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    Polymyxin Antibiotics

    BOXED WARNING

    Intramuscular administration, intrathecal administration, intravenous administration, requires a specialized care setting

    Intrathecal administration, intramuscular administration, or intravenous administration of polymyxin B requires a specialized care setting to allow for constant supervision and monitoring for toxicities. Routine intramuscular administration is not recommended due to severe pain at the injection site. Due to the availability of less toxic alternatives, polymyxin B is rarely used parenterally; most commonly, it is used topically in combination with other agents.

    Nephrotoxicity, neurotoxicity, renal impairment

    Assess baseline renal function prior to treatment and regularly during treatment with polymyxin B. Monitor serum polymyxin B concentrations regularly during treatment. Polymyxin B-induced nephrotoxicity usually presents as albuminuria, cellular casts, and azotemia. If urine output decreases or serum creatinine or BUN increase, discontinue therapy. Polymyxin B is not significantly eliminated by the kidneys, and no dosage adjustment is recommended for patients with impaired renal function, including those receiving renal replacement therapy. If unnecessary renal dose adjustments are made, there is potential for drug underexposure and clinical failure. Neurotoxicity is usually associated with high serum concentrations in patients with renal impairment or renal failure and/or nephrotoxicity. Neurotoxicity may present as ataxia, blurred vision, drowsiness, irritability, numbness of the extremities, perioral paresthesia, and weakness. Do not administer concurrently with or sequentially after other neurotoxic and/or nephrotoxic drugs.

    Pregnancy

    The safety of polymyxin B injection during pregnancy has not been established.

    DEA CLASS

    Rx

    DESCRIPTION

    Parenteral polymyxin antibiotic
    Used for the treatment of bacteremia, meningitis, ophthalmic infection, and urinary tract infection
    Associated with nephrotoxicity and neurotoxicity

    HOW SUPPLIED

    Polymyxin B/Polymyxin B Sulfate Intramuscular Inj Pwd F/Sol: 500000U
    Polymyxin B/Polymyxin B Sulfate Intrathecal Inj Pwd F/Sol: 500000U
    Polymyxin B/Polymyxin B Sulfate Intravenous Inj Pwd F/Sol: 500000U
    Polymyxin B/Polymyxin B Sulfate Ophthalmic Inj Pwd F/Sol: 500000U

    DOSAGE & INDICATIONS

    For the treatment of urinary tract infection (UTI).
    NOTE: 1 mg is equivalent to 10,000 units of polymyxin B.
    Intravenous dosage
    Adults

    2 to 2.5 mg/kg/dose (20,000 to 25,000 units/kg/dose) IV loading dose, followed by 1.25 to 1.5 mg/kg/dose (12,500 to 15,000 units/kg/dose) IV every 12 hours. The FDA-approved dose is 0.75 to 1.25 mg/kg/dose (7,500 to 12,500 units/kg/dose) IV every 12 hours.

    Children and Adolescents

    0.75 to 1.25 mg/kg/dose (7,500 to 12,500 units/kg/dose) IV every 12 hours.

    Infants

    1.25 mg/kg/dose (12,500 units/kg/dose) IV every 12 hours. Up to 4 mg/kg/day (40,000 units/kg/day) may be used.

    Intramuscular dosage

    NOTE: Intramuscular administration is not routinely recommended because of severe pain at injection sites, particularly in infants and children.

    Adults

    2.5 to 3 mg/kg/day (25,000 to 30,000 units/kg/day) IM divided every 4 to 6 hours.

    Children and Adolescents

    2.5 to 3 mg/kg/day (25,000 to 30,000 units/kg/day) IM divided every 4 to 6 hours.

    Infants

    Up to 4 mg/kg/day (40,000 units/kg/day) IM divided every 4 to 6 hours.

    For the treatment of meningitis.
    NOTE: 1 mg is equivalent to 10,000 units of polymyxin B.
    Intrathecal dosage
    Adults

    5 mg/dose (50,000 units/dose) intrathecally once daily as part of combination therapy. The FDA-approved dose is 5 mg/dose (50,000 units/dose) intrathecally for 3 to 4 days, then 5 mg/dose (50,000 units/day) every other day for at least 2 weeks after cerebrospinal fluid (CSF) cultures are negative and glucose content is normal.

