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Tigecycline

Pronunciation

Class: Glycylcyclines
VA Class: AM250
Chemical Name: (4S,4aS,5aR,12aS) - 4,7 - bis(dimethylamino) - 9 - [[[(1,1 - dimethylethyl)amino]acetyl]amino] - 1,4,4a,5,5a,6,11,12a - octahydro - 3,10,12,12a - tetrahydroxy - 1,11 - dioxo - 2 - naphthacenecarboxamide
Molecular Formula: C29H39N5O8
CAS Number: 220620-09-7

Introduction

Antibacterial; glycylcycline antibiotic.1 2

Uses for Tigecycline

Community-acquired Pneumonia

Treatment of community-acquired pneumonia caused by Streptococcus pneumoniae (penicillin-susceptible strains only), including cases with concurrent bacteremia, or caused by Haemophilus influenzae (β-lactamase-negative strains only) or Legionella pneumophila.1

Intra-abdominal Infections

Treatment of complicated intra-abdominal infections caused by susceptible 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

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Skin and Skin Structure Infections

Treatment of complicated skin and skin structure infections caused by susceptible S. aureus (including MRSA), S. 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 Dosage and Administration

Administration

Administer by IV infusion.1

For solution and drug compatibility information, see Compatibility under Stability.

IV Infusion

Must be reconstituted and diluted prior to IV infusion.1 Final solution should have a maximum concentration of 1 mg/mL.1

May be administered through a dedicated line or a Y-site.1 If same IV line is used for sequential infusion of several drugs, flush line before and after tigecycline infusion using 0.9% sodium chloride, 5% dextrose, or lactated Ringer's injection.1

Reconstitution and Dilution

Reconstitute vial containing 50 mg of tigecycline by adding 5.3 mL of 0.9% sodium chloride, 5% dextrose, or lactated Ringer's injection to provide solution containing 10 mg/mL.1 Swirl gently until drug dissolves; reconstituted solution should be yellow to orange in color.1

To prepare a 50-mg dose, withdraw 5 mL of reconstituted solution from the vial and dilute this in 100 mL of compatible IV solution.1 To prepare a 100-mg dose, reconstitute two 50-mg tigecycline vials and dilute 10 mL of reconstituted solution in 100 mL of compatible IV solution.1 (See Compatibility and see Storage under Stability.)

Rate of Administration

IV infusions should be given over 30–60 minutes.1

Dosage

Adults

Community-acquired Pneumonia
IV

Initial dose of 100 mg, followed by 50 mg every 12 hours.1

Recommended duration of treatment is 7–14 days.1 Duration should be guided by severity and site of infection and patient's clinical and bacteriological progress.1

Complicated Intra-abdominal Infections
IV

Initial dose of 100 mg, followed by 50 mg every 12 hours.1

Recommended duration of treatment is 5–14 days.1 Duration should be guided by severity and site of infection and patient's clinical and bacteriological progress.1

Complicated Skin and Skin Structure Infections
IV

Initial dose of 100 mg, followed by 50 mg every 12 hours.1

Recommended duration of treatment is 5–14 days.1 Duration should be guided by severity and site of infection and patient's clinical and bacteriological progress.1

Prescribing Limits

Adults

IV

Maximum 100 mg daily.1

Special Populations

Hepatic Impairment

Mild to moderate hepatic impairment (Child-Pugh class A or B): Dosage adjustment not necessary.1

Severe hepatic impairment (Child-Pugh class C): Initial dose of 100 mg, followed by 25 mg every 12 hours.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustment not necessary in patients with renal impairment or undergoing hemodialysis.1

Geriatric Patients

Routine dosage adjustment based on age not necessary.1

Cautions for Tigecycline

Contraindications

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

Warnings/Precautions

Increased Mortality

Increased risk of all-cause mortality reported in pooled analysis of phase 3 and 4, active-controlled clinical trials evaluating tigecycline for treatment of serious infections.1 10 Data indicate a 4% mortality rate in tigecycline-treated patients versus 3% in patients treated with comparator anti-infectives.1 10 Overall adjusted risk difference in all-cause mortality between patients receiving tigecycline and those receiving comparators was 0.6%.1 10 Reason for increased risk of mortality not established;1 10 likely to be related to progression of infection.10

Higher incidence of mortality was observed in patients receiving tigecycline for treatment of complicated skin and skin structure infections, complicated intra-abdominal infections, diabetic foot infections, and hospital-acquired pneumonia compared with comparator anti-infectives.1 10 Mortality risk was greatest when tigecycline was used for treatment of hospital-acquired pneumonia, particularly ventilator-associated pneumonia, a use not approved by FDA.1 10 (See Patients with Ventilator-associated Pneumonia under Cautions.)

