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Polymyxin B Sulfate topical

Pronunciation

Class: Polymyxins
VA Class: AM900
CAS Number: 1405-20-5
Brands: Poly-Rx, Neosporin G.U. Irrigant

Warning(s)

  • Administer IV, IM, or intrathecally only to hospitalized patients under constant supervision by a clinician.100 101 102

  • Nephrotoxic.100 101 102 Assess renal function prior to therapy.100 101 102 Reduce dosage in patients with renal damage and nitrogen retention.100 101 102 Polymyxin B-associated nephrotoxicity usually manifests as albuminuria, cellular casts, and azotemia.100 101 102 Discontinue in patients with decreasing urine output and increasing BUN.100 101 102

  • Neurotoxic.100 101 102 Neurotoxicity may be manifested by irritability, weakness, drowsiness, ataxia, perioral paresthesia, numbness of the extremities, and vision blurring.100 101 102 Usually associated with high polymyxin B serum concentrations found in patients with impaired renal function and/or nephrotoxicity.100 101 102

  • Neurotoxicity may result in respiratory paralysis from neuromuscular blockade, especially when given soon after anesthesia and/or muscle relaxants.100 101 102

  • Avoid concomitant or sequential use of neurotoxic and/or nephrotoxic drugs, particularly bacitracin, aminoglycosides (amikacin, gentamicin, kanamycin, neomycin, paromomycin, streptomycin, tobramycin), cephaloridine (not commercially available in the US), colistimethate/colistin, and viomycin (not commercially available in the US).100 101 102 145

  • Safety not established in pregnant women.100 101 102

Introduction

Antibacterial; polymyxin antibiotic structurally and pharmacologically related to colistin.14 105

Uses for Polymyxin B Sulfate

Meningitis and Other CNS Infections

Alternative for treatment of meningeal infections caused by susceptible gram-negative bacteria, including Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Haemophilus influenzae.100 101 102 113 136

Used intrathecally100 101 102 136 or intraventricularly for treatment of meningitis or other CNS infections.113 136 May be effective when used intrathecally alone, but usually used in conjunction with a parenteral anti-infective (e.g., IV or IM polymyxin B, IV meropenem, IV penicillin, IV cephalosporin).113 136

Penetrates poorly into CSF following IM or IV administration;100 101 102 do not use parenteral polymyxin B alone for treatment of meningitis or other CNS infections.146

Used for infections that are resistant to or do not respond to regimens of choice.100 101 102 105 136

Respiratory Tract Infections

Alternative for treatment of respiratory tract infections, including nosocomial pneumonia, ventilator-associated pneumonia, or healthcare-associated pneumonia, caused by multidrug-resistant gram-negative bacteria (e.g., Ps. aeruginosa,115 122 126 Acinetobacter baumannii).115 117 122 Used in these infections only when other less toxic anti-infectives are ineffective or contraindicated.100 101 102 105 117 121 122

Slideshow: View Frightful (But Dead Serious) Drug Side Effects

IV polymyxin B has been used alone or in conjunction with IV aztreonam for treatment of nosocomial pneumonia caused by multidrug-resistant Ps. aeruginosa, including those that produce metallo-β-lactamases.126 Nosocomial infections caused by metallo-β-lactamase-producing Ps. aeruginosa have a high mortality rate, and fatalities may occur despite appropriate anti-infective therapy.126 Optimal regimens for treatment of these infections not identified to date.126

Administered by oral inhalation via nebulization for treatment of respiratory tract infections caused by susceptible gram-negative bacteria (e.g., Ps. aeruginosa, A. baumannii).105 109 112 116 117 122 127 Generally used in conjunction with a parenteral anti-infective (e.g., IV polymyxin B);116 117 122 has been effective when given by oral inhalation alone in some patients with infections caused by susceptible gram-negative bacteria.116 122

Although safety and efficacy not established and additional study needed, ATS, IDSA, and other clinicians suggest that adjunctive use of aerosolized polymyxin B can be considered for treatment of serious respiratory tract infections (e.g., ventilator-associated pneumonia) caused by multidrug-resistant gram-negative bacteria that have not responded to treatment with parenteral anti-infectives alone.107 112 116 122

Septicemia

Treatment of septicemia or bacteremia caused by susceptible Ps. aeruginosa, Enterobacter aerogenes, or K. pneumoniae.100 101 102 124 Also has been used for treatment of bloodstream infections caused by multidrug-resistant A. baumannii.117

Generally used only when other less toxic anti-infectives are ineffective or contraindicated.100 101 102 105 121 124

May be a drug of choice for treatment of septicemia or bacteremia caused by Ps. aeruginosa.100 101 102 Has been used alone or in conjunction with other anti-infectives (e.g., aztreonam) for infections caused by multidrug-resistant Ps. aeruginosa, including those that produce metallo-β-lactamases.124 Nosocomial blood stream infections caused by metallo-β-lactamase-producing Ps. aeruginosa have a high mortality rate, and fatalities may occur despite appropriate anti-infective therapy.124 Optimal regimens for treatment of these infections not identified to date.124

