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    Aminoglycoside Antibiotics
    Urinary Antibiotics and/or Sulfonamides

    BOXED WARNING

    Nephrotoxicity, renal disease, renal failure, renal impairment

    Closely monitor patients receiving systemic aminoglycosides, such as plazomicin, for nephrotoxicity. Assess creatinine clearance (CrCl) in all patients before plazomicin therapy and daily during therapy, particularly in those at increased risk of nephrotoxicity. In patients with pre-existing renal impairment, renal failure, or renal disease or in those with normal renal function who receive high doses or prolonged therapy, the risks of severe nephrotoxic adverse reactions are sharply increased. Elderly patients and those receiving concomitant nephrotoxic medications have a higher risk. Avoid concurrent and/or sequential coadministration of aminoglycosides with other drugs that are potentially nephrotoxic because toxicity may be additive. In the setting of worsening renal function, assess the benefit of continuing plazomicin therapy. Therapeutic drug monitoring is recommended for all patients with a CrCl less than 90 mL/minute. The incidence of nephrotoxicity was higher in plazomicin-treated patients compared to meropenem. Increases in serum creatinine of 0.5 mg/dL or more above baseline also occurred more frequently in plazomicin-treated patients vs. meropenem and occurred mainly in patients with a CrCl of 90 mL/minute or less and were associated with a plazomicin trough concentration of 3 mcg/mL or more. Aminoglycosides are associated with major toxic effects on renal tubules. Hemodialysis may aid in removal in the event of overdose or toxic reactions, especially if renal function is or becomes impaired. In rare cases, nephrotoxicity may not be evident until soon after completion of therapy. Aminoglycoside-induced nephrotoxicity usually is reversible.

    Hearing impairment, ototoxicity

    Closely monitor patients receiving systemic aminoglycosides, such as plazomicin, for ototoxicity and hearing impairment. Consider the benefit-risk of plazomicin therapy in patients with preexisting hearing impairment and in patients with a family history of hearing loss, especially eighth-cranial-nerve impairment. In patients with pre-existing renal impairment or renal disease or in those with normal renal function who receive high doses or prolonged therapy, the risks of severe ototoxic adverse reactions are sharply increased. Aminoglycosides are associated with major toxic effects on the auditory and vestibular branches of the eighth nerve. Toxicity is manifested 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. The risk of hearing loss increases with the degree of exposure and continues to progress after stopping the drug. Eighth cranial nerve function should be closely monitored. Aminoglycoside-induced ototoxicity is usually irreversible and may not be evident until after completion of therapy.

    Myasthenia gravis, neuromuscular blockade, neuromuscular disease

    Monitor for adverse reactions associated with neuromuscular blockade during plazomicin therapy, particularly in high-risk patients, such as patients with underlying neuromuscular disease (including myasthenia gravis) or in patients concomitantly receiving neuromuscular blocking agents. Systemic aminoglycosides, such as plazomicin, are associated with exacerbation of muscle weakness or delay in recovery of neuromuscular function in patients receiving concomitant neuromuscular blocking agents.

    Pregnancy

    Systemic exposure to plazomicin may cause fetal harm during human pregnancy. Aminoglycosides cross the placenta. There have been reports of total irreversible bilateral congenital deafness in newborns whose mothers received streptomycin, a related aminoglycoside, during pregnancy. If plazomicin is used during pregnancy or if the patient becomes pregnant during treatment with plazomicin, advise the mother of the potential risk to the fetus.

    DEA CLASS

    Rx

    DESCRIPTION

    Intravenous, aminoglycoside antibiotic
    Used for complicated urinary tract infections, including pyelonephritis, caused by certain Enterobacteriaceae in adults who have limited or no alternative treatment options
    Trough concentration monitoring recommended for patients with diminished renal function

    COMMON BRAND NAMES

    ZEMDRI

    HOW SUPPLIED

    ZEMDRI Intravenous Inj Sol: 1mL, 50mg

    DOSAGE & INDICATIONS

    For the treatment of complicated urinary tract infection (UTI), including pyelonephritis.
    NOTE: In patients with a total body weight (TBW) more than ideal body weight (IBW) by 25% or more, use adjusted body weight based on the following equation: Adjusted body weight = [(TBW - IBW) x 0.4] + IBW.
    Intravenous dosage
    Adults

    15 mg/kg IV every 24 hours for 4 to 7 days. An appropriate oral therapy may be considered after 4 to 7 days to complete a total duration of 7 to 10 days. The maximum duration for plazomicin is 7 days. Due to limited safety and efficacy data, reserve use for patients who have limited or no alternative treatment options.

    MAXIMUM DOSAGE

    Adults

    15 mg/kg/day IV.

    Geriatric

    15 mg/kg/day IV.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    NOTE: Calculate CrCl by the Cockcroft-Gault formula using total body weight (TBW). For patients with a TBW more than ideal body weight (IBW) by 25% or more, use IBW.
    NOTE: Subsequent dosage adjustments may be necessary based on change in renal function or therapeutic drug monitoring as appropriate.
    CrCl 60 mL/minute or more: No dosage adjustment needed.
    CrCl 30 to 59 mL/minute: 10 mg/kg IV every 24 hours.
    CrCl 15 to 29 mL/minute: 10 mg/kg IV every 48 hours.
    CrCl 14 mL/minute or less: There is insufficient information to recommend a dosage regimen.
     
    Intermittent hemodialysis
    There is insufficient information to recommend a dosage regimen in patients receiving hemodialysis.
     
    Continuous renal replacement therapy (CRRT)
    There is insufficient information to recommend a dosage regimen in patients receiving continuous renal replacement therapy.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Plazomicin is a clear, colorless to yellow solution.

