Polymyxin B: A Comprehensive Monograph on a Last-Resort Antibiotic

Section 1: Introduction and Pharmaceutical Profile

1.1. Overview: The Resurgence of a Legacy Antibiotic

Polymyxin B is a polypeptide antibiotic belonging to the polymyxin class, a group of agents that also includes the clinically significant polymyxin E, or colistin.[1] The history of Polymyxin B is a compelling narrative of discovery, disuse, and reluctant revival. It was first discovered in the 1940s, isolated from the soil bacterium Paenibacillus polymyxa (previously known as Bacillus polymyxa), and introduced into clinical practice in the 1950s.[4] However, by the 1970s and 1980s, its use for systemic infections had sharply declined. This was a direct result of its significant potential for inducing severe nephrotoxicity (kidney damage) and neurotoxicity (nerve damage), coupled with the concurrent development and introduction of safer and better-tolerated antibiotic classes, such as the aminoglycosides and broad-spectrum beta-lactams.[7]

In recent decades, the medical community has witnessed a remarkable and necessary resurgence in the use of Polymyxin B. This revival is not driven by newfound safety but by a profound crisis: the global spread of antimicrobial resistance. The emergence of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) Gram-negative pathogens has left clinicians with dwindling therapeutic options.[6] For life-threatening infections caused by organisms such as carbapenem-resistant Enterobacteriaceae (CRE), MDR Pseudomonas aeruginosa, and MDR Acinetobacter baumannii, Polymyxin B has been re-established as an antibiotic of "last resort".[1] The clinical trajectory of Polymyxin B is, therefore, a direct reflection of the failures and voids within the modern antibiotic development pipeline. The re-adoption of a therapeutic agent once largely abandoned due to its toxicity profile underscores the critical lack of novel antibiotics effective against these highly resistant Gram-negative bacteria. This paradigm shift has forced a re-evaluation of the risk-benefit calculus, where the substantial risks of Polymyxin B therapy are now weighed against the even greater risk of untreatable infections and patient mortality.

1.2. Chemical Identity and Physicochemical Properties

Polymyxin B is classified as a small molecule, polypeptide antibiotic with a lipopeptide structure, meaning it contains both peptide and lipid-like components.[5] Its structure is characterized by the presence of multiple L-α,γ-diaminobutyric acid (DAB) residues, which are non-proteinogenic amino acids. These residues contain primary amine groups that are protonated at physiological pH, conferring a strong positive charge upon the molecule.[3] This polycationic nature is the cornerstone of its antimicrobial mechanism of action. The overall architecture consists of a cyclic heptapeptide ring attached to a linear tripeptide side chain, which is N-terminally acylated with a fatty acid tail.[3] A consolidated summary of its key identifiers and physicochemical properties is presented in Table 1.

Table 1: Key Identifiers and Physicochemical Properties of Polymyxin B

Property	Value	Source(s)
DrugBank ID	DB00781	4
Type	Small Molecule	5
CAS Number	1404-26-8	5
European Community (EC) Number	215-768-4	5
UNII	19371312D4	4
Chemical Formula (Sulfate Salt)	$C_{56}H_{100}N_{16}O_{17}S$	4
Average Molecular Weight (Sulfate Salt)	1301.57 g/mol	4
IUPAC Name	N-(4-amino-1-((1-((4-amino-1-oxo-1-((6,9,18-tris(2-aminoethyl)-15-benzyl-3-(1-hydroxyethyl)-12-(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl)amino)butan-2-yl)amino)-3-hydroxy-1-oxobutan-2-yl)amino)-1-oxobutan-2-yl)-6-methyloctanamide	5
InChIKey	WQVJHHACXVLGBL-UHFFFAOYSA-N (base)	22
Water Solubility (Predicted)	0.0744 mg/mL	21
logP (Predicted)	-0.89	21
pKa (Strongest Basic, Predicted)	10.23	21
Polar Surface Area (Predicted)	490.66 $Å^2$	21
Rule of Five Violation (Predicted)	Yes	21

The predicted physicochemical properties, such as a high polar surface area and violation of the Rule of Five, are consistent with a large peptide molecule that would be expected to have poor oral bioavailability, necessitating parenteral administration for systemic effect.[21]

1.3. Structural Elucidation and Compositional Analysis

A critical aspect of Polymyxin B pharmacology is that the clinically available drug is not a single, pure chemical entity. Rather, it is a complex mixture of structurally related polypeptides.[4] The formulation is composed predominantly of Polymyxin B1 and Polymyxin B2, which are considered the major active components, often comprising 75% and 15% of the mixture, respectively.[3] Other minor, related components that may be present include Polymyxin B1-I, B3, B4, and B6.[4]

The structural variation among these components is subtle and confined to the fatty acid moiety attached to the N-terminus of the peptide chain. Polymyxin B1 contains (S)-6-methyloctanoic acid, whereas Polymyxin B2 contains 6-methylheptanoic acid.[3] Despite these differences, in vitro studies have demonstrated only marginal variations in the minimum inhibitory concentration (MIC) data among the fractions, suggesting that they possess comparable intrinsic antimicrobial potency.[4]

