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    Aminoglycoside Antibiotics

    BOXED WARNING

    Dehydration, hearing impairment, neonates, nephrotoxicity, neurotoxicity, ototoxicity, renal disease, renal impairment

    Neomycin is an aminoglycoside and is absorbed systemically after oral administration; toxic reactions may occur. Patients receiving aminoglycosides should be closely monitored for ototoxicity, neurotoxicity, and nephrotoxicity. Aminoglycosides are associated with major toxic effects on the auditory and vestibular branches of the eighth nerve and renal tubules. Ototoxicity is manifest by bilateral auditory toxicity which often is permanent and, sometimes, by vestibular ototoxicity. High-frequency hearing loss usually occurs before there is noticeable clinical hearing loss; clinical symptoms may not be present to warn of developing cochlear damage. Vertigo may occur and may indicate vestibular injury. Other neurotoxic manifestations may include numbness, skin tingling, muscle twitching, and seizures. The risk of hearing loss increases with the degree of exposure to either high peak or high trough serum concentrations and continues to progress after stopping the drug. Use aminoglycosides with caution in patients with preexisting hearing impairment, especially eighth-cranial-nerve impairment. Dosages should be carefully chosen and monitored in the patient with renal impairment or renal failure. In patients with renal impairment or renal disease and, in those with normal renal function who receive high doses or prolonged therapy, the risks of severe ototoxic and nephrotoxic adverse reactions are sharply increased. Nephrotoxicity can manifest as decreased creatinine clearance, the presence of cells or casts, oliguria, proteinuria, decreased urine specific gravity, or evidence of increasing nitrogen retention (increasing BUN or serum creatinine). Renal and eighth nerve function should be closely monitored during aminoglycoside therapy. Evidence of ototoxicity or nephrotoxicity requires dosage adjustment or discontinuance of therapy. In rare cases, ototoxicity and nephrotoxicity may not be evident until soon after completion of therapy. Delayed-onset irreversible deafness and renal failure have been reported following irrigation of both small and large surgical fields with minute quantities of neomycin. Aminoglycoside-induced ototoxicity is usually irreversible, however, nephrotoxicity usually is reversible. Avoid concurrent and/or sequential coadministration of aminoglycosides with other drugs that are potentially nephrotoxic and/or neurotoxic because toxicity may be additive. Neonates, the elderly, and patients with dehydration are at increased risk of developing toxicity. Aminoglycosides should not be given concomitantly with potent diuretics since certain diuretics by themselves may cause ototoxicity. Intravenous diuretics may also alter aminoglycoside concentrations in serum and tissue and thereby enhance aminoglycoside toxicity.

    Botulism, myasthenia gravis, neuromuscular blockade, neuromuscular disease, parkinsonism, respiratory depression, respiratory insufficiency

    Aminoglycosides, like neomycin, are associated with neuromuscular blockade and may cause severe neuromuscular weakness lasting hours to days. Respiratory paralysis, respiratory insufficiency, or respiratory depression may occur when aminoglycosides are instilled intraperitoneally concomitantly with anesthesia and muscle-relaxing drugs. Neuromuscular blockade has also been reported with both oral and parenteral use of aminoglycosides. Neuromuscular blockage and respiratory paralysis have been reported following the oral use of neomycin. Delayed-onset death due to neuromuscular blockade (regardless of the status of renal function) have been reported following irrigation of both small and large surgical fields with minute quantities of neomycin. Clinicians should be aware of the possibility of neuromuscular blockade and respiratory paralysis if aminoglycosides are administered by any route, especially in patients receiving anesthetics, neuromuscular-blocking agents (e.g., tubocurarine, succinylcholine, decamethonium, or in patients receiving massive transfusions of citrate-anticoagulated blood). If neuromuscular blockade occurs, calcium salts may reduce these effects but mechanical respiratory assistance may be needed. Aminoglycosides may aggravate muscle weakness in patients with neuromuscular disease such as myasthenia gravis, botulism, or parkinsonism.

    DEA CLASS

    Rx

    DESCRIPTION

    Aminoglycoside antibiotic derived from Streptomyces fradiae. Most often used topically as an antiinfective. Oral bioavailability is poor, but is administered orally in patients with hepatic coma or portal-systemic encephalopathy. Oral neomycin also has a lipid-lowering effect but is infrequently used for this purpose. Administration as a surgical irrigant is no longer recommended. Not indicated for the treatment of systemic infections because it can cause irreversible ototoxicity.

