Gentamicin Sulfate In Ns (gentamicin sulfate in sodium chloride, iso-osmotic)

Dosage of gentamicin sulfate is expressed in terms of gentamicin. IM and IV dosage is identical.

Like other aminoglycosides, dosage of gentamicin should be individualized taking into consideration the patient's pretreatment body weight, renal status, severity of the infection, and susceptibility of the causative organism. The manufacturers state that dosage in obese patients should be based on the patient's estimated lean body weight. Many clinicians recommend that gentamicin dosage be determined using appropriate pharmacokinetic methods for calculating dosage requirements and patient-specific pharmacokinetic parameters (e.g., elimination rate constant, volume of distribution) derived from serum concentration-time data.

Whenever possible, especially in patients with life-threatening infections, suspected toxicity or nonresponse to treatment, decreased or varying renal function, and/or when increased aminoglycoside clearance (e.g., patients with cystic fibrosis, burns) or prolonged therapy is likely, peak and trough serum concentrations of gentamicin should be determined periodically and dosage should be adjusted to maintain desired serum concentrations. (See Dosage and Administration: Dosage, in the Aminoglycosides General Statement 8:12.02.) A causal relationship between maintenance of certain peak or trough serum concentrations or other pharmacodynamic endpoints and clinical response or toxicity has not been established to date for gentamicin dosing regimens. However, for gentamicin administered in conventional dosage regimens (i.e., multiple daily doses), peak serum concentrations of 4-10 mcg/mL and trough concentrations that do not exceed 1-2 mcg/mL have been suggested. An increased risk of toxicity may be associated with peak serum gentamicin concentrations greater than 10-12 mcg/mL and/or trough concentrations greater than 2 mcg/mL. The manufacturers state that prolonged peak serum concentrations greater than 12 mcg/mL and trough concentrations greater than 2 mcg/mL should be avoided.

Parenteral aminoglycosides historically have been administered in dosage regimens that include multiple daily doses, and current prescribing information for IM or IV gentamicin only includes dosage regimens that involve multiple daily doses (usually 3 or 4 doses daily). However, there is evidence that once-daily+ (single-daily) aminoglycoside dosage regimens are at least as effective as, may provide superior pharmacokinetics, and may be less toxic than conventional dosage regimens employing multiple daily doses of the drugs. Although once-daily gentamicin regimens are recommended for some indications, once-daily gentamicin regimens should not be used in all patients and should not be used for the treatment of enterococcal or staphylococcal endocarditis+. Additional controlled studies in children, patients with renal dysfunction, and other appropriate patient groups are needed to fully define the optimal use of once-daily aminoglycoside dosing regimens. In addition, the most appropriate methods for optimizing dosage selection for once-daily regimens and monitoring serum aminoglycoside concentrations in patients receiving such regimens have not been clearly established. (See Dosage and Administration: Dosage, in the Aminoglycosides General Statement 8:12.02.)

The usual duration of gentamicin treatment is 7-10 days. In difficult and complicated infections, a longer course of treatment may be necessary. However, toxicity is more likely to occur if treatment is continued for longer than 10 days and renal, auditory, and vestibular functions should be monitored closely.

In patients with impaired renal function, doses and/or frequency of administration must be modified in response to serum concentrations of the drug and the degree of renal impairment. There are various methods to determine dosage and a wide variation in dosage recommendations for these patients. However, even when one of these methods is used, peak and trough serum concentrations of the drug should be monitored, especially in patients with changing renal function.

The manufacturers recommend that adults with renal impairment receive an initial dose of 1-1.7 mg/kg. For subsequent therapy, the manufacturers state that 1 mg/kg doses can be given at intervals (in hours) calculated by multiplying the patient's steady-state serum creatinine (in mg/dL) by 8. Alternatively, many clinicians recommend the dosing method of Sarubbi and Hull, which is based on corrected creatinine clearance. (See Dosage and Administration: Dosage in Renal Impairment, in the Aminoglycosides General Statement 8:12.02.) These dosage calculation methods should not be used in patients undergoing hemodialysis or peritoneal dialysis.