However, this multi-component nature introduces a significant layer of complexity and variability into its clinical use. The precise ratio of the different polymyxin components can vary from batch to batch of the manufactured drug.[11] This issue is compounded by the fact that the quality assurance assays used to determine the potency of Polymyxin B are legacy methods established in the 1940s. Recent investigations have revealed these assays to be significantly flawed, with the potential for the true potency of a given vial to vary by as much as 40% from the content stated in the prescribing information.[8] This combination of inherent compositional variability and inaccurate potency measurement presents a formidable challenge to precise pharmacodynamic modeling and may be a key, yet underappreciated, contributor to the inconsistent clinical outcomes observed in patients. While the individual components may exhibit similar activity in a laboratory setting, it is plausible that they possess distinct pharmacokinetic or toxicodynamic profiles in vivo. Consequently, two patients receiving the "same" prescribed dose of Polymyxin B, but from different manufacturing lots, could be exposed to substantially different concentrations of the active components. This uncertainty fundamentally challenges the ability to define and adhere to a narrow therapeutic window and complicates the interpretation of clinical studies on efficacy and toxicity. This reality provides a compelling rationale for the urgent development and implementation of modern, component-specific analytical methods, such as liquid chromatography-tandem mass spectrometry (LC-MS/MS), for both pharmaceutical quality control and clinical therapeutic drug monitoring.[25]

Section 2: Pharmacology and Mechanism of Action

2.1. Molecular Basis of Bactericidal Activity: Targeting the Gram-Negative Envelope

The mechanism of action of Polymyxin B is a rapid, potent, and targeted assault on the structural integrity of the Gram-negative bacterial cell envelope. Its activity is highly specific, which explains its narrow spectrum of activity; it is ineffective against Gram-positive bacteria, fungi, and Gram-negative cocci, as these organisms lack the primary molecular target.[3]

The bactericidal cascade can be described in a series of molecular events:

1. Electrostatic Interaction: The primary target of Polymyxin B is the lipopolysaccharide (LPS) molecule, an essential component of the outer membrane of Gram-negative bacteria.[3] The initial and critical step is an electrostatic interaction between the polycationic cyclic peptide portion of the antibiotic and the anionic (negatively charged) phosphate groups of the Lipid A region of LPS.[2]
2. Membrane Destabilization: The outer membrane of Gram-negative bacteria is stabilized by divalent cations, specifically calcium ($Ca^{2+}$) and magnesium ($Mg^{2+}$), which form ionic bridges between adjacent LPS molecules. Polymyxin B binds to the phosphate groups of Lipid A with an affinity that is orders of magnitude higher than that of these cations.[11] This high-affinity binding leads to the competitive displacement of $Ca^{2+}$ and $Mg^{2+}$, disrupting the cross-bridges and profoundly destabilizing the tightly packed LPS layer.[4]
3. Permeabilization and Insertion: Following the initial electrostatic binding and destabilization, the hydrophobic fatty acid tail of Polymyxin B inserts into and dissolves within the hydrophobic regions of the bacterial cell membranes.[3] This action is analogous to that of a cationic detergent, causing further disorganization and disruption of both the outer and inner (cytoplasmic) membranes.[3] This process creates transient pores or channels, leading to a dramatic increase in membrane permeability.[20]
4. Cell Death: The loss of membrane integrity is catastrophic for the bacterium. The increased permeability allows for the uncontrolled efflux of essential intracellular contents, such as ions, ATP, and nucleotides. Concurrently, cellular respiration is inhibited, and the proton motive force is dissipated.[2] This culmination of events leads to rapid bacterial cell death, defining Polymyxin B as a potent bactericidal agent.[2]

This entire process is amplified through a mechanism known as "self-promoted uptake." The initial damage to the outer membrane facilitates the passage of additional polymyxin molecules across the barrier, allowing them to reach the inner membrane and accelerate the lethal damage.[11]

2.2. Antimicrobial Spectrum and Potency

Polymyxin B exhibits a targeted spectrum of activity, exclusively targeting Gram-negative bacilli.[4] It is particularly valued for its potent activity against some of the most challenging MDR pathogens encountered in modern clinical practice.

• Key Susceptible Pathogens: The drug demonstrates excellent in vitro activity against Pseudomonas aeruginosa, Acinetobacter baumannii, and carbapenem-resistant Enterobacteriaceae, including Klebsiella pneumoniae and Escherichia coli. It is also active against Haemophilus influenzae.[2] Its utility is most pronounced against isolates that have developed resistance to nearly all other classes of antibiotics.[11]
• Intrinsically Resistant Pathogens: Several genera of Gram-negative bacteria are intrinsically resistant to polymyxins. These include Proteus spp., Providencia spp., Morganella spp., Serratia spp., and the Burkholderia cepacia complex.[28] This natural resistance is typically attributed to constitutive modifications of their LPS structure that prevent effective binding of the antibiotic.[29]

2.3. Endotoxin Neutralization: A Secondary Therapeutic Benefit

Beyond its direct bactericidal effects, Polymyxin B possesses a distinct and clinically relevant pharmacological property: the ability to bind and neutralize endotoxin.[2] Endotoxin is the Lipid A component of LPS, which is released from dying Gram-negative bacteria and is a powerful trigger of the systemic inflammatory cascade that leads to sepsis and septic shock.