    Intravenous Administration

    Dilution
    Withdraw the appropriate volume of solution (50 mg/mL) for the required dose from the plazomicin vial.
    Dilute in 0.9% Sodium Chloride Injection or Lactated Ringers Injection to achieve a final volume of 50 mL.
    Storage: Discard any unused portion of the plazomicin vial. The dilution may be stored at room temperature for 24 hours at concentrations of 2.5 to 45 mg/mL.
     
    Intermittent IV infusion
    Infuse over 30 minutes.

    STORAGE

    ZEMDRI:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Aminoglycoside hypersensitivity

    Plazomicin is contraindicated in patients with known aminoglycoside hypersensitivity. Serious and occasionally fatal hypersensitivity reactions have been reported with aminoglycosides. Cross-sensitivity among aminoglycosides has been established. Before starting plazomicin therapy, carefully inquire about any previous hypersensitivity reactions to other aminoglycosides. Discontinue plazomicin if an allergic reaction occurs.

    Nephrotoxicity, renal disease, renal failure, renal impairment

    Closely monitor patients receiving systemic aminoglycosides, such as plazomicin, for nephrotoxicity. Assess creatinine clearance (CrCl) in all patients before plazomicin therapy and daily during therapy, particularly in those at increased risk of nephrotoxicity. In patients with pre-existing renal impairment, renal failure, or renal disease or in those with normal renal function who receive high doses or prolonged therapy, the risks of severe nephrotoxic adverse reactions are sharply increased. Elderly patients and those receiving concomitant nephrotoxic medications have a higher risk. Avoid concurrent and/or sequential coadministration of aminoglycosides with other drugs that are potentially nephrotoxic because toxicity may be additive. In the setting of worsening renal function, assess the benefit of continuing plazomicin therapy. Therapeutic drug monitoring is recommended for all patients with a CrCl less than 90 mL/minute. The incidence of nephrotoxicity was higher in plazomicin-treated patients compared to meropenem. Increases in serum creatinine of 0.5 mg/dL or more above baseline also occurred more frequently in plazomicin-treated patients vs. meropenem and occurred mainly in patients with a CrCl of 90 mL/minute or less and were associated with a plazomicin trough concentration of 3 mcg/mL or more. Aminoglycosides are associated with major toxic effects on renal tubules. Hemodialysis may aid in removal in the event of overdose or toxic reactions, especially if renal function is or becomes impaired. In rare cases, nephrotoxicity may not be evident until soon after completion of therapy. Aminoglycoside-induced nephrotoxicity usually is reversible.

    Hearing impairment, ototoxicity

    Closely monitor patients receiving systemic aminoglycosides, such as plazomicin, for ototoxicity and hearing impairment. Consider the benefit-risk of plazomicin therapy in patients with preexisting hearing impairment and in patients with a family history of hearing loss, especially eighth-cranial-nerve impairment. In patients with pre-existing renal impairment or renal disease or in those with normal renal function who receive high doses or prolonged therapy, the risks of severe ototoxic adverse reactions are sharply increased. Aminoglycosides are associated with major toxic effects on the auditory and vestibular branches of the eighth nerve. Toxicity is manifested 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. The risk of hearing loss increases with the degree of exposure and continues to progress after stopping the drug. Eighth cranial nerve function should be closely monitored. Aminoglycoside-induced ototoxicity is usually irreversible and may not be evident until after completion of therapy.

    Myasthenia gravis, neuromuscular blockade, neuromuscular disease

    Monitor for adverse reactions associated with neuromuscular blockade during plazomicin therapy, particularly in high-risk patients, such as patients with underlying neuromuscular disease (including myasthenia gravis) or in patients concomitantly receiving neuromuscular blocking agents. Systemic aminoglycosides, such as plazomicin, are associated with exacerbation of muscle weakness or delay in recovery of neuromuscular function in patients receiving concomitant neuromuscular blocking agents.

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

    Almost all antibacterial agents, such as plazomicin, 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 occur when normal flora is altered subsequent to antibacterial administration. The toxin produced by Clostridium difficile is a primary cause of pseudomembranous colitis. Consider pseudomembranous colitis as a potential diagnosis in patients presenting with diarrhea after antibacterial administration. Systemic antibiotics should be prescribed with caution to patients with inflammatory bowel disease such as ulcerative colitis or other GI disease. If C. difficile-associated diarrhea is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte concentrations as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated. Practitioners should be aware that antibiotic-associated colitis has been observed to occur over 2 months or more after discontinuation of systemic antibiotic therapy; a careful medical history should be taken.

    Geriatric

    Geriatric patients may be at increased risk of plazomicin nephrotoxicity. Elderly patients may have decreased renal function; therefore, care should be taken in dose selection and plazomicin monitoring during therapy. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, use of parenteral aminoglycosides must be accompanied by monitoring of renal function tests, including a baseline value, and serum aminoglycoside concentrations, with the exception of single dose prophylactic administration. Serious consequences may occur insidiously if adequate monitoring does not occur; the drug may cause or worsen hearing loss and renal failure. 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.

    Pregnancy

    Systemic exposure to plazomicin may cause fetal harm during human pregnancy. Aminoglycosides cross the placenta. There have been reports of total irreversible bilateral congenital deafness in newborns whose mothers received streptomycin, a related aminoglycoside, during pregnancy. If plazomicin is used during pregnancy or if the patient becomes pregnant during treatment with plazomicin, advise the mother of the potential risk to the fetus.

