What are the adverse effects of Polymyxin B (antibiotic)?

Adverse Effects of Polymyxin B

Nephrotoxicity is the most common and clinically significant adverse effect of polymyxin B, occurring in approximately 14% of patients with normal baseline renal function and up to 45.8% in broader populations, though it is typically reversible upon drug discontinuation. 1, 2

Nephrotoxicity (Renal Toxicity)

Incidence and Mechanism:

• Nephrotoxicity occurs in 14% of patients with normal baseline renal function, but can reach 40-45.8% in mixed populations 1, 2, 3
• The mechanism involves tubular damage, as polymyxin B causes tubule injury even at therapeutic doses 4
• Acute kidney injury (AKI) typically develops with a median onset of 7-9 days after therapy initiation 2, 3
• The nephrotoxicity is dose-dependent and related to both the size of individual doses and cumulative duration of therapy 5, 6

Risk Factors for Nephrotoxicity:

• Higher daily dose by actual body weight (ABW) is an independent risk factor (HR = 1.73) 2
• Concurrent use of vancomycin increases risk significantly (HR = 1.89) 2
• Concurrent use of contrast media (HR = 1.79) 2
• Older age (OR 1.05 per year) 3
• Higher baseline serum creatinine (OR 2.99) 3
• Use of two or more nephrotoxic drugs simultaneously (OR 2.45) 3

Reversibility:

• Nephrotoxicity is reversible in 79-91.6% of patients after drug withdrawal 3
• The reversibility rate is slightly higher with colistin (91.6%) compared to polymyxin B (79%), though both demonstrate good recovery 3

Comparative Toxicity:

• Earlier studies suggested polymyxin B had lower nephrotoxicity than colistin, but recent evidence shows similar rates between the two agents 7, 5, 6
• One retrospective study showed colistin had higher RIFLE-defined nephrotoxicity (adjusted HR 2.27) compared to polymyxin B in critically ill patients 7

Neurotoxicity

Incidence and Manifestations:

• Neurotoxicity is less common than nephrotoxicity but clinically significant 5, 6
• Polymyxin B causes neurotoxic adverse events in 16.9% of conscious patients (13 of 77 patients), compared to only 1.4% with colistin (1 of 70 patients) 3
• The most common manifestation is paresthesias (abnormal sensations) 3
• All neurotoxic events are reversible after drug discontinuation 3
• Neurotoxicity is a relatively common reason for drug withdrawal, particularly with polymyxin B 3

Hypersensitivity Reactions

• Hypersensitivity reactions occur but are less common than nephrotoxicity and neurotoxicity 5
• These reactions are mentioned in the FDA label as potential adverse effects 4

Skin Hyperpigmentation

• Diffuse skin darkening can occur, most prominent on the face and forearms 8
• Hyperpigmentation typically peaks around 2 weeks after polymyxin B initiation 8
• Skin biopsy shows hypermelanosis of the basal layer and melanin deposition in the dermis 8
• The hyperpigmentation demonstrates some improvement within 4 weeks of drug discontinuation 8

Clostridium difficile-Associated Diarrhea (CDAD)

• CDAD has been reported with polymyxin B use, ranging from mild diarrhea to fatal colitis 4
• This occurs due to alteration of normal colonic flora, leading to C. difficile overgrowth 4
• CDAD can occur up to 2 months after antibiotic administration 4

Monitoring and Mitigation Strategies

Essential Monitoring:

• Monitor renal function closely during treatment, particularly in elderly patients and those with elevated baseline creatinine 1, 3
• Therapeutic drug monitoring (TDM) should be performed when available due to high interpatient variability 1
• Close monitoring for neurotoxic symptoms, especially paresthesias 3

Avoidance Strategies:

• Avoid concurrent use of other nephrotoxic drugs (vancomycin, contrast media, aminoglycosides) whenever possible 1, 2
• Avoid concurrent use of ototoxic drugs 1
• Use appropriate dosing: loading dose of 2-2.5 mg/kg followed by maintenance of 1.5-3 mg/kg/day divided into two doses 1
• The daily dose by ABW is a modifiable risk factor that should be optimized 2

Clinical Pearls:

• Polymyxin B has a narrow therapeutic range, requiring careful dosing 6
• Most toxicities are mild to moderate in magnitude and reversible upon discontinuation 6
• The drug loses 50% of its activity in the presence of serum, resulting in low active blood levels 4
• Repeated injections may produce cumulative effects 4
• Tissue diffusion is poor and the drug does not cross the blood-brain barrier 4