Urinary Tract Infections (UTIs)

Treatment of serious UTIs caused by susceptible Ps. aeruginosa or E. coli,100 101 102

Generally used only when other less toxic anti-infectives are ineffective or contraindicated.100 101 102 105 121

Bacteriuria and Bacteremia Associated with Indwelling Catheters

Fixed-combination solution for irrigation containing polymyxin B and neomycin used in abacteriuric patients for short-term (≤10 days) irrigation or rinse of the urinary bladder to help prevent bacteriuria and gram-negative rod septicemia associated with use of indwelling catheters.103 104

Some clinicians state that irrigation or rinse of the urinary bladder with anti-infective solutions is unlikely to be of benefit while the catheter is in place and such a strategy is not recommended.146

Use fixed-combination solution for irrigation only for irrigation of the bladder; do not use for irrigation of other areas.103 104

Polymyxin B Sulfate Dosage and Administration

Administration

Usually administered IV.100 101 102 May be given by IM injection, but IM administration not routinely recommended because severe pain occurs at injection site, especially in infants and children.100 101 102

Administer intrathecally100 101 102 136 or intraventricularly for treatment of meningitis or other CNS infections.113 114 136 Do not use IV or IM administration alone for treatment of meningitis or other CNS infections since distribution into CNS is expected to be low following these routes.100 101 102 136

Although safety and efficacy not established, has been administered by oral inhalation via nebulization for adjunctive treatment of respiratory tract infections.105 107 112 116 117 127

Fixed-combination solution for irrigation containing polymyxin B and neomycin is administered by continuous irrigation of the urinary bladder.103 104

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Reconstitution

Reconstitute polymyxin B powder for injection by dissolving 500,000 units of the drug in 300–500 mL of 5% dextrose injection100 101 102 to provide solutions containing approximately 1000–1667 units/mL.

Rate of Administration

IV infusions of polymyxin B usually are given over 60–90 minutes.105 An infusion period <30 minutes should not be used.105 Because of risk of neuromuscular blockade, avoid rapid IV injections.105

IM Administration

Inject deeply into upper outer quadrant of gluteal muscle;146 a alternate injection sites.146 Severe injection site pain may occur, especially in infants and children.100 101 102

Reconstitution

Reconstitute polymyxin B powder for injection by adding 2 mL of sterile water for injection, 0.9% sodium chloride injection, or 1% procaine hydrochloride injection to vial containing 500,000 units100 101 102 to provide a solution containing approximately 250,000 units/mL.

Intrathecal Administration

Reconstitution

Reconstitute polymyxin B powder for injection by adding 10 mL of 0.9% sodium chloride injection to a vial containing 500,000 units to provide a solution containing approximately 50,000 units/mL.100 101 102 Do not use procaine hydrochloride solutions to prepare intrathecal injections.146 a

Oral Inhalation

For oral inhalation via nebulization, 0.5% solutions have been prepared using 0.9% sodium chloride.112 Polymyxin B concentrations >10 mg/mL should not be used for administration by oral inhalation since bronchial irritation may occur.105

Urinary Bladder Irrigation

Dilution

Add contents of a 1-mL ampul of the fixed-combination solution for irrigation containing 200,000 units of polymyxin B and 40 mg of neomycin to 1 L of 0.9% sodium chloride solution using strict aseptic technique.103 104

Administer diluted solution for irrigation via a 3-way catheter at a rate of 1 L every 24 hours (approximately 40 mL/hour).103 104 If patient's urine output is >2 L/day, the manufacturers recommend that inflow rate be adjusted to deliver 2 L every 24 hours.103 104

If not used immediately, store diluted irrigation solution at 4°C and use within 48 hours.103 104

Administer continuously for up to 10 days; do not interrupt the inflow or rinse solution for more than a few minutes.103 104

Dosage

Available as polymyxin B sulfate; dosage expressed in terms of polymyxin B activity (units of polymyxin B)100 101 102 105 or mg of polymyxin B base.100 101 102

Each mg of polymyxin B is equivalent to 10,000 units of polymyxin B.100 101 102 105

Pediatric Patients

Meningitis and Other CNS Infections
Intrathecal

Infants <2 years of age: Initially, 20,000 units once daily for 3–4 days or 25,000 units once every other day.100 101 102 With either regimen, continue treatment with 25,000 units once every other day given for at least 2 weeks after CSF cultures are negative and CSF glucose is normal.100 101 102

Children ≥2 years: 50,000 units once daily for 3 to 4 days, followed by 50,000 units once every other day given for at least 2 weeks after CSF cultures are negative and CSF glucose is normal.100 101 102

