Antibiotic Otic

Uses

Hydrocortisone is used for the use in the following conditions: Primary or secondary adrenocortical insufficiency, Acute adrenocortical insufficiency, Shock unresponsive to conventional therapy, Congenital adrenal hyperplasia, Hypercalcemia associated with cancer, Nonsuppurative thyroiditis, Rheumatic Disorders, Dermatologic Diseases (Allergic States, Severe seborrheic dermatitis, Severe psoriasis, Pemphigus, Severe erythema multiforme), Control of severe or incapacitating allergic conditions (Bronchial asthma, Contact dermatitis, Atopic dermatitis, Serum sickness, Seasonal or perennial allergic rhinitis, Drug hypersensitivity reactions, Urticarial transfusion reactions, Acute noninfectious laryngeal edema), Ophthalmic Diseases (Herpes zoster ophthalmicus, Iritis, iridocyclitis, Chorioretinitis, Diffuse posterior uveitis and choroiditis, Optic neuritis), Gastrointestinal Diseases, Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, Loeffler's syndrome, Aspiration pneumonitis, Hematologic Disorders (Acquired, autoimmune hemolytic anemia, Idiopathic thrombocytopenic purpura in adults, Secondary thrombocytopenia, Erythroblastopenia), Neoplastic Diseases (Leukemias and lymphomas in adults, Acute leukemia of childhood), Edematous States, Acute exacerbations of multiple sclerosis

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

Antibiotic Otic is also used to associated treatment for these conditions: Acute Gouty Arthritis, Acute Otitis Externa, Adrenal Insufficiency, Allergic Rhinitis (AR), Allergic corneal marginal ulcers, Anal Fissures, Ankylosing Spondylitis (AS), Anterior Segment Inflammation, Aspiration Pneumonitis, Asthma, Atopic Dermatitis (AD), Berylliosis, Bullous dermatitis herpetiformis, Chorioretinitis, Choroiditis, Congenital Adrenal Hyperplasia (CAH), Congenital Hypoplastic Anemia, Corneal Inflammation, Crohn's Disease (CD), Dermatitis, Dermatitis exfoliative generalised, Dermatitis, Contact, Dermatomyositis, Dermatosis, Drug hypersensitivity reaction, Epicondylitis, Erythroblastopenia, Hemorrhoids, Herpes Labialis, Hypercalcemia of Malignancy, Idiopathic Thrombocytopenic Purpura, Infection of the Fenestration Cavity, Infection of the Mastoidectomy Cavity, Iridocyclitis, Iritis, Itching caused by Hemorrhoids, Itching of the Anus, Leukemia, Acute, Leukemias, Loeffler's syndrome, Lymphomas NEC, Malignant Lymphomas, Mycosis Fungoides (MF), Ophthalmia, Sympathetic, Optic Neuritis, Pain caused by Hemorrhoids, Pemphigus, Post-traumatic Osteoarthritis, Primary adrenocortical insufficiency, Proctitis, Proteinuria, Psoriatic Arthritis, Rectal inflammations NEC, Rheumatic heart disease, unspecified, Rheumatoid Arthritis, Rheumatoid Arthritis, Juvenile, Seasonal Allergic Conjunctivitis, Secondary adrenocortical insufficiency, Secondary thrombocytopenia, Serum Sickness, Severe Seborrheic Dermatitis, Skin Diseases, Stevens-Johnson Syndrome, Synovitis, Systemic Lupus Erythematosus (SLE), Trichinosis, Tuberculous Meningitis, Ulcerative Colitis, Acquired immune hemolytic anemia, Acute Bursitis, Acute Tenosynovitis, Acute rheumatic carditis, Cryptitis, Disseminated Pulmonary Tuberculosis, Fulminating Pulmonary Tuberculosis, Itching skin, Non-suppurative Thyroiditis, Severe Erythema multiforme, Severe Psoriasis, Subacute Bursitis, Superficial infection of the external auditory canal with inflammation, Symptomatic Sarcoidosis, Systemic Dermatomyositis, Varicella-zoster virus acute retinal necrosis, PalliativeAcne 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 Antibiotic Otic works

The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation.[A187463] Corticosteroids binding to the glucocorticoid receptor mediates changes in gene expression that lead to multiple downstream effects over hours to days.[A187463]

Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10.[A187463]

Lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive.[A187463] High doses of glucocorticoids for an extended period bind to the mineralocorticoid receptor, raising sodium levels and decreasing potassium levels.[A187463]

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

Antibiotic Otic dosage

Tablet: The initial dosage of Hydrocortisone Tablets may vary from 20 mg to 240 mg of hydrocortisone per day depending on the specific disease entity being treated. In situations of less severity, lower doses will generally suffice, while in selected patients higher initial doses may be required. The initial dosage should be maintained or adjusted until a satisfactory response is noted. If after a reasonable period of time there is a lack of satisfactory clinical response, Hydrocortisone Tablets should be discontinued and the patient transferred to other appropriate therapy.