    Children and Adolescents 2 to 17 years

    5 mg/dose (50,000 units/dose) intrathecally once daily as part of combination therapy. The FDA-approved dose is 5 mg/dose (50,000 units/dose) intrathecally for 3 to 4 days, then 5 mg/dose (50,000 units/day) every other day for at least 2 weeks after cerebrospinal fluid (CSF) cultures are negative and glucose content is normal.

    Infants and Children 1 year

    2 mg/dose (20,000 units/dose) intrathecally once daily as part of combination therapy. The FDA-approved dose is 2 mg/dose (20,000 units/dose) intrathecally once daily for 3 to 4 days or 2.5 mg/dose (25,000 units/dose) intrathecally every other day, then 2.5 mg/dose (25,000 units/dose) intrathecally for at least 2 weeks after cerebrospinal fluid (CSF) cultures are negative and glucose content is normal.

    Intraventricular dosage†
    Adults

    5 mg/dose (50,000 units/dose) intraventricularly once daily as part of combination therapy.

    Infants, Children, and Adolescents

    2 mg/dose (20,000 units/dose) intraventricularly once daily as part of combination therapy. 

    For the treatment of ophthalmic infection.
    NOTE: 1 mg is equivalent to 10,000 units of polymyxin B.
    Ophthalmic dosage (0.1% to 0.25% solution)
    Adults

    1 to 3 drops to the affected eye(s) every 1 hour, increasing the interval as response indicates. Maximum total systemic and ophthalmic dose is 2.5 mg/kg/day (25,000 units/kg/day).

    Infants, Children, and Adolescents

    1 to 3 drops to the affected eye(s) every 1 hour, increasing the interval as response indicates. Maximum total systemic and ophthalmic dose is 2.5 mg/kg/day (25,000 units/kg/day).

    Subconjunctival dosage
    Adults

    Up to 10 mg/day (100,000 units/day) via subconjunctival injection may be used for infections of the cornea or conjunctiva. Maximum total systemic and ophthalmic dose is 2.5 mg/kg/day (25,000 units/kg/day).

    Infants, Children, and Adolescents

    Up to 10 mg/day (100,000 units/day) via subconjunctival injection may be used for infections of the cornea or conjunctiva. Maximum total systemic and ophthalmic dose is 2.5 mg/kg/day (25,000 units/kg/day).

    For the treatment of bacteremia.
    NOTE: 1 mg is equivalent to 10,000 units of polymyxin B.
    Intravenous dosage
    Adults

    2 to 2.5 mg/kg/dose (20,000 to 25,000 units/kg/dose) IV loading dose, followed by 1.25 to 1.5 mg/kg/dose (12,500 to 15,000 units/kg/dose) IV every 12 hours. The FDA-approved dose is 0.75 to 1.25 mg/kg/dose (7,500 to 12,500 units/kg/dose) IV every 12 hours.

    Children and Adolescents

    0.75 to 1.25 mg/kg/dose (7,500 to 12,500 units/kg/dose) IV every 12 hours.

    Infants

    1.25 mg/kg/dose (12,500 units/kg/dose) IV every 12 hours. Up to 4 mg/kg/day (40,000 units/kg/day) may be used.

    Intramuscular dosage

    NOTE: Intramuscular administration is not routinely recommended because of severe pain at injection sites, particularly in infants and children.

    Adults

    2.5 to 3 mg/kg/day (25,000 to 30,000 units/kg/day) IM divided every 4 to 6 hours.

    Children and Adolescents

    2.5 to 3 mg/kg/day (25,000 to 30,000 units/kg/day) IM divided every 4 to 6 hours.

    Infants

    Up to 4 mg/kg/day (40,000 units/kg/day) IM divided every 4 to 6 hours.

    Neonates

    Up to 4.5 mg/kg/day (45,000 units/kg/day) IM divided every 4 to 6 hours has been used in limited clinical studies.

    For the treatment of nosocomial pneumonia†, including ventilator-associated pneumonia†.
    NOTE: 1 mg is equivalent to 10,000 units of polymyxin B.
    Intravenous dosage
    Adults

    2 to 2.5 mg/kg/dose (20,000 to 25,000 units/kg/dose) IV loading dose, followed by 1.25 to 1.5 mg/kg/dose (12,500 to 15,000 units/kg/dose) IV every 12 hours for 7 days as part of combination therapy.

    Infants, Children, and Adolescents

    1.25 mg/kg/dose (12,500 units/kg/dose) IV every 12 hours.

