregnant women of risk to the fetus.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Pfizer. Tygacil^® (tigecycline) for injection prescribing information. Philadelphia, PA; 2013 Oct.

2. Zhanel GG, Homenuik K, Nichol K et al. The glycylcyclines: a comparative review with the tetracyclines. Drugs . 2004; 64:63-88. [PubMed 14723559]

3. Wyeth Pharmaceuticals Inc., Philadelphia, PA: Personal communication.

4. Muralidharan G, Micalizzi M, Speth J et al. Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects. Antimicrob Agents Chemother . 2005; 49:220-9. [PubMedCentral][PubMed 15616299]

6. Ellis-Grosse EJ, Babinchak T, Dartois N et al. The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double-blind phase 3 comparison studies with vancomycin-aztreonam. Clin Infect Dis . 2005; 41(Suppl 5):S341-53.

7. Babinchak T, Ellis-Grosse E, Dartois N et al. The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infections: analysis of pooled clinical trial data. Clin Infect Dis . 2005; 41(Suppl 5P:S354-67.

8. Bergallo C, Jasovich A, Teglia O et al. Safety and efficacy of intravenous tigecycline in treatment of community-acquired pneumonia: results from a double-blind randomized phase 3 comparison study with levofloxacin. Diagn Microbiol Infect Dis . 2009; 63:52-61. [PubMed 18990531]

9. Tanaseanu C, Milutinovic S, Calistru PI et al. Efficacy and safety of tigecycline versus levofloxacin for community-acquired pneumonia. BMC Pulm Med . 2009; 9:44. [PubMedCentral][PubMed 19740418]

10. US Food and Drug Administration. FDA drug safety communication: Increased risk of death with Tygacil (tigecycline) compared to other antibiotics used to treat similar infections. 2010 Sep 1. From FDA website. [Web]

12. Cohen SH, Gerding DN, Johnson S et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Rpidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol . 2010; 31:431-55. [PubMed 20307191]

14. Fekety R for the American College of Gastroenterology Practice Parameters Committee. Guidelines for the diagnosis and management of Clostridium difficile -associated diarrhea and colitis. Am J Gastroenterol . 1997; 92:739-50. [PubMed 9149180]

15. American Society of Health-System Pharmacists Commission on Therapeutics. ASHP therapeutic position statement on the preferential use of metronidazole for the treatment of Clostridium difficile -associated disease. Am J Health-Syst Pharm . 1998; 55:1407-11. [PubMed 9659970]

16. Pfizer, New York, NY: Personal communication.

17. US Food and Drug Administration. FDA drug safety communication: FDA warns of increased risk of death with IV antibacterial Tygacil (tigecycline) and approves new Boxed Warning. 2013 Sep 27. From FDA website. [Web]

18. McGovern PC, Wible M, El-Tahtawy A et al. All-cause mortality imbalance in the tigecycline phase 3 and 4 clinical trials. Int J Antimicrob Agents . 2013; 41:463-7. [PubMed 23537581]

19. Qvist N, Warren B, Leister-Tebbe H et al. Efficacy of tigecycline versus ceftriaxone plus metronidazole for the treatment of complicated intra-abdominal infections: results from a randomized, controlled trial. Surg Infect (Larchmt) . 2012; 13:102-9. [PubMed 22439781]

20. Matthews P, Alpert M, Rahav G et al. A randomized trial of tigecycline versus ampicillin-sulbactam or amoxicillin-clavulanate for the treatment of complicated skin and skin structure infections. BMC Infect Dis . 2012; 12:297. [PubMedCentral][PubMed 23145952]

21. Lauf L, Ozsvár Z, Mitha I et al. Phase 3 study comparing tigecycline and ertapenem in patients with diabetic foot infections with and without osteomyelitis. Diagn Microbiol Infect Dis . 2014; 78:469-80. [PubMed 24439136]

22. McGovern PC, Wible M, Korth-Bradley JM et al. Pancreatitis in tigecycline Phase 3 and 4 clinical studies. J Antimicrob Chemother . 2014; 69:773-8. [PubMed 24216769]

23. Purdy J, Jouve S, Yan JL et al. Pharmacokinetics and safety profile of tigecycline in children aged 8 to 11 years with selected serious infections: a multicenter, open-label, ascending-dose study. Clin Ther . 2012; 34:496-507.e1. [PubMed 22249106]

24. Korth-Bradley JM, Baird-Bellaire SJ, Patat AA et al. Pharmacokinetics and safety of a single intravenous dose of the antibiotic tigecycline in patients with cirrhosis. J Clin Pharmacol . 2011; 51:93-101. [PubMed 20308689]

25. Korth-Bradley JM, Troy SM, Matschke K et al. Tigecycline pharmacokinetics in subjects with various degrees of renal function. J Clin Pharmacol . 2012; 52:1379-87. [PubMed 21953572]

26. Pai MP. Serum and urine pharmacokinetics of tigecycline in obese class III and normal weight adults. J Antimicrob Chemother . 2014; 69:190-9. [PubMed 23883872]

27. Towfigh S, Pasternak J, Poirier A et al. A multicentre, open-label, randomized comparative study of tigecycline versus ceftriaxone sodium plus metronidazole for the treatment of hospitalized subjects with complicated intra-abdominal infections. Clin Microbiol Infect . 2010; 16:1274-81. [PubMed 20670293]

28. Betts JW, Phee LM, Hornsey M et al. In vitro and in vivo Activity of Tigecycline/Colistin Combination Therapies against Carbapenem Resistant Enterobacteriaceae. Antimicrob Agents Chemother . 2014; :. [PubMedCentral][PubMed 24687491]

29. Karaoglan I, Zer Y, Bosnak VK et al. In vitro synergistic activity of colistin with tigecycline or β-lactam antibiotic/β-lactamase inhibitor combinations against carbapenem-resistant Acinetobacter baumannii. J Int Med Res . 2013; 41:1830-7. [PubMed 24265334]

30. Principe L, D'Arezzo S, Capone A et al. In vitro activity of tigecycline in combination with various antimicrobials against multidrug resistant Acinetobacter baumannii. Ann Clin Microbiol Antimicrob . 2009; 8:18. [PubMedCentral][PubMed 19460166]

39. Solomkin JS, Mazuski JE, Bradley JS et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis . 2010; 50:133-64. [PubMed 20034345]