    COMMON BRAND NAMES

    Neo-Fradin

    HOW SUPPLIED

    Neo-Fradin/Neomycin/Neomycin Sulfate Oral Sol: 5mL, 125mg
    Neomycin/Neomycin Sulfate Oral Tab: 500mg

    DOSAGE & INDICATIONS

    For use in preoperative bowel preparation for patients undergoing colorectal surgery.
    Oral dosage
    Adults

    1 g PO in combination with metronidazole or erythromycin for 3 doses given over 10 hours beginning the afternoon and evening prior to the surgery. Intravenous antibmicrobial prophylaxis should also be given prior to the surgical incision.

    Infants†, Children†, and Adolescents†

    15 mg/kg/dose (Max: 1 g/dose) PO in combination with metronidazole or erythromycin for 3 doses given over 10 hours beginning the afternoon and evening prior to the surgery. Intravenous antibmicrobial prophylaxis should also be given prior to the surgical incision.

    For the adjunctive treatment of hepatic encephalopathy or hepatic coma.
    Oral dosage (tablets or solution)
    Adults

    The recommended dose is 1—3 g PO every 6 hours for 5—6 days.

    Children†

    Safety and efficacy have not been established by the manufacturer. A dose of 50—100 mg/kg/day PO in divided doses every 6 hours, or 0.625—1.75 g/m2 PO every 6 hours for 5—6 days has been used.

    For the treatment of superficial skin and skin structure infections (i.e., minor cuts and wounds) due to susceptible organisms.
    Topical dosage
    Adults, Adolescents, and Children

    Apply a thin film of 0.5% cream or ointment to the affected area 1—4 times daily.

    For the treatment of infectious diarrhea† or bacterial overgrowth syndrome†.
    Oral dosage
    Adults

    The recommended dose is 50 mg/kg/day PO given in 4 divided doses for 2—3 days.

    Children

    Safety and efficacy have not been established by the manufacturer. A dose of 50 mg/kg/day PO given in 4 divided doses for 2—3 days has been used.

    Neonates

    Safety and efficacy have not been established by the manufacturer. 50 mg/kg/day PO divided every 6 hours has been used.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    12 g/day PO; specific maximum dosage information is not available for topical preparations.

    Elderly

    12 g/day PO; specific maximum dosage information is not available for topical preparations.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment required. Use aminoglycosides with caution in patients with severe hepatic disease (cirrhosis), as use may precipitate hepato-renal syndrome.

    Renal Impairment

    Dosage should be modified depending on clinical response and degree of renal impairment, but no quantitative recommendations are available.

    ADMINISTRATION

    Oral Administration

    May be administered without regard to meals.

    Topical Administration

    Topical formulations are not for ophthalmic use.
    Rub cream or ointment gently into cleansed affected area. Care should be taken to avoid further contamination of the infected skin.
    Treated area may be covered with sterile gauze if desired.

    STORAGE

    Generic:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Neo-Fradin:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Colitis, diarrhea, GI disease, GI obstruction, ileus, inflammatory bowel disease, pseudomembranous colitis, ulcerative colitis

    Neomycin is contraindicated for use in patients with GI obstruction, colitis, ileus, or inflammatory or ulcerative gastrointestinal disease including ulcerative colitis, and inflammatory bowel disease because increased absorption is possible, resulting in increased adverse effects. Almost all antibacterial agents have been associated with pseudomembranous colitis (antibiotic-associated colitis) which may range in severity from mild to life-threatening. In the colon, overgrowth of Clostridia may exist when normal flora is altered subsequent to antibacterial administration. The toxin produced by Clostridium difficile is a primary cause of pseudomembranous colitis. It is known that systemic use of antibiotics predisposes patients to development of pseudomembranous colitis. Consideration should be given to the diagnosis of pseudomembranous colitis in patients presenting with diarrhea following antibacterial administration. Systemic antibiotics should be prescribed with caution to patients with inflammatory bowel disease such as ulcerative colitis or other GI disease. If diarrhea develops during therapy, the drug should be discontinued. Following diagnosis of pseudomembranous colitis, therapeutic measures should be instituted. In milder cases, the colitis may respond to discontinuation of the offending agent. In moderate to severe cases, fluids and electrolytes, protein supplementation, and treatment with an antibacterial effective against Clostridium difficile may be warranted. Products inhibiting peristalsis are contraindicated in this clinical situation. Practitioners should be aware that antibiotic-associated colitis has been observed to occur over two months or more following discontinuation of systemic antibiotic therapy; a careful medical history should be taken.

