Polymyxin- B

Polymyxin- B belongs to the pharmacological class of Polypeptide Antibiotics.

Polymyxin- B has been approved to relieve symptoms and also for the treatment and maintenance of CNS infections, Ocular infections, Pulmonary infections, and Systemic infections due to multidrug-resistant gram-negative bacilli.

Polymyxin B exhibits minimal absorption when administered orally. The exact volume of distribution remains uncertain, with estimates ranging from 34.3L to 47.2L based on one-compartment models. Protein binding studies indicate that polymyxin B is bound to proteins by 79% to 92%, potentially reaching up to 99% in circulation, although the specific proteins involved have not been identified. Limited data is available regarding the metabolism of polymyxin B, suggesting that it is primarily eliminated unchanged, with less than 1% excreted through the kidneys. The primary route of elimination is proposed to be through renal tubular reabsorption and non-renal pathways, with urine collection studies showing less than 5% excretion in the urine. However, there is a discrepancy in the literature regarding the extent of renal elimination, with some sources suggesting that 60% of polymyxin B is recovered in the urine. Non-renal elimination occurs through unknown mechanisms, with all four components of polymyxin B detected in bile. Further research is needed to fully understand the pharmacokinetic profile of polymyxin B.

The common side effects involved in using Polymyxin- B are Nephrotoxicity (kidney damage), Neurotoxicity (nerve damage), Ototoxicity (ear damage), Gastrointestinal disturbances (nausea, vomiting, abdominal pain, diarrhea), Hypersensitivity reactions (allergic reactions), Injection site reactions (pain, redness, swelling), Rarely, blood disorders such as agranulocytosis or thrombocytopenia.

Polymyxin- B is available in the form of Injectable solution ,Ophthalmic Solution.

Polymyxin- B is approved in Germany, Japan, Malaysia, India, the U.K., the U.S., and China.

Polymyxin- B belongs to the pharmacological class of Polypeptide Antibiotics.

The positively charged polymyxin B forms an electrostatic interaction with the phosphate groups of the negatively charged lipid A on the outer membrane of Gram-negative bacteria, specifically through its alpha and gamma diaminobutyric acid. This interaction results in the displacement of calcium and magnesium ions from the phosphates of membrane lipids, leading to the destabilization of lipopolysaccharide (LPS) and an increase in membrane permeability. Consequently, the bacterial cell experiences cytoplasmic leaking, ultimately resulting in cell death.

Additionally, polymyxin B has the ability to bind to and neutralize LPS that is released during bacterial lysis, effectively preventing adverse reactions to endotoxin.

Furthermore, polymyxin B exhibits a third activity by inhibiting type II NADH-quinone oxidoreductases found in the bacterial inner membrane. These enzymes are vital for bacterial respiration.

Polymyxin- B has been approved to relieve symptoms and also for the treatment and maintenance of CNS infections, Ocular infections, Pulmonary infections, and Systemic infections due to multidrug-resistant gram-negative bacilli.

When administered at clinically prescribed doses, the average maximum serum concentration (Cmax) of polymyxin B at steady-state ranges from approximately 2 to 14 mcg/mL, and the half-life of polymyxin B is approximately 9 to 11.5 hours. The average duration of polymyxin B therapy was 19 days, with a range of 2 to 57 days.

Polymyxin- B is found to be available in the form of Injectable solution , Ophthalmic Solution.

Polymyxin- B can be used in the following treatment:

• CNS infection
• Ocular infections
• Pulmonary infection
• Systemic infections due to multidrug-resistant gram-negative bacilli

Polymyxin- B can help to relieve symptoms and also for the treatment and maintenance of CNS infections, Ocular infections, Pulmonary infections, and Systemic infections due to multidrug-resistant gram-negative bacilli.