This property is exploited in a unique therapeutic modality for patients with refractory septic shock. Extracorporeal blood purification devices, such as the Toraymyxin™ cartridge, utilize fibers to which Polymyxin B is covalently bound.[4] When a patient's blood is circulated through this device, the immobilized Polymyxin B avidly binds and removes circulating endotoxin from the bloodstream. This approach allows the therapeutic benefit of endotoxin removal to be realized while bypassing the systemic administration of the drug, thereby avoiding its severe toxicities.[4]

This dual functionality—bactericidal activity and endotoxin neutralization—reveals a deeper complexity in the molecule's design. The two functions are structurally separable. Research has shown that removing the hydrophobic fatty acid tail from Polymyxin B yields a derivative known as polymyxin nonapeptide. This modified molecule retains the ability to bind to LPS but loses its capacity to disrupt the cell membrane and kill the bacterial cell.[3] This observation demonstrates that the polycationic peptide ring is responsible for LPS binding, while the fatty acid tail is crucial for the detergent-like killing mechanism. This structural-functional distinction suggests a promising path for future drug development. It may be possible to design novel therapeutic agents based on the polymyxin scaffold that are engineered to retain high-affinity LPS binding but lack the membrane-disrupting tail. Such a molecule could potentially be administered systemically as a direct anti-endotoxin agent to modulate the inflammatory response in sepsis, offering a targeted immunomodulatory therapy without the profound nephrotoxicity and neurotoxicity of the parent compound. This reframes Polymyxin B not merely as an antibiotic but as a valuable molecular template for creating safer, next-generation anti-sepsis treatments.

Section 3: Clinical Pharmacokinetics and Pharmacodynamics

3.1. Administration, Distribution, and Elimination Pathways

The pharmacokinetic profile of Polymyxin B is complex, characterized by poor oral absorption, variable tissue distribution, and a unique elimination pathway that is intrinsically linked to its primary toxicity.

• Routes of Administration and Absorption: Polymyxin B is not absorbed from the gastrointestinal tract and therefore must be administered parenterally for systemic infections.[3] The primary routes are intravenous (IV), intramuscular (IM), and intrathecal (IT).[4] It is also widely used in topical formulations for the skin, eye, and ear, and can be administered via inhalation.[4] IM administration is often painful, particularly in children, and is generally not the preferred route.[4] A key pharmacokinetic advantage of Polymyxin B over colistin is that it is administered intravenously as the active sulfate salt. In contrast, colistin is administered as an inactive prodrug, colistin methanesulfonate, which must be hydrolyzed in vivo to its active form. This distinction means that Polymyxin B achieves therapeutic plasma concentrations more rapidly and reliably than colistin.[1]
• Distribution: Following IV administration, Polymyxin B is widely distributed into body tissues.[30] However, its penetration into certain compartments is poor. Notably, it does not adequately cross the blood-brain barrier, making direct intrathecal administration necessary for the treatment of meningitis.[15] Plasma protein binding is extensive and appears to be concentration-dependent. Crucially, protein binding is significantly higher in critically ill patients, with reported bound fractions ranging from 78% to 92.4%, compared to approximately 56% in healthy volunteers.[13]
• Metabolism and Elimination: Polymyxin B is not extensively metabolized.[30] Its elimination is predominantly mediated by non-renal pathways.[13] This is evidenced by the extremely low recovery of unchanged drug in the urine, which is typically less than 5% and has been reported to be as low as <1% of the administered dose.[13] This finding indicates that while the drug is filtered by the glomerulus, it undergoes massive reabsorption by the renal tubules. This extensive tubular reabsorption leads to the accumulation of Polymyxin B in renal tissue, a process that is mechanistically central to its nephrotoxicity.[25] The precise non-renal clearance mechanisms have not been fully elucidated, though some evidence suggests that biliary excretion may play a role.[25]

3.2. Pharmacokinetic Profile: Predictability and Therapeutic Window

The pharmacokinetic properties of Polymyxin B present both advantages and significant clinical challenges. Its plasma half-life is approximately 9 to 11.5 hours.[25] Because it is administered in its active form, Polymyxin B exhibits less inter-patient pharmacokinetic variability compared to the prodrug colistin, making it the preferred polymyxin for systemic therapy in many clinical centers.[18]

Despite this relative predictability, the most formidable challenge in its clinical use is its exceptionally narrow therapeutic window. The plasma concentrations required to achieve bactericidal activity against target pathogens overlap significantly with the concentrations known to cause toxicity, particularly nephrotoxicity.[18] This leaves very little margin for error in dosing.