    Breast-feeding

    There are no data on the presence of plazomicin in human breast milk, the effects on the breast-fed infant, or on milk production. Plazomicin was detected in rat milk. Consider the benefits of breast-feeding along with the mother's clinical need for plazomicin and any potential adverse effects on the breast-fed infant from plazomicin or the underlying maternal condition. Aminoglycosides are generally excreted into human breast milk in low concentrations. However, aminoglycosides are poorly absorbed from the gastrointestinal tract and are not likely to cause adverse events in nursing infants; thus, aminoglycosides are generally considered compatible with breast-feeding.

    ADVERSE REACTIONS

    Severe

    renal failure (unspecified) / Delayed / 3.6-3.6
    nephrotoxicity / Delayed / Incidence not known
    renal tubular acidosis (RTA) / Delayed / Incidence not known
    renal tubular necrosis / Delayed / Incidence not known
    hearing loss / Delayed / Incidence not known
    ototoxicity / Delayed / Incidence not known

    Moderate

    hypertension / Early / 2.3-2.3
    hypotension / Rapid / 1.0-1.0
    constipation / Delayed / Incidence not known
    gastritis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hypokalemia / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    pseudomembranous colitis / Delayed / Incidence not known

    Mild

    diarrhea / Early / 2.3-2.3
    nausea / Early / 1.3-1.3
    vomiting / Early / 1.3-1.3
    headache / Early / 1.3-1.3
    tinnitus / Delayed / 0.3-0.3
    vertigo / Early / Incidence not known
    weakness / Early / Incidence not known
    dizziness / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Acetaminophen; Diphenhydramine: (Minor) Diphenhydramine may mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Acyclovir: (Major) Additive nephrotoxicity is possible if systemic aminoglycosides are used with acyclovir. Carefully monitor renal function during concomitant therapy.
    Adefovir: (Moderate) Chronic coadministration of adefovir with nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity, even in patients who have normal renal function.
    Aldesleukin, IL-2: (Moderate) Aldesleukin, IL 2 may cause nephrotoxicity. Concurrent administration of drugs possessing nephrotoxic effects, such as the aminoglycosides, with Aldesleukin, IL 2 may increase the risk of kidney dysfunction. In addition, reduced kidney function secondary to Aldesleukin, IL 2 treatment may delay elimination of concomitant medications and increase the risk of adverse events from those drugs.
    Aminosalicylate sodium, Aminosalicylic acid: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Aprotinin: (Moderate) The manufacturer recommends using aprotinin cautiously in patients that are receiving drugs that can affect renal function, such as the aminoglycosides, as the risk of renal impairment may be increased.
    Aspirin, ASA: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Aspirin, ASA; Butalbital; Caffeine: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Aspirin, ASA; Carisoprodol: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Aspirin, ASA; Carisoprodol; Codeine: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Aspirin, ASA; Dipyridamole: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Aspirin, ASA; Omeprazole: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Aspirin, ASA; Oxycodone: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Aspirin, ASA; Pravastatin: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Atracurium: (Moderate) Aminoglycosides traditionally have been associated with neuromuscular blockade, but this event is most likely to occur when aminoglycoside solutions are used to irrigate wounds intraoperatively. Neuromuscular blockers should be used cautiously in patients receiving aminoglycosides.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Minor) Antiemetics, like scopolamine, should be used carefully with amikacin because they can mask symptoms of ototoxicity (e.g., nausea secondary to vertigo). These agents block the histamine or acetylcholine response that causes nausea due to vestibular (inner ear) emetic stimuli such as motion.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Bismuth Subsalicylate: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Bleomycin: (Moderate) Previous treatment with nephrotoxic agents, like aminoglycosides, may result in decreased clearance of bleomycin if renal function has been impaired.
    Bumetanide: (Moderate) The risk of ototoxicity or nephrotoxicity secondary to aminoglycosides may be increased by the addition of concomitant therapies with similar side effects, including loop diuretics. If loop diuretics and aminoglycosides are used together, it would be prudent to monitor renal function parameters, serum electrolytes, and serum aminoglycoside concentrations during therapy. Audiologic monitoring may be advisable during high dose therapy or therapy of long duration, when hearing loss is suspected, or in selected risk groups (e.g., neonates).
    Capreomycin: (Major) The concomitant use of capreomycin and aminoglycosides may increase the risk of nephrotoxicity and neurotoxicity. Since capreomycin is eliminated by the kidney, coadministration of capreomycin with other potentially nephrotoxic drugs, including aminoglycosides may increase serum concentrations of either capreomycin or aminoglycosides. Theoretically, coadministration may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered. Additionally, neuromuscular blockade has been associated with capreomycin resulting from administration of large doses or rapid intravenous infusion. Aminoglycosides have also been reported to interfere with nerve transmission at the neuromuscular junction. Concomitant administration of capreomycin with aminoglycosides should be avoided if possible; however, if they must be coadministered, use extreme caution.
    Carbetapentane; Chlorpheniramine: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Minor) Diphenhydramine may mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Carboplatin: (Moderate) Patients previously or currently treated with other potentially nephrotoxic agents, such as systemic aminoglycosides, can have a greater risk of developing carboplatin-induced nephrotoxicity. These patients may benefit from hydration prior to carboplatin therapy to lessen the incidence of nephrotoxicity. Monitor renal function closely.
    Cefepime: (Minor) Cefepime's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides and loop diuretics. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Cefotaxime: (Minor) Cefotaxime's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides and loop diuretics. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Cefotetan: (Minor) Cefotetan's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Cefoxitin: (Minor) Cefoxitin's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Cefprozil: (Minor) Cefprozil's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides and loop diuretics. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Ceftazidime: (Minor) Ceftazidime's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides and loop diuretics. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Ceftazidime; Avibactam: (Minor) Ceftazidime's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides and loop diuretics. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Ceftizoxime: (Minor) Ceftizoxime's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Cefuroxime: (Minor) Cefuroxime's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides and loop diuretics. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Chlorpheniramine: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Chlorpheniramine; Codeine: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Chlorpheniramine; Dextromethorphan: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Chlorpheniramine; Hydrocodone: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Chlorpheniramine; Phenylephrine: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Chlorpheniramine; Pseudoephedrine: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Chlorpromazine: (Minor) When used for the treatment of nausea and vomiting, antiemetic phenothiazines may effectively mask symptoms that are associated with ototoxicity induced by the aminoglycosides.