    For the treatment of complicated intraabdominal infections†, including peritonitis†, appendicitis†, intraabdominal abscess†, and peritoneal dialysis-related peritonitis†.
    For the treatment of complicated healthcare-acquire or hospital-acquired intraabdominal infections† with adequate source control due to resistant gram-negative organisms.
    Intravenous dosage
    Adults

    2 to 2.5 mg/kg/dose (20,000 to 25,000 units/kg/dose) IV loading dose followed by 1.25 to 1.5 mg/kg/dose (12,500 to 15,000 units/kg/dose) IV every 12 hours as part of combination therapy for 3 to 7 days. Complicated infections include peritonitis and appendicitis complicated by rupture, and intraabdominal abscess.

    Infants, Children, and Adolescents

    1.25 mg/kg/dose (12,500 units/kg/dose) IV every 12 hours as part of combination therapy for 3 to 7 days. Complicated infections include peritonitis and appendicitis complicated by rupture, and intraabdominal abscess.

    For the treatment of peritoneal dialysis-related peritonitis†.
    Continuous Intraperitoneal dosage†
    Adults

    300,000 units/L in each dialysate exchange. Treat for 21 to 28 days.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    2.5 mg/kg/day (25,000 units/kg/dose) IV is FDA-approved maximum with 3 mg/kg/day (30,000 units/kg/day) IV used off-label; 3 mg/kg/day (30,000 units/kg/day) IM; 5 mg/day (50,000 units/day) intrathecally; 5 mg/day (50,000 units/day) intraventricularly used off-label; 10 g/day (100,000 units/day) via subconjunctival injection; 3 drops/hour of 0.25% solution via topical ophthalmic administration. Avoid total systemic and ophthalmic instillation over 2.5 mg/kg/day (25,000 units/kg/day).

    Geriatric

    2.5 mg/kg/day (25,000 units/kg/dose) IV is FDA-approved maximum with 3 mg/kg/day (30,000 units/kg/day) IV used off-label; 3 mg/kg/day (30,000 units/kg/day) IM; 5 mg/day (50,000 units/day) intrathecally; 5 mg/day (50,000 units/day) intraventricularly used off-label; 10 g/day (100,000 units/day) via subconjunctival injection; 3 drops/hour of 0.25% solution via topical ophthalmic administration. Avoid total systemic and ophthalmic instillation over 2.5 mg/kg/day (25,000 units/kg/day).

    Adolescents

    2.5 mg/kg/day (25,000 units/kg/day) IV; 3 mg/kg/day (30,000 units/kg/day) IM; 5 mg/kg/day (50,000 units/day) intrathecally; 2 mg/kg/day (20,000 units/day) intraventricularly used off-label; 10 mg/day (100,000 units/day) via subconjunctival injection; 3 drops/hour of 0.25% solution via topical ophthalmic administration. Avoid total systemic and ophthalmic instillation over 2.5 mg/kg/day (25,000 units/kg/day).

    Children

    2 to 12 years: 2.5 mg/kg/day (25,000 units/kg/day) IV; 3 mg/kg/day (30,000 units/kg/day) IM; 5 mg/kg/day (50,000 units/day) intrathecally; 2 mg/kg/day (20,000 units/day) intraventricularly used off-label; 10 mg/day (100,000 units/day) via subconjunctival injection; 3 drops/hour of 0.25% solution via topical ophthalmic administration. Avoid total systemic and ophthalmic instillation over 2.5 mg/kg/day (25,000 units/kg/day).
    1 year: 2.5 mg/kg/day (25,000 units/kg/day) IV; 3 mg/kg/day (30,000 units/kg/day) IM; 2 mg/day (20,000 units/day) or 2.5 mg every other day (25,000 units every other day) intrathecally; 2 mg/kg/day (20,000 units/day) intraventricularly used off-label; 10 mg/day (100,000 units/day) via subconjunctival injection; 3 drops/hour of 0.25% solution via topical ophthalmic administration. Avoid total systemic and ophthalmic instillation over 2.5 mg/kg/day (25,000 units/kg/day).

    Infants

    4 mg/kg/day (40,000 units/kg/day) IV/IM; 2 mg/day (20,000 units/day) or 2.5 mg every other day (25,000 units every other day) intrathecally; 2 mg/kg/day (20,000 units/day) intraventricularly used off-label; 10 mg/day (100,000 units/day) via subconjunctival injection; 3 drops/hour of 0.25% solution via topical ophthalmic administration. Avoid total systemic and ophthalmic instillation over 2.5 mg/kg/day (25,000 units/kg/day).

