Neomycin and Polymyxin B Sulfates

Uses

Acute infections caused by susceptible strains of Pseudomonas aeruginosa:

Polymyxin B Sulfate is a drug of choice in the treatment of infections of the urinary tract, meninges, and bloodstream caused by susceptible strains of Pseudomonas aeruginosa.

It may be used for serious infections caused by susceptible strains of the following organisms, when less potentially toxic drugs are ineffective or contraused:

• H. influenzae: Specifically meningeal infections
• Escherichia coli: Specifically urinary tract infections
• Aerobacter aerogenes: Specifically bacteremia
• Klebsiella pneumoniae: Specifically bacteremia

Neomycin and Polymyxin B Sulfates is also used to associated treatment for these conditions: Acute Otitis Media, Bacteremia caused by Enterobacter aerogenes, Bacterial Conjunctivitis, Bacterial Infections, Chronic Otitis Media, Escherichia urinary tract infection, Klebsiella bacteraemia, Meningitis caused by Haemophilus influenzae, Meningitis, Bacterial, Ocular Inflammation, Otitis Externa, Otorrhoea, Superficial ocular infections of the conjunctiva caused by susceptible bacteria, Superficial ocular infections of the cornea caused by susceptible bacteria, Urinary Tract Infection, Ocular bacterial infections

How Neomycin and Polymyxin B Sulfates works

The alpha and gamma diaminobutyric acid of a positively charged polymyxin B forms an electrostatic interaction with the phosphate groups of a negatively charged lipid A on the outer membrane of a Gram negative bacterium. Calcium and Magnesium ions are displaced from phosphates of the membrane lipids, destabalising the lipopolysaccharide (LPS), increasing membrane permeability, causing cytoplasmic leaking, and killing the cell.

Polymyxin B can also bind and neutralize LPS released during bacterial lysis, preventing reactions to endotoxin.

A third activity of polymyxin B is the inhibition of type II NADH-quinone oxidoreductases in the bacterial inner membrane, which are essential for respiration.

Polymyxin is active against common Gram negative bacteria but not Gram negative cocci, Gram positive bacteria, or anaerobic bacteria.

Dosage

Neomycin and Polymyxin B Sulfates dosage

Intravenous: Dissolve Polymyxin B 500,000 units in 300 to 500 ml solutions for parenteral Dextrose injection 5% for continuous drip.

Intramuscular: Dissolve Polymyxin B 500,000 units in 2 ml 0.9% Sodium Chloride solution. It is not recommended routinely because of severe pain at injection site, particularly in infants and children.

Intrathecal: Dissolve Polymyxin B 500,000 units in 10 ml 0.9% Sodium Chloride solution for 50,000 units per ml dosage unit.

In meningeal infections, Polymyxin B Sulfate should be administered only by the intrathecal route.

For IV route:

• Adult & Children (Normal kidney function): Dose (Units/kg/day) is 15,000-25,000(Not exceed 25,000) and Dosage frequency/Duration is infusions may be given every 12 hours over a period of approximately 60 to 90 minutes.
• Adult & Children (Renal impairment): Dose (Units/kg/day) is Less than 15,000 and Dosage frequency/Duration is Infusions may be given every 12 hours over a period of approximately 60 to 90 minutes.
• Infants (Normal kidney function): Dose (Units/kg/day) is Maximum 40,000

• Adult & Children: Dose (Units/kg/day) is 25,000-30,000 and Dosage frequency/Duration is Dose should be reduced in the presence of renal impairment. The dosage may be divided and given at either 4 or 6 hour intervals.
• Infants (Normal kidney function): Dose (Units/kg/day) is Maximum 40,000

• Children under 2 years of age: Dosage frequency/Duration is 20,000 units once daily, intrathecally for 3 to 4 days or 25,000 units once every other day. Continue with a dose of 25,000 units once every other day for at least 2 weeks after cultures of the cerebrospinal fluid are negative and sugar content has returned to normal.
• Adults and children over 2 years of age: 50,000 units once daily for 3 to 4 days, then 50,000 units once every other day for at least 2 weeks after cultures of the cerebrospinal fluid are negative and sugar content has returned to normal.

