Can a tigecycline (generic) and colistin (generic) combination be used to treat severe infections caused by multidrug-resistant Gram-negative bacteria?

Tigecycline and Colistin Combination Therapy for Multidrug-Resistant Gram-Negative Bacterial Infections

For severe infections caused by multidrug-resistant Gram-negative bacteria, particularly carbapenem-resistant Acinetobacter baumannii (CRAB), combination therapy with tigecycline and colistin can be considered when newer agents are unavailable, though this combination is not strongly supported by high-quality evidence. 1

Recommendations Based on Pathogen Type

For Carbapenem-Resistant Acinetobacter baumannii (CRAB):

• For severe and high-risk CRAB infections, combination therapy including two in vitro active antibiotics among available options (polymyxin, aminoglycoside, tigecycline, sulbactam combinations) is conditionally recommended 1
• Strong recommendation AGAINST polymyxin-meropenem combination therapy for CRAB infections based on high-certainty evidence 1
• Strong recommendation AGAINST polymyxin-rifampin combination therapy for CRAB infections based on moderate-certainty evidence 1

For Carbapenem-Resistant Enterobacterales (CRE):

• For patients with severe infections caused by CRE susceptible in vitro only to polymyxins, aminoglycosides, tigecycline or fosfomycin, combination therapy with more than one drug active in vitro is suggested 1
• Tigecycline has shown inferior outcomes compared to aminoglycosides for CRE urinary tract infections and bloodstream infections 1
• If using tigecycline for CRE infections, high-dose regimens should be considered, especially for ventilator-associated pneumonia 1

Evidence for Tigecycline-Colistin Combination

Efficacy:

• In vitro studies and animal models have shown that colistin-tigecycline combination demonstrates promising efficacy against multidrug-resistant pathogens 2, 3
• Recent in vitro time-killing assays showed that the combination of colistin (2 mg/L) and tigecycline (4 or 8 mg/L) inhibited bacterial growth of colistin- and carbapenem-resistant K. pneumoniae and A. baumannii, while monotherapy with either agent was ineffective 3
• Galleria mellonella larvae survival models demonstrated improved survival with combination therapy versus monotherapy with either agent 3

Clinical Considerations:

• Tigecycline monotherapy has been associated with higher mortality (OR 2.73,95% CI 1.53-4.87) compared to tigecycline-based combination therapy in CRE bloodstream infections 1
• High-dose tigecycline regimen (200 mg loading dose, 100 mg every 12h maintenance) has shown significantly lower mortality rates compared to standard dosing when used in combination therapy 1
• Tigecycline has limited efficacy for bacteremia and urinary tract infections due to its low serum and urinary concentrations 1

Dosing Recommendations

Tigecycline:

• Standard dose: 100 mg IV loading dose, then 50 mg IV q12h 1
• High dose (recommended for severe infections): 200 mg IV loading dose, then 100 mg IV q12h 1

Colistin:

• Loading dose of 300 mg colistimethate sodium (9 MU) infused over 0.5-1 hour 1
• Maintenance dose of 300-360 mg colistimethate sodium (9-10.9 MU) divided in two doses 1
• Requires renal dose adjustment and monitoring of renal function 4

Alternative Approaches

• For non-severe or low-risk infections, monotherapy with an in vitro active agent may be considered for antibiotic stewardship purposes 1, 4
• Newer agents such as ceftazidime-avibactam, meropenem-vaborbactam, or cefiderocol are preferred when the pathogen is susceptible 1
• For CRE infections with meropenem MIC ≤8 mg/L, high-dose extended-infusion carbapenem may be used as part of combination therapy 1

Monitoring and Safety

• Regular monitoring of renal function is essential during colistin therapy due to nephrotoxicity risk 4, 5
• Deterioration of renal function during colistin therapy has been observed in approximately 8% of patients 5
• Follow-up cultures should be obtained in case of treatment failure to detect resistance development 4

Limitations of Evidence

• Most data on tigecycline-colistin combination comes from in vitro and animal studies rather than randomized controlled trials 2
• Observational studies have significant risk of bias due to confounding factors like disease severity and delays in initiating effective therapy 6
• The AIDA and OVERCOME randomized controlled trials showed no benefit of colistin-meropenem combination over colistin monotherapy for CRAB infections 1, 4