    Neonates

    4.5 mg/kg/day (45,000 units/kg/day) IM. Safety and efficacy have not been established for other routes of administration.

    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

    No dosage adjustment needed in patients with renal impairment or receiving renal replacement therapy. Polymyxin B is not significantly eliminated by the kidneys.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.
    NOTE: 1 mg is equivalent to 10,000 units of polymyxin B.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Powder Vials for Injection
    Reconstitution
    Reconstitute polymyxin B 50 mg (500,000 units) in 300 to 500 mL of 5% Dextrose Injection.
    Storage: Store reconstituted solutions under refrigeration, 2 to 8 degrees C (36 to 46 degrees F). Discard any unused portions after 72 hours.
     
    Intermittent IV Infusion
    Infuse IV over 60 minutes.

    Intramuscular Administration

    Powder Vials for Injection
    Reconstitution
    Reconstitute polymyxin B 50 mg (500,000 units) in 2 mL of Sterile Water for Injection, 0.9% Sodium Chloride Injection, or 1% Procaine Hydrochloride Injection.
    Storage: Store reconstituted solutions under refrigeration, 2 to 8 degrees C (36 to 46 degrees F). Discard any unused portions after 72 hours.
     
    Intermittent IM Injection
    IM administration should not be used routinely, particularly in infants and children, because of severe pain, which occurs at the injection site.

    Intrathecal Administration

    Powder Vials for Injection
    Reconstitution
    Use preservative-free product.
    Reconstitute polymyxin B 50 mg (500,000 units) in 10 mL of 0.9% Sodium Chloride Injection to yield 5 mg/mL (50,000 units/mL).
    Storage: Store reconstituted solutions under refrigeration, 2 to 8 degrees C (36 to 46 degrees F). Discard any unused portions after 72 hours.
     
    Intrathecal Administration
    Administer via lumbar puncture.

    Other Injectable Administration

    Intraventricular Administration†
    NOTE: Polymyxin B is not FDA-approved for intraventricular administration.
    Powder Vials for Injection
    Reconstitution
    Use preservative-free product.
    Storage: Store reconstituted solutions under refrigeration, 2 to 8 degrees C (36 to 46 degrees F). Discard any unused portions after 72 hours.
     
    Intraventricular Administration
    When administered through a ventricular drain, the drain should be clamped for 15 to 60 minutes to allow the antimicrobial solution to equilibrate in the CSF before opening the drain.

    Ophthalmic Administration
    Extemporaneous Compounding-Ophthalmic

    Powder Vials for Injection
    Reconstitution
    Reconstitute polymyxin B 50 mg (500,000 units) in 20 to 50 mL of Sterile Water for Injection or 0.9% Sodium Chloride Injection to yield 1 to 2.5 mg/mL (10,000 to 25,000 units/mL or 0.1% to 0.25%).
    Storage: Store reconstituted solutions under refrigeration, 2 to 8 degrees C (36 to 46 degrees F). Discard any unused portions after 72 hours.
     
    Topical Ophthalmic Administration
    Instill topically in the affected eye(s).
     
    Subconjunctival Administration
    Inject subconjunctivally.

    STORAGE

    Generic:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from heat
    - Protect from light
    - Reconstituted product must be stored under refrigeration (36 to 46 degrees F) and any unused product discarded after 72 hours
    - Store in a cool, well ventilated, dry place
    - Store in carton until time of use
    - Store unreconstituted product at 68 to 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    C. difficile-associated diarrhea, diarrhea, pseudomembranous colitis

    Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial use. Careful medical history is necessary as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. Almost all antibacterial agents, including polymyxin B, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

    Intramuscular administration, intrathecal administration, intravenous administration, requires a specialized care setting

    Intrathecal administration, intramuscular administration, or intravenous administration of polymyxin B requires a specialized care setting to allow for constant supervision and monitoring for toxicities. Routine intramuscular administration is not recommended due to severe pain at the injection site. Due to the availability of less toxic alternatives, polymyxin B is rarely used parenterally; most commonly, it is used topically in combination with other agents.

