Pharmacology of Neomycin

Introduction/Overview

Neomycin is an aminoglycoside antibiotic derived from Streptomyces fradiae. First isolated in 1949, it has occupied a significant, though increasingly specialized, niche in antimicrobial therapy for over seven decades. Its clinical utility is now largely defined by its pharmacokinetic profile, specifically its minimal systemic absorption when administered via the oral or topical routes, which confines its therapeutic applications to specific clinical scenarios. The pharmacology of neomycin is dominated by two principal characteristics: its potent bactericidal activity against a spectrum of Gram-negative and some Gram-positive organisms, and its potential for severe dose-dependent toxicities, namely ototoxicity and nephrotoxicity, when systemic exposure occurs. Consequently, its systemic use has been largely abandoned in favor of less toxic alternatives, relegating its primary role to topical, oral non-absorbable, and preoperative bowel preparation applications.

The enduring clinical relevance of neomycin stems from its efficacy in these circumscribed roles. It remains a cornerstone agent for the topical management of superficial skin and eye infections, a key component of regimens for the prophylaxis and treatment of hepatic encephalopathy, and an effective option for preoperative bowel decontamination. Understanding its pharmacology is essential for medical and pharmacy students to appreciate the delicate balance between its therapeutic benefits and its significant toxic potential, thereby ensuring its safe and appropriate use in clinical practice.

Learning Objectives

• Describe the chemical classification of neomycin as an aminoglycoside and explain its bactericidal mechanism of action involving irreversible inhibition of bacterial protein synthesis.
• Analyze the pharmacokinetic profile of neomycin, emphasizing its poor oral bioavailability, negligible systemic absorption from topical application, and renal excretion as the primary route of elimination.
• Identify the primary therapeutic applications of neomycin, including topical use for skin and eye infections, oral use for hepatic encephalopathy and bowel preparation, and its role in combination products.
• Evaluate the major adverse effects associated with neomycin, with particular focus on the mechanisms, risk factors, and monitoring strategies for ototoxicity and nephrotoxicity.
• Apply knowledge of neomycin’s drug interactions, contraindications, and special population considerations to develop safe therapeutic plans for patients with renal impairment, in pediatric or geriatric populations, and during pregnancy or lactation.

Classification

Neomycin is classified within the broad therapeutic category of anti-infective agents, specifically under the antibiotic subclass of aminoglycosides. This classification is based on its chemical structure and shared mechanism of action with other members of this class, such as gentamicin, tobramycin, and amikacin.

Chemical and Pharmacological Classification

Chemically, neomycin is an aminoglycoside antibiotic, a designation derived from its structure comprising amino sugars linked by glycosidic bonds to a central aglycone component, 2-deoxystreptamine. Neomycin sulfate, the form used clinically, is actually a complex of closely related compounds, primarily neomycin B (framycetin) with smaller amounts of neomycin C. Its polycationic nature at physiological pH, due to the abundance of amino groups, is fundamental to its pharmacokinetic behavior and mechanism of antibacterial action. Pharmacologically, it is categorized as a bactericidal antibiotic with concentration-dependent killing activity and a significant post-antibiotic effect against susceptible organisms.

Mechanism of Action

The bactericidal action of neomycin, like other aminoglycosides, results from a multi-step process that ultimately disrupts bacterial protein synthesis and compromises the integrity of the bacterial cell membrane. This process is concentration-dependent and irreversible, leading to bacterial cell death.

Molecular and Cellular Mechanisms

The primary mechanism involves several sequential steps. Initially, the polycationic neomycin molecule is attracted to and interacts with the anionic components of the outer membrane of Gram-negative bacteria, primarily lipopolysaccharides. This interaction displaces divalent cations (Mg²⁺ and Ca²⁺) that stabilize the membrane, increasing its permeability. This energy-dependent phase, termed the “energy-dependent phase I,” facilitates further uptake of the antibiotic.

Subsequently, neomycin traverses the bacterial cell wall and cytoplasmic membrane via an oxygen-dependent active transport process. This step explains the marked reduction in aminoglycoside activity against anaerobic bacteria and the diminished efficacy in hypoxic environments, such as abscesses. Once inside the bacterial cytoplasm, neomycin binds with high affinity to specific components of the bacterial 30S ribosomal subunit, namely the 16S ribosomal RNA (rRNA) within the A-site. This binding is highly specific and involves interactions with conserved nucleotide sequences.

