Kitabis Pak (tobramycin/nebulizer)

Aminoglycoside dosage should be individualized taking into consideration the patient's pretreatment body weight, renal status, serum concentrations of the drug, severity of the infection, and susceptibility of the causative organism. Because of the potential toxicity of aminoglycosides, fixed-dosage recommendations that are not based on patient weight or serum drug concentrations are not advised.

In patients with impaired renal function, doses and/or frequency of administration of aminoglycosides must be modified in response to serum concentrations of the drugs and the degree of renal impairment. Various formulae, tables, nomograms, and computer-assisted programs based on serum creatinine or creatinine clearance have been used to aid in dosage adjustment in patients with renal impairment. One frequently used method that has been recommended for determining dosage of amikacin, gentamicin, kanamycin, or tobramycin in patients with renal impairment is the method of Sarubbi and Hull, which is based on corrected creatinine clearance. (See Table.) However, even when one of these methods is used, peak and trough serum aminoglycoside concentrations should be monitored, especially in patients with changing renal function. These dosage calculation methods should not be used in patients undergoing hemodialysis or peritoneal dialysis; supplemental doses of aminoglycosides may be required after dialysis.

Amikacin, gentamicin, kanamycin, and tobramycin are administered by IM injection or IV infusion. IV administration generally is recommended in patients with life-threatening infections, septicemia, shock, severe hypotension, congestive heart failure, hematologic disorders, severe burns, or reduced muscle mass. Streptomycin is administered by IM injection, but also has been given by IV infusion+.

Neomycin and paromomycin are administered orally. Although kanamycin also has been administered orally, an oral dosage form is no longer commercially available in the US.

Tobramycin solution for oral inhalation is administered via a nebulizer. Tobramycin+, kanamycin, and gentamicin+ also have been administered by oral inhalation as aerosols prepared extemporaneously from parenteral preparations of the drugs.

Amikacin, gentamicin, and tobramycin have been administered intrathecally+ or intraventricularly+ for the treatment of CNS infections. Intraventricular administration of aminoglycosides usually is preferred to intrathecal administration, especially in cases of ventriculitis, to ensure adequate drug concentrations throughout the CSF.

Although some aminoglycosides (e.g., kanamycin, neomycin) have been administered by intraperitoneal instillation or local irrigation (abscess cavities, pleural space, peritoneal and ventricular cavities), there is an increased risk of toxicity with these routes. (See Other Precautions under Cautions: Precautions and Contraindications.)

Aminoglycosides should not be admixed with other drugs or infused simultaneously through the same tubing with other drugs.

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

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)

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)

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.

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

Tobramycin Inhalation/Selected Diuretics

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

MECHANISM OF ACTION: The combination may have additive or synergistic risks for ototoxicity and/or nephrotoxicity.(1,2)

CLINICAL EFFECTS: Concurrent use may result in an increased risk of aminoglycoside toxicity.(1)

PREDISPOSING FACTORS: Severe renal impairment, sepsis, or concomitant use of additional ototoxic or nephrotoxic agents may further increase the risk for toxicity. Patients carrying certain variants in the MT-RNR1 gene (m.1555A>G, m.1095T>C, and m.1494C>T) are at greatly 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.(3)

PATIENT MANAGEMENT: Instruct patients to contact their provider for new onset or worsening tinnitus. Tinnitus may be a sentinel symptom of ototoxicity. In clinical trials of tobramycin inhalation 8 patients (3%) receiving tobramycin reported tinnitus while no patients in the placebo group reported this symptom.(1) For renally impaired patients receiving long term tobramycin inhalation therapy, consider measurement of serum tobramycin to assure low systemic levels. The manufacturer of tobramycin for inhalation states that the product should not be administered concurrently with ethacrynic acid, furosemide, intravenous mannitol, or urea.(1)

DISCUSSION: Although systemic absorption of inhaled tobramycin is limited, the manufacturer states that because these diuretics may enhance the risk for aminoglycoside toxicity, they should not be administered concurrently with inhaled tobramycin.(1)

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

• Kidney disease with reduction in glomerular filtration rate (GFr)
• Myasthenia gravis

• Asthma
• Chronic obstructive pulmonary disease
• Disorder of the vestibulocochlear nerve
• Hemoptysis
• Parkinsonism
• Tinnitus
• Vertigo

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Rare or Very Rare

• Aphonia
• Auditory neurotoxicity
• Bronchospastic pulmonary disease
• Nephrotoxicity
• Neuromuscular blockade
• Ototoxicity

More Frequent

• Cough
• Diarrhea
• Dysgeusia
• Dyspnea
• Fever
• Headache disorder
• Hemoptysis
• Increased sputum
• Pain in oropharynx
• Pharyngitis
• Skin rash
• Voice change

Less Frequent

• Laryngitis
• Myalgia
• Nausea
• Non-cardiac chest pain
• Vomiting
• Weight loss

Rare or Very Rare

• Anorexia
• Ataxia
• Dizziness
• Malaise
• Pruritus of skin
• Sputum discoloration
• Tinnitus
• Urticaria
• Vertigo
• Wheezing

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Aminoglycosides can cause fetal harm when administered to pregnant women. Aminoglycosides cross the placenta and there have been several reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Although serious adverse effects have not been reported in fetuses or neonates whose mothers received other aminoglycosides during pregnancy, the potential for fetal toxicity exists with these antibiotics.

If an aminoglycoside is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.

Small amounts of aminoglycosides are distributed into milk following IM or IV administration. Although it is not known whether neomycin is distributed into human milk following oral administration, it is distributed into cow milk following IM injection. It is not know whether tobramycin is distributed into milk following oral inhalation. Because of the potential for serious adverse reactions to aminoglycosides in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

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