When choosing among treatment options, consider the increased risk of all-cause mortality reported in patients receiving tigecycline for treatment of severe infections.1 10

Sensitivity Reactions

Hypersensitivity Reactions

Potentially life-threatening anaphylaxis/anaphylactoid reactions reported.1

Use with caution in patients with known hypersensitivity to tetracyclines.1

Hepatic Effects

Elevated total bilirubin and aminotransferase concentrations and prolonged prothrombin time reported.1 Clinically important hepatic dysfunction and hepatic failure reported rarely.1 Adverse hepatic effects may occur after the drug is discontinued.1

If abnormal liver function tests develop during tigecycline therapy, monitor for worsening hepatic function; consider risks and benefits of continuing the drug.1

Patients with Ventilator-associated Pneumonia

Not effective and not approved for treatment of hospital-acquired pneumonia, including ventilator-associated pneumonia.1

Increased mortality rate in patients with ventilator-associated pneumonia who received tigecycline (19.1%) versus a comparator anti-infective (12.3%).1 Mortality was particularly high in tigecycline-treated patients who had bacteremia at baseline (50%).1 (See Increased Mortality under Cautions.)

Pancreatitis

Acute pancreatitis reported; sometimes fatal.1 Risk factors for pancreatitis not always present; improvement usually occurs after tigecycline is discontinued.1

Consider diagnosis of pancreatitis in any patient receiving tigecycline who develops symptoms, signs, or laboratory abnormalities suggestive of acute pancreatitis.1 If pancreatitis is suspected, consider discontinuing tigecycline.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.1

Pregnancy should be avoided.3 If patient becomes pregnant while receiving tigecycline, patient should be apprised of the potential hazard to the fetus.1 (See Pregnancy under Cautions.)

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

Possible emergence and overgrowth of nonsusceptible organisms, including fungi.1 Monitor carefully; institute appropriate therapy if superinfection occurs.1

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile.1 11 12 13 14 15 C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) has been reported with nearly all anti-infectives, including tigecycline, and may range in severity from mild diarrhea to fatal colitis.1 Hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.1

Consider CDAD if diarrhea develops during or after therapy and manage accordingly.1 11 12 13 14 15 Obtain a careful medical history since CDAD may occur as late as 2 months or longer after anti-infective therapy is discontinued.1

If CDAD is suspected or confirmed, anti-infectives not directed against C. difficile may need to be discontinued.1 Manage moderate to severe cases with fluid, electrolyte, and protein supplementation, anti-infective therapy active against C. difficile (e.g., oral metronidazole or vancomycin), and surgical evaluation when clinically indicated.1 11 12 13 14 15

Patients with Intestinal Perforation

Use with caution in complicated intra-abdominal infections secondary to clinically apparent intestinal perforation.1 Although causal relationship not established, sepsis or septic shock reported in several patients who received tigecycline for treatment of complicated intra-abdominal infections secondary to intestinal perforation.1

Tetracycline-class Effects

Adverse effects reported with tetracyclines (e.g., photosensitivity, pseudotumor cerebri, pancreatitis, antianabolic activity that may result in increased BUN, azotemia, acidosis, and hypophosphatemia) possible.1 (See Pancreatitis under Cautions.)