    Choline Salicylate; Magnesium Salicylate: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Cidofovir: (Severe) The administration of cidofovir with other potentially nephrotoxic agents, such as aminoglycosides, is contraindicated. These agents should be discontinued at least 7 days prior to beginning cidofovir.
    Cisatracurium: (Moderate) Aminoglycosides traditionally have been associated with neuromuscular blockade, but this event is most likely to occur when aminoglycoside solutions are used to irrigate wounds intraoperatively. Neuromuscular blockers should be used cautiously in patients receiving aminoglycosides.
    Cisplatin: (Major) Aminoglycosides should be used cautiously in patients receiving cisplatin. Aminoglycosides can aggravate the nephrotoxicity and electrolyte loss seen with cisplatin if given concurrently or shortly after cisplatin therapy. Concurrent use of cisplatin and other nephrotoxic agents also known to be ototoxic (i.e., aminoglycosides) may increase the risk of cisplatin-induced ototoxicity.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
    Codeine; Phenylephrine; Promethazine: (Minor) Antiemetics, like promethazine, should be used carefully with aminoglycosides because they can mask symptoms of ototoxicity (e.g., nausea secondary to vertigo). These agents block the histamine or acetylcholine response that causes nausea due to vestibular (inner ear) emetic stimuli such as motion.
    Codeine; Promethazine: (Minor) Antiemetics, like promethazine, should be used carefully with aminoglycosides because they can mask symptoms of ototoxicity (e.g., nausea secondary to vertigo). These agents block the histamine or acetylcholine response that causes nausea due to vestibular (inner ear) emetic stimuli such as motion.
    Cyclizine: (Minor) Cyclizine may effectively mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Deferasirox: (Moderate) Acute renal failure has been reported during treatment with deferasirox. Coadministration of deferasirox with other potentially nephrotoxic drugs, including aminoglycosides, may increase the risk of this toxicity. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and aminoglycosides concomitantly.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) Diphenhydramine may mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Dextromethorphan; Promethazine: (Minor) Antiemetics, like promethazine, should be used carefully with aminoglycosides because they can mask symptoms of ototoxicity (e.g., nausea secondary to vertigo). These agents block the histamine or acetylcholine response that causes nausea due to vestibular (inner ear) emetic stimuli such as motion.
    Dimenhydrinate: (Minor) Dimenhydrinate and other antiemetics should be used carefully with aminoglycosides because they can mask symptoms of ototoxicity, including nausea secondary to vertigo.
    Diphenhydramine: (Minor) Diphenhydramine may mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Minor) Diphenhydramine may mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Diphenhydramine; Ibuprofen: (Minor) Diphenhydramine may mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Diphenhydramine; Naproxen: (Minor) Diphenhydramine may mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Diphenhydramine; Phenylephrine: (Minor) Diphenhydramine may mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
    Doxacurium: (Moderate) Aminoglycosides traditionally have been associated with neuromuscular blockade, but this event is most likely to occur when aminoglycoside solutions are used to irrigate wounds intraoperatively. Neuromuscular blockers should be used cautiously in patients receiving aminoglycosides.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
    Entecavir: (Moderate) Because entecavir is primarily eliminated by the kidneys and aminoglycosides can affect renal function, concurrent administration with aminoglycosides may increase the serum concentrations of entecavir and adverse events. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Ethacrynic Acid: (Moderate) The risk of ototoxicity or nephrotoxicity secondary to aminoglycosides may be increased by the addition of concomitant therapies with similar side effects, including loop diuretics. If loop diuretics and aminoglycosides are used together, it would be prudent to monitor renal function parameters, serum electrolytes, and serum aminoglycoside concentrations during therapy. Audiologic monitoring may be advisable during high dose therapy or therapy of long duration, when hearing loss is suspected, or in selected risk groups (e.g., neonates).
    Fluphenazine: (Minor) When used for the treatment of nausea and vomiting, antiemetic phenothiazines may effectively mask symptoms that are associated with ototoxicity induced by aminoglycosides.
    Foscarnet: (Major) The risk of renal toxicity may be increased if foscarnet is used in conjunction with other nephrotoxic agents such as aminoglycosides.
    Furosemide: (Moderate) The risk of ototoxicity or nephrotoxicity secondary to aminoglycosides may be increased by the addition of concomitant therapies with similar side effects, including loop diuretics. If loop diuretics and aminoglycosides are used together, it would be prudent to monitor renal function parameters, serum electrolytes, and serum aminoglycoside concentrations during therapy. Audiologic monitoring may be advisable during high dose therapy or therapy of long duration, when hearing loss is suspected, or in selected risk groups (e.g., neonates).
    Gallium Ga 68 Dotatate: (Major) Avoid concomitant use of mannitol and aminoglycosides, if possible. Concomitant administration of systemic therapy may increase the risk of ototoxicity and nephrotoxicity. In addition, systemic mannitol may alter the serum and tissue concentrations of aminoglycosides and increase the risk for aminoglycoside toxicity. If use together is necessary, monitor renal function and serum aminoglycoside concentrations. Audiologic monitoring may be advisable during high dose therapy or therapy of long duration, when hearing loss is suspected, or in selected risk groups (e.g., neonates). Studies to evaluate a potential interaction between inhaled formulations of mannitol and tobramycin have not been conducted.
    Gallium: (Severe) Concurrent use of gallium nitrate with other potentially nephrotoxic drugs, such as aminoglycosides, may increase the risk for developing severe renal insufficiency. If use of an aminoglycoside is indicated, gallium nitrate administration should be discontinued, and hydration for several days after administration of the aminoglycoside is recommended. Serum creatinine concentrations and urine output should be closely monitored during and subsequent to this period. Gallium nitrate should be discontinued if the serum creatinine concentration exceeds 2.5 mg/dl.
    Ganciclovir: (Major) Concurrent use of nephrotoxic agents, such as the aminoglycosides, with ganciclovir should be done cautiously to avoid additive nephrotoxicity.
    Ginger, Zingiber officinale: (Minor) Ginger may mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Gold: (Minor) Both aminoglycosides and gold compounds can cause nephrotoxicity. Auranofin has been reported to cause a nephrotic syndrome or glomerulonephritis with proteinuria and hematuria. Monitor renal function carefully during concurrent therapy.
