Clodide

Uses

Bacitracin is a cyclic polypeptide antibiotic used to prevent wound infections, treat pneumonia and empyema in infants, and to treat skin and eye infections.

Bacitracin is indicated in topical formulations for acute and chronic localized skin infections. Occasionally, it is also used intramuscularly for infantile streptococcal pneumonia and empyema. Bacitracin is also formulated as an ointment with neomycin and polymyxin B for over the counter use. A bacitracin ointment formulated with neomycin and polymyxin B along with hydrocortisone is indicated for the treatment of corticosteroid responsive dermatoses with secondary infection.

Neomycin is an aminoglycoside antibiotic agent used orally and topically to treat a wide variety of infections in the body.

Oral neomycin sulfate is indicated as an adjunctive therapy in hepatic coma (portal-system encephalopathy) by reducing ammonia-forming bacteria in the intestinal tract. It is strongly recommended that oral neomycin is only used in infections that are proven or strongly suspected to be caused by susceptible bacteria to reduce the risk of the development of drug-resistant bacteria.

Neomycin, in combination with polymyxin B sulfates and hydrocortisone in otic suspensions, is used in the treatment of superficial bacterial infections of the external auditory canal caused by organisms susceptible to the antibiotics. This otic formulation is also used in the treatment of infections of mastoidectomy and fenestration cavities caused by organisms susceptible to the antibiotics.

The ophthalmic solution containing neomycin in combination with polymyxin B sulfates and dexamethasone is used to treat steroid-responsive inflammatory ocular conditions for which a corticosteroid is indicated and where bacterial infection or a risk of bacterial infection exists.

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

Clodide is also used to associated treatment for these conditions: Acne, Bacterial Infections of the Intestine, Empyema, Eye Infections, Infected Wound, Infection, Inflammatory Reaction caused by Acne, Ocular Inflammatory Disease, Pneumonia, Skin Ulcer, Corticosteroid-responsive dermatoses, Infection in minor cuts, scrapes, or burns, Wound siteAcne pustular, Allergic Contact Dermatitis, Allergy Skin, Atopic Dermatitis (AD), Atopic Dermatitis (AD) of the external ear canal, Bacterial diarrhoea, Burns, Carbuncle, Cradle Cap, Dermatitis, Dermatitis, Contact, Dermatitis, Eczematous, Diarrhoea, Discoid Lupus Erythematosus (DLE), Ear infection bacterial, Ear infection bacterial caused by susceptible bacteria, Gastrointestinal Infections, Hepatic coma, Hidradenitis Suppurativa (HS), Hot Water Burns (Scalds), Impetigo, Impetigo contagious, Infantile Eczema, Infected Wounds, Infected skin ulcer, Infection of the outer ear caused by susceptible bacteria, Infectious diarrhea, Inflammatory Reaction caused by Acne, Intertrigo, Itching caused by Infection, Lichen Planus (LP), Localized Infection caused by susceptible bacteria, Nail infection, Neurodermatitis, Otitis Externa, Postoperative Wound Infection, Psoriasis Vulgaris (Plaque Psoriasis), Pustular Dermatosis, Radiodermatitis, Secondarily Infected Eczema, Secondary Bacterial Infection, Skin Burns, Skin Infections, Skin Infections, Bacterial, Skin Irritation, Skin Ulcer, Solar erythema, Abrasions, Blistering caused by Staphylococcus, Erythematous eruptions, Intertriginous erythema of the anogenital, Ocular bacterial infections caused by susceptible bacteria, Resistant to other corticosteroids Dermatosis, Susceptible Bacterial InfectionsAcute 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 Clodide works

Bacitracin binds to a divalent metal ion such as Mn(II), Co(II), Ni(II), Cu(II), or Zn(II). These complexes bind C₅₅-isoprenyl pyrophosphate, preventing the hydrolysis of a lipid dolichol pyrophosphate, which finally inhibits cell wall synthesis. Bacitracin metal complexes also bind and oxidatively cleave DNA.

Like other aminoglycoside antibiotic drugs, neomycin inhibits bacterial ribosomes by binding to the 30S ribosomal subunit of susceptible bacteria and disrupting the translational machinery of bacterial protein synthesis. Bacterial translation is normally initiated by the mRNA binding to the 30S ribosomal subunit and subsequent binding with 50S subunit for elongation.

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

Clodide 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

The oral LD₅₀ of bacitracin in rats is >2000mg/kg.

Specific data regarding bacitracin overdoses is not readily available. An overdose of bacitracin may lead to nephrotoxicity and patients should be treated with supportive measures.

The oral LD₅₀ of neomycin sulfate in mouse is > 8 g/kg. The subcutaneous LD₅₀ is 200 mg/kg in rat and 190 mg/kg in mouse. The intraperitoneal LD₅₀ in mouse is 305 mg/kg. The oral Lowest published toxic dose (TDLo) in woman is 12600 mg/kg/7D.

Because of low absorption, acute overdosage from oral neomycin is not likely to occur. However, prolonged administration of neomycin should be avoided because of the possibility of some systemic absorption and the risk of neurotoxicity, ototoxicity, and/or nephrotoxicity. Hemodialysis will remove neomycin from the blood. While nephrotoxicity and ototoxicity have been reported in otherwise patients without compromised renal function, the risk for developing these toxicities is increased in patients with renal impairment. Like other aminoglycosides, neomycin may cause fetal harm and total irreversible bilateral congenital deafness when administered in pregnant women.

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

Data regarding the volume of distribution of bacitracin in humans is not readily available.

The small fraction of absorbed neomycin is rapidly distributed in the tissues. The amount of systemically absorbed neomycin is reported to increase cumulatively with each repeated dose administered until a steady state is reached.

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

Topical, ophthalmic, and oral formulations of bacitracin are poorly absorbed systemically. Intramuscular bacitracin is readily and completely absorbed.

Neomycin is poorly absorbed from the gastrointestinal tract. Gastrointestinal absorption of the drug may be increased if inflammatory or ulcerative gastrointestinal disease is present.

Administration by the oral route does not lead to absorption.

Half Life

Data regarding the half life of bacitracin in humans is not readily available.

There is limited information on the half-life of neomycin.

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

Data regarding the clearance of bacitracin in humans has not been well studied. A study of 9 subjects in 1947 shows a renal clearance of 105-283mL/min with an average renal clearance of 159mL/min.

There is limited information on the clearance rate of neomycin.

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

Elimination Route

Bacitracin is mainly excreted renally with 87% of and intramuscular dose being recovered in the urine after 6 hours.

The small absorbed fraction of neomycin is excreted by the kidney. The unabsorbed portion of the drug is excreted unchanged in the feces.

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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