    Dehydration, hearing impairment, neonates, nephrotoxicity, neurotoxicity, ototoxicity, renal disease, renal impairment

    Neomycin is an aminoglycoside and is absorbed systemically after oral administration; toxic reactions may occur. Patients receiving aminoglycosides should be closely monitored for ototoxicity, neurotoxicity, and nephrotoxicity. Aminoglycosides are associated with major toxic effects on the auditory and vestibular branches of the eighth nerve and renal tubules. Ototoxicity is manifest by bilateral auditory toxicity which often is permanent and, sometimes, by vestibular ototoxicity. High-frequency hearing loss usually occurs before there is noticeable clinical hearing loss; clinical symptoms may not be present to warn of developing cochlear damage. Vertigo may occur and may indicate vestibular injury. Other neurotoxic manifestations may include numbness, skin tingling, muscle twitching, and seizures. The risk of hearing loss increases with the degree of exposure to either high peak or high trough serum concentrations and continues to progress after stopping the drug. Use aminoglycosides with caution in patients with preexisting hearing impairment, especially eighth-cranial-nerve impairment. Dosages should be carefully chosen and monitored in the patient with renal impairment or renal failure. In patients with renal impairment or renal disease and, in those with normal renal function who receive high doses or prolonged therapy, the risks of severe ototoxic and nephrotoxic adverse reactions are sharply increased. Nephrotoxicity can manifest as decreased creatinine clearance, the presence of cells or casts, oliguria, proteinuria, decreased urine specific gravity, or evidence of increasing nitrogen retention (increasing BUN or serum creatinine). Renal and eighth nerve function should be closely monitored during aminoglycoside therapy. Evidence of ototoxicity or nephrotoxicity requires dosage adjustment or discontinuance of therapy. In rare cases, ototoxicity and nephrotoxicity may not be evident until soon after completion of therapy. Delayed-onset irreversible deafness and renal failure have been reported following irrigation of both small and large surgical fields with minute quantities of neomycin. Aminoglycoside-induced ototoxicity is usually irreversible, however, nephrotoxicity usually is reversible. Avoid concurrent and/or sequential coadministration of aminoglycosides with other drugs that are potentially nephrotoxic and/or neurotoxic because toxicity may be additive. Neonates, the elderly, and patients with dehydration are at increased risk of developing toxicity. Aminoglycosides should not be given concomitantly with potent diuretics since certain diuretics by themselves may cause ototoxicity. Intravenous diuretics may also alter aminoglycoside concentrations in serum and tissue and thereby enhance aminoglycoside toxicity.

    Botulism, myasthenia gravis, neuromuscular blockade, neuromuscular disease, parkinsonism, respiratory depression, respiratory insufficiency

    Aminoglycosides, like neomycin, are associated with neuromuscular blockade and may cause severe neuromuscular weakness lasting hours to days. Respiratory paralysis, respiratory insufficiency, or respiratory depression may occur when aminoglycosides are instilled intraperitoneally concomitantly with anesthesia and muscle-relaxing drugs. Neuromuscular blockade has also been reported with both oral and parenteral use of aminoglycosides. Neuromuscular blockage and respiratory paralysis have been reported following the oral use of neomycin. Delayed-onset death due to neuromuscular blockade (regardless of the status of renal function) have been reported following irrigation of both small and large surgical fields with minute quantities of neomycin. Clinicians should be aware of the possibility of neuromuscular blockade and respiratory paralysis if aminoglycosides are administered by any route, especially in patients receiving anesthetics, neuromuscular-blocking agents (e.g., tubocurarine, succinylcholine, decamethonium, or in patients receiving massive transfusions of citrate-anticoagulated blood). If neuromuscular blockade occurs, calcium salts may reduce these effects but mechanical respiratory assistance may be needed. Aminoglycosides may aggravate muscle weakness in patients with neuromuscular disease such as myasthenia gravis, botulism, or parkinsonism.

    Pregnancy

    Neomycin crosses the placenta. Aminoglycosides are known to cause fetal nephrotoxicity and permanent ototoxicity in children whose mothers received them during pregnancy. Neomycin is classified as a FDA pregnancy risk category D drug and should not be used in pregnancy unless the potential benefit justifies the added risk to the fetus.

