Tigecycline: Approved Indications, Dosing, Contraindications, and Safety
FDA-Approved Indications
Tigecycline is FDA-approved for three specific indications 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: Active against 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: Covers Citrobacter freundii, E. cloacae, E. coli, Klebsiella species, E. faecalis (vancomycin-susceptible), S. aureus (MRSA and MSSA), anaerobes including Bacteroides species, Clostridium perfringens, and Peptostreptococcus micros 1
Community-acquired bacterial pneumonia: Effective against S. pneumoniae (penicillin-susceptible isolates including concurrent bacteremia), H. influenzae, and Legionella pneumophila 1
Critical FDA Limitations:
- Tigecycline is NOT indicated for diabetic foot infections (clinical trial failed to demonstrate non-inferiority) 1
- Tigecycline is NOT indicated for hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP) due to greater mortality and decreased efficacy in comparative trials 1
FDA Boxed Warning: Increased All-Cause Mortality
The FDA issued a boxed warning for tigecycline due to increased all-cause mortality observed in meta-analysis of Phase 3 and 4 trials, with a mortality risk difference of 0.6% (95% CI 0.1-1.2). 1 Tigecycline should be reserved only for situations when alternative treatments are not suitable 1. This warning is reinforced by guideline recommendations that consultation with an infectious disease specialist is recommended when considering tigecycline use 2
Standard Dosing Regimen
Adult Dosing (FDA-Approved):
The standard FDA-approved regimen is 100 mg IV loading dose followed by 50 mg IV every 12 hours, infused over 30-60 minutes. 1
- Duration for cSSSI and cIAI: 5-14 days 1
- Duration for CAP: 7-14 days 1
- No renal adjustment required: Tigecycline does not require dose modification in renal impairment or continuous renal replacement therapy 3, 1
High-Dose Regimen for Severe Infections:
For severe infections, particularly pulmonary infections and multidrug-resistant organisms, a high-dose regimen of 200 mg IV loading dose followed by 100 mg IV every 12 hours achieves superior outcomes (85% cure rate vs. 69.6% with standard dosing). 2, 3 This higher dosing is particularly important for:
- Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) when no alternatives exist 3
- Acinetobacter baumannii infections (especially pulmonary) with MIC ≤1 mg/L 2, 3
- Carbapenem-resistant Enterobacterales (CRE) infections in combination therapy 3
Combination therapy with another active agent is strongly recommended for severe infections and non-approved indications, as tigecycline monotherapy has poor outcomes. 2, 4
Hepatic Impairment Dosing
- Mild to moderate hepatic impairment (Child-Pugh A and B): No dose adjustment needed 1
- Severe hepatic impairment (Child-Pugh C): 100 mg loading dose, then reduce maintenance to 25 mg IV every 12 hours 1 Patients require close monitoring for treatment response 1
Pediatric Dosing
Avoid tigecycline in pediatric patients unless no alternative antibacterial drugs are available due to increased mortality risk observed in adults. 1
When absolutely necessary:
- Ages 8-11 years: 1.2 mg/kg IV every 12 hours (maximum 50 mg per dose) 1
- Ages 12-17 years: Adult dosing (100 mg loading, then 50 mg every 12 hours) 1
- Contraindicated in children <8 years: Risk of permanent tooth discoloration 3, 1
Absolute Contraindications
Tigecycline is contraindicated in the following situations:
- Known hypersensitivity to tigecycline or any tetracycline-class antibiotic 3, 1
- Pregnancy and breastfeeding (animal studies demonstrated fetal harm) 3, 1
- Children under 8 years of age (permanent tooth discoloration risk) 3, 1
Critical Clinical Limitations and Warnings
Bacteremia and Bloodstream Infections:
Tigecycline should NOT be used as monotherapy for bacteremia due to poor serum concentrations (maximum serum Cmax only 0.87 mg/L with standard dosing) and documented treatment failures. 4, 3 The Infectious Diseases Society of America specifically recommends against tigecycline monotherapy for bacteremia 4
Urinary Tract Infections:
Tigecycline should generally be avoided for urinary tract infections due to inadequate urinary and serum concentrations resulting from its large volume of distribution. 5 It should only be considered as a last-resort option when no other susceptible antimicrobial agents are available for multidrug-resistant organisms 5
- Never use for pyelonephritis or upper tract infections 5
- Never use for bacteremic UTIs (unacceptably high treatment failure rates) 5
- For CRE-causing UTIs, preferred options include ceftazidime-avibactam, fosfomycin, plazomicin, and aminoglycosides 5
Pneumonia Considerations:
Tigecycline has extremely low concentrations in endothelial lining fluid (0.01-0.02 mg/L), explaining poor pulmonary efficacy with standard dosing. 2, 4 In VAP trials, cure rates with standard-dose tigecycline were significantly lower than imipenem (47.9% vs. 70.1%) 2
Monitoring Requirements
The following parameters require monitoring during tigecycline therapy:
- Coagulation parameters: Tigecycline can prolong prothrombin time (PT) and activated partial thromboplastin time (aPTT) 3
- Liver function tests: Elevated hepatic enzymes have been reported 3
- Metabolic monitoring: Cases of hypoglycemia and hypoproteinemia have been observed 3
Common Adverse Effects
Nausea and vomiting are the most frequently reported adverse effects with tigecycline. 6 These gastrointestinal effects were consistently noted across clinical trials but were generally well-tolerated 7, 6
Pharmacokinetic Profile
Tigecycline exhibits a large volume of distribution (7-9 L/kg) indicating extensive tissue penetration, with a long terminal elimination half-life of approximately 40 hours. 8, 9
- Excellent tissue penetration: Particularly into skin and soft tissues 7, 8
- Poor penetration: Into serum, urine, and endothelial lining fluid 4, 3, 5
- Minimal metabolism: Primary elimination through feces as unchanged drug, with glucuronidation and renal elimination as secondary routes 8
- No CYP450 interactions: Does not affect medications metabolized by cytochrome P-450 enzymes 9
Spectrum of Activity
Tigecycline has broad-spectrum activity against gram-positive, gram-negative, anaerobic, and atypical bacteria, including many multidrug-resistant organisms. 7, 10, 9
Key Coverage:
- MRSA and MSSA 7, 10, 9
- Vancomycin-resistant Enterococcus (VRE) 7, 10, 9
- Extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae 10, 9, 6
- Acinetobacter baumannii (inhibits 91-98% of isolates at ≤2 mg/L) 4
- Penicillin-resistant Streptococcus pneumoniae 7
Notable Gaps in Coverage:
- Inadequate activity against Pseudomonas aeruginosa 9, 6
- Inadequate activity against Proteus species 9
Clinical Pitfalls to Avoid
Common errors in tigecycline use that compromise patient outcomes:
Using standard dosing for severe infections: High-dose regimen (200 mg loading, 100 mg q12h) is essential for serious infections 2, 3
Monotherapy for resistant organisms: Always combine with another active agent for MDR pathogens 2, 4
Use in bacteremia: Poor serum levels make tigecycline inappropriate for bloodstream infections 4, 3
Empiric use without susceptibility testing: Should only be used after confirming no other options exist 5
Use in HAP/VAP: FDA explicitly contraindicates this due to increased mortality 1