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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 disease, renal failure, renal impairment

    Polymyxin B requires dosage adjustment for patients with renal disease, renal impairment, or renal failure. Assess baseline renal-function prior to treatment and regularly during treatment. 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. Patients with renal impairment are also at increased risk for neurotoxicity due to increased serum levels. 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, particularly amikacin, bacitracin, cephaloridine, colistin, gentamicin, kanamycin, neomycin, paromomycin, streptomycin, tobramycin, and viomycin.

    Pregnancy

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

    DEA CLASS

    Rx

    DESCRIPTION

    Antibiotic derived from a strain of Bacillus polymyxa; activity is limited to gram-negative bacteria. Rarely used systemically due to nephrotoxicity and neurotoxicity; most commonly found in topical, irrigant, ophthalmic or otic products in combination with neomycin and/or bacitracin.

    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) or bacteremia when other antibiotics are ineffective or contraindicated.
    Intravenous dosage
    Adults

    15,000 to 25,000 units/kg/day IV divided every 12 hours. Maximum daily dose is 25,000 units/kg/day IV.

    Children and Adolescents

    15,000 to 25,000 units/kg/day IV divided every 12 hours. Maximum daily dose is 25,000 units/kg/day IV.

    Infants

    15,000 to 40,000 units/kg/day IV divided every 12 hours. Maximum daily dose is 40,000 units/kg/day IV.

    Intramuscular dosage

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

    Adults

    25,000 to 30,000 units/kg/day IM divided every 4 to 6 hours.

    Children and Adolescents

    25,000 to 30,000 units/kg/day IM divided every 4 to 6 hours.

    Infants

    25,000 to 40,000 units/kg/day IM divided every 4 to 6 hours. Maximum daily dose is 40,000 units/kg/day.

    Neonates

    Up to 45,000 units/kg/day IM has been used in limited clinical studies for the treatment of P. aeruginosa sepsis.

    For the treatment of meningitis caused by sensitive strains of Pseudomonas aeruginosa or by other sensitive organisms when other antibiotics are ineffective or contraindicated.
    NOTE: Intravenous or intramuscular administration of polymyxin B are not effective in the treatment of meningitis.
    Intrathecal dosage
    Adults

    50,000 units intrathecally once daily for 3 to 4 days, then 50,000 units intrathecally once every other day for at least 2 weeks after cerebrospinal fluid (CSF) cultures are negative and glucose content is normal.

    Children 2 years and older and Adolescents

    50,000 units intrathecally once daily for 3 to 4 days, then 50,000 units intrathecally once every other day for at least 2 weeks after cerebrospinal fluid (CSF) cultures are negative and glucose content is normal.

    Infants and Children younger than 2 years

    20,000 units intrathecally once daily for 3 to 4 days or 25,000 units intrathecally once every other day. Continue with 25,000 units intrathecally once every other day for at least 2 weeks after cerebrospinal fluid (CSF) cultures are negative and glucose content is normal.

    For the treatment of ophthalmic infection caused by sensitive strains of Pseudomonas aeruginosa.
    Topical ophthalmic dosage
    Adults

    1 to 3 drops (0.1% to 0.25% solution) to the affected eye(s) every 1 hour, increasing the interval as response indicates. Maximum total systemic and ophthalmic dose is 25,000 units/kg/day.

    Infants, Children, and Adolescents

    1 to 3 drops (0.1% to 0.25% solution) to the affected eye(s) every 1 hour, increasing the interval as response indicates. Maximum total systemic and ophthalmic dose is 25,000 units/kg/day.

    Subconjunctival dosage
    Adults

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

    Infants, Children, and Adolescents

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

    For the treatment of nosocomial pneumonia†, including ventilator-associated pneumonia†.
    NOTE: Generally, the FDA-approved labeling provides doses as units/kg. Clinical practice guidelines provide doses as mg/kg (1 mg = 10,000 units).
    Intravenous dosage
    Adults

    2.5 to 3 mg/kg/day (25,000 to 30,000 units/kg/day) IV divided twice daily for 7 days. Clinical practice guidelines suggest polymyxin B as a second antipseudomonal agent for ventilator-associated pneumonia in settings with a high prevalence of multidrug resistance. For patients with suspected MRSA, add linezolid or vancomycin.

    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

    25,000 units/kg/day IV; 30,000 units/kg/day IM; 50,000 units/day intrathecally; 100,000 units/day via subconjunctival injection. Avoid total systemic and ophthalmic instillation over 25,000 units/kg/day.

    Geriatric

    25,000 units/kg/day IV; 30,000 units/kg/day IM; 50,000 units/day intrathecally; 100,000 units/day via subconjunctival injection. Avoid total systemic and ophthalmic instillation over 25,000 units/kg/day.

    Adolescents

    25,000 units/kg/day IV; 30,000 units/kg/day IM; 50,000 units/day intrathecally; 100,000 units/day via subconjunctival injection. Avoid total systemic and ophthalmic instillation over 25,000 units/kg/day.