The binding event induces conformational changes in the ribosome that lead to multiple catastrophic effects on protein synthesis. First, it causes misreading of the mRNA template, leading to the incorporation of incorrect amino acids into the growing polypeptide chain, resulting in non-functional or toxic proteins. Second, and more critically, it inhibits the translocation step of protein synthesis, freezing the ribosome complex and preventing the progression of the polypeptide chain. This results in the accumulation of abnormal initiation complexes and the sequestration of functional ribosomes. Finally, the stalled ribosome-aminoglycoside complexes are thought to promote the dissociation of peptidyl-tRNA from the ribosome, leading to premature termination of protein synthesis. The cumulative effect is irreversible inhibition of vital bacterial protein production, culminating in bacterial cell death.

An additional, secondary mechanism contributing to bacterial killing involves the induction of membrane damage. Following the initial disruption of the outer membrane, the accumulated intracellular neomycin may further disrupt the electrochemical gradient of the cytoplasmic membrane, leading to increased permeability, leakage of intracellular contents, and ultimately, cell lysis.

Pharmacokinetics

The pharmacokinetic profile of neomycin is characterized by very poor absorption from the gastrointestinal tract and negligible absorption through intact skin, which largely confines its systemic effects and toxicities to situations involving parenteral administration (now obsolete) or significant impairment of integumentary or mucosal barriers.

Absorption

Oral bioavailability is exceptionally low, typically estimated at less than 3% in individuals with normal gastrointestinal anatomy and function. The drug is not absorbed to a clinically significant extent from a healthy, intact gastrointestinal mucosa. However, absorption can increase substantially in the presence of inflammatory or ulcerative bowel disease, mucosal damage, or conditions that increase intestinal permeability. Following topical application to intact skin, systemic absorption is negligible. However, application to large areas of denuded skin, severe burns, or open wounds can lead to measurable, and potentially toxic, systemic concentrations. Instillation into body cavities, such as during intraperitoneal irrigation, can also result in significant absorption.

Distribution

Upon systemic absorption, neomycin distributes primarily into the extracellular fluid compartment. Its high hydrophilicity and polycationic nature limit its penetration into most cells and across physiological barriers. Volume of distribution is relatively low, typically approximating the extracellular fluid volume (approximately 0.25 L/kg). It exhibits poor penetration into the cerebrospinal fluid, bile, and prostatic fluid, even in the presence of inflammation. A critical aspect of its distribution is its selective accumulation in the renal cortex and the perilymph of the inner ear. This accumulation is concentration-dependent, time-dependent, and largely irreversible, forming the pharmacokinetic basis for its characteristic nephrotoxic and ototoxic potentials. Protein binding is considered minimal.

Metabolism

Neomycin is not metabolized to a significant extent in humans. It is excreted unchanged, primarily by the kidneys. This lack of hepatic metabolism simplifies its pharmacokinetics but also means that renal function is the sole major determinant of its systemic clearance.

Excretion

Renal excretion is the principal route of elimination for systemically absorbed neomycin. The drug is filtered freely at the glomerulus and undergoes minimal tubular reabsorption. It is excreted almost entirely unchanged in the urine. In patients with normal renal function, a high percentage of an intravenously administered dose can be recovered in the urine within 24 hours. The elimination half-life (t_1/2) is directly dependent on renal function. In individuals with normal glomerular filtration rate (GFR), the t_1/2 is approximately 2 to 3 hours. This half-life increases exponentially as renal function declines; in anuric patients, it may be prolonged to 30 hours or more. This profound dependence on renal excretion is a critical consideration for dosing and toxicity monitoring. Orally administered, unabsorbed neomycin is excreted almost quantitatively in the feces.

Therapeutic Uses/Clinical Applications

The clinical use of neomycin is strategically limited to situations where its poor absorption can be leveraged for local effect or where systemic absorption is intentionally minimal. Its systemic use via injection has been abandoned due to toxicity.