    Nephrotoxicity, neurotoxicity, renal impairment

    Assess baseline renal function prior to treatment and regularly during treatment with polymyxin B. Monitor serum polymyxin B concentrations regularly during treatment. Polymyxin B-induced nephrotoxicity usually presents as albuminuria, cellular casts, and azotemia. If urine output decreases or serum creatinine or BUN increase, discontinue therapy. Polymyxin B is not significantly eliminated by the kidneys, and no dosage adjustment is recommended for patients with impaired renal function, including those receiving renal replacement therapy. If unnecessary renal dose adjustments are made, there is potential for drug underexposure and clinical failure. Neurotoxicity is usually associated with high serum concentrations in patients with renal impairment or renal failure and/or nephrotoxicity. Neurotoxicity may present as ataxia, blurred vision, drowsiness, irritability, numbness of the extremities, perioral paresthesia, and weakness. Do not administer concurrently with or sequentially after other neurotoxic and/or nephrotoxic drugs.

    Myasthenia gravis, neuromuscular disease, pulmonary disease, respiratory insufficiency, surgery

    Polymyxin B treatment can cause respiratory paralysis as a result of neuromuscular blockade, and concurrent administration with neuromuscular blockers during surgery should be avoided. Patients with pulmonary disease, myasthenia gravis, or other neuromuscular disease are at risk for increased side effects during systemic polymyxin B therapy, especially when given shortly after anesthesia and/or muscle relaxants. If signs of respiratory insufficiency or nephrotoxicity occur, the drug should be discontinued.

    Infection

    Polymyxin B can cause the overgrowth of non susceptible organisms, resulting in suprainfection. Susceptibility tests should be performed if the infection does not improve.

    Polymyxin hypersensitivity

    Polymyxin B should not be used in patients with polymyxin hypersensitivity. Since polymyxin B can cause hypersensitivity reactions it should be used with caution in patients known to have hypersensitivity reactions to other antibiotics. Reactions to other ingredients in combination products also should be considered.

    Pregnancy

    The safety of polymyxin B injection during pregnancy has not been established.

    Breast-feeding

    There is no information regarding polymyxin B injection treatment during breast-feeding. However, polymyxin B is not absorbed from the GI tract. Therefore, risk to the nursing infant would be expected to be minimal.

    Contact lenses

    Patients who wear contact lenses should avoid wearing them while being treated with polymyxin B for an ocular infection.

    ADVERSE REACTIONS

    Severe

    anuria / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    nephrotoxicity / Delayed / Incidence not known
    glomerulonephritis / Delayed / Incidence not known
    oliguria / Early / Incidence not known
    azotemia / Delayed / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    C. difficile-associated diarrhea / Delayed / Incidence not known

    Moderate

    hematuria / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    dysarthria / Delayed / Incidence not known
    myasthenia / Delayed / Incidence not known
    nystagmus / Delayed / Incidence not known
    neurotoxicity / Early / Incidence not known
    confusion / Early / Incidence not known
    phlebitis / Rapid / Incidence not known
    superinfection / Delayed / Incidence not known
    pseudomembranous colitis / Delayed / Incidence not known