    Breast-feeding

    The manufacturer of neomycin states that due to the potential for serious adverse reactions, a decision should be made whether to discontinue nursing or to discontinue neomycin while nursing. However, neomycin administered orally has minimal systemic absorption. If there were maternal systemic concentrations of neomycin, aminoglycosides are generally excreted into breast milk in low concentrations. Due to the fact that they are poorly absorbed from the gastrointestinal tract, aminoglycosides are not likely to cause adverse events in nursing infants. Several aminoglycosides are considered compatible with breast-feeding by the American Academy of Pediatrics (AAP). Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Aminoglycoside hypersensitivity

    Patients with aminoglycoside hypersensitivity should not receive neomycin. Allergenic reactions to aminoglycoside are generally uncommon, but hypersensitivity with one agent may demonstrate cross sensitivity with another aminoglycoside.

    Geriatric

    Patients with renal insufficiency may develop toxic neomycin blood levels unless doses are properly adjusted and monitored. Since geriatric patients may have reduced renal function which may not be evident in the results of routine screening tests such as BUN or serum creatinine, a creatinine clearance determination may be more useful in adjusting dosages. Geriatric patients may be particularly susceptible to ototoxic, vestibular, neurotoxic and nephrotoxic adverse effects. Serial, vestibular, and audiometric tests, as well as tests of renal function, should be performed, especially in high-risk patients such as the elderly. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, use of antibiotics should be limited to confirmed or suspected bacterial infections. Antibiotics are non-selective and may result in the eradication of beneficial microorganisms while promoting the emergence of undesired ones, causing secondary infections such as oral thrush, colitis, or vaginitis. Any antibiotic may cause diarrhea, nausea, vomiting, anorexia, and hypersensitivity reactions.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / Incidence not known
    ototoxicity / Delayed / Incidence not known
    hearing loss / Delayed / Incidence not known
    azotemia / Delayed / Incidence not known
    hyposthenuria / Delayed / Incidence not known
    nephrotoxicity / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    renal tubular necrosis / Delayed / Incidence not known
    renal tubular acidosis (RTA) / Delayed / Incidence not known

    Moderate

    myasthenia / Delayed / Incidence not known
    neurotoxicity / Early / Incidence not known
    pyuria / Delayed / Incidence not known
    superinfection / Delayed / Incidence not known
    folate deficiency / Delayed / Incidence not known
    vitamin D deficiency / Delayed / Incidence not known
    vitamin B12 deficiency / Delayed / Incidence not known
    iron deficiency / Delayed / Incidence not known

    Mild

    tinnitus / Delayed / Incidence not known
    vertigo / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    maculopapular rash / Early / Incidence not known
    cylindruria / Delayed / Incidence not known
    nausea / Early / Incidence not known
    steatorrhea / Delayed / Incidence not known
    diarrhea / Early / Incidence not known
    vomiting / Early / Incidence not known
    vitamin B6 deficiency / Delayed / Incidence not known