This challenge is further exacerbated by the altered pharmacokinetics observed in critically ill patients. The significantly increased plasma protein binding in this population (up to 92.4%) has profound clinical implications.[13] According to fundamental pharmacological principles, only the unbound, or "free," fraction of a drug is microbiologically active and available to exert its effect at the site of infection. A study conducted in critically ill patients revealed that while total plasma concentrations of Polymyxin B might appear adequate, the corresponding unbound concentrations were often at or even below the MIC of the infecting pathogen.[13] This creates a critical disconnect between the standard laboratory measurement (total drug level) and the biologically effective concentration. Standard dosing regimens, therefore, may be insufficient to overcome this extensive protein binding in the sickest patients, leading to sub-therapeutic free drug exposure at the infection site. This not only increases the risk of therapeutic failure but also creates an ideal selective pressure for the emergence of bacterial resistance, as the organisms are exposed to sustained, sub-lethal concentrations of the antibiotic. This phenomenon strongly supports the clinical need for therapeutic drug monitoring (TDM), and specifically, TDM that can measure the free drug fraction, to guide individualized dosing and ensure that therapeutic targets are met.

3.3. Pharmacodynamic Principles for Optimal Dosing

The efficacy of Polymyxin B is best described by its pharmacodynamic relationship with the target pathogen. The key pharmacokinetic/pharmacodynamic (PK/PD) index that correlates with bacterial killing is the ratio of the area under the free drug concentration-time curve to the minimum inhibitory concentration (fAUC/MIC).[36] To balance efficacy with the risk of toxicity, international consensus guidelines have proposed a target total drug AUC of 50–100 mg∙h/L, although it is acknowledged that this target is based on limited clinical efficacy data.[36]

Furthermore, the pharmacodynamics of Polymyxin B appear to be site-specific. For instance, one clinical study found that achieving an AUC greater than 50 mg∙h/L was associated with a lower 14-day mortality rate in patients with intra-abdominal infections. However, this same exposure target was not associated with improved survival in patients with lower respiratory tract infections, suggesting that higher drug exposures may be necessary to effectively treat infections in certain body compartments like the lungs.[36] This highlights the need for more refined, infection-site-specific PK/PD targets to truly optimize therapy.

Section 4: Therapeutic Applications and Clinical Practice

4.1. Systemic Treatment of Multi-Drug-Resistant Infections

The contemporary clinical role of systemic Polymyxin B is almost exclusively as a last-resort agent for severe, life-threatening infections caused by susceptible MDR Gram-negative bacteria, particularly when all less toxic therapeutic options are ineffective or contraindicated.[2] While its original FDA-approved indications from the pre-MDR era included a broader range of infections like urinary tract infections, pneumonia, and sepsis caused by susceptible strains of P. aeruginosa, H. influenzae, E. coli, and Klebsiella spp., its modern application is more focused.[4] Today, it is primarily deployed against infections caused by CRE, MDR P. aeruginosa, and MDR A. baumannii, which are often responsible for challenging nosocomial infections such as hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP).[2]

To enhance efficacy and potentially delay the emergence of resistance, Polymyxin B is frequently used as part of a combination therapy regimen, often alongside a carbapenem like meropenem.[16] However, the clinical evidence supporting specific combinations is often limited, and some combinations, such as polymyxin-meropenem or polymyxin-rifampin for carbapenem-resistant A. baumannii (CRAB), are not recommended.[15]

4.2. Topical and Localized Formulations

In stark contrast to its restricted systemic use, Polymyxin B is a ubiquitous component of many widely available topical preparations. The primary rationale for topical use is that it allows for high local concentrations of the antibiotic at the site of infection with minimal systemic absorption, thereby greatly reducing the risk of nephrotoxicity and neurotoxicity.[27]

• Ophthalmic Use: Polymyxin B is a key ingredient in ophthalmic solutions and ointments for the treatment of bacterial conjunctivitis and other superficial ocular infections. It is commonly formulated in combination with other antibiotics, such as trimethoprim (e.g., Polytrim®) or neomycin and bacitracin.[1]
• Otic Use: For the treatment of otitis externa (commonly known as "swimmer's ear"), Polymyxin B is included in otic drops, often combined with neomycin and a corticosteroid like hydrocortisone, to provide activity against the common causative pathogen, P. aeruginosa.[2]
• Dermatologic Use: Polymyxin B is a cornerstone of many over-the-counter (OTC) topical antibiotic ointments, most famously in "triple antibiotic" formulations (e.g., Neosporin®) that also contain bacitracin and neomycin. These products are used for the prevention and treatment of infections in minor cuts, scrapes, and burns.[1]

4.3. Dosing and Administration: Evidence-Based Guidelines

The dosing of systemic Polymyxin B is complex and requires careful consideration of the patient's weight, the route of administration, and the site of infection. Dosing is often expressed in either milligrams (mg) or international units (IU), with the conversion factor being 1 mg = 10,000 IU.[9] A summary of common dosing regimens is provided in Table 2.