    Mild

    cylindruria / Delayed / Incidence not known
    fever / Early / Incidence not known
    headache / Early / Incidence not known
    dizziness / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    drowsiness / Early / Incidence not known
    flushing / Rapid / Incidence not known
    irritability / Delayed / Incidence not known
    injection site reaction / Rapid / Incidence not known
    ocular irritation / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Amikacin: (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.
    Aminoglycosides: (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.
    Amlodipine; Celecoxib: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Major) Systemic polymyxin B should not be used concurrently or sequentially with other drugs that have the potential for nephrotoxicity or neurotoxicity such as amphotericin B. Topical products containing polymyxin B, especially when they are applied over a large body surface area, should be used cautiously.
    Amphotericin B lipid complex (ABLC): (Major) Systemic polymyxin B should not be used concurrently or sequentially with other drugs that have the potential for nephrotoxicity or neurotoxicity such as amphotericin B. Topical products containing polymyxin B, especially when they are applied over a large body surface area, should be used cautiously.
    Amphotericin B liposomal (LAmB): (Major) Systemic polymyxin B should not be used concurrently or sequentially with other drugs that have the potential for nephrotoxicity or neurotoxicity such as amphotericin B. Topical products containing polymyxin B, especially when they are applied over a large body surface area, should be used cautiously.
    Amphotericin B: (Major) Systemic polymyxin B should not be used concurrently or sequentially with other drugs that have the potential for nephrotoxicity or neurotoxicity such as amphotericin B. Topical products containing polymyxin B, especially when they are applied over a large body surface area, should be used cautiously.
    Bacitracin: (Major) Additive nephrotoxicity may occur with concurrent use of systemic bacitracin and other nephrotoxic agents, such as polymyxin B; when possible, avoid concomitant administration. Topical administration of any preparation containing bacitracin, especially when applied to large surface areas, should also not be given with other drugs that have a nephrotoxic potential.
    Bumetanide: (Moderate) Systemic polymyxin B is nephrotoxic and should be used cautiously with loop diuretics, which may cause azotemia and may increase the risk for renal toxicity when coadministered. Close monitoring of renal status and for drug toxicity is recommended. Diminishing urine output and a rising BUN are indications to discontinue systemic polymyxin B therapy.
    Bupivacaine; Meloxicam: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Capreomycin: (Major) The concomitant use of capreomycin and polymyxin B may increase the risk of nephrotoxicity and neurotoxicity. Since capreomycin is eliminated by the kidney, coadministration of capreomycin with other potentially nephrotoxic drugs, including polymyxin B, may increase serum concentrations of either capreomycin or polymyxin B. Coadministration may increase the risk of developing nephrotoxicity, even in patients who have normal renal function; monitor 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. Polymyxin B has also been reported to interfere with nerve transmission at the neuromuscular junction. Avoid coadministration if possible; however, if these drugs must be coadministered, use extreme caution.
    Carboplatin: (Major) Patients previously or currently treated with other potentially nephrotoxic agents, such as systemic polymyxins like Polymyxin B injection, can have a greater risk of developing carboplatin-induced nephrooxicity. These patients may benefit from hydration prior to carboplatin therapy to lessen the incidence of nephrotoxicity. Monitor renal function closely.
    Celecoxib: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Celecoxib; Tramadol: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Cisplatin: (Major) Avoid the concurrent or sequential use of polymyxin B with cisplatin due to the risk of additive nephrotoxicity. Cisplatin can cause nephrotoxicity. In therapeutic doses, polymyxin B also causes nephrotoxicity with tubule damage.
    Colistin: (Major) The concomitant use of colistimethate sodium (also known as colistin or Polymyxin E) and Polymyxin B may increase the risk of nephrotoxicity and neurotoxicity. Since colistimethate sodium is eliminated by the kidney, coadministration of colistimethate sodium with other potentially nephrotoxic drugs, including polymyxin B, may increase serum concentrations of either colistimethate sodium or polymyxin B. 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 colistimethate sodium, and is more likely to occur in patients with renal dysfunction.
    Cyclosporine: (Moderate) Cyclosporine should be used cautiously with nephrotoxic drugs, as cyclosporine itself can cause structural kidney damage and there is potential for additive nephrotoxicity. Systemic polymyxin B should generally not be used concurrently or sequentially with other drugs that have the potential for nephrotoxicity or neurotoxicity. Monitor renal function and fluid status carefully during co-use.
    Diclofenac: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Diclofenac; Misoprostol: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Diflunisal: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Diphenhydramine; Ibuprofen: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Diphenhydramine; Naproxen: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as polymyxin B. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir 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.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as polymyxin B. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir 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.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as polymyxin B. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir 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.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as polymyxin B. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir 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.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as polymyxin B. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir 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.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as polymyxin B. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir 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.
    Ethacrynic Acid: (Moderate) Systemic polymyxin B is nephrotoxic and should be used cautiously with loop diuretics, which may cause azotemia and may increase the risk for renal toxicity when coadministered. Close monitoring of renal status and for drug toxicity is recommended. Diminishing urine output and a rising BUN are indications to discontinue systemic polymyxin B therapy.
    Etodolac: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Famotidine; Ibuprofen: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Fenoprofen: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Flurbiprofen: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Foscarnet: (Major) Systemic polymyxin B should not be used concurrently or sequentially with other drugs that have the potential for nephrotoxicity or neurotoxicity such as foscarnet. Topical products containing polymyxin B, especially when they are applied over a large body surface area, should be used cautiously with any of the above drugs.