    Hyaluronidase, Recombinant; Immune Globulin: (Moderate) Immune globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like aminoglycosides. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Closely monitor renal function.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Ibandronate: (Moderate) Theoretically, coadministration of intravenous ibandronate with other potentially nephrotoxic drugs like the aminoglycosides may increase the risk of developing nephrotoxicity.
    Ibuprofen lysine: (Moderate) Use caution in combining ibuprofen lysine with renally eliminated medications, like aminoglycosides, as ibuprofen lysine may reduce the clearance of aminoglycosides. Closely monitor renal function and adjust aminoglycoside doses based on renal function and serum aminoglycoside concentrations as clinically indicated.
    Immune Globulin IV, IVIG, IGIV: (Moderate) Immune globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like aminoglycosides. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Closely monitor renal function.
    Inotersen: (Moderate) Use caution with concomitant use of inotersen and aminoglycosides due to the risk of glomerulonephritis and nephrotoxicity.
    Iohexol: (Moderate) Because the use of other nephrotoxic drugs, such as aminoglycoside antibiotics, is an additive risk factor for nephrotoxicity in patients receiving radiopaque contrast agents, concomitant use should be avoided when possible.
    Iopamidol: (Moderate) Because the use of other nephrotoxic drugs, such as aminoglycoside antibiotics, is an additive risk factor for nephrotoxicity in patients receiving radiopaque contrast agents, concomitant use should be avoided when possible.
    Iopromide: (Moderate) Because the use of other nephrotoxic drugs, such as aminoglycoside antibiotics, is an additive risk factor for nephrotoxicity in patients receiving radiopaque contrast agents, concomitant use should be avoided when possible.
    Ioversol: (Moderate) Because the use of other nephrotoxic drugs, such as aminoglycoside antibiotics, is an additive risk factor for nephrotoxicity in patients receiving radiopaque contrast agents, concomitant use should be avoided when possible.
    Isosulfan Blue: (Moderate) Because the use of other nephrotoxic drugs, such as aminoglycoside antibiotics, is an additive risk factor for nephrotoxicity in patients receiving radiopaque contrast agents, concomitant use should be avoided when possible.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
    Magnesium Salicylate: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Mannitol: (Major) Avoid concomitant use of mannitol and aminoglycosides, if possible. Concomitant administration of systemic therapy may increase the risk of ototoxicity and nephrotoxicity. In addition, systemic mannitol may alter the serum and tissue concentrations of aminoglycosides and increase the risk for aminoglycoside toxicity. If use together is necessary, monitor renal function and serum aminoglycoside concentrations. Audiologic monitoring may be advisable during high dose therapy or therapy of long duration, when hearing loss is suspected, or in selected risk groups (e.g., neonates). Studies to evaluate a potential interaction between inhaled formulations of mannitol and tobramycin have not been conducted.
    Meclizine: (Minor) Meclizine and other antiemetics should be used carefully with aminoglycosides because they can mask symptoms of ototoxicity (e.g., nausea secondary to vertigo).
    Meperidine; Promethazine: (Minor) Antiemetics, like promethazine, should be used carefully with aminoglycosides because they can mask symptoms of ototoxicity (e.g., nausea secondary to vertigo). These agents block the histamine or acetylcholine response that causes nausea due to vestibular (inner ear) emetic stimuli such as motion.
    Mesoridazine: (Minor) When used for the treatment of nausea and vomiting, antiemetic phenothiazines may effectively mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by various medications, including the aminoglycosides.
    Mivacurium: (Moderate) Aminoglycosides traditionally have been associated with neuromuscular blockade, but this event is most likely to occur when aminoglycoside solutions are used to irrigate wounds intraoperatively. Neuromuscular blockers should be used cautiously in patients receiving aminoglycosides.
    Neuromuscular blockers: (Moderate) Aminoglycosides traditionally have been associated with neuromuscular blockade, but this event is most likely to occur when aminoglycoside solutions are used to irrigate wounds intraoperatively. Neuromuscular blockers should be used cautiously in patients receiving aminoglycosides.
    Non-Ionic Contrast Media: (Moderate) Because the use of other nephrotoxic drugs, such as aminoglycoside antibiotics, is an additive risk factor for nephrotoxicity in patients receiving radiopaque contrast agents, concomitant use should be avoided when possible.
    Oral Contraceptives: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in 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 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 concentrations of OCs. 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 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.
    Pamidronate: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
    Pancuronium: (Moderate) Aminoglycosides traditionally have been associated with neuromuscular blockade, but this event is most likely to occur when aminoglycoside solutions are used to irrigate wounds intraoperatively. Neuromuscular blockers should be used cautiously in patients receiving aminoglycosides.
    Pentamidine: (Major) Additive nephrotoxicity may be seen with the combination of pentamidine and other agents that cause nephrotoxicity, such as systemic aminoglycosides. Renal function and aminoglycoside concentratons should be closely monitored.
    Perphenazine: (Minor) When used for the treatment of nausea and vomiting, antiemetic phenothiazines may effectively mask symptoms that are associated with ototoxicity induced by the aminoglycosides.
    Perphenazine; Amitriptyline: (Minor) When used for the treatment of nausea and vomiting, antiemetic phenothiazines may effectively mask symptoms that are associated with ototoxicity induced by the aminoglycosides.
    Phenylephrine; Promethazine: (Minor) Antiemetics, like promethazine, should be used carefully with aminoglycosides because they can mask symptoms of ototoxicity (e.g., nausea secondary to vertigo). These agents block the histamine or acetylcholine response that causes nausea due to vestibular (inner ear) emetic stimuli such as motion.
    Polymyxin B: (Major) The concomitant use of systemic Polymyxin B with systemic aminoglycosides increases the risk of nephrotoxicity, ototoxicity, and neurotoxicity. Since polymyxins and aminoglycosides are both eliminated by the kidney, coadministration may increase serum concentrations of either drug class. Monitor patients for changes in renal function if these drugs are coadministered. Additionally, neuromuscular blockade has been associated with both polymyxins and aminoglycosides, and is more likely to occur in patients with renal dysfunction.
    Polymyxins: (Major) The concomitant use of colistimethate sodium with systemic aminoglycosides may increase the risk of nephrotoxicity, ototoxicity, and neurotoxicity. Since polymyxins and aminoglycosides are both eliminated by the kidney, coadministration may increase serum concentrations of either drug class. If these drugs are used in combination, monitor renal function and patients for increased adverse effects. Additionally, neuromuscular blockade has been associated with both polymyxins and aminoglycosides, and is more likely to occur in patients with renal dysfunction.
