Polymyxin B Sulfate (polymyxin B sulfate)

Dosage of polymyxin B sulfate usually is expressed in terms of polymyxin B activity (units of polymyxin B). Dosage of the drug also may be expressed as mg of polymyxin B base. Each mg of polymyxin B is equivalent to 10,000 units of polymyxin B.

Potency and dosage of polymyxin B sulfate are expressed in terms of polymyxin B activity (units of polymyxin B).

Dosage of polymyxin B should be decreased in patients with renal impairment. Serum polymyxin B concentrations should be monitored and IV or IM dosage adjusted to maintain desired serum concentrations of the drug.

Various dosage regimens have been recommended for use of polymyxin B in patients with renal impairment; however, these regimens are not well established and are not based on pharmacokinetic data from patients with renal impairment.

It has been recommended that patients with creatinine clearances of 30-80 mL/minute receive an IV loading dose of polymyxin B of 2.5 mg/kg on the first day of treatment followed by 1-1.5 mg/kg daily and that those with creatinine clearances less than 25-30 mL/minute receive these doses once every 2-3 days. For anuric patients, some clinicians have recommended an IV loading dose of 2.5 mg/kg followed by 1-1.5 mg/kg given once every 5-7 days.

Alternatively, it has been suggested that patients with creatinine clearances greater than 20 mL/minute receive 75-100% of the usual daily dose in 2 divided doses every 12 hours, those with creatinine clearances of 5-20 mL/minute receive 50% of the usual daily dose in 2 divided doses every 12 hours, and those with creatinine clearances less than 5 mL/minute receive 30% of the usual daily dose every 12-18 hours. Some clinicians have used 75% of the usual daily dose in those with creatinine clearances 20-50 mL/minute and 33% of the usual daily dose in those with creatinine clearances less than 20 mL/minute.

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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)

Polymyxin B/Selected Nephrotoxic Agents

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)

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

Polypeptide Antibiotics/Neuromuscular Blocking Agents

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

MECHANISM OF ACTION: Synergistic pharmacologic activity. Polymyxin B affects neuromuscular transmission by blocking acetylcholine receptors. Its action is thus post-synaptic and the neuromuscular block has no antagonists. Polymyxin B causes neostigmine resistance to d-tubocurarine blockade and calcium resistance to the blockade evoked by aminoglycoside antibiotics (1,2,3,4). A pre-synaptic mechanism may also be involved with decreased release of acetylcholine.

CLINICAL EFFECTS: May see an increase in the neuromuscular blocking effects, including profound sedation, respiratory depression, coma, and/or death.

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. If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: Concomitant administration of polypeptide antibiotics and 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 apnea. This interaction has been documented with colistimethate, polymyxin B, bacitracin, and vancomycin.

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• Kidney disease with reduction in glomerular filtration rate (GFr)
• Oliguria
• Pregnancy

• Clostridioides difficile infection
• Myasthenia gravis
• Systemic mastocytosis

There are no moderate contraindications for this drug.

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Rare or Very Rare

• CNS toxicity
• Fever
• Nephrotoxicity
• Neuromuscular blockade
• Skin rash

There are no less severe adverse reactions for this drug.

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The safety of polymyxin B sulfate in pregnant women has not been established.

Some clinicians state that polymyxin B should not be used during pregnancy, except in rare situations when other appropriate anti-infectives cannot be used.

If use of the fixed-combination solution for irrigation containing polymyxin B sulfate and neomycin sulfate is being considered for a pregnant woman, the woman should be informed of the potential hazard to the fetus. Aminoglycosides cross the placenta and there have been reports of complete, irreversible, bilateral congenital deafness in children whose mothers received an aminoglycoside (i.e., streptomycin) during pregnancy.

Animal reproduction studies have not been performed with polymyxin B sulfate. It is not known whether ophthalmic preparations containing polymyxin B sulfate can cause fetal harm when administered to pregnant women.

Fixed-combination ophthalmic preparations of polymyxin B sulfate and bacitracin zinc or polymyxin B sulfate, neomycin sulfate, and either bacitracin zinc or gramicidin should be used during pregnancy only if clearly needed.

Because trimethoprim may interfere with folic acid metabolism, fixed-combination ophthalmic preparations containing polymyxin B sulfate and trimethoprim sulfate should be used during pregnancy only if potential benefits justify potential risks to the fetus.

Fixed-combination ophthalmic preparations containing polymyxin B sulfate, other anti-infectives (i.e., neomycin sulfate, bacitracin zinc), and a corticosteroid (i.e., dexamethasone, hydrocortisone, hydrocortisone acetate) should be used during pregnancy only if potential benefits justify potential risks to the fetus.

Fixed-combination otic preparations containing polymyxin B sulfate, neomycin sulfate, and hydrocortisone should be used during pregnancy only if potential benefits justify potential risks to the fetus.

Fixed-combination ophthalmic preparations containing polymyxin B sulfate and other anti-infectives (i.e., bacitracin zinc, gramicidin, neomycin sulfate, trimethoprim sulfate) should be used with caution in nursing women.

Fixed-combination ophthalmic preparations containing polymyxin B sulfate, neomycin sulfate, and dexamethasone should be used with caution in nursing women.

The manufacturers of fixed-combination ophthalmic preparations containing polymyxin B sulfate, neomycin sulfate, bacitracin zinc, and hydrocortisone or hydrocortisone acetate state that a decision should be made whether to discontinue nursing or the ophthalmic preparation, taking into account the importance of the drug to the woman.

Fixed-combination otic preparations containing polymyxin B sulfate, neomycin sulfate, and hydrocortisone should be used with caution in nursing women.

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