    Children

    2 years and older: 25,000 units/kg/day IV; 30,000 units/kg/day IM; 50,000 units/day intrathecally; 100,000 units/day via subconjunctival injection. Avoid total systemic and ophthalmic instillation over 25,000 units/kg/day.
    Younger than 2 years: 25,000 units/kg/day IV; 30,000 units/kg/day IM; 20,000 units/day intrathecally; 100,000 units/day via subconjunctival injection. Avoid total systemic and ophthalmic instillation over 25,000 units/kg/day.

    Infants

    40,000 units/kg/day IV or IM; 20,000 units/day intrathecally; 100,000 units/day via subconjunctival injection. Avoid total systemic and ophthalmic instillation over 25,000 units/kg/day.

    Neonates

    45,000 units/kg/day IM.

    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

    Dose adjustments are recommended in patients with renal impairment. Different dosage adjustment schemes based on limited information suggest increasing the dosing interval in patients with renal dysfunction. However, while renal clearance varied substantially (20 to 240 mL/minute) due to a wide range of renal function in 8 critically ill patients, the range of total body clearance was substantially smaller (0.27 to 0.81 mL/minute/kg) suggesting that total body clearance of polymyxin B may not be overtly affected by renal clearance alone. Overall, the urinary recovery of polymyxin B in these patients was less than 1% of the administered dose.
    NOTE: 1 mg polymyxin B = 10,000 units.
    CrCl 80% or more of normal: 2.5 to 3 mg/kg/day IM/IV divided every 12 hours.
    CrCl more than 30% to less than 80% of normal: 2.5 mg/kg IM/IV on day 1, then 1 to 1.5 mg/kg IM/IV once daily.
    CrCl less than 25% of normal: 2.5 mg/kg IM/IV on day 1, then 1 to 1.5 mg/kg IM/IV every 2 to 3 days.
    Oliguria: dose every 3 to 4 days.
    Anuria: 2.5 mg/kg IM/IV on day 1, then 1.5 mg/kg IM/IV every 5 to 7 days.

    ADMINISTRATION

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

    Injectable Administration

    Administered via IM injection or IV infusion.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    Parenteral solutions should be stored under refrigeration and any unused portion should be discarded after 72 hours. Avoid reconstitution of polymyxin B with alkaline solutions due to decreased stability.

    Intravenous Administration

    Reconstitute 500,000 units polymyxin B powder for injection and dilute with 300 of D5W injection; final concentration is polymyxin B 1667 units/ml. Alternatively, reconstitute 500,000 units polymyxin B powder for injection and dilute with 500 ml of D5W injection to a final concentration of 1000 units/ml.
    Infuse IV over 60—90 minutes.
    Solutions should be refrigerated and discarded within 72 hours.

    Intramuscular Administration

    Although polymyxin B may be given IM, IM administration should not be used routinely, particularly in infants and children, because of severe pain, which occurs at the injection site.
    Reconstitute powder for injection with 2 mL of sterile water for injection, NS injection, or 1 to 2% procaine HCl injection. Final concentration is polymyxin B 250,000 units/mL.
    Inject IM deeply into upper outer quadrant of the gluteal muscles.

    Intrathecal Administration

    Do not use procaine HCl or preserved solutions to reconstitute.
    Reconstitute powder for injection with 10 ml of preservative-free NS injection. Final concentration is polymyxin 50,000 units/ml.
    Using aseptic technique, withdraw the appropriate dose.
    After ensuring proper placement of the needle or catheter, inject appropriate dose intrathecally.

    Topical Administration

    Reconstitute 50 mg polymyxin B powder with 10 ml sterile water for injection or NS injection to provide a 0.5% polymyxin B solution. The solution may be further diluted to 50 ml to provide a 0.1% solution.
    Apply as part of wet dressings or as a topical solution.

    Ophthalmic Administration

    Do not use commercially available ophthalmic solutions for subconjunctival injection.
    Reconstitute powder for injection with 20—50 ml of sterile water for injection or NS injection. Final concentration is polymyxin B 25,000—10,000 units/ml.

    Other Administration Route(s)

    Bladder Irrigation
    NOTE: Polymyxin B is not approved by the FDA for administration as a bladder irrigation.
    For bladder irrigation, dilute 20—40 mg (200,000—400,000 units) of polymyxin B powder in 1000 ml sterile 0.9% Sodium Chloride (NS).

    STORAGE

    Generic:
    - 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 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 disease, renal failure, renal impairment

    Polymyxin B requires dosage adjustment for patients with renal disease, renal impairment, or renal failure. Assess baseline renal-function prior to treatment and regularly during treatment. 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. Patients with renal impairment are also at increased risk for neurotoxicity due to increased serum levels. 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, particularly amikacin, bacitracin, cephaloridine, colistin, gentamicin, kanamycin, neomycin, paromomycin, streptomycin, tobramycin, and viomycin.

    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

    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

    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.
    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.