    Promethazine: (Minor) Antiemetics, like promethazine, should be used carefully with aminoglycosides because they can mask symptoms of ototoxicity (e.g., nausea secondary to vertigo). These agents block the histamine or acetylcholine response that causes nausea due to vestibular (inner ear) emetic stimuli such as motion.
    Pyridostigmine: (Moderate) Aminoglycosides have been associated with neuromuscular blockade when used as an abdominal irrigant intraoperatively. Although the risk of neuromuscular blockade is remote with parenteral aminoglycoside therapy, these antibiotics should be used cautiously in myasthenic patients. This represents a pharmacodynamic interaction with cholinesterase inhibitors when used to treat myasthenia gravis, rather than a pharmacokinetic interaction.
    Rapacuronium: (Moderate) Aminoglycosides traditionally have been associated with neuromuscular blockade, but this event is most likely to occur when aminoglycoside solutions are used to irrigate wounds intraoperatively. Neuromuscular blockers should be used cautiously in patients receiving aminoglycosides.
    Rocuronium: (Moderate) Aminoglycosides traditionally have been associated with neuromuscular blockade, but this event is most likely to occur when aminoglycoside solutions are used to irrigate wounds intraoperatively. Neuromuscular blockers should be used cautiously in patients receiving aminoglycosides.
    Salicylates: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Salsalate: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
    Scopolamine: (Minor) Antiemetics, like scopolamine, should be used carefully with amikacin because they can mask symptoms of ototoxicity (e.g., nausea secondary to vertigo). These agents block the histamine or acetylcholine response that causes nausea due to vestibular (inner ear) emetic stimuli such as motion.
    Streptozocin: (Moderate) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents, including aminoglycosides, could exacerbate the renal insult.
    Succinylcholine: (Moderate) Aminoglycosides traditionally have been associated with neuromuscular blockade, but this event is most likely to occur when aminoglycoside solutions are used to irrigate wounds intraoperatively. Neuromuscular blockers should be used cautiously in patients receiving aminoglycosides.
    Tacrolimus: (Moderate) Additive nephrotoxicity is possible if aminoglycosides are used with tacrolimus. Care should be taken in using tacrolimus with other nephrotoxic drugs. Assessment of renal function in patients who have received tacrolimus is recommended, as the tacrolimus dosage may need to be reduced
    Telavancin: (Major) Concurrent or sequential use of telavancin with other potentially nephrotoxic drugs (e.g., systemic aminoglycosides) may lead to additive nephrotoxicity. Televancin is closely related to vancomycin. In one clinical study, vancomycin coadministration, high aminoglycoside trough levels, and heart failure independently predicted acute kidney injury during aminoglycoside treatment. Closely monitor renal function and adjust telavancin doses based on creatinine clearance/renal function, and aminoglycoside doses based on renal function and serum aminoglycoside concentrations as clinically indicated.
    Tenofovir Alafenamide: (Moderate) Tenofovir-containing products, should be avoided with concurrent or recent use of a nephrotoxic agent, such as aminoglycosides. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Tenofovir, PMPA: (Moderate) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
    Thioridazine: (Minor) When used for the treatment of nausea and vomiting, antiemetic phenothiazines may effectively mask vestibular symptoms that are associated with ototoxicity induced by various medications, including the aminoglycosides.
    Torsemide: (Moderate) The risk of ototoxicity or nephrotoxicity secondary to aminoglycosides may be increased by the addition of concomitant therapies with similar side effects, including loop diuretics. If loop diuretics and aminoglycosides are used together, it would be prudent to monitor renal function parameters, serum electrolytes, and serum aminoglycoside concentrations during therapy. Audiologic monitoring may be advisable during high dose therapy or therapy of long duration, when hearing loss is suspected, or in selected risk groups (e.g., neonates).
    Trifluoperazine: (Minor) When used for the treatment of nausea and vomiting, antiemetic phenothiazines may mask symptoms that are associated with ototoxicity induced by the aminoglycosides.
    Trimethobenzamide: (Minor) Because of trimethobenzamide's antiemetic pharmacology, the drug may effectively mask dizziness, tinnitus, or vertigo that are associated with ototoxicity induced by various medications, including the aminoglycosides. Clinicians should be aware of this potential interaction and take it into consideration when monitoring for aminoglycoside-induced side effects.
    Tubocurarine: (Moderate) Aminoglycosides traditionally have been associated with neuromuscular blockade, but this event is most likely to occur when aminoglycoside solutions are used to irrigate wounds intraoperatively. Neuromuscular blockers should be used cautiously in patients receiving aminoglycosides.
    Urea: (Moderate) The risk of ototoxicity or nephrotoxicity secondary to aminoglycosides may be increased by the addition of concomitant therapies with similar side effects, including urea. In addition, urea may alter the serum and tissue concentrations of tobramycin, thereby, increasing the risk for aminoglycoside toxicities. If possible, avoid concurrent use. If these drugs must be used together, it would be prudent to monitor renal function, serum electrolytes, and serum aminoglycoside concentrations. Audiologic monitoring may be advisable during high dose therapy or therapy of long duration, when hearing loss is suspected, or in selected risk groups (e.g., neonates).
    Valganciclovir: (Major) Concurrent use of nephrotoxic agents, such as aminoglycosides, with valganciclovir should be done cautiously to avoid additive nephrotoxicity.
    Vancomycin: (Major) Concomitant use of parenteral vancomycin with other nephrotoxic drugs, such as aminoglycosides, can lead to additive nephrotoxicity. Both vancomycin and aminoglycosides may cause ototoxicity as well. In a clinical study, vancomycin coadministration, high aminoglycoside trough concentrations, and heart failure independently predicted acute kidney injury during aminoglycoside treatment. Renal function should be monitored closely, and vancomycin and aminoglycoside doses should be adjusted according to serum concentrations as clinically indicated.
    Vecuronium: (Moderate) Aminoglycosides traditionally have been associated with neuromuscular blockade, but this event is most likely to occur when aminoglycoside solutions are used to irrigate wounds intraoperatively. Neuromuscular blockers should be used cautiously in patients receiving aminoglycosides.
    Zalcitabine, ddC: (Moderate) Drugs such as parenteral aminoglycosides may increase the risk of developing peripheral neuropathy or other zalcitabine-associated adverse events by interfering with the renal clearance of zalcitabine and thereby raising systemic drug exposure. Coadministration of these drugs with zalcitabine requires frequent clinical and laboratory monitoring, with dosage adjustment for any significant change in renal function.
    Zoledronic Acid: (Moderate) Since zoledronic acid is eliminated by the kidney, coadministration of zoledronic acid with other potentially nephrotoxic drugs may increase serum concentrations of either zoledronic acid and/or these coadministered drugs. Theoretically, the chronic coadministration of zoledronic acid with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity.

