What is the recommended adult dosing schedule, approved indications, contraindications, and monitoring parameters for tigecycline?

Tigecycline: Dosing, Indications, Contraindications, and Monitoring

FDA-Approved Adult Dosing

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

• Treatment duration is 5-14 days for complicated skin and skin structure infections (cSSSI) and complicated intra-abdominal infections (cIAI), and 7-14 days for community-acquired bacterial pneumonia (CABP). 1
• No dose adjustment is required for renal impairment or patients on continuous renal replacement therapy. 1

Hepatic Impairment Dosing

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

High-Dose Regimen for Severe Infections

For severe infections, particularly hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and multidrug-resistant organism (MDRO) infections, use a 200 mg IV loading dose followed by 100 mg IV every 12 hours. 2

• This high-dose regimen achieves 85% cure rates compared to 69.6% with standard dosing in severe pulmonary infections. 2
• Standard dosing achieves inadequate endothelial lining fluid concentrations (0.01-0.02 mg/L), explaining poor efficacy in VAP with conventional doses. 2
• High-dose tigecycline significantly reduced mortality (OR 0.44,95% CI 0.30-0.66) in carbapenem-resistant Enterobacterales (CRE) infections compared to standard dosing. 2

FDA-Approved Indications

Complicated Skin and Skin Structure Infections (cSSSI)

Approved for patients ≥18 years with cSSSI caused by: 1

• Escherichia coli
• Enterococcus faecalis (vancomycin-susceptible)
• Staphylococcus aureus (methicillin-susceptible and -resistant)
• Streptococcus agalactiae, S. pyogenes, Streptococcus anginosus group
• Enterobacter cloacae, Klebsiella pneumoniae
• Bacteroides fragilis

Complicated Intra-Abdominal Infections (cIAI)

Approved for patients ≥18 years with cIAI caused by: 1

• Citrobacter freundii, Enterobacter cloacae, E. coli, Klebsiella oxytoca, K. pneumoniae
• Enterococcus faecalis (vancomycin-susceptible)
• S. aureus (methicillin-susceptible and -resistant)
• Streptococcus anginosus group
• Bacteroides species (B. fragilis, B. thetaiotaomicron, B. uniformis, B. vulgatus)
• Clostridium perfringens, Peptostreptococcus micros

Community-Acquired Bacterial Pneumonia (CABP)

Approved for patients ≥18 years with CABP caused by: 1

• Streptococcus pneumoniae (penicillin-susceptible), including concurrent bacteremia
• Haemophilus influenzae
• Legionella pneumophila

Off-Label Use for Multidrug-Resistant Organisms

Carbapenem-Resistant Acinetobacter baumannii (CRAB)

For CRAB infections, tigecycline should only be used if the MIC is ≤1 mg/L and the isolate is resistant to other agents. 2

• For approved indications (cSSSI, cIAI): Standard dosing (100 mg loading, then 50 mg every 12 hours) may be appropriate. 2
• For non-approved indications (especially pulmonary infections): Use high-dose regimen (200 mg loading, then 100 mg every 12 hours) in combination with another active agent. 2
• Tigecycline monotherapy is NOT recommended for CRAB pneumonia due to poor serum and lung concentrations. 2

Carbapenem-Resistant Enterobacterales (CRE)

For CRE bloodstream infections, use standard dosing (100 mg loading, then 50 mg every 12 hours) in combination with colistin or meropenem for 7-14 days. 2

• For CRE complicated intra-abdominal infections: Standard dosing for 5-7 days in combination therapy. 2
• High-dose tigecycline (200 mg loading, then 100 mg every 12 hours) in combination therapy significantly reduces mortality in critically ill CRE patients. 2
• Tigecycline monotherapy for CRE bacteremia is associated with higher mortality (OR 2.73,95% CI 1.53-4.87) compared to combination therapy. 2

Vancomycin-Resistant Enterococci (VRE)

For VRE complicated intra-abdominal infections: Standard dosing (100 mg loading, then 50 mg every 12 hours) for 5-7 days. 2

Contraindications

Absolute contraindications include: 1

• Known hypersensitivity to tigecycline or any tetracycline-class antibiotic
• Pregnancy (fetal harm demonstrated in animal studies)
• Breastfeeding
• Children <8 years of age (risk of permanent tooth discoloration)

Black Box Warning: Increased All-Cause Mortality

Tigecycline carries an FDA black box warning for increased all-cause mortality (0.6% absolute risk increase, 95% CI 0.1-1.2) compared to comparators in meta-analysis of Phase 3 and 4 trials. 1

• Reserve tigecycline for situations when alternative treatments are not suitable. 1
• The FDA recommends against use in hospital-acquired or ventilator-associated pneumonia due to greater mortality and decreased efficacy in comparative trials. 1
• Tigecycline is NOT indicated for diabetic foot infections (failed to demonstrate non-inferiority). 1

Pediatric Dosing (Use Only When No Alternatives Exist)

Avoid tigecycline in pediatric patients due to increased mortality risk in adults; use only when no alternative antibiotics are available. 1

• 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 due to permanent tooth discoloration risk. 1

Monitoring Parameters

Coagulation Monitoring

Monitor prothrombin time (PT) and activated partial thromboplastin time (aPTT) during therapy, as tigecycline can prolong both parameters. 3

Hepatic Function

Check liver function tests periodically, as elevated hepatic enzymes have been reported during tigecycline therapy. 3

Metabolic Monitoring

Monitor for hypoglycemia and hypoproteinemia, which have been observed in patients receiving tigecycline. 3

Clinical Response Monitoring

• Assess clinical and bacteriological progress to guide duration of therapy. 1
• For severe infections with MDROs, monitor for treatment failure and consider combination therapy. 2

Critical Clinical Caveats

Poor Pharmacokinetic Profile for Certain Infections

Tigecycline has poor serum concentrations (Cmax 0.87 mg/L with standard dosing) and extremely low urinary concentrations, limiting its use in bacteremia and urinary tract infections. 2

• Tigecycline should NOT be used as monotherapy for bacteremia due to poor outcomes. 2
• Endothelial lining fluid concentrations are inadequate (0.01-0.02 mg/L), explaining lower cure rates in VAP (47.9% vs 70.1% with imipenem). 2

Combination Therapy Strongly Recommended

For severe MDRO infections, always use tigecycline in combination with another active agent (colistin, meropenem, or sulbactam) rather than monotherapy. 2

Common Adverse Effects

The most frequent adverse events (>5%) are: 1, 4

• Nausea (28.5%)
• Vomiting (19.4%)
• Diarrhea (11.6%)
• Local IV-site reaction (8.2%)
• Infection (6.7%)
• Fever (6.3%)
• Abdominal pain (6.0%)
• Headache (5.6%)

Reconstitution 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, then dilute to 1 mg/mL in 100 mL for IV infusion. 1