    Furosemide: (Moderate) Systemic polymyxin B is nephrotoxic and should be used cautiously with loop diuretics, which may cause azotemia and may increase the risk for renal toxicity when coadministered. Close monitoring of renal status and for drug toxicity is recommended. Diminishing urine output and a rising BUN are indications to discontinue systemic polymyxin B therapy.
    Ganciclovir: (Minor) Concurrent use of nephrotoxic agents, such as polymyxin b, with ganciclovir should be done cautiously to avoid additive nephrotoxicity.
    General anesthetics: (Moderate) Systemic polymyxin B can increase the neuromuscular blockade effects of neuromuscular blockers, general anesthetics, and skeletal muscle relaxants. Polymyxin B affects both pre- and post-synaptic myoneural areas by inhibiting release of acetylcholine pre-synaptically and/or blocking acetylcholine activity post-synaptically. Thus, polymyxin B acts synergistically with these agents.
    Gentamicin: (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.
    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 polymyxin B. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
    Hydrocodone; Ibuprofen: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Ibuprofen: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Ibuprofen; Oxycodone: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Ibuprofen; Pseudoephedrine: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    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 polymyxin B. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
    Indomethacin: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Kanamycin: (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.
    Ketoprofen: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Ketorolac: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as polymyxin B. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir 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.
    Lansoprazole; Naproxen: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Loop diuretics: (Moderate) Systemic polymyxin B is nephrotoxic and should be used cautiously with loop diuretics, which may cause azotemia and may increase the risk for renal toxicity when coadministered. Close monitoring of renal status and for drug toxicity is recommended. Diminishing urine output and a rising BUN are indications to discontinue systemic polymyxin B therapy.
    Meclofenamate Sodium: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Mefenamic Acid: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Meloxicam: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Nabumetone: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Naproxen: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Naproxen; Esomeprazole: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Naproxen; Pseudoephedrine: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Neuromuscular blockers: (Major) Avoid concomitant use of systemic polymyxin B and neuromuscular blockers due to the risk of respiratory depression. The neurotoxicity of polymyxin B may can result in neuromuscular blockade, especially when given soon after neuromuscular blockers. If signs of respiratory paralysis appear, assist respiration and discontinue drug therapy.
    Nonsteroidal antiinflammatory drugs: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Oral Contraceptives: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Oxaprozin: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Paromomycin: (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.
    Piroxicam: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Plazomicin: (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.
    Pyridostigmine: (Moderate) Parenteral administration of high systemic doses of certain antibiotics, such as Polymyxin B, may intensify or produce neuromuscular block or paralysis through its pharmacologic actions. If Polymyxin B or other newly introduced antibiotics are used in conjunction with nondepolarizing neuromuscular blocking drugs during surgery, unexpected prolongation of neuromuscular block or resistance to its reversal should be considered a possibility.
    Rofecoxib: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Major) Prior or concomitant use of antibiotics with sodium picosulfate; magnesium oxide; anhydrous citric acid may reduce efficacy of the bowel preparation as conversion of sodium picosulfate to its active metabolite bis-(p-hydroxy-phenyl)-pyridyl-2-methane (BHPM) is mediated by colonic bacteria. If possible, avoid coadministration. Certain antibiotics (i.e., tetracyclines and quinolones) may chelate with the magnesium in sodium picosulfate; magnesium oxide; anhydrous citric acid solution. Therefore, these antibiotics should be taken at least 2 hours before and not less than 6 hours after the administration of sodium picosulfate; magnesium oxide; anhydrous citric acid solution.
    Streptomycin: (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.
    Sulindac: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Sumatriptan; Naproxen: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Tacrolimus: (Minor) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including Polymixin B. 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 such as polymyxin B may lead to additive nephrotoxicity. Closely monitor renal function and adjust telavancin doses based on calculated creatinine clearance.
    Tenofovir Alafenamide: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as polymyxin B. 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) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as polymyxin B. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir 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.
    Tobramycin: (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.
    Tolmetin: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Torsemide: (Moderate) Systemic polymyxin B is nephrotoxic and should be used cautiously with loop diuretics, which may cause azotemia and may increase the risk for renal toxicity when coadministered. Close monitoring of renal status and for drug toxicity is recommended. Diminishing urine output and a rising BUN are indications to discontinue systemic polymyxin B therapy.
    Valdecoxib: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Valganciclovir: (Minor) Concurrent use of nephrotoxic agents, such as polymyxin b, with valganciclovir should be done cautiously to avoid additive nephrotoxicity.
    Vancomycin: (Major) Systemic polymyxin B should not be used concurrently or sequentially with other drugs that have the potential for nephrotoxicity or neurotoxicity such as vancomycin. Topical products containing polymyxin B, especially when they are applied over a large body surface area, should be used cautiously with any of the above drugs. If concurrent systemic use is necessary, renal function should be monitored closely and vancomycin doses should be adjusted according to vancomycin serum concentrations. Diminishing urine output and a rising BUN are indications to discontinue systemic polymyxin B therapy.
    Verteporfin: (Moderate) Use caution if coadministration of verteporfin with polymyxin B is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use with polymyxin B could enhance the rate of verteporfin uptake by the vascular endothelium, resulting in enhanced photosensitivity.
    Warfarin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including polymyxin B, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
    Zoledronic Acid: (Major) Coadministration of parenteral polymyxin B with other potentially nephrotoxic drugs, including zoledronic acid, 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. Since polymyxin B injection is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including zoledronic acid, may theoretically increase serum concentrations of either drug.