    DRUG INTERACTIONS

    Alpha-glucosidase Inhibitors: (Minor) Neomycin increased the unpleasant gastrointestinal side-effects of acarbose. A similar reaction may be expected with miglitol. If such adverse effects are severe, the dosage of miglitol can be reduced during neomycin treatment.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Minor) Because the systemic absorption of neomycin is minimal, the risk of this interaction is expected to be low; however, the combined use of amphotericin B and systemic neomycin may increase the risk of nephrotoxicity or ototoxicity. Intensive monitoring of renal function is recommended. Amphotericin B dosage reduction may be necessary if renal impairment occurs.
    Amphotericin B lipid complex (ABLC): (Minor) Because the systemic absorption of neomycin is minimal, the risk of this interaction is expected to be low; however, the combined use of amphotericin B and systemic neomycin may increase the risk of nephrotoxicity or ototoxicity. Intensive monitoring of renal function is recommended. Amphotericin B dosage reduction may be necessary if renal impairment occurs.
    Amphotericin B liposomal (LAmB): (Minor) Because the systemic absorption of neomycin is minimal, the risk of this interaction is expected to be low; however, the combined use of amphotericin B and systemic neomycin may increase the risk of nephrotoxicity or ototoxicity. Intensive monitoring of renal function is recommended. Amphotericin B dosage reduction may be necessary if renal impairment occurs.
    Amphotericin B: (Minor) Because the systemic absorption of neomycin is minimal, the risk of this interaction is expected to be low; however, the combined use of amphotericin B and systemic neomycin may increase the risk of nephrotoxicity or ototoxicity. Intensive monitoring of renal function is recommended. Amphotericin B dosage reduction may be necessary if renal impairment occurs.
    Bacitracin: (Minor) Additive nephrotoxicity may occur with concurrent use of bacitracin and other nephrotoxic agents. When possible, avoid concomitant administration of systemic bacitracin and other nephrotoxic drugs such as aminoglycosides (particularly kanamycin, streptomycin, and neomycin).Use of topically administrated preparations containing bacitracin, especially when applied to large surface areas, with aminoglycosides may have additive nephrotoxic potential.
    Beractant: (Major) Some surfactant antiinfective mixtures have been shown to affect the in vivo activity of exogenous pulmonary surfactants when they are administered via inhalation.
    Botulinum Toxins: (Minor) The effects of botulinum toxin can be potentiated by systemic aminoglycosides or other drugs that interfere with neuromuscular transmission. However, neomycin oral and topical products are not well absorbed systemically; interactions are not expected.
    Calfactant: (Major) Some surfactant antiinfective mixtures have been shown to affect the in vivo activity of exogenous pulmonary surfactants when they are administered via inhalation.
    Colfosceril; Cetyl Alcohol; Tyloxapol: (Major) Some surfactant antiinfective mixtures have been shown to affect the in vivo activity of exogenous pulmonary surfactants when they are administered via inhalation.
    Cyanocobalamin, Vitamin B12: (Minor) Oral neomycin has been shown to inhibit the gastrointestinal absorption of cyanocobalamin, Vitamin B12. Caution is warranted with concomitant use.
    Cyclosporine: (Minor) Because the systemic absorption of neomycin is minimal, the risk of this interaction is expected to be low; however, the combined use of cyclosporine and systemic neomycin may increase the risk of nephrotoxicity or ototoxicity.
    Dienogest; Estradiol valerate: (Moderate) Anti-infectives that disrupt the normal GI flora, including neomycin, may potentially decrease the effectiveness of estrogen-containing oral contraceptives.
    Digoxin: (Moderate) Large doses of neomycin have been reported to reduce the absorption of digoxin leading to reduced steady-state digoxin concentrations of 28%. It is thought that the decrease in digoxin absorption is due to alterations in the properties of the gut wall. Therefore, separating the time of administration between these drugs and digoxin will probably not reduce the potential interaction. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of neomycin. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
    Enflurane: (Minor) Halogenated anesthetics may be associated with enhanced neuromuscular blocking effects. Many pharmacy references mention neuromuscular blockade as an adverse reaction of aminoglycoside antibiotics, however, it appears this is only seen when aminoglycosides are used to irrigate the abdominal cavity during surgery, a practice which has been discouraged. It is believed that this problem is less likely to occur with parenteral aminoglycoside therapy since patients are exposed to smaller amounts of drug. Nevertheless, patients receiving halogenated anesthetics should be observed for exaggerated effects if they are receiving aminoglycosides.
    Estradiol Cypionate; Medroxyprogesterone: (Moderate) Anti-infectives which disrupt the normal GI flora, including neomycin, may potentially decrease the effectiveness of estrogen containing oral contraceptives. Alternative or additional contraception may be advisable.
    Estradiol: (Moderate) Anti-infectives that disrupt the normal GI flora, including neomycin, may potentially decrease the effectiveness of estrogen-containing oral contraceptives. (Moderate) Anti-infectives which disrupt the normal GI flora, including neomycin, may potentially decrease the effectiveness of estrogen containing oral contraceptives. Alternative or additional contraception may be advisable.
    Fluorouracil, 5-FU: (Moderate) Oral neomycin has been shown to inhibit the gastrointestinal absorption of fluorouracil, 5-FU. Caution is warranted with concomitant use.
    Lactulose: (Moderate) Antibiotics that reduce colonic flora theoretically interfere with the biological conversion of lactulose to its active, acidic products. Since neomycin is also used in the treatment of hepatic encephalopathy, concomitant use may interfere with the effectiveness of lactulose. Patients taking both drugs concurrently should be monitored for the possibility of a decreased response to lactulose.
    Methotrexate: (Moderate) Oral neomycin has been shown to inhibit the gastrointestinal absorption of methotrexate. Caution is warranted with concomitant use.
    Nonsteroidal antiinflammatory drugs: (Minor) It is possible that additive nephrotoxicity may occur in patients who receive NSAIDs concurrently with other nephrotoxic agents, such as aminoglycosides.
    Oral Contraceptives: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Penicillin V: (Minor) Oral neomycin has been shown to reduce the bioavailability of oral penicillin V.
    Poractant Alfa: (Major) Some surfactant antiinfective mixtures have been shown to affect the in vivo activity of exogenous pulmonary surfactants when they are administered via inhalation.
    Regorafenib: (Major) Avoid coadministration of neomycin and regorafenib if possible, due to decreased efficacy of regorafenib. A clinically meaningful effect on the mean AUC of regorafenib was not observed when neomycin (1 gram PO three times daily for 5 days), a non-absorbable antibiotic, was administered to healthy men (n = 27) followed by a single dose of regorafenib (160 mg); however, the AUC of active metabolites M-2 and M-5 was decreased by 76% and 86%, respectively.
    Sorafenib: (Major) Concomitant administration of oral neomycin and sorafenib resulted in a decrease in sorafenib concentrations. The AUC of sorafenib was decreased by 54% in healthy volunteers who first received neomycin 1 gm by mouth three times daily for 5 days. Coadministration of these agents should be done with caution.
    Surfactants: (Major) Some surfactant antiinfective mixtures have been shown to affect the in vivo activity of exogenous pulmonary surfactants when they are administered via inhalation.
    Warfarin: (Moderate) Oral administration of neomycin inhibits vitamin K-synthesizing intestinal bacteria and can potentiate the effects of warfarin.