Approved Indications

Topical Applications: Neomycin is widely used, often in combination with other antibiotics (e.g., polymyxin B, bacitracin) and corticosteroids, for the topical treatment of superficial bacterial infections of the skin and eye. These include infected wounds, burns, skin ulcers, and primary pyodermas such as impetigo, caused by susceptible organisms. Ophthalmic preparations are indicated for superficial ocular infections like bacterial conjunctivitis and blepharitis.

Hepatic Encephalopathy: The oral administration of neomycin is a standard therapy for the prophylaxis and treatment of hepatic encephalopathy associated with portal-systemic shunting and chronic liver disease. Its efficacy stems from its action as a poorly absorbed antibiotic that suppresses the colonic bacterial flora. These bacteria are responsible for producing ammonia and other nitrogenous compounds from dietary protein and endogenous urea. By reducing this bacterial load, neomycin decreases the production and subsequent absorption of ammonia, leading to a reduction in blood ammonia levels and an improvement in neuropsychiatric symptoms.

Preoperative Bowel Preparation: Neomycin, administered orally in combination with erythromycin base or metronidazole, is used for mechanical and antimicrobial preparation of the bowel prior to elective colorectal surgery. The goal is to reduce the population of intraluminal bacteria, thereby decreasing the risk of postoperative infectious complications such as wound infection and anastomotic leakage.

Other Gastrointestinal Uses: It has been used as an adjunct in the management of traveler’s diarrhea and other infectious diarrheas, though its use for this purpose has declined in favor of other agents.

Off-Label and Historical Uses

Historically, neomycin was used parenterally for serious systemic Gram-negative infections. This practice is now obsolete. Off-label, a solution of neomycin is sometimes used for bladder irrigation to prevent bacteriuria in patients with long-term indwelling catheters, though evidence is limited. Its inclusion in various over-the-counter topical first-aid ointments represents its most common contemporary exposure.

Adverse Effects

The adverse effect profile of neomycin is dominated by toxicities associated with systemic exposure. When used appropriately in its current indications, serious adverse effects are uncommon but remain a significant concern, particularly with prolonged use or in the presence of risk factors.

Common Side Effects

With oral administration, the most frequently reported adverse effects are gastrointestinal in nature, including nausea, vomiting, and diarrhea. A non-infectious diarrhea or loose stools are common due to alteration of the gut flora. Topical application can infrequently cause localized allergic contact dermatitis, characterized by itching, redness, and swelling at the site of application. Neomycin is recognized as a common topical sensitizer.

Serious and Rare Adverse Reactions

Ototoxicity: Ototoxicity is the most feared adverse effect of systemic neomycin exposure. It can manifest as both auditory (cochlear) and vestibular toxicity. Auditory toxicity typically presents as bilateral, high-frequency sensorineural hearing loss, which may be irreversible and progressive even after discontinuation of the drug. Tinnitus may be a preceding symptom. Vestibular toxicity results in symptoms such as dizziness, vertigo, ataxia, and nystagmus. The mechanism involves irreversible damage to the hair cells of the organ of Corti and the vestibular sensory epithelium. Risk is cumulative and dose-dependent, and increased by factors such as renal impairment, concurrent use of other ototoxic drugs, pre-existing hearing loss, and advanced age.

Nephrotoxicity: Neomycin-induced nephrotoxicity typically presents as non-oliguric renal failure with a rise in serum creatinine and blood urea nitrogen. The injury is primarily to the proximal tubular cells, where the drug accumulates. The damage is often reversible if the drug is discontinued promptly, but prolonged exposure can lead to permanent injury. Risk factors include pre-existing renal disease, dehydration, hypovolemia, concurrent use of other nephrotoxic agents (e.g., vancomycin, cyclosporine, NSAIDs), and advanced age.

Neuromuscular Blockade: Neomycin can inhibit acetylcholine release from presynaptic nerve terminals and may reduce postsynaptic sensitivity to acetylcholine, leading to a curare-like neuromuscular blockade. This effect is rare with current uses but can be severe, potentially leading to acute respiratory paralysis, particularly when the drug is instilled into body cavities (e.g., peritoneal irrigation) or used in patients with underlying neuromuscular disorders (e.g., myasthenia gravis) or in those receiving general anesthetics or neuromuscular blocking agents.