Polymyxin- B is approved for use in the following clinical indications:

• CNS infection
• Ocular infections
• Pulmonary infection
• Systemic infections due to multidrug-resistant gram-negative bacilli

CNS Infection

Intrathecal/Intraventricular Administration (Adjunctive Agent):

• Dosage: 50,000 units once daily in combination with systemic therapy.
• Administration via Ventricular Drain: When administering intraventricular polymyxin B through a ventricular drain, clamp the drain for 15 to 60 minutes after administration to allow the solution to equilibrate in the cerebrospinal fluid (CSF).
• Important Note: Use a preservative-free preparation. Intraventricular administration is generally reserved for patients who do not respond to parenteral therapy after CSF shunt removal or when CSF shunt removal is not possible .

Ocular Infections

Ophthalmic Administration:

• Dosage: Administer a concentration of 0.1% to 0.25% (10,000 to 25,000 units/mL) as 1 to 3 drops every hour, gradually increasing the interval based on response.
• Subconjunctival Injection: For Pseudomonas aeruginosa corneal and conjunctival infections, a subconjunctival injection of up to 100,000 units per day may be used.
• Important Note: Avoid exceeding a total combined systemic and ophthalmic dose of 25,000 units/kg/day.

Pulmonary Infection

Adjunctive Agent (Off-label Route):

• Inhalation for Nebulization: Dosage of 500,000 units every 12 hours. Administer an aerosolized beta-2 agonist approximately 20 minutes prior to administering polymyxin B .
• Important Note: Use in combination with systemic antimicrobial therapy . Some experts may choose not to use inhaled polymyxin B .

Systemic Infections Due to Multidrug-Resistant Gram-Negative Bacilli

Dosage for Systemic Infections (e.g., bacteremia, intra-abdominal infections, meningitis, pneumonia [hospital-acquired or ventilator-associated], sepsis) caused by multidrug-resistant gram-negative bacilli (e.g., Pseudomonas aeruginosa, Acinetobacter spp.):

• IV Administration: Initial loading dose of 20,000 to 25,000 units/kg, followed by a 12,500 to 15,000 units/kg maintenance dose every 12 hours .
• Safety and Dosing Limitations: Limited safety data for single infusions exceeding 2,000,000 units. Although pharmacokinetic data do not support a maximum dose limit, higher doses may increase infusion-related adverse effects such as sudden thoracic pain, paresthesias, dizziness, dyspnea, and hypoxemia.

Injectable Solution:500,000 units or 1,000,000 units of polymyxin B sulfate.

Ophthalmic Suspension:0.1% to 0.25% (prepared from parenteral injection).

The injectable solution, Ophthalmic Solution.

Dosage Adjustments in Kidney Patients:

• When the creatinine clearance (CrCl) is greater than 20 mL/minute, administer 75-100% of the usual daily dose divided every 12 hours.
• When the CrCl ranges from 5 to 20 mL/minute, administer 50% of the usual daily dose divided every 12 hours.

• When the CrCl is less than 5 mL/minute, administer 15% of the usual daily dose once every 12 hours.

Dosage Adjustments in Pediatric Patients:

Infants:

• Intravenous (IV): The usual dose is 25,000 to 30,000 units/kg/day divided every 12 hours. The reported range is 15,000 to 40,000 units/kg/day divided every 12 hours. An initial loading dose of 25,000 units/kg has also been recommended based on adult recommendations.
• Intramuscular (IM): The recommended dose is 25,000 to 40,000 units/kg/day divided every 4 to 6 hours. However, routine IM administration is not recommended due to severe pain at the injection site.

Children and Adolescents:

• IV: The usual dose is 25,000 to 30,000 units/kg/day divided every 12 hours. The reported range is 15,000 to 40,000 units/kg/day. The manufacturer's labeling recommends a maximum dose of 25,000 units/kg/day, but doses up to 40,000 units/kg/day have been reported in patients ≤12 years in a small case series. An initial loading dose of 25,000 units/kg has also been recommended based on adult recommendations.
• IM: The recommended dose is 25,000 to 30,000 units/kg/day divided every 4 to 6 hours. Routine IM administration is not recommended due to severe pain at the injection site.
• Central nervous system (CNS) infections, including meningitis, ventriculitis, and cerebrospinal fluid (CSF) shunt infections:

Manufacturer's labeling:

• Children <2 years: Intrathecal administration: 20,000 units/dose once daily for 3 to 4 days or 25,000 units/dose once every other day. Continue with 25,000 units/dose once every other day for at least 2 weeks after CSF cultures are negative.
• Children ≥2 years and Adolescents: Intrathecal administration: 50,000 units/dose daily for 3 to 4 days, then every other day for at least 2 weeks after CSF cultures are negative.
• Alternate recommendations: Limited data available:
• Children and Adolescents: Intraventricular or intrathecal administration: 20,000 to 50,000 units/day. Guidelines suggest decreasing the infant dose due to smaller CSF volume, and smaller doses should be used in smaller patients based on adult dosage recommendations.
• Ocular infections:

For infants, children, and adolescents:

• Ophthalmic (topical): Use a 0.1% to 0.25% solution prepared from parenteral injection. Administer 1 to 3 drops every hour and adjust the interval based on response.
• Subconjunctival injection: The maximum dose is up to 100,000 units/day, not exceeding 25,000 units/kg/day. It's important to ensure that the combined total therapy (systemic and ophthalmic instillation) does not exceed 25,000 units/kg/day.

There are no specific dietary restrictions related to the use of Polymyxin- B mentioned in the available information. However, it is always advisable to follow a healthy and balanced diet while undergoing any medical treatment.

Polymyxin- B may be contraindicated under the following conditions:

1. Patients with a known hypersensitivity to polymyxins, including polymyxin B sulfate or any ingredient present in the container, should not use the medication.
2. Polymyxin B for Injection USP should not be used in patients with myasthenia gravis as it is contraindicated.

• Renal Function: Prior to and during treatment with Polymyxin B for Injection USP, renal function should be assessed regularly due to the nephrotoxic nature of the drug. Dose adjustment is necessary for patients with reduced renal function.
• Neurotoxicity: Polymyxin B at therapeutic doses can lead to serious neurotoxic symptoms such as ataxia, seizures, and neuromuscular blockade. These symptoms are more likely to occur in patients with impaired renal function and/or nephrotoxicity.
• Concurrent Use of Nephrotoxic Drugs: The use of other nephrotoxic drugs, including certain antimicrobials, should be avoided when undergoing treatment with Polymyxin B for Injection USP.
• Concurrent Use of Neurotoxic Drugs: It is advised to avoid the concurrent use of anesthesia and other neurotoxic drugs with Polymyxin B treatment. The neurotoxicity of Polymyxin B can cause respiratory paralysis from neuromuscular blockade, especially when used soon after anesthesia or muscle relaxants.

General:

• Clinical Supervision: The administration of Polymyxin B for Injection USP via intramuscular, intravenous, or intrathecal routes should be limited to hospitalized patients to ensure constant clinical supervision.
• Maximum Dosage: The maximum daily dosage of Polymyxin B for patients with normal renal function should not exceed 2.5 mg/kg/day or a total of 200 mg/day.
• Intramuscular Use: Routine use of intramuscular administration is not recommended due to severe pain at injection sites. If procaine is used with Polymyxin B to reduce injection pain, caution must be exercised to prevent inadvertent intrathecal or intravenous administration.
• Porphyria: Patients with porphyria should use Polymyxin B with extreme caution.
• Bacterial Infections: Polymyxin B is not effective against gram-negative bacteria (Proteus spp., Providencia spp., Morganella spp., Serratia marcescens, Burkholderia spp., Neisseria spp.), gram-positive bacteria, and anaerobes. Immediate adjunct therapy is crucial if a concomitant bacterial pathogen is present or suspected.

While there is no specific food interaction between Polymyxin- B and alcohol, it's generally recommended to avoid alcohol when taking any antibiotic medication. Alcohol can interfere with the effectiveness of the medication and may also exacerbate certain side effects.