It should be emphasized that dosage requirements are variable and must be individualized on the basis of the disease under treatment and the response of the patients.After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response. It should be kept in mind that constant monitoring is needed in regard to drug dosage. If, after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually, rather than abruptly.

Injection:

• Adult: By IM injection or slow IV injection or infusion. The initial dose of Hydrocortisone sterile powder is 100 mg to 500 mg, depending on the severity of the condition. This dose may be repeated at intervals of 2, 4 or 6 hours as indicated by the patient's response and clinical condition.
• Children: By slow IV injection, up to 1 year 25 mg, 1-5 years 50 mg, 6-12 years 100 mg.

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

Hydrocortisone is generally well tolerated except in prolonged high doses. It may cause cardiac arrhythmia, esophageal candidiasis, menstrual irregularity, decreased carbohydrate & glucose tolerance, fluid retention, increased appetite, weight gain, euphoria, mood swings, depression, insomnia, acne etc.

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

Data regarding acute overdoses of glucocorticoids are rare. Chronic high doses of glucocorticoids can lead to the development of cataract, glaucoma, hypertension, water retention, hyperlipidemia, peptic ulcer, pancreatitis, myopathy, osteoporosis, mood changes, psychosis, dermal atrophy, allergy, acne, hypertrichosis, immune suppression, decreased resistance to infection, moon face, hyperglycemia, hypocalcemia, hypophosphatemia, metabolic acidosis, growth suppression, and secondary adrenal insufficiency. Overdose may be treated by adjusting the dose or stopping the corticosteroid as well as initiating symptomatic and supportive treatment.

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

Hydrocortisone should be used with caution in patients with a history of peptic ulceration as it increases the incidence of peptic ulceration. This drug should be used with caution in patients with congestive heart failure, hypertension, glaucoma, diabetic mellitus and epilepsy.

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

Drug interaction of hydrocortisone has been reported with amphotericin B, potassium-depleting agents, macrolide antibiotics, warfarin, antidiabetics, isoniazid, digitalis glycosides, estrogens, barbiturates, phenytoin, carbamazepine, ketoconazole, aspirin etc.

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

Total hydrocortisone has a volume of distribution of 39.82L, while the free fraction has a volume of distribution of 474.38L.

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

Oral hydrocortisone at a dose of 0.2-0.3mg/kg/day reached a mean C_max of 32.69nmol/L with a mean AUC of 90.63h*nmol/L A 0.4-0.6mg/kg/day dose reached a mean C_max of 70.81nmol/L with a mean AUC of 199.11h*nmol/L. However, the pharmacokinetics of hydrocortisone can vary by 10 times from patient to patient.

Topical hydrocortisone cream is 4-19% bioavailable[8546995] with a T_max of 24h.

Hydrocortisone retention enemas are have a bioavailability of 0.810 for slow absorbers and 0.502 in rapid absorbers. Slow absorbers take up hydrocortisone at a rate of 0.361±0.255/h while fast absorbers take up hydrocortisone at a rate of 1.05±0.255/h.

A 20mg IV dose of hydrocortisone has an AUC of 1163±277ng*h/mL.

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

Total hydrocortisone via the oral route has a half life of 2.15h while the free fraction has a half life of 1.39h. A 20mg IV dose of hydrocortisone has a terminal half life of 1.9±0.4h.

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

Total hydrocortisone by the oral route has a mean clearance of 12.85L/h, while the free fraction has a mean clearance of 235.78L/h. A 20mg IV dose of hydrocortisone has a clearance of 18.2±4.2L/h.

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

Corticosteroids are eliminated predominantly in the urine.[A187436] However, data regarding the exact proportion is not readily available.

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

Pregnancy category C. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Use in nursing mother: Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from corticosteroids, a decision should be made whether to continue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

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.

Contraindication

Hydrocortisone is contraindicated in severe systemic fungal infections and patients with known hypersensitivity to any component of this product.

Special Warning

Use in elderly patients: Clinical studies were not done in patients’ aged 65 and above. In general dose selection for an elderly patients should be cautious, usually starting at the low end of the dosing range.

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

Store at 15-30°C.

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.

Innovators Monograph

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