Table 2: Summary of Dosing Regimens for Systemic Polymyxin B

Route	Patient Population	Dosing Regimen	Source(s)
Intravenous (IV)	Adults	Loading Dose: 2.0-2.5 mg/kg (20,000-25,000 units/kg) infused over 1-2 hours. Maintenance Dose: 1.25-1.5 mg/kg (12,500-15,000 units/kg) every 12 hours.	28
	Children	15,000-25,000 units/kg/day divided every 12 hours.	31
	Infants	15,000-40,000 units/kg/day divided every 12 hours.	31
Intramuscular (IM)	Adults	25,000-30,000 units/kg/day divided every 4-6 hours.	31
	Children	25,000-30,000 units/kg/day divided every 12 hours.	40
	Infants	Up to 40,000 units/kg/day divided every 6 hours.	40
Intrathecal (IT)	Adults & Children >2 years	50,000 units once daily for 3-4 days, then every other day.	31
	Infants & Children <2 years	20,000 units once daily for 3-4 days, then 25,000 units every other day.	31

For intravenous administration in adults, modern guidelines strongly advocate for the use of a loading dose to rapidly achieve target plasma concentrations, which is critical in treating severe infections.[28] Dosing for obese patients may require the use of adjusted body weight to avoid excessive dosage.[28] Intrathecal administration is reserved for meningeal infections and should be continued for at least two weeks after cerebrospinal fluid (CSF) cultures become negative.[31]

4.4. The Clinical Dilemma: Dosing in Renal Impairment

One of the most significant and unresolved controversies in the clinical use of Polymyxin B is how to dose the drug in patients with renal impairment. This issue has created a deep schism between traditional prescribing information and modern, evidence-based guidelines, placing clinicians in a difficult position.

• The Traditional View (FDA-Approved Labeling): The package insert and older resources recommend substantial dose reductions for patients with impaired renal function, with the dose adjusted based on creatinine clearance (CrCl).[9] For patients with severe renal failure (e.g., CrCl <5 mL/min), this guidance suggests reducing the dose to as little as 15% of the standard daily dose.[40]
• The Modern Pharmacokinetic View (International Consensus Guidelines): In stark contrast, contemporary international consensus guidelines, informed by modern pharmacokinetic studies, recommend no dose adjustment for renal impairment.[14] This recommendation is based on the robust evidence that Polymyxin B is predominantly eliminated via non-renal pathways and that renal function has little to no impact on its clearance from the plasma.[13] According to this paradigm, a full loading dose and standard maintenance doses should be administered regardless of the patient's kidney function.[33]

This profound disagreement represents a critical knowledge gap with serious clinical implications. Following the outdated package insert information is pharmacokinetically illogical; since the drug is not cleared by the kidneys, reducing the dose in a patient with renal failure will almost certainly lead to sub-therapeutic drug exposure (low fAUC/MIC), increasing the risk of treatment failure, the emergence of resistance, and mortality. Indeed, one study found that mortality was higher in a cohort of patients whose doses were adjusted for renal function compared to those who received full doses.[33] Conversely, following the modern "no adjustment" guideline without the ability to perform therapeutic drug monitoring also carries risk. The drug is known to accumulate in renal tissue, and some recent studies have suggested a weak relationship between creatinine clearance and polymyxin clearance, raising concerns that full dosing in anuric patients could lead to excessive drug accumulation and an unacceptably high risk of severe toxicity.[14] This clinical dilemma highlights that Polymyxin B is being used at the very edge of the available medical evidence. The ultimate resolution will require prospective, controlled clinical trials in patients with varying degrees of renal failure, coupled with the widespread adoption of TDM, to enable the development of truly individualized dosing regimens that can safely and effectively navigate this drug's treacherous therapeutic index.

Section 5: Toxicology and Safety Profile

The clinical utility of Polymyxin B is fundamentally constrained by its significant toxicity profile. The primary dose-limiting adverse effects are nephrotoxicity and neurotoxicity, which are detailed in the drug's black box warnings in the United States.[31]

5.1. Nephrotoxicity: Mechanisms, Risk Factors, and Clinical Management

Nephrotoxicity is the most common and clinically concerning adverse effect of systemic Polymyxin B therapy.