The excretion of polymyxin B sulfate in breast milk or animal milk has not been established. Since the effects of the drug on nursing infants are unknown, a decision should be made whether to discontinue breastfeeding or discontinue the treatment with polymyxin B sulfate. This decision should consider both the importance of the Polymyxin B for Injection USP drug treatment for the mother and the potential risk to the infant.

Pregnancy Category C

There is a lack of clinical data regarding the use of polymyxin B sulfate in pregnant women. Therefore, unless the anticipated benefits to the mother significantly outweigh any potential risks to the fetus, Polymyxin B for Injection USP should not be used during pregnancy.

Additionally, there is a scarcity of animal studies examining the potential embryotoxicity and/or teratogenicity of polymyxin B sulfate.

Polymyxin- B does not have significant interactions with food, and its absorption is not significantly affected by co-administration with meals. Therefore, Polymyxin- B can generally be taken with or without food.

The adverse reactions related to Polymyxin- B can be categorized as follows:

Common:

• Nephrotoxicity (kidney damage)
• Neurotoxicity (nerve damage)
• Ototoxicity (ear damage)
• Gastrointestinal disturbances (nausea, vomiting, abdominal pain, diarrhea)
• Injection site reactions (pain, redness, swelling)

Less common:

• Hypersensitivity reactions (allergic reactions)
• Blood disorders such as agranulocytosis or thrombocytopenia
• Rash or skin irritation

Rare:

• Anaphylaxis (severe allergic reaction)
• Seizures or convulsions
• Hallucinations or confusion
• Muscular weakness or paralysis
• Visual disturbances
• Respiratory arrest

It is advised to avoid the simultaneous use of other nephrotoxic and/or neurotoxic drugs, including bacitracin, kanamycin, streptomycin, tobramycin, amikacin, cephaloridine, cephalothin, paromycin, polymyxin E (colistin), neomycin, gentamicin, and vancomycin, along with polymyxin B sulfate .

Due to the impact of polymyxin B sulfate on acetylcholine release, the concurrent use of non-polarizing muscle relaxants (ether, tubocurarine, gallamine, decamethonium, sodium citrate), depolarizing muscle relaxant succinylcholine, and other neurotoxic drugs should be avoided while using polymyxin B sulfate .

It is recommended to avoid combining polymyxin B sulfate with potent diuretics like ethacrynic acid or furosemide since diuretics may increase the potential for polymyxin B sulfate toxicity by altering its concentration in the bloodstream and tissues.

The following are the side effects involving Polymyxin- B:

• Nephrotoxicity (kidney damage)
• Neurotoxicity (nerve damage)
• Ototoxicity (ear damage)
• Gastrointestinal disturbances (nausea, vomiting, abdominal pain, diarrhea)
• Hypersensitivity reactions (allergic reactions)
• Injection site reactions (pain, redness, swelling)
• Rarely, blood disorders such as agranulocytosis or thrombocytopenia

Pregnancy:

Pregnancy Category C

There is a lack of clinical data regarding the use of polymyxin B sulfate in pregnant women. Therefore, unless the anticipated benefits to the mother significantly outweigh any potential risks to the fetus, Polymyxin B for Injection USP should not be used during pregnancy.

Additionally, there is a scarcity of animal studies examining the potential embryotoxicity and/or teratogenicity of polymyxin B sulfate.

Lactation:

The excretion of polymyxin B sulfate in breast milk or animal milk has not been established. Since the effects of the drug on nursing infants are unknown, a decision should be made whether to discontinue breastfeeding or discontinue the treatment with polymyxin B sulfate. This decision should consider both the importance of the Polymyxin B for Injection USP drug treatment for the mother and the potential risk to the infant.

Pediatric:

The available data on the safety and effectiveness of polymyxin B sulfate in children older than 2 years of age is limited. It is important to regularly monitor renal function in this age group.

When it comes to infants younger than 2 years of age, the safety and efficacy of parenteral polymyxin B sulfate are also limited. There have been reports of potentially higher serum levels and prolonged half-life in infants and neonates. Due to these factors, there are no specific dosage recommendations available for this population.

