What is Tigecycline?

What is Tigecycline?

Tigecycline is a first-in-class glycylcycline broad-spectrum intravenous antibiotic that was specifically developed to overcome tetracycline resistance mechanisms, approved for complicated intra-abdominal infections and complicated skin and soft tissue infections in adults. 1

Drug Classification and Mechanism

• Tigecycline is a tetracycline class antibacterial agent that evades the two major tetracycline resistance mechanisms: ribosomal protection and efflux pumps, through the addition of a glycyclamide moiety to the 9-position of minocycline 1, 2
• It is administered exclusively as an intravenous formulation, available as 50 mg powder for solution for infusion 3, 1

Spectrum of Activity

Tigecycline demonstrates broad-spectrum activity against both Gram-positive and Gram-negative organisms, including many multidrug-resistant pathogens:

• Gram-positive coverage: Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and Streptococcus pneumoniae 4, 2
• Gram-negative coverage: Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, some carbapenem-resistant Enterobacteriaceae (CRE), and Acinetobacter baumannii 3, 4
• Anaerobic coverage: Favorable activity against anaerobic organisms including Bacteroides fragilis group 3

Critical coverage gaps exist: Tigecycline lacks activity against Pseudomonas aeruginosa and certain Enterobacteriaceae (Proteus spp., Serratia spp., Morganella morganii, Providencia stuartii) 3

FDA-Approved Indications

• Complicated intra-abdominal infections (cIAIs) 1, 5
• Complicated skin and skin structure infections (cSSSIs) 1, 5
• Community-acquired bacterial pneumonia (CAP) 6, 4

Important caveat: Tigecycline is NOT licensed for treatment of non-tuberculous mycobacterial infections in the UK, though it may be used off-label in specific circumstances 3

Standard Dosing Regimen

The FDA-approved dosing is:

• Loading dose: 100 mg IV initially 1
• Maintenance dose: 50 mg IV every 12 hours 1
• Duration: Typically 5-14 days depending on infection type 5
• Infusion time: Administered over 30-60 minutes 1

Pharmacokinetic Properties

• Large volume of distribution: 500-700 L (7-9 L/kg), indicating extensive tissue penetration beyond plasma 1, 7
• Long elimination half-life: Approximately 27-42 hours, allowing twice-daily dosing 1, 7
• Protein binding: 71-89% at therapeutic concentrations 1
• Tissue penetration: Concentrations are 38-fold higher in gallbladder, 3.7-fold higher in lung, and 2.3-fold higher in colon compared to serum 1
• Poor serum concentrations: Standard dosing achieves maximum serum concentration (Cmax) of only 0.87 mcg/mL, which is problematic for bloodstream infections 3, 1

Dose Adjustments

Hepatic impairment:

• No adjustment needed for mild to moderate impairment (Child-Pugh A and B) 1
• Severe hepatic impairment (Child-Pugh C): Reduce maintenance dose to 25 mg every 12 hours after standard 100 mg loading dose 8, 1

Renal impairment:

• No dose adjustment required, including for patients on continuous renal replacement therapy 9, 1

Pediatric dosing (off-label):

• Ages 12-18 years: 100 mg loading dose, then 50 mg twice daily 3
• Ages 8-11 years: 1.2 mg/kg twice daily (maximum 50 mg twice daily) 3
• Contraindicated in children <8 years due to risk of tooth discoloration 3, 1

Higher Dosing for Severe Infections

For hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), higher doses demonstrate superior efficacy:

• High-dose regimen: 200 mg IV loading dose followed by 100 mg IV every 12 hours 8, 9
• This regimen achieved 85% cure rates compared to 69.6% with standard dosing in clinical trials 3, 8, 9
• Standard dosing resulted in very low epithelial lining fluid concentrations (0.01-0.02 mg/L), explaining poor VAP outcomes 3

Critical Clinical Limitations

Tigecycline should NOT be used as monotherapy for:

• Bacteremia/bloodstream infections: Poor outcomes due to inadequate serum concentrations with standard dosing 3, 8, 9
• Healthcare-associated pneumonia with bacteremia 3

For Acinetobacter baumannii infections:

• Efficacy is MIC-dependent: comparable to polymyxins when MIC ≤2 mg/L, but inferior when MIC >2 mg/L 8
• Should not be used as monotherapy for carbapenem-resistant A. baumannii (CRAB) pneumonia 8
• Combination therapy with another active agent is recommended 3, 8

Role in Multidrug-Resistant Infections

Tigecycline serves as a carbapenem-sparing option for:

• ESBL-producing Enterobacteriaceae in complicated intra-abdominal infections 3, 9
• VRE in polymicrobial intra-abdominal infections (preferred over linezolid for polymicrobial infections) 3
• Some carbapenem-resistant Enterobacteriaceae, though combination therapy is generally preferred 3, 8

Important consideration: Tigecycline use should be prioritized in settings with high incidence of carbapenem-resistant organisms to preserve carbapenem effectiveness 3

Common Adverse Effects

Gastrointestinal effects are most frequent:

• Nausea, vomiting, diarrhea, abdominal pain, dyspepsia, anorexia 3, 5

Other common effects:

• Elevated liver function tests 3
• Prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT) 3
• Hypoglycemia, hypoproteinemia 3
• Phlebitis at infusion site 3

Significant safety concern: Clinical studies demonstrated numerically higher mortality rates in tigecycline-treated patients compared to comparator antibiotics across multiple infection types; the cause remains unclear but poorer efficacy and safety cannot be ruled out 3, 1

Contraindications and Cautions

Absolute contraindications:

• Hypersensitivity to tigecycline or tetracyclines 3

Use with caution in:

• Pregnancy and breastfeeding (evidence of fetal harm in animal studies) 3, 1
• Severe hepatic impairment (requires dose reduction and close monitoring) 8, 10, 1
• Patients with coagulopathy (may prolong PT and aPTT) 3

Advantages Over Other Antibiotics

• Lower nephrotoxicity: Significantly lower incidence compared to colistin-based therapy for multidrug-resistant organisms 8
• No renal dose adjustment needed: Unlike many other antibiotics for resistant pathogens 9, 1
• Minimal metabolism: Not extensively metabolized, with primary elimination through feces 1