In adults with renal failure undergoing hemodialysis, the manufacturers recommend supplemental doses of 1-1.7 mg/kg at the end of each dialysis period in adults and supplemental doses of 2-2.5 mg/kg at the end of each dialysis period in children. Some clinicians suggest supplemental doses of 50-75% of the initial loading dose at the end of each dialysis period. Serum gentamicin concentrations should be monitored in dialysis patients and dosage adjusted as needed to maintain desired serum concentrations.

Gentamicin sulfate is administered by IM injection or IV infusion. IV administration may be preferred in patients with septicemia, shock, congestive heart failure, hematologic disorders, severe burns, or reduced muscle mass.

Gentamicin sulfate has been administered intrathecally+ or intraventricularly+ as an adjunct to IM or IV administration of the drug for the treatment of meningitis and other CNS infections.

Patients should be well hydrated prior to and during gentamicin therapy since dehydration increases the risk of toxicity.

Renal function should be assessed prior to and monitored during gentamicin therapy. Patients should be under close clinical observation because of the risk of ototoxicity and nephrotoxicity. (See Cautions in the Aminoglycosides General Statement 8:12.02.)

Prior to administration, gentamicin solutions should be inspected visually for particulate matter or discoloration.

No dosing information is available for this tab.

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Aminoglycosides/Ataluren

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The mechanism of this interaction is not known.

CLINICAL EFFECTS: The combination of an aminoglycoside and ataluren may increase risk for serious nephrotoxicity.(1)

PREDISPOSING FACTORS: Preexisting renal impairment, dehydration, extended duration of aminoglycoside therapy, greater than one aminoglycoside dose per day, or concomitant use of additional nephrotoxic agents such as iodinated contrast media or vancomycin appear to increase the risk for nephrotoxicity.(1-5).

PATIENT MANAGEMENT: The manufacturer states that ataluren should not be co-administered with intravenous aminoglycosides based upon cases of decreased renal function observed in a clinical trial with cystic fibrosis patients. If aminoglycoside therapy is required, stop ataluren and resume therapy 2 days after aminoglycoside therapy has ended.(1)

DISCUSSION: In a clinical trial with cystic fibrosis patients, 18 of 118 (15%) patients in the ataluren group developed increased creatinine concentrations compared with one of 120 patients in the placebo group.(2)

Antibiotics/Fecal Microbiota

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota is a suspension of live bacteria, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota. Antibacterial treatment should be completed for 24 to 72 hours before initiating treatment with fecal microbiota. Do not use antibiotics for up to 8 weeks after fecal microbiota.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota.

Antibiotics/Fecal Microbiota Spores

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota spores is a suspension of live bacterial spores, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota spores.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota spores. Antibacterial treatment should be completed for 2 to 4 days before initiating treatment with fecal microbiota spores.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota spores.

Antimicrobials/Live Typhoid Vaccine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The antimicrobial may be active against the organism in the live-vaccine. Antimicrobial therapy may prevent the vaccine organism from replicating enough to trigger an immune response.(1)

CLINICAL EFFECTS: Vaccination may be ineffective.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Do not give oral typhoid vaccine until 72 hours after the last dose of antimicrobial. If possible, to optimize vaccine effectiveness, do not start antibacterial drugs for 72 hours after the last dose of oral typhoid vaccine. A longer interval should be considered for long-acting antimicrobials, such as azithromycin.(3)

DISCUSSION: Because antimicrobial therapy may prevent sufficient vaccine-organism replication to generate an immune response, the manufacturer of live-attenuated typhoid vaccine and the Centers for Disease Control (CDC) state that the vaccine should not be administered to patients receiving antimicrobial therapy.(1-3)

Gentamicin/Agalsidase

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Gentamicin may inhibit the intracellular activity of alpha-galactosidase.(1,2)

CLINICAL EFFECTS: Concurrent use of agalsidase with gentamicin may result in decreased effectiveness of agalsidase.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of agalsidase alpha in Canada(1) and the manufacturer of agalsidase beta in the United Kingdom(2) state that agalsidase should not be administered with gentamicin.