Selection and Use of Anti-infectives

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

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

Specific Populations

Pregnancy

Category D. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)1 Crosses placenta and distributed into fetal tissues in animals.1

Use during tooth development (last half of pregnancy) may cause permanent discoloration (yellow-gray-brown) of teeth.1

Use during pregnancy only if potential benefits outweigh risks to the fetus.1

Lactation

Distributed into milk in rats; not known if distributed into milk in humans.1

Use with caution in nursing women.1

Pediatric Use

Safety and efficacy not established in patients <18 years of age; use in this age group not recommended.1

Use during tooth development (i.e., in infants and children <8 years of age) may cause permanent discoloration (yellow-gray-brown) of teeth.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Hepatic Impairment

Moderate hepatic impairment (Child-Pugh class B): Systemic clearance reduced and half-life prolonged.1 Dosage adjustment not necessary.1

Severe hepatic impairment (Child-Pugh class C): Use with caution and at a reduced dosage.1 (See Hepatic Impairment under Dosage and Administration.) Monitor for treatment response.1 Systemic clearance reduced and half-life prolonged.1

Renal Impairment

Pharmacokinetics not substantially altered.1 Dosage adjustment not necessary in patients with renal impairment or undergoing hemodialysis.1

Common Adverse Effects

GI effects (nausea, vomiting, diarrhea).1

Interactions for Tigecycline

Not metabolized by and does not inhibit CYP isoenzymes 1A2, 2C8, 2C9, 2C19, 2D6, or 3A4.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions unlikely with drugs metabolized by or affecting CYP1A2, 2C8, 2C9, 2C19, 2D6, or 3A4.1

Specific Drugs

Drug

Interaction

Comments

Digoxin

Peak digoxin plasma concentration decreased slightly; no change in digoxin AUC or clearance; no effect on digoxin pharmacodynamics (as measured by ECG parameters)1

No effect on tigecycline pharmacokinetics1

Dosage adjustments not necessary1

Oral contraceptives

Possible decreased effectiveness of oral contraceptives1

Warfarin

Decreased warfarin clearance resulting in increased warfarin concentrations and AUC; pharmacologic interaction unlikely1

No effect on tigecycline pharmacokinetics1

Monitor PT or other suitable coagulation test1

Tigecycline Pharmacokinetics

Distribution

Extent

Following IV administration, widely distributed into body tissues and fluids, including epithelial lining fluid, skin blister fluid, synovial fluid, bone, colon, gallbladder, and lung.1 4 Concentrations in certain tissues (i.e., alveolar cells, gallbladder, lung, colon, epithelial fluid) higher than serum concentrations.1

Animal studies indicate tigecycline crosses the placenta and is distributed into fetal tissues.1

Distributed into milk in animals.1

Plasma Protein Binding

71–89%.1

Elimination

Metabolism

Not extensively metabolized.1 Each recovered metabolite (a glucuronide, an N-acetyl metabolite, a tigecycline epimer) constitutes <10% of administered dose.1

Elimination Route

Eliminated by renal and nonrenal mechanisms; approximately 59% of a dose eliminated by biliary/fecal excretion and 33% eliminated in urine (22% as unchanged drug).1

Not substantially removed by hemodialysis.1

Half-life

Adults: 27.1 or 42.4 hours following single or multiple doses, respectively.1

Special Populations

Pediatric patients <18 years of age: Pharmacokinetics not established.1

Geriatric patients >65 years of age: Pharmacokinetics similar to younger adults.1

Mild hepatic impairment (Child-Pugh class A): Pharmacokinetics not substantially altered compared with normal hepatic function.1

Moderate hepatic impairment (Child-Pugh class B): Systemic clearance reduced by 25% and half-life prolonged by 23%.1

Severe hepatic impairment (Child-Pugh class C): Systemic clearance reduced by 55% and half-life prolonged by 43%.1

Renal impairment, including severe renal impairment Clcr <30 mL/minute): Pharmacokinetics not substantially altered compared with normal renal function.1

Stability

Storage

Parenteral

Powder for Infusion

20–25°C (may be exposed to 15–30°C).1

Following reconstitution with 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer's injection, may be stored at room temperature for up to a total of 24 hours (up to 6 hours in original vial, remaining time after dose is diluted in IV bag containing 0.9% sodium chloride or 5% dextrose injection).1 16 Alternatively, may be stored at 2–8°C for up to 48 hours if dose of reconstituted tigecycline is immediately diluted in IV bag containing 0.9% sodium chloride or 5% dextrose.1 16

