Polymyxin B is an antibiotic belonging to the polymyxin class, produced by the bacterium Paenibacillus polymyxa. Discovered in the 1940s, it was initially used for treating Gram-negative bacterial infections but declined in the 1970s due to serious side effects, particularly toxicity to the kidneys and nervous system. The drug has recently experienced a resurgence because of the global increase in multi-drug resistant (MDR) Gram-negative pathogens. It is now frequently reserved as a “last-resort” treatment option against bacteria resistant to nearly all other available antibiotics.
Mechanism of Action and Bacterial Targets
Polymyxin B is a polypeptide antibiotic that exerts a bactericidal effect by targeting the outer membrane of susceptible Gram-negative bacteria. Its molecular structure contains multiple positively charged groups, which are attracted to the negatively charged outer surface of the bacterial cell membrane, composed of lipopolysaccharide (LPS). The drug initiates its action by displacing divalent cations, such as calcium and magnesium, from the phosphate groups within the LPS layer. This displacement destabilizes the outer membrane and increases its permeability.
The hydrophobic portion of the molecule then integrates into the compromised membrane, disrupting the integrity of both the outer and inner membranes. This damage leads to the leakage of essential intracellular contents, causing the death of the bacterial cell. Polymyxin B’s primary targets include Pseudomonas aeruginosa, Acinetobacter baumannii, and certain carbapenemase-producing Enterobacteriaceae. The drug also binds and neutralizes the endotoxin component of LPS released when bacteria are destroyed, potentially mitigating the severe inflammatory reaction known as endotoxemia.
Clinical Applications and Routes of Administration
Polymyxin B is reserved for treating severe, life-threatening infections caused by MDR Gram-negative organisms when few other therapeutic options remain viable. This includes systemic infections like sepsis and bloodstream infections (bacteremia), as well as complicated infections such as hospital-acquired and ventilator-associated pneumonia. Use is considered only when susceptibility testing confirms the pathogen is resistant to less toxic, first-line agents.
For systemic infections, Polymyxin B is administered intravenously (IV) as an infusion. The dosing regimen often begins with a loading dose to rapidly achieve target plasma levels, followed by a maintenance dose. This approach is used for deep-seated infections, although its penetration into the central nervous system (CNS) is poor, sometimes requiring intrathecal injection for meningitis.
The drug is also used via other routes for localized infections. It can be delivered through a nebulizer or inhaler for treating lung infections, such as in patients with cystic fibrosis or severe pneumonia. Polymyxin B is commonly formulated for topical use, such as in ophthalmic drops for eye infections or in combination ointments for skin infections, because it is not significantly absorbed from the skin or gastrointestinal tract.
Pharmacokinetics: Absorption, Distribution, and Elimination
Polymyxin B exhibits poor absorption characteristics. When administered orally, it is not absorbed into the systemic circulation in any meaningful quantity, making the oral route ineffective for treating systemic infections. Systemic treatment therefore requires parenteral administration.
Once in the bloodstream, Polymyxin B exhibits high protein binding, typically 79% to 92% bound to plasma proteins. It has a relatively small volume of distribution, estimated to be around 12.7 to 47.2 liters, indicating that it does not distribute extensively into most tissues. Its penetration into sites like bone, cerebrospinal fluid (CNS), and synovial fluid is notably limited, posing a challenge for treating infections in these areas.
The elimination of Polymyxin B is complex, with non-renal mechanisms being the major route of clearance. Studies show that less than 5% of the administered dose is recovered unchanged in the urine, suggesting the primary elimination pathway is non-renal clearance or inactivation. Despite low urinary recovery, the kidneys play an important role in the drug’s disposition. Polymyxin B demonstrates preferential uptake and prolonged retention within renal tissue, accumulating in the tubular epithelial cells.
This accumulation is a crucial factor in the development of its dose-limiting toxicity. The drug’s typical half-life ranges from 9 to 11.5 hours.
Critical Safety Considerations: Adverse Effects and Drug Interactions
The clinical utility of Polymyxin B is constrained by its potential for toxicity, with nephrotoxicity being the most serious and common adverse effect. Acute kidney injury (AKI) results from the drug’s accumulation in renal tubular cells, causing cellular damage that manifests as a rise in serum creatinine or a decrease in urine output. Monitoring kidney function through regular measurement of serum creatinine and blood urea nitrogen (BUN) is necessary during treatment. The risk of developing AKI is dose-dependent, and the drug has a narrow therapeutic window, meaning the effective dose is often close to the toxic dose.
A secondary concern is neurotoxicity, which can present with symptoms such as paresthesia, dizziness, and muscle weakness. This effect is generally reversible upon discontinuation of the drug. The potential for neuromuscular blockade also exists, particularly at high concentrations, which can lead to respiratory depression.
The risk of toxicity is amplified when Polymyxin B is co-administered with other nephrotoxic agents. Combining it with drugs such as aminoglycosides, certain antifungals (e.g., amphotericin B), or nonsteroidal anti-inflammatory drugs (NSAIDs) significantly increases the burden on the kidneys and the risk of AKI.