DISCUSSION: Because of a theoretical risk of inhibited intracellular activity of alpha-galactosidase activity, the manufacturer of agalsidase alpha in Canada(1) and the manufacturer of agalsidase beta in the United Kingdom(2) state that agalsidase should not be administered with gentamicin.

Selected Nephrotoxic Agents/Bacitracin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Bacitracin may cause renal failure due to glomerular and tubular necrosis. Concurrent administration of other nephrotoxic agents may result in additive renal toxicity.(1-3)

CLINICAL EFFECTS: Concurrent use of bacitracin with other potentially nephrotoxic agents may result in renal toxicity.(1-3)

PREDISPOSING FACTORS: Dehydration and high-dose bacitracin may predispose to adverse renal effects.(1)

PATIENT MANAGEMENT: Health Canada states that bacitracin is contraindicated in patients with renal impairment, including those taking other nephrotoxic drugs.(1) The Canadian and US manufacturers of bacitracin state that concomitant use of bacitracin with other potentially nephrotoxic agents should be avoided.(2,3)

DISCUSSION: Renal impairment is a major toxicity of bacitracin. Cases of nephrotoxicity have been reported when bacitracin was used off-label.(1-3)

Selected Nephrotoxic Agents/Cidofovir

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Cidofovir is nephrotoxic. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1-3)

CLINICAL EFFECTS: Concurrent use of cidofovir with nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, foscarnet, intravenous pentamidine, tenofovir, vancomycin, voclosporin and non-steroidal anti-inflammatory agents may result in renal toxicity.(1-3) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Australian,(1) UK,(2) and US(3) manufacturers of cidofovir state that concurrent administration of potentially nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, foscarnet, intravenous pentamidine, tenofovir, vancomycin, voclosporin and non-steroidal anti-inflammatory agents may result in renal toxicity.(1-3) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin. These agents should be discontinued at least 7 days before the administration of cidofovir.

DISCUSSION: The safety of cidofovir has not been studied in patients receiving other known potentially nephrotoxic agents. Renal impairment is the major toxicity of cidofovir.(1-3)

Selected Nephrotoxic Agents/Polymyxin B

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Polymyxin B can cause nephrotoxicity with a slight degree of tubular damage. Concurrent administration of other nephrotoxic agents may result in an increased risk of nephrotoxicity.(1)

CLINICAL EFFECTS: Concurrent use of polymyxin B with other nephrotoxic agents may result in additive nephrotoxic effects. Polymyxin B nephrotoxicity is characterized by albuminuria, cellular casts, azotemia, diminished urine output, elevated BUN and rising blood levels usually after about 4 days of therapy.(1,2)

PREDISPOSING FACTORS: Factors predisposing to nephrotoxicity include higher cumulative doses and longer duration of therapy of polymyxin B and exposure to multiple nephrotoxins.(2)

PATIENT MANAGEMENT: Concurrent or sequential use of potentially nephrotoxic agents with polymyxin B should be avoided. If concurrent use is necessary, it should be undertaken with great caution. Check renal function at baseline and monitor renal function and polymyxin B blood levels frequently during therapy.(1)

DISCUSSION: Polymyxin B is associated with high rates of nephrotoxicity. Concurrent use with other nephrotoxins may increase the risk of nephrotoxicity.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Aminoglycosides/Anesthetics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The neuromuscular blocking activity of aminoglycosides results from a decreased sensitivity at the postjunctional membrane and interfere with transmitter release.(1) These actions produce a synergistic effect with anesthetic agents that produce neuromuscular blockade.(2,3) Some anesthetics cause renal failure due to release of fluoride ion. Aminoglycosides cause nephrotoxicity when high doses are given.(4,5)

CLINICAL EFFECTS: Increased neuromuscular blockade activity, profound sedation, respiratory depression, coma, and/or death. Circulatory collapse may also occur secondary to the neuromuscular blockade.(6-10) Decreased urinary output and increased BUN and serum creatinine may indicate renal impairment.

PREDISPOSING FACTORS: Patients in respiratory distress, history of renal impairment and high doses of aminoglycosides and anesthetics.