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible

Dextrose 5% in Ringer's injection, lactated

Dextrose 5% in sodium chloride 0.9%

Dextrose 5% in water1

Sodium chloride 0.9%1

Ringer's injection, lactated1

Y-Site Compatibility

Compatible

Amikacin sulfate1 HID

AzithromycinHID

AztreonamHID

Cefepime HClHID

Cefotaxime sodiumHID

CeftazidimeHID

Ceftriaxone sodiumHID

CiprofloxacinHID

Dobutamine HCl1 HID

Dopamine HCl1 HID

DoripenemHID

Epinephrine HClHID

Ertapenem sodiumHID

FluconazoleHID

Gentamicin sulfate1 HID

Haloperidol lactate1 HID

Heparin sodiumHID

Imipenem-cilastatin sodiumHID

Lidocaine HCl1 HID

LinezolidHID

Metoclopramide HCl1 HID

Morphine1

Norepinephrine1

Piperacillin sodium-tazobactam sodium1 HID

Potassium chloride1 HID

Propofol1

Ranitidine HCl1 HID

Telavancin HClHID

Theophylline1 HID

Tobramycin sulfate1 HID

Vancomycin HClHID

Incompatible

Amphotericin B1 HID

Amphotericin B lipid complex1 HID

Chlorpromazine HClHID

Diazepam1

Esomeprazole1

Methylprednisolone sodium succinateHID

Omeprazole1

VoriconazoleHID

Actions

  • Glycylcycline antibiotic; synthetic derivative of minocycline.1 2

  • 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

  • Broad spectrum of antibacterial activity; usually bacteriostatic.1 2

  • Spectrum of activity includes various gram-positive aerobic and facultatively aerobic bacteria, including Staphylococcus aureus (including oxacillin-resistant [methicillin-resistant] strains), Streptococcus agalactiae (group B streptococci), S. anginosusgroup (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

  • Also active against various gram-negative aerobic and facultatively aerobic bacteria, including Citrobacter freundii, Enterobacter cloacae, Escherichia coli, H. influenzae (β-lactamase-negative strains), Klebsiella oxytoca, and K. pneumoniae, L. pneumophila, and some anaerobic bacteria, including Bacteroides fragilis, B. thetaiotaomicron, B. uniformis, B. vulgatus, Clostridium perfringens, and Peptostreptococcus micros.1

  • May be active against some bacteria resistant to conventional tetracyclines since tigecycline susceptibility not affected by the 2 major tetracycline resistance mechanisms (i.e., ribosomal protection, efflux).1 2 Susceptibility to tigecycline also not affected by many other common resistance mechanisms, including β–lactamases (including extended-spectrum β–lactamases), target site modifications, macrolide efflux pumps, or enzyme target (e.g., gyrase, topoisomerase) changes.1

  • Resistance to tigecycline in some bacteria (e.g., Acinetobacter calcoaceticus-baumannii complex) is attributed to multidrug-resistant efflux pumps.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, and 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 advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Tigecycline

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

50 mg

Tygacil

Wyeth

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 4, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Wyeth Pharmaceuticals Inc. Tygacil (tigecycline) for injection prescribing information. Philadelphia, PA; 2010 Jul.

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. [IDIS 530254] [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. [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.

11. Johnson S, Gerding DN. Clostridium difficile-associated diarrhea. Clin Infect Dis. 1998; 26:1027-36. [IDIS 407733] [PubMed 9597221]

12. Gerding DN, Johnson S, Peterson LR et al for the Society for Healthcare Epidemiology of America. Position paper on Clostridium difficile-associated diarrhea and colitis. Infect Control Hosp Epidemiol. 1995; 16:459-77. [PubMed 7594392]

13. 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. [IDIS 386628] [PubMed 9149180]

14. 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. [IDIS 407213] [PubMed 9659970]

15. Wilcox MH. Treatment of Clostridium difficile infection. J Antimicrob Chemother. 1998; 41(Suppl C):41-6. [IDIS 407246] [PubMed 9630373]

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

HID. Trissel LA. Handbook on injectable drugs. 17th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2013:1089-90.

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