Side Effects

Clostridium difficile associated diarrhea has been reported with use of Polymyxin B. Nephrotixic reactions: Albuminuria, cylinduria, azotemia, and rising blood levels, Neurotoxic reactions: Facial flushing, dizziness progressing to ataxia, drowsiness, peripheral aresthesias (circumoral and stocking glove), apnea due to concurrent use of curariform muscle relaxants, other neurotoxic drugs or inadvertent overdosage, and signs of meningeal irritation with intrathecal administration, e.g., fever, headache, stiff neck. Other reactions occasionally reported: Drug fever, urticaria rash, severe pain at IM injections sites and thrombophelbitis at IV injections sites.

Toxicity

Nephrotoxicity can occur in patients as polymyxin B is thought to accumulate in renal cells after renal tubular reabsorption. This accumulation can lead to apoptosis of renal cells and decrease in renal function. In recent studies, acute kidney injury (AKI) has been seen in 31.3% to 39.4% of patients receiving polymyxin B.

Overdose cases can cause neuromuscular block leading to apnea, muscular weakness, vertigo, transient facial parasthesia, slurred speed, vasomotor instability, visual disturbance, confusion, psychosis, and respiratory arrest. Renal failure has also been seen through decreased urine output, and increased serum concentrations of blood urea nitrogen.

Overdose of polymyxin B is treated by stopping the drug and beginning symptomatic treatment. Intravenous administration of mannitol may enhance renal clearance, and hemodialysis may manage renal complications.

Safety of polymyxin B has not been established in pregnancy, breast feeding, pediatrics, and geriatrics. Polymyxin B should no be used in pregnancy unless the benefit outweighs the risk. Nursing mothers should either stop nursing or stop polymyxin B treatment depending on the risks to both the mother and child. Pediatric patients should be frequently monitored for renal function and no dosing information is available in children under 2 years of age. Geriatric patients should have renal function assessed before and regularly during therapy.

Precaution

Baseline renal function should be done prior to therapy, with frequent monitoring of renal function and blood levels of the drug during parenteral therapy.

Interaction

The concurrent or sequential use of other neurotoxic and/or nephrotox-ic drugs with Polymyxin B sulfate, particularly bacitracin, kanamycin, streptomycin, tobramycin, amikacin, cephaloridine, cephalothin, paromycin, polymyxin E (colistin), neomycin, gentamicin, and vancomycin, Bumetanide, celecoxib, cisplatin, cyclosporine, diclofenac, misoprostol, diphenhydramine, ibuprofen, naproxen, esomeprazole, etodolac, general anesthetic, gentamycin, ketorolac, meloxicam, tenofovir etc should be avoided.

Volume of Distribution

1 compartment models estimate the volume of distribution to be 34.3L to 47.2L. However, the general consensus is that the volume of distribution is yet to be determined.

Elimination Route

Administration by the oral route does not lead to absorption.

Half Life

In one study the half life was 9 to 11.5 hours. However, a Canadian monograph states the half life to be 6 hours, and 48-72 hours in patients with renal insufficiency.

Clearance

1 compartment models estimate clearance to be 2.37L/h to 2.5L/h.

Elimination Route

Polymyxin B is proposed to be primarily eliminated through renal tubular reabsorption and non-renal pathways. Urine collection in humans and animals show 1. However, a Canadian product monograph states the drug is primarily eliminated through the kidneys and that 60% of polymyxin B is recovered in the urine. This discrepancy can be explained by the 12 to 24 hour lag time between administration and significant elimination of polymyxin B. Non-renal elimination is not well understood but all 4 components of polymyxin B have been detected in bile.

Pregnancy & Breastfeeding use

There are no controlled data in human pregnancy. Safety has not been established during pregnancy. There is no recommendation regarding use during lactation. There is no study on whether it is secreted with human milk.

Acute Overdose

Polymyxin-induced toxicity associated with overdose has been reported. Overdose of Polymyxin can result in neuromuscular blockade, which can lead to apnea, muscular weakness, vertigo, transient facial paresthesia, slurred speech, vasomotor instability, visual disturbance, confusion, psychosis and possible respiratory arrest. Overdose can also cause renal failure characterized by decreased urine output and increased serum concentrations of BUN and creatinine. There is no specific antidote for Polymyxin B Sulfate overdose. In case of Polymyxin B Sulfate overdose, the drug should be stopped and symptomatic treatment instituted. Quick diuresis by IV administered mannitol may help to enhance renal clearance of the drug and thus to reduce serum drug levels. Hemodialysis or peritoneal dialysis may help in order to manage renal complications.

Storage Condition

Before reconstitution, do not store above 30°C; and keep away from light and out of the reach of children. After reconstitution or dilution, unused portion must be stored at 2° to 8°C and should be discarded after 72 hours if not used.

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