PATIENT MANAGEMENT: Monitor neuromuscular blockade with train-of-four stimulus. Monitor vital signs, and respiratory rate. Intravenous neostigmine (0.2 to 2.5 mg), calcium (1 G), and possibly sodium bicarbonate (dose not reported) may be beneficial in reversal of neuromuscular blockade and respiratory depression.(6-10) Supportive care and ventilation should be utilized until the neuromuscular blockade is resolved. Volume replacement may be necessary for circulatory collapse.(6-10) Monitor BUN, serum creatinine, and urinary output and adjust aminoglycoside and anesthetic doses according to renal function.

DISCUSSION: Aminoglycosides including kanamycin(6,11), streptomycin(6,13), amikacin(13), gentamicin(7,13-15), neomycin, and tobramycin(13) have been documented to have neuromuscular blocking activity. There is no documentation with netilmicin and paromomycin, though it is assumed that they produce the same effects as the other members of this class. Neomycin has been shown to interact with cyclopropane(8,9), halothane(6), methoxyflurane(6), and nitrous oxide(6). Enflurane, ethylene, and isoflurane share similar properties to the previous inhalation anesthetics and would likely interact with neomycin. Kanamycin(6,11) and streptomycin (6,12) are known to interact with ether. Gentamicin has been reported to potentiate atracurium.(16) Therefore it is hypothesized that all aminoglycosides interact with the inhaled anesthetics. One study evaluating gentamicin and halothane in animals did not exhibit a decrease in muscle strength.(17) Aminoglycosides have been proven to be nephrotoxic at high doses. Anesthetics containing fluoride also produce renal dysfunction. Nephrotoxicity occurred more often when gentamicin or tobramycin were given with enflurane than when enflurane was given alone or in patients who received nitrous oxide and opioid anesthesia.(4)

Aminoglycosides/Cyclosporine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Cyclosporine and aminoglycosides can both cause nephrotoxicity. Concurrent administration may result in an additive or synergistic risk of nephrotoxicity.(1-3)

CLINICAL EFFECTS: Concurrent use of cyclosporine with aminoglycosides may result in a higher risk of renal dysfunction, including structural kidney damage.(1-3)

PREDISPOSING FACTORS: Factors predisposing to nephrotoxicity include pre-existing renal impairment, older age, higher doses or longer treatment duration of either drug, and dehydration.(1-3)

PATIENT MANAGEMENT: Avoid the concurrent use of cyclosporine and aminoglycosides whenever possible.(2,3) If concurrent use cannot be avoided, it should be undertaken with great caution. Minimize the cyclosporine dose and monitor renal function carefully. Frequent dose adjustment may be indicated. If renal function deteriorates, the aminoglycoside may need to be decreased or discontinued.(1-4)

DISCUSSION: Coadministration of cyclosporine with other drugs that may impair renal function, like aminoglycosides, may cause additive or synergistic impairment of renal function. A meta-analysis of 30 studies that evaluated the correlation and risk factors between cyclosporine and kidney injury in allogeneic hematopoietic stem cell transplant (allo-HSCT) patients included 7 studies that examined the role of the combination with other drugs in the development of nephrotoxicity. Coadministration of aminoglycosides and amphotericin B were independent risk factors for acute or chronic kidney diseases related to cyclosporine in allo-HSCT patients.(5)

Misc Antibiotics/Neuromuscular Blocking Agents

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Aminoglycosides, bacitracin, clindamycin, lincomycin, and polymyxins may enhance the pharmacologic effects of neuromuscular blocking agents.

CLINICAL EFFECTS: May see an increase in the pharmacologic effects of neuromuscular blocking agents, including prolonged respiratory depression and apnea.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If it is necessary to administer these drugs concurrently, do so with extreme caution. Monitor neuromuscular function and adjust the dose of the neuromuscular blocking agent accordingly.