    PREGNANCY AND LACTATION

    Pregnancy

    Systemic exposure to plazomicin may cause fetal harm during human pregnancy. Aminoglycosides cross the placenta. There have been reports of total irreversible bilateral congenital deafness in newborns whose mothers received streptomycin, a related aminoglycoside, during pregnancy. If plazomicin is used during pregnancy or if the patient becomes pregnant during treatment with plazomicin, advise the mother of the potential risk to the fetus.

    There are no data on the presence of plazomicin in human breast milk, the effects on the breast-fed infant, or on milk production. Plazomicin was detected in rat milk. Consider the benefits of breast-feeding along with the mother's clinical need for plazomicin and any potential adverse effects on the breast-fed infant from plazomicin or the underlying maternal condition. Aminoglycosides are generally excreted into human breast milk in low concentrations. However, aminoglycosides are poorly absorbed from the gastrointestinal tract and are not likely to cause adverse events in nursing infants; thus, aminoglycosides are generally considered compatible with breast-feeding.

    MECHANISM OF ACTION

    Plazomicin is bactericidal in action. Similar to other aminoglycosides, it works by inhibiting bacterial protein synthesis through irreversible binding to the 30 S ribosomal subunit of susceptible bacteria. Aminoglycosides are actively transported into the bacterial cell where they bind to receptors present on the 30 S ribosomal subunit. This binding interferes with messenger RNA (mRNA). 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. One aspect essential to aminoglycoside lethality is the need to achieve intracellular concentrations in excess of extracellular. Anaerobic bacteria are not susceptible to aminoglycosides due, at least in part, to a lack of an active transport mechanism for aminoglycoside uptake. The uptake of aminoglycosides may be facilitated by the presence of inhibitors of the bacterial cell wall (i.e. beta-lactams, vancomycin).
     
