How should polymyxin B be dosed and monitored in ICU patients with multidrug‑resistant Gram‑negative infections (e.g., carbapenem‑resistant Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae), especially in the setting of severe renal impairment?

Polymyxin B Dosing and Monitoring in ICU Patients with Multidrug-Resistant Gram-Negative Infections

Loading and Maintenance Dosing

For critically ill ICU patients, administer polymyxin B with a loading dose of 2–2.5 mg/kg followed by maintenance doses of 1.25–1.5 mg/kg every 12 hours, adjusted for patient weight and renal function. 1

• Weight-based dosing is critical: Patients weighing 50 kg require 2 mg/kg every 12 hours, while those weighing 75 kg need 1.25 mg/kg every 12 hours, and 100 kg patients require 1 mg/kg every 12 hours to achieve optimal exposure while minimizing toxicity. 2
• Inadequate dosing (<15,000 units/kg/day or approximately <1.5 mg/kg/day) is independently associated with treatment failure and increased mortality in critically ill patients. 3
• Higher daily doses (150–200 mg total daily) demonstrate significantly better effectiveness (85.7–87.5%) and microbial clearance rates (71.4–87.5%) compared to 100 mg daily (41.7% effectiveness, 33.3% clearance). 4

Therapeutic Drug Monitoring (TDM)

Therapeutic drug monitoring should be performed whenever available to optimize polymyxin B dosing, targeting an AUCss,24h of 50–100 mg·h/L. 5, 6

• Achieving the therapeutic AUC target is independently associated with favorable clinical outcomes (OR 13.15, p=0.015). 6
• Only 54.3% of patients reach therapeutic targets with standard dosing, and 65–75% of patients with creatinine clearance ≥80 mL/min fail to achieve adequate concentrations without TDM-guided adjustment. 5, 6
• TDM allows timely dose adjustments to improve treatment efficacy while reducing nephrotoxicity risk. 5

Renal Impairment Considerations

Polymyxin B requires careful dose adjustment in renal impairment, but paradoxically, pre-existing renal dysfunction is an independent predictor of treatment failure (p=0.021) and mortality (p=0.022). 3

• Lower creatinine clearance (OR 0.96, p=0.008) and concomitant loop diuretics (OR 5.93, p=0.046) independently predict nephrotoxicity. 6
• Creatinine clearance ≥60 mL/min is a protective factor for survival in polymyxin B-treated patients. 7
• Monitor renal function closely: Acute kidney injury occurs in 45.2% of ICU patients receiving polymyxin B. 6
• Polymyxin B demonstrates lower nephrotoxicity than colistin (adjusted HR 2.27,95% CI 1.35–3.82), making it the preferred polymyxin when either agent could be used. 1, 8

Combination Therapy Requirements

For severe infections in ICU patients, polymyxin B must be combined with at least one additional in-vitro active agent rather than used as monotherapy. 5, 1, 8

Pathogen-Specific Combinations:

Carbapenem-Resistant Acinetobacter baumannii (CRAB):

• Combine polymyxin B with high-dose ampicillin-sulbactam (3 g sulbactam every 8 hours as 4-hour infusion) when sulbactam MIC ≤4 mg/L. 1, 9
• Add a carbapenem (meropenem) only if carbapenem MIC ≤32 mg/L; avoid polymyxin-meropenem combinations when MIC >16 mg/L (strong recommendation against). 5, 1, 9
• Do not combine polymyxin with rifampicin (strong recommendation against; no mortality benefit at 30 days). 5, 1
• Avoid polymyxin plus glycopeptides (vancomycin) due to increased nephrotoxicity without added benefit. 5, 9, 8
• Combining with cefoperazone/sulbactam is independently associated with reduced treatment failure (p=0.030) and mortality (p=0.024). 3

Carbapenem-Resistant Pseudomonas aeruginosa (CRPA):

• Combine polymyxin B with a second active agent: aminoglycoside, fosfomycin, or carbapenem if MIC ≤8 mg/L. 1, 8
• Very low-certainty evidence suggests combination therapy improves outcomes over monotherapy. 1

Carbapenem-Resistant Enterobacterales (CRE):

• Combination therapy reduces 28–30 day mortality (35.7% vs 55.5% monotherapy; OR 0.46,95% CI 0.30–0.69). 1
• Combination is independently associated with lower 30-day mortality (HR 0.33,95% CI 0.17–0.64). 1, 7

Adjunctive Inhaled Therapy

For respiratory tract infections, add aerosolized polymyxin B (2–6 million IU daily) to intravenous therapy to improve pulmonary drug penetration and clinical outcomes. 1, 9, 8

• Combination of inhaled plus intravenous polymyxin reduces mortality (RR 0.86), clinical treatment failure (RR 0.82), and pathogen eradication failure (RR 0.84). 1

Treatment Duration

Administer polymyxin B for a minimum of 5 days; treatment courses ≥5 days are associated with better outcomes in ICU patients. 4

• For severe infections including bacteremia or pneumonia with septic shock, maintain therapy for 10–14 days. 9, 8
• Shorter duration of therapy is an independent predictor of treatment failure (p=0.009). 3

Critical Monitoring Parameters

Monitor the following parameters throughout polymyxin B therapy:

• Renal function: Check serum creatinine and creatinine clearance at baseline, daily during the first week, then every 2–3 days. 8, 6
• Plasma polymyxin B concentrations: Perform TDM when available, targeting AUCss,24h 50–100 mg·h/L. 5, 6
• Clinical response: Assess APACHE II scores; significant reductions indicate treatment effectiveness (16.20±9.24 vs 24.40±4.73 pre-treatment, p<0.05). 4
• Microbiological response: Obtain follow-up cultures to document pathogen clearance and detect emerging resistance. 5, 8

Common Pitfalls to Avoid

• Do not use inadequate doses: Doses <15,000 units/kg/day are associated with poor outcomes. 3
• Do not delay loading dose: Without a loading dose, plasma concentrations remain insufficient before steady state. 8
• Do not use monotherapy for severe infections: Combination therapy significantly reduces mortality in critically ill patients. 1, 7
• Do not combine with nephrotoxic agents unnecessarily: Concomitant loop diuretics increase nephrotoxicity risk nearly 6-fold. 6
• Do not use ineffective combinations: Polymyxin-rifampicin and polymyxin-glycopeptide combinations lack benefit and increase toxicity. 5, 1, 9

Special Considerations for Severe Renal Impairment

In patients with severe renal impairment (CrCl <30 mL/min), polymyxin B dosing becomes particularly challenging because these patients face both higher treatment failure risk and increased nephrotoxicity. 3, 6

• Prioritize aggressive source control to shorten antibiotic duration and reduce cumulative toxicity. 5, 8
• Consider alternative agents (high-dose ampicillin-sulbactam for CRAB with sulbactam MIC ≤4 mg/L) when possible. 5, 9
• If polymyxin B is unavoidable, mandatory TDM with dose adjustment to maintain AUC 50–100 mg·h/L while accepting higher nephrotoxicity risk. 5, 6
• Discontinue or avoid concomitant nephrotoxins (loop diuretics, vancomycin, aminoglycosides) when feasible. 6