• Incidence: Acute kidney injury (AKI) is a frequent complication, with reported rates varying widely in different studies, from approximately 14% in patients with normal baseline renal function to as high as 45-60% in other cohorts of critically ill patients.[15]
• Mechanism of Toxicity: The pathophysiology of Polymyxin B-induced nephrotoxicity is directly related to its renal handling. The drug is filtered at the glomerulus and then undergoes extensive reabsorption in the proximal tubules.[34] This process is mediated by transporters on the apical membrane of tubular cells, including the endocytic receptor megalin and the peptide transporter PEPT2.[34] This avid reabsorption leads to a massive accumulation of the drug within the proximal tubular cells, where intracellular concentrations can become several thousand-fold higher than in the plasma.[34] These exceedingly high intracellular concentrations are directly cytotoxic, inducing cellular apoptosis and necrosis through multiple pathways. These include the generation of reactive oxygen species (oxidative stress), direct mitochondrial damage, activation of cellular death receptors, and induction of endoplasmic reticulum stress.[34] Histopathologically, this damage manifests as acute tubular necrosis.[37]
• Risk Factors: The risk of developing nephrotoxicity is increased by several factors, including higher daily and cumulative doses of Polymyxin B, longer duration of therapy, advanced age, and pre-existing renal insufficiency.[9] A major modifiable risk factor is the concurrent administration of other nephrotoxic medications, such as vancomycin, aminoglycosides, amphotericin B, cyclosporine, and iodinated contrast media.[2]
• Clinical Management: Nephrotoxicity typically presents as a rise in serum creatinine and blood urea nitrogen (BUN), often accompanied by proteinuria, hematuria, and oliguria.[2] Due to the high incidence of this complication, daily monitoring of renal function is mandatory for all patients receiving systemic Polymyxin B.[2] If significant renal impairment develops, discontinuation of the drug may be necessary.[2]
• Comparison with Colistin: An important clinical consideration is the relative nephrotoxicity of the two available polymyxins. A growing body of evidence from observational studies suggests that Polymyxin B is associated with a lower incidence of AKI compared to colistin.[2] This potential safety advantage is a primary reason why Polymyxin B is often preferred over colistin for the treatment of systemic infections.

5.2. Neurotoxicity: Manifestations, Pathophysiology, and Prevention

Neurotoxicity is a less common but potentially severe adverse effect of Polymyxin B.

• Incidence: Historical studies reported an incidence of approximately 7%.[2]
• Clinical Manifestations: The symptoms of neurotoxicity can range from mild sensory disturbances to life-threatening respiratory failure. Common manifestations include perioral and peripheral paresthesias (numbness or tingling sensations, especially around the mouth and in the extremities), dizziness, vertigo, visual disturbances, ataxia (loss of coordination), and slurred speech.[1]
• Neuromuscular Blockade: The most severe neurological complication is neuromuscular blockade, which can cause profound muscle weakness leading to respiratory muscle paralysis, respiratory failure, and apnea.[2] This is a rare but potentially fatal event that requires immediate recognition and intervention, including discontinuation of the drug and mechanical ventilation.[2]
• Mechanism of Toxicity: The neurotoxicity of Polymyxin B is thought to be dose-dependent and results from its interaction with the lipid-rich membranes of neurons.[7] The neuromuscular blockade is mediated by effects at both the pre-synaptic and post-synaptic terminals of the neuromuscular junction. At the pre-synaptic level, it can reduce the release of acetylcholine into the synaptic cleft. At the post-synaptic level, it can decrease the sensitivity of the muscle membrane to acetylcholine.[7]
• Risk Factors: The risk of neurotoxicity is elevated in patients receiving high doses, those with renal impairment (which leads to drug accumulation), and those receiving concomitant therapy with other neurotoxic drugs or agents that can potentiate neuromuscular blockade, such as general anesthetics, neuromuscular blocking agents, and sedatives.[7]

5.3. Other Adverse Reactions, Contraindications, and Drug Interactions

In addition to its major toxicities, Polymyxin B can cause other adverse reactions, including hypersensitivity reactions (rash, pruritus, urticaria), fever, and pain at the site of intramuscular injection.[2] Skin hyperpigmentation, a reversible darkening of the skin on the face, neck, and upper chest, has also been reported.[2] When administered via inhalation, it can induce bronchospasm.[2] Like other broad-spectrum antibiotics, its use carries a risk of Clostridioides difficile-associated diarrhea.[35]

The primary contraindication to the use of Polymyxin B is a known history of hypersensitivity to any of the polymyxin antibiotics.[2] It should be used with extreme caution in patients with pre-existing severe renal disease.[42]

Polymyxin B has numerous clinically significant drug interactions, which are primarily pharmacodynamic in nature and relate to additive toxicities. These are summarized in Table 3.

Table 3: Clinically Significant Drug Interactions with Polymyxin B

Interaction Class	Interacting Agents	Clinical Consequence and Management	Source(s)
Additive Nephrotoxicity	Aminoglycosides (e.g., amikacin, gentamicin), vancomycin, amphotericin B, cyclosporine, acyclovir, certain NSAIDs (e.g., acetylsalicylic acid), cefotiam	Concurrent use significantly increases the risk of developing severe acute kidney injury. Co-administration should be avoided whenever possible. If unavoidable, renal function must be monitored with extreme vigilance.	14
Potentiation of Neurotoxicity / Neuromuscular Blockade	Curare-type neuromuscular blockers (e.g., atracurium, rocuronium), general anesthetics, certain antipsychotics (e.g., phenothiazines), narcotics, sedatives	Co-administration can potentiate the neuromuscular blocking effects of Polymyxin B, increasing the risk of respiratory muscle paralysis and apnea. Concurrent use should be avoided. Patients require close monitoring of respiratory status.	35
Other Significant Interactions	Anticoagulants (e.g., acenocoumarol)	May increase the risk of bleeding. Monitoring of coagulation parameters is advised.	46
	Live bacterial vaccines (e.g., BCG, cholera vaccine)	The antibacterial activity of Polymyxin B can decrease the therapeutic efficacy of live bacterial vaccines. Concurrent use should be avoided.	46

Section 6: The Challenge of Bacterial Resistance

Given its critical role as a last-resort antibiotic, the emergence and spread of bacterial resistance to Polymyxin B is a major public health threat. Bacteria have evolved several sophisticated mechanisms to evade the bactericidal action of polymyxins.