Malabsorption Syndrome: Prolonged oral administration can lead to a malabsorption syndrome characterized by steatorrhea, diarrhea, and deficiencies of vitamins (particularly fat-soluble vitamins A, D, E, and K), minerals, and electrolytes due to structural and functional alterations of the intestinal mucosa and disruption of the normal gut flora.

Black Box Warnings

Formulations intended for injection carry a black box warning from regulatory agencies highlighting the risks of nephrotoxicity, ototoxicity, and neuromuscular blockade. The warning emphasizes that the drug’s use should be restricted to severe, life-threatening infections where less toxic alternatives are not suitable—a scenario that is exceptionally rare in modern practice, effectively rendering systemic use contraindicated. Furthermore, there is a specific warning against using neomycin for irrigation of surgical wounds or body cavities due to the risk of significant systemic absorption and subsequent toxicity.

Drug Interactions

Neomycin participates in several clinically significant pharmacokinetic and pharmacodynamic drug interactions.

Major Drug-Drug Interactions

• Other Ototoxic or Nephrotoxic Agents: Concurrent use with other drugs possessing ototoxic or nephrotoxic potential (e.g., loop diuretics like furosemide, platinum-based chemotherapeutics like cisplatin, other aminoglycosides, vancomycin, amphotericin B) can have additive or synergistic toxic effects, significantly increasing the risk of permanent hearing loss or kidney damage.
• Neuromuscular Blocking Agents: Neomycin can potentiate the effects of both depolarizing (succinylcholine) and non-depolarizing (e.g., rocuronium, vecuronium) neuromuscular blockers used in anesthesia, potentially leading to prolonged respiratory depression and apnea. Caution is also warranted with drugs that inherently possess neuromuscular blocking activity, such as botulinum toxin.
• Oral Medications: By altering intestinal flora and potentially causing mild mucosal damage, prolonged oral neomycin therapy may reduce the absorption of several concurrently administered oral drugs. The most notable example is digoxin, where neomycin can decrease its bioavailability, potentially leading to reduced therapeutic effect. It may also decrease the absorption of methotrexate, penicillin V, and vitamin K.
• Warfarin: An interaction exists where neomycin may potentiate the anticoagulant effect of warfarin. The mechanism is multifactorial, potentially involving reduction of vitamin K-producing gut flora and neomycin-induced vitamin K malabsorption, leading to a reduction in vitamin K-dependent clotting factor synthesis.

Contraindications

Absolute contraindications to neomycin use include a history of hypersensitivity to neomycin or any other aminoglycoside antibiotic. Cross-reactivity among aminoglycosides can occur. It is also contraindicated in patients with intestinal obstruction, due to the risk of stasis and enhanced local toxicity or absorption. The use of systemic (injectable) formulations is contraindicated in most clinical situations given the availability of safer alternatives. Topical application over large ulcerated or burned body surfaces is relatively contraindicated due to the risk of significant systemic absorption and toxicity.

Special Considerations

Use in Pregnancy and Lactation

Pregnancy (Category D): Neomycin is classified as FDA Pregnancy Category D. Aminoglycosides cross the placenta, and there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience. The principal concern is the potential for ototoxicity in the developing fetus. Therefore, neomycin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, and systemic use should be avoided. Topical or short-term oral use for bowel preparation may be acceptable when clearly needed.

Lactation: Neomycin is excreted in human milk in small amounts following systemic administration. Because of the potential for serious adverse reactions in nursing infants, including modification of bowel flora and potential for sensitization, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. For topical application on limited areas, the risk to the infant is considered minimal.

Pediatric and Geriatric Considerations

Pediatric Patients: Safety and effectiveness in pediatric populations for systemic use have not been established, and such use is not recommended. Topical otic and ophthalmic preparations are used in children. Dosing for oral administration in conditions like hepatic encephalopathy must be carefully adjusted based on body weight and renal function. Immature renal function in neonates and infants increases the risk of toxicity.