    PREGNANCY AND LACTATION

    Pregnancy

    The safety of polymyxin B injection during pregnancy has not been established.

    There is no information regarding polymyxin B injection treatment during breast-feeding. However, polymyxin B is not absorbed from the GI tract. Therefore, risk to the nursing infant would be expected to be minimal.

    MECHANISM OF ACTION

    Polymyxin B is a cationic agent that binds to the anionic bacterial outer membrane, leading to a detergent effect that disrupts membrane integrity. It can preferentially bind to the lipid A of lipopolysaccharide and displace magnesium and calcium from cationic binding sites. This binding can have neutralizing effects on the biological properties of endotoxins. Due to this disruptive effect, increased susceptibility to hydrophobic antimicrobials may occur after exposure.[28447] [65111] [65113]
     
    Polymyxins exhibit concentration-dependent pharmacodynamics where the free-drug area under the concentration-time curve to minimal inhibitory concentration ratio (AUC/MIC) appears to best correlate with antibacterial activity. Concentrations above the MIC result in extremely rapid initial killing with large decreases in colony-forming units per milliliter occurring as early as 5 minutes after exposure. An AUC over 24 hours at steady-steady of approximately 50 mg x hour/L is required and equates to a target average steady-state plasma concentration of approximately 2 mg/L for total drug. There is a modest postantibiotic effect for high concentrations of polymyxin B.[65112] [65114] [65475]
     
    The susceptibility interpretive criteria for polymyxin B are delineated by pathogen. The Clinical and Laboratory Standards Institute (CLSI) defines MICs for Enterobacterales, P. aueriginosa and A. baumanni as intermediate at 2 mcg/mL or less and resistant at 4 mcg/mL or more. The CLSI recommends that polymyxin should generally be given with a loading dose and at maximum recommended doses in combination with other agents and that systemic use is not likely to be effective for pneumonia. The only approved MIC method for testing is broth microdilution. The FDA does not support these breakpoints.[63320] [63321]
     
    Resistance to polymyxins include alterations in lipid A that reduce binding and a decrease in anionic surface charges that may correlate with decreased binding sites for the cationic polymyxins.[65111]

    PHARMACOKINETICS

    Polymyxin B is most often administered topically, either to the skin or eye. It can be administered parenterally although this is rarely done. Polymyxin B does not penetrate into the CSF, synovial fluid, aqueous humor of the eye, or across the placenta, even when there is inflammation present. There appears to be minimal binding to plasma protein. Polymyxin B loses about 50% of its potency in the presence of serum due to the presence of divalent cations that prevent the drug from binding to the cell membrane.
     
    Little is known about polymyxin B metabolism. About 60% of a dose is excreted by the kidneys in patients with normal renal function, but excretion is delayed following the first dose, possibly due to binding of polymyxin B to phospholipids in the cell walls of the kidneys. The serum half-life is 4—6 hours with normal renal function. After the final dose is given, excretion continues for 24—72 hours in patients with normal renal function.

    Oral Route

    Absorption of polymyxin B from the GI tract is minimal; so it is not administered orally.

    Intravenous Route

    Following intravenous administration of polymyxin B, about 50% of the dose is reversibly bound to phospholipids in the cell membranes of the liver, heart, muscle, brain, kidneys, and other tissues.

    Intramuscular Route

    Absorption of polymyxin B is rapid following intramuscular (IM) administration, giving peak serum levels in about 2 hours. Following IM administration, about 50% of the dose is reversibly bound to phospholipids in the cell membranes of the liver, heart, muscle, brain, kidneys, and other tissues.

    Topical Route

    Because polymyxin B has a very high affinity for cell membranes, there is little systemic absorption even when applied to open wounds.