6.1. Molecular Mechanisms of Acquired and Intrinsic Resistance

The primary mechanism of resistance involves modification of the drug's molecular target, the Lipid A component of LPS. The goal of these modifications is to reduce the net negative charge of the bacterial outer membrane, thereby weakening the initial electrostatic attraction that is essential for Polymyxin B's activity.[3]

Table 4: Primary Mechanisms of Bacterial Resistance to Polymyxin B

Mechanism Type	Molecular Change	Key Genes / Regulatory Systems	Common Pathogens	Source(s)
LPS Target Modification (Chromosomal)	Covalent addition of positively charged moieties (L-Ara4N or PEtn) to Lipid A phosphate groups, neutralizing its negative charge.	Two-component systems PhoP/PhoQ and PmrA/PmrB, which upregulate the arn operon (for L-Ara4N) or pmrC (for PEtn).	P. aeruginosa, A. baumannii, K. pneumoniae, Salmonella spp.	11
LPS Target Modification (Plasmid-Mediated)	Addition of PEtn to Lipid A.	Mobile colistin resistance (mcr) genes (e.g., mcr-1), which encode phosphoethanolamine transferase enzymes.	E. coli, K. pneumoniae, Salmonella spp.	24
Complete Loss of LPS	Mutations in lipid A biosynthesis genes leading to the complete absence of LPS on the outer membrane.	lpxA, lpxC, lpxD	A. baumannii	29
Efflux Pumps	Active transport of the drug out of the bacterial cell.	Various efflux pump systems.	Gram-negative bacteria	29
Capsule Formation	Production of an extracellular polysaccharide capsule that can act as a physical barrier.	Capsule synthesis genes.	K. pneumoniae	29

The most prevalent resistance strategy is the covalent modification of Lipid A, which is regulated by complex two-component systems (TCS) like PhoP/PhoQ and PmrA/PmrB. In response to environmental signals (such as low magnesium levels or the presence of the antibiotic itself), these systems become activated and upregulate the expression of genes that encode the enzymes responsible for adding positively charged groups—either 4-amino-4-deoxy-L-arabinose (L-Ara4N) or phosphoethanolamine (PEtn)—to the phosphate groups of Lipid A.[11] This effectively neutralizes the negative charge of the outer membrane and repels the cationic polymyxin molecule.

A particularly alarming development has been the discovery of plasmid-mediated resistance, conferred by the mobile colistin resistance (mcr) genes. The mcr-1 gene, first identified in 2015, encodes a phosphoethanolamine transferase that modifies Lipid A. Because it is located on a plasmid, this resistance mechanism can be easily transferred between different bacteria, including between different species, facilitating the rapid and widespread dissemination of polymyxin resistance.[24]

6.2. Epidemiological Trends and Surveillance

While acquired resistance to polymyxins was once considered rare, its prevalence has been steadily increasing worldwide.[3] Surveillance data show that resistance rates vary considerably by geographical region and by bacterial species, with particularly concerning trends reported for A. baumannii and K. pneumoniae in parts of Asia and Southern Europe.[3] The global spread of mcr-carrying plasmids represents a dire threat to the continued clinical viability of both Polymyxin B and colistin, potentially heralding an era where even these last-resort antibiotics are rendered ineffective.

Section 7: Regulatory and Commercial Landscape

7.1. Global Regulatory Status and Historical Context

The regulatory status of Polymyxin B varies significantly across different regions, reflecting its complex history and challenging safety profile.

• United States (Food and Drug Administration - FDA): Polymyxin B was approved for medical use in the U.S. in 1964, with some sources indicating an even earlier original approval in 1951.[4] Critically, its approval predates the modern, rigorous drug development and review processes established in the 1960s. As a result, the robust clinical trial data on its pharmacokinetics, efficacy, and safety that are required for new drugs today are largely absent for Polymyxin B.[11] This historical legacy contributes to the current uncertainty surrounding its optimal use. Reflecting this uncertainty, the FDA currently does not recognize established susceptibility interpretive criteria (STIC), or "breakpoints," for Polymyxin B against key Gram-negative pathogens, citing the limited and inconclusive nature of the available pharmacokinetic, pharmacodynamic, and clinical data.[48]
• European Union (European Medicines Agency - EMA): In the European Union, the systemic use of Polymyxin B is not approved. As of 2015, its approval is restricted to topical formulations for application to the skin.[4]
• Australia (Therapeutic Goods Administration - TGA): Intravenous Polymyxin B is not registered on the Australian Register of Therapeutic Goods (ARTG). Its use in Australia is highly restricted and requires specific approval for individual patients under the TGA's Special Access Scheme (SAS). This designates it as an "unapproved" therapeutic good, reserved for exceptional circumstances where no suitable approved alternative exists.[28]
• World Health Organization (WHO): Despite its toxicity, Polymyxin B is included on the WHO's List of Essential Medicines, a testament to its indispensable role in treating life-threatening infections in the face of widespread antimicrobial resistance.[4]

