What is the recommended treatment regimen for patients with severe or complicated infections, particularly those with hospital-acquired pneumonia, intra-abdominal infections, or skin and soft tissue infections caused by multidrug-resistant organisms, using tigecycline plus adjuvant antibiotics, such as beta-lactam (e.g. ceftriaxone) or aminoglycoside?

Tigecycline Plus Adjuvant Antibiotics for Severe Multidrug-Resistant Infections

Direct Recommendation

Tigecycline should NOT be used as monotherapy for bloodstream infections or hospital-acquired/ventilator-associated pneumonia, and is generally NOT recommended for severe infections caused by carbapenem-resistant Enterobacterales (CRE) or multidrug-resistant Pseudomonas aeruginosa. 1 When tigecycline must be used for these severe infections, high-dose tigecycline (100 mg loading, then 50 mg IV q12h or higher) in combination with other active agents is conditionally acceptable only when newer beta-lactam/beta-lactamase inhibitors are unavailable. 1

Evidence-Based Treatment Algorithm

Step 1: Determine if Tigecycline is Appropriate

Tigecycline is CONTRAINDICATED or NOT RECOMMENDED for:

• Bloodstream infections (BSI): Strong recommendation against use 1
• Hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP): Conditional recommendation against use; if absolutely necessary, use only high-dose tigecycline 1
• Infections caused by 3rd-generation cephalosporin-resistant Enterobacterales (3GCephRE): Strong recommendation against use 1
• Any infection where newer agents (ceftazidime-avibactam, meropenem-vaborbactam, cefiderocol) are available and active: Strong recommendation to use newer agents instead 1

Critical FDA Warning: Tigecycline is associated with increased all-cause mortality compared to control antibiotics in meta-analyses of phase III and IV clinical trials, resulting in an FDA boxed warning. 1

Step 2: Acceptable Tigecycline Use Scenarios

Tigecycline may be considered ONLY in these specific situations:

For Complicated Intra-Abdominal Infections (cIAI):

• Non-severe CRE infections when newer beta-lactam/beta-lactamase inhibitors are unavailable: Tigecycline 100 mg IV loading dose, then 50 mg IV q12h for 5-7 days 1
• VRE intra-abdominal infections: Tigecycline 100 mg IV loading, then 50 mg IV q12h (conditional recommendation, very low evidence) 1
• Must be combined with adequate source control (drainage/surgery) 1

For Complicated Skin and Soft Tissue Infections (cSSTI):

• MRSA infections: Tigecycline monotherapy acceptable (94% clinical success rate in documented MRSA infections) 2
• VRE skin infections: Tigecycline monotherapy showed 93-100% success rates 2
• Standard dosing: 100 mg IV loading, then 50 mg IV q12h 2, 3

Step 3: Mandatory Combination Therapy Scenarios

When tigecycline MUST be used for severe CRE infections (only when newer agents unavailable):

Combination regimens for CRE susceptible only to polymyxins, aminoglycosides, tigecycline, or fosfomycin:

• Tigecycline + Colistin: Tigecycline 100 mg IV loading, then 50 mg IV q12h PLUS Colistin 5 mg CBA/kg IV loading, then 2.5 mg (1.5 × CrCl + 30) IV q12h 1
• Tigecycline + Meropenem (if meropenem MIC ≤8 mg/L): Tigecycline standard dose PLUS Meropenem 1 g IV q8h by extended 3-hour infusion 1
• Conditional recommendation: Use more than one drug active in vitro, but no specific combination is definitively recommended over others 1

For severe CRE pneumonia (when absolutely no other option):

• High-dose tigecycline: 100 mg IV loading, then 75-100 mg IV q12h (off-label high dosing) 1, 4
• Must be combined with at least one other active agent (polymyxin, aminoglycoside, or carbapenem if MIC ≤8 mg/L) 1

Step 4: Preferred Alternatives to Tigecycline

For severe CRE infections, prioritize these agents FIRST:

1. Meropenem-vaborbactam 4 g IV q8h (conditional recommendation, moderate/low evidence) 1
2. Ceftazidime-avibactam 2.5 g IV q8h (conditional recommendation, moderate/low evidence) 1
3. Cefiderocol for metallo-beta-lactamase producers or when above agents fail (conditional recommendation, low evidence) 1

For non-severe CRE complicated UTI:

• Aminoglycosides preferred over tigecycline: Gentamicin 5-7 mg/kg IV q24h or Amikacin 15 mg/kg IV q24h 1
• Plazomicin 15 mg/kg IV q24h (conditional recommendation over tigecycline) 1

Step 5: Adjuvant Antibiotic Selection

Beta-lactam adjuvants (e.g., ceftriaxone) with tigecycline:

• NOT recommended: No evidence supports adding ceftriaxone or other beta-lactams to tigecycline for CRE or ESBL infections 1
• Beta-lactams are ineffective against carbapenem-resistant or ESBL-producing organisms by definition 1

Aminoglycoside adjuvants with tigecycline:

• Acceptable for severe CRE infections: Gentamicin 5-7 mg/kg IV q24h or Amikacin 15-20 mg/kg IV q24h as part of combination therapy 1
• Monitor aminoglycoside levels and renal function closely 1

Critical Pitfalls to Avoid

Common Errors:

1. Using tigecycline monotherapy for BSI or HAP/VAP: This is associated with treatment failure and increased mortality 1
2. Using standard-dose tigecycline for severe pneumonia: If tigecycline must be used for pneumonia, high-dose regimens are necessary (though still not preferred) 1, 4
3. Adding ineffective beta-lactams: Do not add ceftriaxone or other non-carbapenem beta-lactams to tigecycline for MDR Gram-negative infections—they provide no benefit 1
4. Ignoring antibiotic stewardship: Reserve tigecycline for situations where newer agents are truly unavailable or inactive 1
5. Inadequate source control: Tigecycline efficacy is negated without proper drainage or surgical intervention for intra-abdominal infections 1

Treatment Duration

• Complicated intra-abdominal infections: 5-7 days with adequate source control 1
• Complicated skin/soft tissue infections: 5-7 days 1
• Pneumonia (if tigecycline used): At least 7 days 1
• Duration should be individualized based on infection site, source control adequacy, underlying comorbidities, and clinical response 1

Monitoring Requirements

• Clinical response assessment: Daily evaluation for fever resolution, hemodynamic stability, and organ function improvement 2
• Superinfection surveillance: 29.6% rate of superinfection reported, particularly with Pseudomonas aeruginosa (46.9% of superinfections) 5
• Aminoglycoside levels: Monitor trough levels and renal function when used in combination 1
• Infectious disease consultation: Strongly recommended for all MDR infections, especially when considering tigecycline 6