DISCUSSION: Concomitant administration of aminoglycosides, bacitracin, clindamycin, lincomycin, and polymixins with neuromuscular blocking agents has been shown to produce synergism of the effects on skeletal muscles. Concurrent administration of these drugs has been associated with prolonged respiratory depression, respiratory paralysis, and fatal apnea. The interaction usually occurs when the antibiotic is given prior to or concurrently with the neuromuscular blocking drug, but it may also occur when given after administration. Any antibiotic dosage or route of administration may produce respiratory depression.

Selected Nephrotoxic Agents/Foscarnet

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Foscarnet is nephrotoxic. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1) Concurrent intravenous pentamidine may also result in hypocalcemia.(1)

CLINICAL EFFECTS: Concurrent use of foscarnet with nephrotoxic agents such as acyclovir, adefovir, intravenous aminoglycosides, amphotericin B, cyclosporine, methotrexate, non-steroidal anti-inflammatory agents, intravenous pentamidine, tacrolimus, tenofovir, vancomycin and voclosporin may result in renal toxicity.(1) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of foscarnet state that concurrent administration of potentially nephrotoxic agents such as acyclovir, intravenous aminoglycosides, amphotericin B, cyclosporine, methotrexate, tacrolimus, and intravenous pentamidine should be avoided.(1) Other nephrotoxic agents include adefovir, capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, non-steroidal anti-inflammatory agents, streptozocin, tenofovir, vancomycin and voclosporin. If concurrent therapy is warranted, monitor renal function closely. In patients receiving concurrent foscarnet and pentamidine, also monitor serum calcium levels and instruct patients to report severe muscle spasms, mental/mood changes, and/or seizures.(1)

DISCUSSION: The safety of foscarnet has not been studied in patients receiving other known potentially nephrotoxic agents. Renal impairment is the major toxicity of foscarnet.(1)

Selected Nephrotoxic Agents/Inotersen

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inotersen can cause glomerulonephritis and renal toxicity. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1)

CLINICAL EFFECTS: Concurrent use of inotersen with nephrotoxic agents such as acyclovir, adefovir, intravenous aminoglycosides, amphotericin B, cyclosporine, methotrexate, non-steroidal anti-inflammatory agents, intravenous pentamidine, tacrolimus, tenofovir, vancomycin and voclosporin may result in renal toxicity.(1) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin.

PREDISPOSING FACTORS: Patients with pre-existing renal impairment.

PATIENT MANAGEMENT: The US manufacturer of inotersen state that caution should be used when administered concurrently with potentially nephrotoxic agents or agents that impair renal function.(1) If concurrent therapy is warranted, monitor renal function closely.(1)

DISCUSSION: The safety of inotersen has not been studied in patients receiving other known potentially nephrotoxic agents. Inotersen is only available through a Tegsedi REMS program because of the risk of glomerulonephritis and severe thrombocytopenia.(1)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Aminoglycosides/Loop Diuretics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The coadministration of aminoglycosides and loop diuretics may result in additive or synergistic ototoxicity and/or nephrotoxicity.

CLINICAL EFFECTS: The combination of an aminoglycoside and a loop diuretic may increase risk for serious nephrotoxicity or ototoxicity.(1,2) Vestibular or auditory ototoxicity may be permanent.(1,3)

PREDISPOSING FACTORS: Preexisting renal impairment, extended duration of aminoglycoside therapy, greater than one aminoglycoside dose per day, rapid injection or high doses of loop diuretics, concomitant use of additional nephrotoxic agents such as iodinated contrast media or vancomycin, or sepsis appear to increase the risk for nephrotoxicity and ototoxicity.(1-6). Patients carrying certain variants in the MT-RNR1 gene (m.1555A>G, m.1095T>C, and m.1494C>T) are at increased risk of developing ototoxicity. An additional risk factor includes patients with a maternal relative known to have a clinically relevant MT-RNR1 variant. The risk of ototoxicity can occur at standard recommended doses of aminoglycosides.(7)

PATIENT MANAGEMENT: Administer aminoglycoside dosage every 24 to > 48 hours based upon renal function and continue therapy for less than 4 to 7 days, whenever possible.(4,5) The recommended maximal infusion rate for high dose furosemide therapy is 4 mg/minute.(2) When concurrent therapy is necessary monitor renal, hearing, and vestibular function. Signs of vestibular dysfunction include loss of balance and/or the visual sensation that stationary objects are moving (oscillopsia). In hospitalized or bedbound patients these symptoms may not be noticed or may be ascribed to other etiologies.(3)

DISCUSSION: Several studies and case reports have documented altered aminoglycoside levels, nephrotoxicity, and ototoxicity with concurrent therapy.(8-14) Otic aminoglycosides are included in this interaction because high aminoglycoside concentrations in the ear have been associated with an increased risk for hearing loss.