    Plazomicin exhibits 'concentration-dependent killing' and a 'post-antibiotic effect' (PAE). 'Concentration-dependent killing' describes the principle that bactericidal effects increase as the concentration increases. The major pharmacodynamic parameter that determines efficacy of plazomicin is the ratio of area under the plasma concentration-time curve to the minimum inhibitory concentration (AUC:MIC) in animal and in vitro models. PAE is where suppression of bacterial growth continues after the antibiotic concentration falls below the bacterial MIC. In vitro studies demonstrated a plazomicin PAE ranging from 0.2 to 2.6 hours at 2 times the MIC against Enterobacteriaceae.
     
    The mechanism of renal toxicity with aminoglycosides is associated with accumulation in the renal tubule, which is a saturable process. Elevated serum trough concentrations are associated with an increased risk of toxicity.
     
    The mechanism of ototoxicity relates to the aminoglycoside-induced destruction of sensory hair cells of the inner ear. The cochlear sensory cells that are most vulnerable are in the basal end, thereby leading to high-frequency hearing loss first. As ototoxicity ascends toward the apex of the cochlea, the lower frequencies are affected. Sensory cells that deal with vestibular function may also be affected. Aminoglycosides may cause free-radical damage to sensory cells and neurons. Biochemically, aminoglycosides may bind to polyphosphoinositides, which are part of the transmembrane signaling system mediating physiological effects of hormones, neurotransmitters, and neuromodulators which may interfere with essential mechanisms of cell physiology. Neural destruction without any cochlear hair cell damage has also been described. There may also be a genetic mitochondrial RNA mutation that may predispose some patients to aminoglycoside ototoxicity. Aminoglycosides enter the inner ear rapidly, but it is suggested that concentrations do not correlate with the development of ototoxicity. Likely, aminoglycoside concentrations in the inner ear dissipate slowly, which is consistent with the possibility of developing ototoxicity days to weeks after drug discontinuation.
     
    The interpretive breakpoint criteria define MICs of 2 mcg/mL or less as susceptible, 4 mcg/mL as intermediate, and 8 mcg/mL or more as resistant for plazomicin against Enterobacteriaceae. Plazomicin has no in vitro activity against streptococci, enterococci, anaerobes, Stenotrophomonas maltophilia, and Acinetobacter sp. It has variable activity against Pseudomonas aeruginosa.
     
    Aminoglycoside resistance is well documented. There are a variety of resistance mechanisms employed by different pathogens. Enzymatic inhibition via aminoglycoside-modifying enzymes (AMEs) is achieved by modification of the aminoglycoside as it is transported across the cytoplasmic membrane. Plazomicin is not inhibited by most AMEs known to affect gentamicin, amikacin, and tobramycin, including acetyltransferases (AACs), phosphotransferases (APHs), and nucleotidyltransferases (ANTs). Other mechanisms include alteration of the ribosomal target sites through production of 16S rRNA methyltransferases, up-regulation of efflux pumps, and reduced permeability into the bacterial cell due to loss of outer membrane porins. Plazomicin, like other aminoglycosides, is inactive against bacterial isolates that produce 16S rRNA methyltransferases and may have reduced activity against Enterobacteriaceae that overexpress certain efflux pumps (e.g., acrAB-tolC) or lower expression of porins (e.g., ompF or ompK36). Plazomicin demonstrates in vitro activity in the presence of certain beta-lactamases, including extended-spectrum beta-lactamases (TEM, SHV, CTX-M, AmpC), serine carbapenemases (KPC-2, KPC-3), and oxacillinase (OXA-48). Bacteria producing metallo-beta-lactamases often co-express 16S rRNA methyltransferase, conferring resistance to plazomicin.
     
    No antagonism was observed during in vitro studies of plazomicin in combination with clindamycin, colistin, daptomycin, fosfomycin, levofloxacin, linezolid, rifampin, tigecycline, and vancomycin. Few isolates showed synergy with ceftazidime, meropenem, and piperacillin; tazobactam, but the clinical significance of these findings is unknown.

    PHARMACOKINETICS

    Plazomicin is administered intravenously. The average binding of plazomicin to human plasma proteins is approximately 20% and is concentration-independent. The mean volume of distribution is 17.9 L (+/- 4.8 L) in healthy adults and 30.8 L (+/- 12.1 L) in patients with complicated urinary tract infections.
     
    Plazomicin does not appear to be metabolized to any appreciable extent and is primarily eliminated by the kidneys. After a single radiolabeled plazomicin 15 mg/kg IV dose, 97.5% of the dose was recovered in the urine as unchanged plazomicin; 56% of the total administered radioactivity was recovered in urine within 4 hours with less than 0.2% in feces. The mean renal clearance of plazomicin is similar to total body clearance.
     
    Affected cytochrome P450 isoenzymes and drug transporters: MATE1, MATE2-K
    Plazomicin selectively inhibits the MATE1 and MATE2-K renal transporters in vitro. However, a clinical drug-drug interaction study that evaluated the effect of a single plazomicin 15 mg/kg dose on the single-dose pharmacokinetics of a MATE substrate did not demonstrate any affect of plazomicin on the pharmacokinetics of the MATE substrate.

    Intravenous Route

    The pharmacokinetic parameters of plazomicin are similar for single- and multiple-dose administration with no appreciable accumulation after multiple IV infusions in patients with normal renal function. The AUC, Cmax, and Cmin increase in proportion to the dose over the dose range of 4 to 15 mg/kg. The mean AUC is 257 mcg x hour/mL in healthy patients and 226 mcg x hour/mL in patients with complicated urinary tract infections (cUTIs). The mean Cmax is 73.7 mcg/mL in healthy patients and 51 mcg/mL in patients with cUTIs. The mean Cmin is 0.3 mcg/mL in healthy patients and 0.5 mcg/mL in patients with cUTIs.