Geriatric Patients: Elderly patients are at increased risk for neomycin toxicity. Age-related decline in renal function, even in the absence of overt renal disease, can lead to decreased clearance and drug accumulation. Furthermore, pre-existing subclinical hearing loss and a higher prevalence of comorbidities that increase toxicity risk (e.g., dehydration, use of other nephrotoxic medications) necessitate extreme caution. Renal function should be assessed prior to and during therapy, and doses should be adjusted accordingly. Auditory and vestibular function should be monitored if prolonged oral therapy is unavoidable.

Renal and Hepatic Impairment

Renal Impairment: Renal dysfunction is the single most important factor modifying neomycin pharmacokinetics and toxicity risk. In patients with impaired renal function, the clearance of systemically absorbed neomycin is markedly reduced, leading to prolonged half-life and drug accumulation. This significantly elevates the risk of both ototoxicity and nephrotoxicity. Oral or topical neomycin should be used with great caution, if at all, in patients with significant renal impairment (e.g., creatinine clearance less than 30 mL/min). If use is deemed essential, dosing intervals must be dramatically extended, or the daily dose reduced, based on estimated creatinine clearance. Serum drug concentration monitoring, if available for oral therapy, may be considered. Frequent monitoring of renal function, urinalysis, and auditory/vestibular symptoms is mandatory.

Hepatic Impairment: Since neomycin is not metabolized by the liver, hepatic impairment does not directly affect its pharmacokinetics. However, its primary indication in patients with hepatic impairment—hepatic encephalopathy—requires careful management. In patients with advanced liver disease and associated hepatorenal syndrome or other causes of renal impairment, the risk of neomycin toxicity is compounded. Furthermore, the malabsorption induced by prolonged neomycin use can exacerbate nutritional deficiencies common in chronic liver disease. Lactulose is often preferred as first-line therapy for hepatic encephalopathy, with neomycin reserved as an adjunct or for patients intolerant of lactulose.

Summary/Key Points

• Neomycin is a bactericidal aminoglycoside antibiotic whose clinical use is now restricted primarily to topical applications, oral therapy for hepatic encephalopathy, and preoperative bowel preparation due to significant systemic toxicities.
• Its mechanism of action involves irreversible binding to the bacterial 30S ribosomal subunit, causing misreading of mRNA, inhibition of translocation, and ultimately, disruption of protein synthesis leading to cell death.
• Pharmacokinetically, it is poorly absorbed orally or topically, is not metabolized, and is excreted unchanged by the kidneys. Its half-life is critically dependent on renal function.
• Therapeutic applications leverage its local effects: topical treatment of skin/eye infections, reduction of ammonia-producing gut flora in hepatic encephalopathy, and bowel decontamination before colorectal surgery.
• Dose-dependent ototoxicity (auditory and vestibular) and nephrotoxicity are the most severe adverse effects, with risk dramatically increased by renal impairment, concurrent ototoxic/nephrotoxic drugs, and prolonged therapy.
• Significant drug interactions include potentiation of other ototoxic/nephrotoxic agents, enhancement of neuromuscular blockade, and reduced absorption of drugs like digoxin. It can also potentiate warfarin’s effect.
• Special caution is required in patients with renal impairment, the elderly, and during pregnancy (Category D). Dosing must be meticulously adjusted for renal function to avoid life-threatening toxicity.

Clinical Pearls

• The adage “neomycin is not absorbed” is a dangerous oversimplification. Absorption can be significant with mucosal disease, large topical application areas, or peritoneal instillation, leading to toxicity.
• For oral dosing in hepatic encephalopathy, typical regimens are 1-3 grams every 6-8 hours, but this must be tailored down in renal impairment. Therapy should not be indefinite; periodic attempts to withdraw the drug are recommended.
• Patients prescribed oral neomycin should be counseled to report any symptoms of tinnitus, hearing loss, dizziness, or changes in urine output immediately.
• When used topically, monitor for signs of contact dermatitis. Neomycin should generally not be used for prolonged periods on large wounds.
• In any patient receiving neomycin, a baseline assessment of renal function (serum creatinine, estimated GFR) is essential, and serial monitoring is required for courses longer than a few days.

References

1. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
2. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
3. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
4. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
5. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
6. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
7. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
8. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.