What is the recommended antibiotic regimen, including colistin, for managing sepsis due to multidrug-resistant Gram-negative bacteria?

Colistin Combination Therapy for Sepsis Due to Multidrug-Resistant Gram-Negative Bacteria

For sepsis caused by multidrug-resistant gram-negative bacteria, use colistin in combination with at least one additional in vitro active agent, with a loading dose of 9 MU (5 mg/kg) followed by maintenance dosing of 4.5 MU twice daily, adjusted for renal function. 1

Pathogen-Specific Combination Strategies

Carbapenem-Resistant Enterobacterales (CRE)

• Preferred regimen: Colistin 5 mg CBA/kg IV loading dose, then 2.5 mg CBA × (1.5 × CrCl + 30) IV q12h PLUS tigecycline 100 mg IV loading dose, then 50 mg IV q12h for 7-14 days 1
• Alternative combination partner: Gentamicin or amikacin, particularly for urinary tract infections, where aminoglycosides demonstrate superior outcomes compared to tigecycline-based regimens (adjusted HR 0.30,95% CI 0.11-0.84 for fully susceptible isolates with MIC ≤4 mg/L) 1
• Critical caveat: Do NOT add carbapenems if meropenem MIC is >8 mg/L—this provides no benefit and increases toxicity risk 1

Carbapenem-Resistant Pseudomonas aeruginosa (DTR-PA)

• Combination therapy with two in vitro active drugs is strongly recommended for severe infections, including colistin with dosing of 9 MU (5 mg/kg) loading dose, then 4.5 MU (2.5 mg × [1.5 × CrCl + 30]) IV q12h as maintenance 1
• Consider newer beta-lactam/beta-lactamase inhibitors (ceftolozane-tazobactam 3 g IV q8h or ceftazidime-avibactam 2.5 g IV q8h) as preferred agents if susceptible, with colistin reserved for resistant isolates 2, 3
• Combination therapy reduces 30-day mortality in critically ill patients (adjusted HR 0.56,95% CI 0.34-0.91) 1

Carbapenem-Resistant Acinetobacter baumannii (CRAB)

• Use colistin-based combination therapy over monotherapy for severe and high-risk CRAB infections 4
• Do NOT use colistin-meropenem combination—this is a strong recommendation against this combination based on high-certainty RCT evidence showing no mortality benefit (OVERCOME and AIDA trials) 1, 4
• If meropenem MIC is ≤32 mg/L, colistin-carbapenem combinations may be considered, but evidence remains controversial 1
• Consider adding ampicillin-sulbactam if susceptible for double-covering therapy 3

Critical Dosing Algorithm

Loading Dose (Essential for All Patients)

• 9 MU (5 mg/kg) of colistin methanesulfonate IV as loading dose 2, 1, 5
• Without a loading dose, plasma colistin concentrations remain insufficient before steady state is reached 1
• Unit conversion critical to avoid errors: 1 million IU colistin methanesulfonate = 33 mg colistin base activity (CBA) 1

Maintenance Dosing Based on Renal Function

• Normal renal function (CrCl ≥80 mL/min): 4.5 MU (2.5 mg × [1.5 × CrCl + 30]) IV q12h 2, 1
• Mild impairment (CrCl 50-79 mL/min): 2.5 to 3.8 mg/kg divided into 2 doses per day 5
• Moderate impairment (CrCl 30-49 mL/min): 2.5 mg/kg once daily or divided into 2 doses per day 5
• Severe impairment (CrCl 10-29 mL/min): 1.5 mg/kg every 36 hours 5
• Use ideal body weight for obese patients 5

Administration Methods

Intravenous Administration Options

• Direct intermittent: Inject one-half of total daily dose over 3-5 minutes every 12 hours 5
• Continuous infusion: Inject one-half of total daily dose over 3-5 minutes, then add remaining half to compatible IV solution (0.9% NaCl, 5% dextrose in water, lactated Ringer's) and infuse over 22-23 hours 5

Adjunctive Aerosolized Therapy

• For respiratory tract infections, adding aerosolized polymyxin to intravenous therapy may improve clinical outcomes by achieving considerably higher colistin concentrations in lung fluids 1, 6

Treatment Duration by Infection Site

• Bloodstream infection: 7-14 days 1, 3
• Complicated urinary tract infection: 5-7 days 1, 3
• Complicated intra-abdominal infection: 5-7 days 1, 3
• Hospital-acquired/ventilator-associated pneumonia: 10-14 days 1, 3

Mandatory Monitoring and Source Control

Nephrotoxicity Surveillance

• Monitor renal function daily with serum creatinine and creatinine clearance calculation 2, 3
• Nephrotoxicity occurs in 10.9-53.7% of patients, with risk factors including pre-existing renal impairment, older age, and concomitant nephrotoxic medications 1
• Acute kidney injury during colistin treatment independently predicts fewer cures and increased mortality 2
• Deterioration of renal function may necessitate dose adjustment or therapy discontinuation 2

Source Control Priority

• Source control is mandatory to optimize outcomes and shorten treatment duration—perform surgical debridement, drainage of abscesses, or removal of infected devices whenever feasible 1, 3
• Follow-up cultures are essential in case of treatment failure to detect resistance development 1, 4

Critical Pitfalls to Avoid

• Never use monotherapy for severe infections or high-risk patients (INCREMENT score ≥8)—combination therapy significantly reduces mortality in this population 1
• Never add carbapenems to colistin for CRE if meropenem MIC is >8 mg/L—no benefit with increased toxicity 1
• Never use colistin-meropenem combination for CRAB if meropenem MIC is >16 mg/L—high-quality RCT evidence shows no mortality benefit 1, 4
• Never skip the loading dose—pharmacokinetic studies demonstrate insufficient plasma concentrations without it 1, 6
• Never dose based on actual body weight in obese patients—use ideal body weight 5

Antibiotic Stewardship Considerations

• Colistin should be reserved as a last resort antibiotic for carbapenem-resistant organisms 2
• For non-severe infections or low-risk sources, consider carbapenem-sparing alternatives or monotherapy to preserve colistin effectiveness 2, 4
• The balance between achieving appropriate empirical therapy and conserving last resort therapies requires local guidelines based on institutional epidemiology 2
• Combination therapy may help prevent emergence of resistant sub-populations, preserving future treatment options 4