    PREGNANCY AND LACTATION

    Pregnancy

    Neomycin crosses the placenta. Aminoglycosides are known to cause fetal nephrotoxicity and permanent ototoxicity in children whose mothers received them during pregnancy. Neomycin is classified as a FDA pregnancy risk category D drug and should not be used in pregnancy unless the potential benefit justifies the added risk to the fetus.

    The manufacturer of neomycin states that due to the potential for serious adverse reactions, a decision should be made whether to discontinue nursing or to discontinue neomycin while nursing. However, neomycin administered orally has minimal systemic absorption. If there were maternal systemic concentrations of neomycin, aminoglycosides are generally excreted into breast milk in low concentrations. Due to the fact that they are poorly absorbed from the gastrointestinal tract, aminoglycosides are not likely to cause adverse events in nursing infants. Several aminoglycosides are considered compatible with breast-feeding by the American Academy of Pediatrics (AAP). Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Neomycin is bactericidal in action. Similar to other aminoglycosides, it inhibits bacterial protein synthesis through irreversible binding to the 30 S ribosomal subunit of susceptible bacteria. Neomycin is actively transported into the bacterial cell where it binds to receptors present on the 30 S ribosomal subunit. This binding interferes with the initiation complex between the messenger RNA (mRNA) and the subunit. As a result, abnormal, nonfunctional proteins are formed due to misreading of the bacterial DNA. Eventually, susceptible bacteria die because of the lack of functional proteins.
     
    In the adjunctive treatment of hepatic encephalopathy or coma, neomycin is used to suppress bacteria in the gut that produce urease, an enzyme that breaks down urea into carbon dioxide (CO2) and ammonia (NH3). By inhibiting the growth of urease-producing bacteria, the amount of ammonia available for absorption from the gut is decreased, resulting in decreased serum and CSF levels and clinical improvement.
     
    Neomycin can form insoluble complexes with bile acids in the intestine. Small doses of neomycin reduce LDL. This mechanism of action is somewhat similar to that of the bile acid sequestrants.

    PHARMACOKINETICS

    Neomycin is used orally or topically. The small absorbed fraction is rapidly distributed in the tissues and excreted by the kidneys. The unabsorbed portion of neomycin (97%) is primarily excreted unchanged in feces. The amount of systemically absorbed neomycin transferred to the tissues increases cumulatively with repeated dosing with the kidneys as the primary excretory path. With repeated dosing, progressive accumulation also occurs in the inner ear. Release of tissue-bound neomycin occurs slowly over a period of several weeks after dosing has been discontinued. Protein binding is low (0—30%).

    Oral Route

    About 3% of an oral dose of neomycin is absorbed from the GI tract; GI obstruction can increase absorption. Growth of most intestinal bacteria is rapidly suppressed after oral administration, with suppression persisting for 48—72 hours.