What is the use and dosage of tigecycline in treating infections?

Tigecycline: Clinical Use and Dosing

Overview and Spectrum of Activity

Tigecycline is a first-in-class glycylcycline antibiotic with broad-spectrum activity against multidrug-resistant Gram-positive and Gram-negative bacteria, but should be reserved for situations when alternative treatments are not suitable due to an observed increase in all-cause mortality. 1

• Tigecycline overcomes the two major tetracycline resistance mechanisms (ribosomal protection and efflux pumps) through a glycyclamide moiety addition 2, 3
• Active against ESBL-producing Enterobacteriaceae, carbapenem-resistant organisms, MRSA, VRE, and anaerobes 4, 5
• Critical limitation: NO activity against Pseudomonas aeruginosa, Proteus spp., Serratia spp., Morganella morganii, or Providencia stuartii 4

FDA-Approved Indications

The FDA has approved tigecycline for three specific indications in adults ≥18 years 1:

1. Complicated skin and skin structure infections (cSSSI) - caused by susceptible E. coli, Enterococcus faecalis (vancomycin-susceptible), MRSA, MSSA, Streptococcus species, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis 1

2. Complicated intra-abdominal infections (cIAI) - caused by susceptible Enterobacteriaceae, Enterococcus faecalis (vancomycin-susceptible), MRSA, MSSA, Streptococcus anginosus group, and multiple anaerobes including Bacteroides and Clostridium species 1

3. Community-acquired bacterial pneumonia (CAP) - caused by susceptible Streptococcus pneumoniae (penicillin-susceptible), Haemophilus influenzae, and Legionella pneumophila 1

Standard Dosing Regimen

The FDA-approved dosing 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 dose adjustment required, even with dialysis 6

Hepatic Impairment Dosing

• Mild to moderate hepatic impairment (Child-Pugh A and B): No adjustment needed 1
• Severe hepatic impairment (Child-Pugh C): 100 mg loading dose, then reduce maintenance to 25 mg every 12 hours 1, 7

High-Dose Regimen for Severe Infections

For severe infections, particularly hospital-acquired pneumonia and ventilator-associated pneumonia, a high-dose regimen of 200 mg IV loading dose followed by 100 mg IV every 12 hours achieves superior cure rates (85% vs 69.6% with standard dosing) 6, 7:

• This higher dosing addresses the pharmacokinetic limitation of low serum concentrations (standard dosing achieves only 0.87 mg/L Cmax) 6
• Particularly important for pulmonary infections where endothelial lining fluid concentrations are extremely low (0.01-0.02 mg/L) with standard dosing 6

Specific Clinical Scenarios

Multidrug-Resistant Organisms

For ESBL-producing Enterobacteriaceae in intra-abdominal infections, tigecycline serves as a carbapenem-sparing option, particularly in settings with high carbapenem-resistant K. pneumoniae prevalence 4:

• Standard dosing: 100 mg loading, then 50 mg every 12 hours 6, 7
• Combination therapy with polymyxins or meropenem is recommended for carbapenem-resistant Enterobacterales (CRE) 6, 7

Vancomycin-Resistant Enterococci (VRE)

For VRE complicated intra-abdominal infections (polymicrobial), tigecycline is appropriate at standard dosing (100 mg loading, then 50 mg every 12 hours) 4, 6:

• For monomicrobial VRE infections, linezolid is preferred 4

Acinetobacter baumannii

Tigecycline efficacy against Acinetobacter is MIC-dependent and should NOT be used as monotherapy for carbapenem-resistant Acinetobacter baumannii (CRAB) pneumonia 7:

• Standard dosing appropriate if MIC ≤1 mg/L 6
• High-dose regimen (200 mg loading, then 100 mg every 12 hours) recommended for non-approved indications 6
• Efficacy comparable to polymyxin when MIC ≤2 mg/L, but inferior when MIC >2 mg/L 7
• Always determine MIC before using tigecycline for MDR Acinetobacter infections 8