Geriatric Use:

There is a scarcity of data regarding the safety and effectiveness of polymyxin B sulfate in the elderly population. Given the age-related decline in renal function, it is essential to take into account this factor and evaluate renal function before initiating therapy. Regular monitoring of renal function should also be conducted throughout the course of treatment.

Physicians should be knowledgeable as well as vigilant about the treatment and identification of overdosage of Polymyxin- B.

• Reported cases have indicated the occurrence of Polymyxin-induced toxicity associated with overdose. Excessive intake of polymyxin can lead to neuromuscular blockade, resulting in various symptoms such as apnea, muscular weakness, vertigo, transient facial paresthesia, slurred speech, vasomotor instability, visual disturbance, confusion, psychosis, and potentially respiratory arrest. Additionally, an overdose can contribute to renal failure, which manifests as reduced urine output and elevated serum concentrations of BUN and creatinine.
• Unfortunately, there is currently no specific antidote available for cases of polymyxin B sulfate overdose. If an overdose occurs, it is crucial to discontinue the drug and initiate symptomatic treatment.
• To enhance renal clearance and reduce serum drug levels, intravenously administered mannitol may be used to induce rapid diuresis. Hemodialysis or peritoneal dialysis can also be considered to manage renal complications.

Pharmacodynamics

• Polymyxin B is an antibiotic that acts by disrupting the outer cell membrane of Gram-negative bacteria, neutralizing lipopolysaccharide, and inhibiting the respiration of Gram-negative bacterial cells. It is used to treat susceptible infections caused by Gram-negative bacteria and can be administered through various routes. While absorption of the drug is limited (although not essential for its activity), it is excreted unchanged without undergoing metabolic processes. Polymyxin B is typically prescribed for susceptible Gram-negative infections affecting the urinary tract, meninges, and bloodstream.

Pharmacokinetics

Absorption

● Absorption via the oral route does not occur4.

Volume of Distribution

● The estimated volume of distribution in one-compartment models ranges from 34.3L to 47.2L. However, the exact volume of distribution is still undetermined according to general consensus8.

Protein Binding

● Polymyxin B exhibits protein binding ranging from 79% to 92%8. It is likely that 92% to 99% of polymyxin B is bound to proteins in circulation, although the specific proteins involved have not been identified.

Metabolism

● Limited data is available on the metabolism of polymyxin B. In one study, it was found that less than 1% of polymyxin B was eliminated unchanged through the kidneys, indicating minimal metabolism6. Additionally, polymyxin B has been detected in bile without undergoing metabolic processes.

Route of Elimination

● Polymyxin B is primarily eliminated through renal tubular reabsorption and non-renal pathways. Urine collection studies in humans and animals have shown that less than 5% of polymyxin B is excreted by the kidneys. However, a Canadian product monograph suggests that the drug is mainly eliminated through the kidneys, with 60% of polymyxin B recovered in urine. This discrepancy can be attributed to the delay of 12 to 24 hours between administration and significant elimination of polymyxin B8. Non-renal elimination mechanisms are not well understood, but all four components of polymyxin B have been detected in bile.

1. https://go.drugbank.com/drugs/DB00781
2. https://reference.medscape.com/drug/polymyxinb-342556
3. https://www.webmd.com/drugs/2/drug-3408/polymyxin-b-sulfate-trimethoprim-ophthalmic-eye/details
4. https://medlineplus.gov/druginfo/meds/a616013.html
5. https://www.rxlist.com/polymyxin-b-drug.htm
6. https://sterimaxinc.com/wp-content/uploads/2016/03/1.3.1-SteriMax-English-PM-February-8-201612.pdf
7. https://pdf.hres.ca/dpd_pm/00014719.PDF
8. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/060716Orig1s020Lbl.pdf
9. https://www.unmc.edu/intmed/_documents/id/asp/protect-polymyxinb_iv_formulary.pdf