Aminoglycosides/Select Cephalosporins

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: Nephrotoxicity may occur.

PREDISPOSING FACTORS: Preexisting renal impairment, older age, and large doses of either drug.

PATIENT MANAGEMENT: Try to avoid this combination in patients at risk of developing nephrotoxicity. Elderly patients, patients receiving large doses of either drug, and renal patients should be considered at risk. Monitor renal function if this combination is used.

DISCUSSION: This interaction is likely to occur in some patients, but clinical documentation is limited. This interaction is usually not a problem in patients with normal renal function.

Gentamicin, Amikacin, Tobramycin/Amphotericin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The ototoxic or nephrotoxic effects of gentamicin, amikacin, or tobramycin may be additive with those of amphotericin.

CLINICAL EFFECTS: The concurrent administration of gentamicin, amikacin, or tobramycin with amphotericin may result in additive ototoxic or nephrotoxic effects.(1)

PREDISPOSING FACTORS: Preexisting renal impairment, sepsis, extended duration of aminoglycoside therapy, greater than one aminoglycoside dose per day, or concomitant use of additional nephrotoxic agents such as iodinated contrast media or vancomycin appear to increase the risk for nephrotoxicity and ototoxicity.(1-6). Patients carrying certain variants in the MT-RNR1 gene (m.1555A>G, m.1095T>C, and m.1494C>T) are at increased risk of developing ototoxicity. An additional risk factor includes patients with a maternal relative known to have a clinically relevant MT-RNR1 variant. The risk of ototoxicity can occur at standard recommended doses of aminoglycosides.(7)

PATIENT MANAGEMENT: The Australian manufacturer of gentamicin, amikacin, and tobramycin state that the concurrent use of gentamicin, amikacin, or tobramycin and amphotericin should be avoided.(1,4,5)

DISCUSSION: The Australian and U.K. manufacturers of gentamicin, amikacin, and tobramycin state that since the ototoxic or nephrotoxic effects of gentamicin, amikacin, or tobramycin may be additive, avoid concurrent or sequential use of other neurotoxic and/or nephrotoxic agents including amphotericin.(1,3,4,5)

Gentamicin, Amikacin, Tobramycin/Vancomycin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The ototoxic or nephrotoxic effects of gentamicin, amikacin, or tobramycin may be additive with those of vancomycin.

CLINICAL EFFECTS: The concurrent administration of gentamicin, amikacin, or tobramycin with vancomycin may result in additive ototoxic or nephrotoxic effects.(1)

PREDISPOSING FACTORS: Preexisting renal impairment, sepsis, extended duration of aminoglycoside therapy, greater than one aminoglycoside dose per day, or concomitant use of additional nephrotoxic agents such as iodinated contrast media or vancomycin appear to increase the risk for nephrotoxicity and ototoxicity.(1-5). Patients carrying certain variants in the MT-RNR1 gene (m.1555A>G, m.1095T>C, and m.1494C>T) are at increased risk of developing ototoxicity. An additional risk factor includes patients with a maternal relative known to have a clinically relevant MT-RNR1 variant. The risk of ototoxicity can occur at standard recommended doses of aminoglycosides.