Critical Contraindications and Warnings

Black Box Warning: Increased Mortality

An FDA black box warning exists for increased all-cause mortality (0.6% absolute risk difference, 95% CI 0.1-1.2%) observed in tigecycline-treated patients versus comparators across Phase 3 and 4 trials 1:

• The cause of this mortality difference has not been established 1
• Reserve tigecycline for situations when alternative treatments are not suitable 1

Specific Clinical Situations to Avoid

Tigecycline is NOT indicated for and should be avoided in 1:

1. Diabetic foot infections - a clinical trial failed to demonstrate non-inferiority 1
2. Hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP) - greater mortality and decreased efficacy reported in comparative trials 1
3. Bacteremia as monotherapy - poor plasma concentrations result in much higher risk of failing to clear bacteremia 4, 6, 7

Additional Contraindications

• Hypersensitivity to tigecycline or tetracyclines 4
• Children <8 years due to risk of tooth discoloration 4, 1
• Pregnancy and breastfeeding (evidence of fetal harm in animal studies) 4

Pediatric Dosing (Use Only When No Alternatives Available)

Avoid tigecycline in pediatric patients unless no alternative antibacterial drugs are available due to the observed increase in mortality in adults 1:

• Ages 8-11 years: 1.2 mg/kg every 12 hours IV (maximum 50 mg every 12 hours) 4, 1
• Ages 12-17 years: 50 mg every 12 hours IV 4, 1
• Children <8 years: Insufficient data 4

Clinical Efficacy Data

Complicated Skin and Skin Structure Infections

Tigecycline monotherapy demonstrated non-inferiority to vancomycin 1g plus aztreonam 2g every 12 hours in two pooled phase III trials (clinical cure rates 86.5% vs 88.6%) 2:

• Treatment response in cSSSI: 73.1% clinical and/or microbiological response 8
• Drug change required in 26.9% of cSSSI patients 8

Complicated Intra-Abdominal Infections

Tigecycline monotherapy was non-inferior to imipenem/cilastatin in two pooled phase III trials (clinical cure rates 86.1% vs 86.2%) 2:

• Treatment response in cIAI: 85.0% clinical and/or microbiological response 8
• Drug change required in only 7.5% of cIAI patients 8
• Treatment response is better and duration shorter in cIAI compared to cSSSI 8

Community-Acquired Pneumonia

Tigecycline (100 mg loading, then 50 mg every 12 hours for 7-14 days) demonstrated non-inferiority to levofloxacin in hospitalized CAP patients 9:

• Clinical cure rates: 89.7% vs 86.3% (clinically evaluable population) 9
• Clinical cure rates: 81.0% vs 79.7% (modified intent-to-treat population) 9

Adverse Effects

Common Adverse Events

The most frequent adverse events are gastrointestinal 4, 1, 2:

• Nausea, vomiting, diarrhea (most common) 4, 2
• Abdominal pain, dyspepsia, anorexia 4
• Pruritus and rash 4
• Elevated liver function tests 4
• Prolonged aPTT and PT 4

Comparative Safety

Tigecycline-based therapy is associated with significantly lower incidence of nephrotoxicity compared to colistin-based therapy 7:

• This represents an important advantage when treating multidrug-resistant organisms 7

Key Clinical Pearls

• Tigecycline penetrates well into tissues but achieves poor serum concentrations, explaining its poor performance in bacteremia 6
• Always use combination therapy for MDR organisms rather than tigecycline monotherapy 6, 7
• Superinfection rates: 14.9% in cSSSI and 7.5% in cIAI 8
• Tigecycline has sustained activity against MRSA with MIC50/90 of 0.12/0.25 mg/L over 5 years of surveillance (2004-2008) 5
• Only 0.03% of MRSA isolates were non-susceptible at FDA breakpoints 5