7.2. Marketed Formulations and Brand Names

Polymyxin B is available globally as a generic medication and under various brand names, both as a single agent and, more commonly, as a component of combination products.[4]

• Monotherapy Formulations: The injectable form of Polymyxin B sulfate is sold under brand names such as Poly-Rx [4] and Aerosporin.[50]
• Combination Products: Polymyxin B is a constituent of a vast array of combination products, primarily for topical, ophthalmic, and otic use. These products are marketed under numerous brand names worldwide. Some of the most well-known examples include:
• Triple Antibiotic (Topical): Combined with bacitracin and neomycin (e.g., Neosporin, Mycitracin).[38]
• Dual Antibiotic (Topical/Ophthalmic): Combined with bacitracin (e.g., Polysporin) or trimethoprim (e.g., Polytrim).[1]
• Antibiotic/Steroid (Ophthalmic/Otic/Topical): Combined with neomycin and a corticosteroid like hydrocortisone (e.g., Cortisporin) or dexamethasone (e.g., Maxitrol, Neo-Poly-Dex).[38]

The combination of Polymyxin B with neomycin and dexamethasone was the 260th most commonly prescribed medication in the United States in 2023, highlighting its widespread use in topical formulations.[4]

Section 8: Conclusion: Optimizing the Role of Polymyxin B in Modern Medicine

8.1. Synthesis of Evidence: A High-Risk, High-Reward Agent

Polymyxin B stands as a paradigmatic example of a high-risk, high-reward therapeutic agent in the modern era of antimicrobial resistance. The evidence synthesized in this report paints a clear picture of a potent, rapidly bactericidal antibiotic with indispensable activity against some of the most formidable multi-drug-resistant Gram-negative pathogens. This life-saving efficacy, however, is inextricably linked to a narrow therapeutic index and a substantial risk of severe nephrotoxicity and neurotoxicity. The clinical use of Polymyxin B is therefore a constant and challenging exercise in balancing its profound benefits against its significant potential for harm. Its cyclical history—from front-line therapy to near-abandonment and back to last-resort necessity—serves as a stark reminder of the clinical consequences of a failing antibiotic pipeline and the difficult decisions forced upon clinicians by the relentless evolution of bacterial resistance.

8.2. Recommendations for Antimicrobial Stewardship and Clinical Use

To maximize the benefits of Polymyxin B while minimizing its risks, its use must be governed by strict principles of antimicrobial stewardship and vigilant clinical practice.

• Restricted Use: Systemic Polymyxin B therapy should be reserved for patients with documented or highly suspected infections caused by MDR Gram-negative pathogens that are susceptible only to polymyxins. Its use should be guided by infectious disease specialists or clinical pharmacists with expertise in its application.[27]
• Evidence-Based Dosing: Clinicians must navigate the conflicting dosing guidelines for patients with renal impairment. The weight of modern pharmacokinetic evidence supports the use of full loading and maintenance doses regardless of renal function to avoid therapeutic failure, but this approach necessitates heightened vigilance for toxicity.[33]
• Therapeutic Drug Monitoring (TDM): Whenever available, TDM should be implemented to individualize dosing regimens. The measurement of free (unbound) drug concentrations, rather than total concentrations, is preferable to ensure that PK/PD targets are met, particularly in critically ill patients with altered protein binding.[15]
• Intensive Monitoring: All patients receiving systemic Polymyxin B require intensive monitoring. This includes daily assessment of renal function (serum creatinine, BUN, urine output) and close observation for any signs of neurotoxicity (paresthesias, dizziness, muscle weakness).[2]

8.3. Future Research Imperatives

The continued and optimized use of Polymyxin B depends on addressing several critical knowledge gaps through focused research.

• Prospective Clinical Trials: There is an urgent need for high-quality, prospective, randomized controlled trials to definitively establish optimal dosing strategies, particularly in special populations such as those with renal failure or obesity. Such trials are also needed to validate PK/PD targets and to provide a head-to-head comparison of the efficacy and safety of Polymyxin B versus colistin.[11]
• Development of Safer Alternatives: Research into the development of novel polymyxin analogues or derivatives that retain the potent antimicrobial activity of Polymyxin B but exhibit a reduced toxicity profile is a high-priority area in medicinal chemistry.[17]
• Non-Antibiotic Applications: The unique endotoxin-neutralizing property of the polymyxin scaffold warrants further investigation. The development of non-bactericidal derivatives for use as systemic anti-endotoxin agents in sepsis could represent a novel therapeutic paradigm.
• Resistance Surveillance and Mitigation: Continuous global surveillance for polymyxin resistance mechanisms, especially the spread of mcr genes, is essential. Further research into the drivers of resistance and strategies to mitigate its emergence, such as optimized combination therapies, is critical to preserving the utility of this invaluable last-resort class of antibiotics.

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