What are the indications, dosage, and precautions for using Tigecycline (generic name) in adults?

Tigecycline: Indications, Dosing, and Precautions in Adults

FDA-Approved Indications

Tigecycline is FDA-approved for three specific infections in adults ≥18 years: complicated skin and skin structure infections (cSSSI), complicated intra-abdominal infections (cIAI), and community-acquired bacterial pneumonia (CAP). 1

Approved Indications with Specific Pathogens:

• Complicated skin and skin structure infections caused by E. coli, Enterococcus faecalis (vancomycin-susceptible), S. aureus (MRSA and MSSA), Streptococcus species, Enterobacter cloacae, K. pneumoniae, and B. fragilis 1

• Complicated intra-abdominal infections caused by Citrobacter freundii, E. cloacae, E. coli, Klebsiella species, E. faecalis (vancomycin-susceptible), S. aureus (MRSA and MSSA), Streptococcus anginosus group, Bacteroides species, C. perfringens, and Peptostreptococcus micros 1

• Community-acquired bacterial pneumonia caused by S. pneumoniae (penicillin-susceptible), H. influenzae, and Legionella pneumophila 1

Additional Guideline-Supported Uses:

• For mild-to-moderate community-acquired intra-abdominal infections, tigecycline is recommended as single-agent therapy as an alternative to other regimens 2

• For carbapenem-resistant Enterobacterales (CRE) intra-abdominal infections, tigecycline 100 mg IV loading dose followed by 50 mg IV every 12 hours is recommended 3, 4

• For vancomycin-resistant Enterococci (VRE) intra-abdominal infections, the same dosing regimen (100 mg loading, then 50 mg every 12 hours) is recommended 3, 4

Standard Dosing Regimen

The FDA-approved standard dosage is 100 mg IV loading dose, followed by 50 mg IV every 12 hours, infused over 30-60 minutes. 1

Duration of Therapy:

• cSSSI and cIAI: 5-14 days 1
• CAP: 7-14 days 1
• Duration should be guided by infection severity, site, and clinical/bacteriological response 1

High-Dose Regimen for Severe Infections:

• For severe infections, particularly hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), a high-dose regimen of 200 mg IV loading dose followed by 100 mg IV every 12 hours achieves cure rates of 85% compared to 69.6% with standard dosing 3, 4

• This higher dosing addresses the pharmacokinetic limitation that standard dosing achieves serum Cmax of only 0.87 mg/L, which is insufficient for bloodstream infections 4

• Tigecycline penetrates well into tissues but has low concentrations in endothelial lining fluid (0.01-0.02 mg/L), explaining lower efficacy in VAP with standard dosing 4

Dosing Adjustments

Hepatic Impairment:

• No adjustment needed for mild-to-moderate hepatic impairment (Child-Pugh A and B) 1

• For severe hepatic impairment (Child-Pugh C): 100 mg loading dose, then reduce maintenance dose to 25 mg every 12 hours due to reduced systemic clearance and prolonged half-life 3, 1

• Monitor these patients closely for treatment response 1

Renal Impairment:

• No dose adjustment required for renal impairment or continuous renal replacement therapy 4

Pediatric Dosing:

• Avoid use in pediatric patients unless no alternative antibacterial drugs are available due to increased mortality risk observed in adults 1

• If absolutely necessary:

  • Ages 8-11 years: 1.2 mg/kg every 12 hours IV (maximum 50 mg every 12 hours) 1
  • Ages 12-17 years: 50 mg every 12 hours IV 1

Critical Precautions and Contraindications

FDA Boxed Warning - Increased Mortality:

The FDA issued a boxed warning noting increased all-cause mortality (0.6% absolute risk difference, 95% CI 0.1-1.2) in tigecycline-treated patients versus comparators in meta-analysis of Phase 3 and 4 trials. 3, 1

• Tigecycline should be reserved for situations when alternative treatments are not suitable 1

• Consultation with an infectious disease specialist is strongly recommended when considering tigecycline use 3

Specific Contraindications and Limitations:

• NOT indicated for diabetic foot infections - a clinical trial failed to demonstrate non-inferiority 1

• NOT indicated for hospital-acquired or ventilator-associated pneumonia - greater mortality and decreased efficacy were reported in comparative trials 1

• Should NOT be used as monotherapy for bacteremia due to poor outcomes with standard dosing 3, 4

• NOT recommended as monotherapy for carbapenem-resistant Acinetobacter baumannii (CRAB) pneumonia 3

• Contraindicated in patients with hypersensitivity to tigecycline or tetracyclines 5

• NOT recommended during pregnancy or breastfeeding due to evidence of fetal harm in animal studies 5

Important Clinical Caveats:

• For CRAB infections, tigecycline efficacy is comparable to polymyxin when MIC ≤2 mg/L, but inferior when MIC >2 mg/L 3, 4

• Combination therapy is essential for pneumonia - tigecycline monotherapy is not recommended due to poor serum concentrations and documented treatment failures 4

• For CRAB pneumonia, triple combination therapy is recommended: tigecycline 100 mg IV loading, then 50 mg IV every 12 hours PLUS colistin PLUS sulbactam for at least 7 days 4

• For CRE bloodstream infections, combine tigecycline with colistin or meropenem (extended infusion) for 7-14 days 4

Adverse Effects and Monitoring

Common Adverse Effects:

• Nausea, vomiting, and diarrhea are the most frequent adverse events 6

• Tigecycline may prolong prothrombin time (PT) and activated partial thromboplastin time (aPTT) 5

Safety Advantages:

• Significantly lower nephrotoxicity compared to colistin-based therapy (RR 0.23,95% CI 0.11-0.46) 3

• Lower incidence of nausea/vomiting (6.3% vs 35.9%) compared to polymyxins 3

• Higher incidence of abdominal pain (18.8% vs 2.6%) compared to polymyxins 3

Special Monitoring:

• Use cautiously in patients with liver insufficiency 3

• Monitor patients with severe hepatic impairment closely for treatment response 1

Preparation and Administration

• Reconstitute each 50 mg vial with 5.3 mL of 0.9% sodium chloride, 5% dextrose, or lactated Ringer's to achieve 10 mg/mL concentration 5, 1

• Withdraw 5 mL of reconstituted solution and add to 100 mL IV bag for infusion (final concentration 1 mg/mL) 5, 1

• Infuse over 30-60 minutes every 12 hours 1

Resistance Considerations

• Given the very broad spectrum of tigecycline, including activity against MRSA and a wide variety of organisms not commonly seen in appendix-derived infection, there is concern for its use in mild-to-moderate complicated intra-abdominal infection 2

• Broad use may facilitate acquisition of more-resistant organisms 2

• For aminoglycosides are superior to tigecycline for complicated urinary tract infections (cUTI) caused by CRE 3