PATIENT MANAGEMENT: The Australian manufacturer of gentamicin, amikacin, and tobramycin state that the concurrent use of gentamicin, amikacin, or tobramycin and vancomycin should be avoided.(1,4,5)

DISCUSSION: The Australian and U.K. manufacturers of gentamicin, amikacin, and tobramycin state that since the ototoxic or nephrotoxic effects of gentamicin, amikacin, or tobramycin may be additive, avoid concurrent or sequential use of other neurotoxic and/or nephrotoxic agents including vancomycin.(1,3,4,5)

Selected Nephrotoxic Agents/Adefovir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Recommended doses of adefovir have been associated with delayed nephrotoxicity.(1-4) Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1)

CLINICAL EFFECTS: Concurrent use of adefovir with nephrotoxic agents such as intravenous aminoglycosides, amphotericin B, cyclosporine, tacrolimus,tenofovir, vancomycin, voclosporin and non-steroidal anti-inflammatory agents may result in renal toxicity.(1) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, intravenous pentamidine, and streptozocin.

PREDISPOSING FACTORS: Patients with pre-existing renal impairment(1,2) or receiving multiple nephrotoxic agents appear to be at greater risk for nephrotoxicity.

PATIENT MANAGEMENT: Evaluate renal function prior to initiation of concurrent therapy and continue renal function monitoring during therapy. Dose adjustments may be required for impaired renal function. Weigh the risks and benefits of concurrent therapy in patients with treatment-emergent nephrotoxicity.

DISCUSSION: Because of the known risks for adefovir nephrotoxicity, particularly at higher than recommended doses, the safety of adefovir has not been studied in patients receiving other known potentially nephrotoxic agents.

Selected Nephrotoxic Agents/Cisplatin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The nephrotoxic effects of aminoglycosides or non-steroidal anti-inflammatory drugs (NSAIDs) may be additive to those of cisplatin.

CLINICAL EFFECTS: The concurrent administration of amikacin, gentamicin, tobramycin, or NSAIDs with cisplatin may result in additive nephrotoxic effects.(1,2,5,6)

PREDISPOSING FACTORS: Pre-existing renal insufficiency, advanced age, dehydration may increase the risk of nephrotoxicity.(1,5,6)

PATIENT MANAGEMENT: The US labeling for aminoglycosides and cisplatin states that the concurrent use of aminoglycosides and cisplatin should be avoided.(1,3,4,6) Inform patients that concurrent cisplatin and aminoglycosides or NSAIDs can cause nephrotoxicity and that renal function and electrolyte monitoring during treatment is necessary.(2)

DISCUSSION: The US manufacturers of amikacin, gentamicin and tobramycin state that since the nephrotoxic effects of these medications may be additive, avoid concurrent or sequential use of other neurotoxic and/or nephrotoxic agents including cisplatin.(1,3,6)

Selected Nephrotoxic Agents/Immune Globulin Iv (Igiv)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Immune Globulin Intravenous (IGIV) products, particularly those containing sucrose, can cause renal dysfunction, acute renal failure, osmotic nephrosis, and/or death. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1-4)

CLINICAL EFFECTS: Concurrent use of Immune Globulin Intravenous (IGIV) products with nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, non-steroidal anti-inflammatory agents, tenofovir, and vancomycin may result in renal toxicity.(1-4) Other nephrotoxic agents include capreomycin, gallium nitrate, and streptozocin.

PREDISPOSING FACTORS: Patients at risk of acute renal failure include those with any degree of pre-existing renal insufficiency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or receiving known nephrotoxic drugs.(1-4) Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose.(3-4)

PATIENT MANAGEMENT: For patients at risk of renal dysfunction or renal failure, the US manufacturers of Immune Globulin Intravenous (IGIV) products recommends administration at the minimum dose and infusion rate practicable; ensure adequate hydration in patients before administration; and monitor renal function and urine output with assessment of blood urea nitrogen (BUN) and serum creatinine before initial infusion and at regular intervals during therapy.(1-3) Concurrent administration of potentially nephrotoxic agents should be avoided.(1) Review prescribing information for IGIV product to be administered for sucrose content. If concurrent therapy is warranted, monitor renal function closely. In high risk patients, consider selecting an IGIV product that does not contain sucrose.

DISCUSSION: The safety of Immune Globulin Intravenous (IGIV) has not been studied in patients receiving other known potentially nephrotoxic agents. Renal impairment is a major toxicity of IGIV products.(1-3) A review of the FDA renal adverse events (RAEs) (i.e. acute renal failure or insufficiency) from June 1985 to November 1998 identified 120 reports worldwide associated with IGIV administration. In the US, the FDA received 88 reports of cases with clinical and/or laboratory findings consistent with RAE (i.e. increased serum creatinine, oliguria, and acute renal failure). Patient cases involved a median age of 60.5 years and 55% were male. Of the 54 patients who developed acute renal failure, 65% were greater than 65 years, 56% had diabetes, and 26% had prior renal insufficiency; 59% had one, 35% had two, and 6% had three of these conditions. Upon review of the IGIV product received, 90% of cases received sucrose-containing IGIV products with the remaining patients receiving either maltose- or glucose-containing products. Approximately 40% of affected patients required dialysis and RAE may have contributed to death in 15% of patients.(4)

Selected Nephrotoxic Agents/Tenofovir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tenofovir and other nephrotoxic agents may result in additive or synergistic effects on renal function and increase nephrotoxicity risk.(1)

CLINICAL EFFECTS: Concurrent use of tenofovir and other nephrotoxic agents may result in renal toxicity and acute renal failure.(1) Reports of acute renal failure and Fanconi syndrome have been reported with tenofovir use.(2,3) However, this has been reported in 3 case reports and the renal failure may have been complicated by other pre-existing conditions.(2)

PREDISPOSING FACTORS: Pre-existing renal dysfunction, long duration of use, low body weight, concomitant use of drugs that may increase tenofovir levels may increase the risk of nephrotoxicity.(1)

PATIENT MANAGEMENT: The US prescribing information for tenofovir recommends avoiding concurrent or recent use of a nephrotoxic agent.(3) Evaluate renal function prior to initiation of concurrent therapy and continue renal function monitoring during therapy. Dose adjustments may be required for impaired renal function. Tenofovir should be avoided with high-dose or multiple NSAIDs. Alternatives to NSAIDs should be considered in patients at risk for renal dysfunction.(3) Patients receiving concurrent NSAIDs with tenofovir should be monitored for possible renal toxicity.(1,2) The dosing interval should be adjusted in patients with a baseline creatinine clearance of less than 50 ml/min.(1-3)

DISCUSSION: From March 18, 2003 to December 1, 2005, Health Canada received 10 reports of nephrotoxic reactions with tenofovir. Three of these occurred following the addition of a NSAID to tenofovir therapy. In the first report, a patient maintained on tenofovir for 29 months developed acute renal failure and acute tubular necrosis requiring dialysis 5 days after beginning indomethacin (100 mg rectally twice daily). In the second report, a patient maintained on tenofovir for 7 months developed acute renal failure and acute tubular necrosis after taking 90 tablets of naproxen (375 mg) over 2 months. The patient died. In the third report, a patient maintained on tenofovir for over a year developed acute renal failure and nephrotic syndrome after 2 months of valdecoxib (20 mg daily) therapy. Symptoms subsided following discontinuation of valdecoxib.(1)

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• Mt-RNr1 increased risk of aminoglycoside-induced hearing loss

• Dehydration
• Disorder of the vestibulocochlear nerve
• Hypocalcemia
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Myasthenia gravis
• Tinnitus
• Vertigo

• Parkinsonism

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More Frequent

• Auditory neurotoxicity
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Nephrotoxicity
• Ototoxicity

Less Frequent

• Allergic dermatitis
• Angioedema
• Erythema
• Pruritus of skin
• Skin rash

Rare or Very Rare

• Anaphylaxis
• Anemia
• Clostridioides difficile infection
• Eosinophilia
• Exfoliative dermatitis
• Hearing loss
• Hypersensitivity drug reaction
• Increased alanine transaminase
• Increased aspartate transaminase
• Leukocytosis
• Leukopenia
• Neuromuscular blockade
• Seizure disorder
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Toxic epidermal necrolysis

Rare or Very Rare

• Acute cognitive impairment
• Diarrhea
• Fever
• Headache disorder
• Hypoesthesia
• Lethargy
• Muscle fasciculation
• Nausea
• Paresthesia
• Urticaria
• Vertigo
• Vomiting

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