Although safety and efficacy not established, a variety of other dosage regimens of intrathecal or intraventricular polymyxin B (with or without concomitant parenteral therapy with IV or IM polymyxin B or other anti-infectives) have been used.136

Septicemia or Urinary Tract Bacterial Infections
IV

Infants with normal renal function: Up to 40,000 units/kg daily.100 101 102

Children with normal renal function: 15,000-25,000 units/kg daily (1.5–2.5 mg/kg daily).100 101 102

Daily dosage may be given in 2 divided doses every 12 hours.100 101 102

IM

Infants with normal renal function: Up to 40,000 units/kg daily.100 101 102 Premature and full-term neonates have received up to 45,000 units/kg daily (4.5 mg/kg daily) for treatment of sepsis caused by Ps. aeruginosa in clinical studies.100 101 102

Children with normal renal function: 25,000-30,000 units/kg daily (2.5–3 mg/kg daily).100 101 102

Daily dosage may be divided and given at 4- or 6-hour intervals.100 101 102

Adults

Meningitis and Other CNS Infections
Intrathecal

50,000 units once daily for 3–4 days, followed by 50,000 units once every other day given for at least 2 weeks after CSF cultures are negative and CSF glucose is normal.100 101 102

Although safety and efficacy not established, a variety of other dosage regimens of intrathecal or intraventricular polymyxin B (with or without concomitant parenteral therapy with IV or IM polymyxin B or other anti-infectives) have been used.136

Respiratory Tract Infections
Oral Inhalation

Adults have received 2.5 mg/kg daily in divided doses every 6 hours for adjunctive treatment of respiratory tract infections caused by susceptible Ps. aeruginosa.122 127 If a 0.5% solution of the drug is prepared using 0.9% sodium chloride and this dosage regimen is used, the average 70-kg patient would receive 6 mL of solution per dose.112

Adults have received 500,000 units twice daily given approximately 20 minutes after an oral inhalation dose of a β2-adrenergic agonist.116

Oral inhalation has been used in conjunction with IV polymyxin B for treatment of pneumonia; oral inhalation has been used alone for treatment of tracheobronchitis caused by Ps. aeruginosa.116

Oral inhalation treatment has been continued for an average of 14 days (range: 4–25 days).116

Septicemia and Urinary Tract Bacterial Infections
IV

Adults with normal renal function: 15,000–25,000 units/kg daily (1.5–2.5 mg/kg daily).100 101 102

Daily dosage may be given in 2 divided doses every 12 hours.100 101 102

IM

Adults with normal renal function: 25,000-30,000 units/kg daily (2.5–3 mg/kg daily).100 101 102

Daily dosage may be divided and given at 4- or 6-hour intervals.100 101 102

Bacteriuria and Bacteremia Associated with Indwelling Urinary Catheters
Urinary Bladder Irrigation

Administer via a 3-way catheter at a rate of 1 L every 24 hours (approximately 40 mL/hour).103 104 If patient’s urine output is >2 L/day, administer at a rate of 2 L every 24 hours.103 104

Duration of irrigation therapy should not exceed 10 days.103 104

Prescribing Limits

Pediatric Patients

Septicemia and Urinary Tract Infections
IV

Infants with normal renal function: Maximum dosage 40,000 units/kg daily.100 101 102

Children with normal renal function: Maximum dosage 25,000 units/kg daily.100 101 102

IM

Premature and full-term neonates: Limited experience with dosages as high as 45,000 units/kg daily.100 101 102

Infants with normal renal function: Maximum dosage 40,000 units/kg daily.100 101 102

Adults

Septicemia and Urinary Tract Infections
IV

Adults with normal renal function: Maximum dosage 25,000 units/kg daily.100 101 102

IM

Adults with normal renal function: Maximum dosage 30,000 units/kg daily.100 101 102

Bacteriuria and Bacteremia Associated with Indwelling Urinary Catheters
Urinary Bladder Irrigation

Maximum duration 10 days.103 104

Special Populations

Renal Impairment

Decrease dosage in patients with renal impairment.14 100 101 102 105 112 125 Monitor serum polymyxin B concentrations and adjust IV or IM dosage to maintain desired serum concentrations of the drug.105 146

Various dosage regimens have been recommended; these regimens are not well established and are not based on pharmacokinetic data from patients with renal impairment.105 109 115 125 134

It has been recommended that patients with Clcr 30–80 mL/minute receive an IV loading dose of 2.5 mg/kg on the first day of treatment followed by 1–1.5 mg/kg daily and that those with Clcr <25–30 mL/minute receive these doses once every 2–3 days.134 For anuric patients, some clinicians recommend an IV loading dose of 2.5 mg/kg followed by 1–1.5 mg/kg given once every 5–7 days.112 134

Some clinicians suggest that patients with Clcr >20 mL/minute receive 75–100% of the usual daily dose in 2 divided doses every 12 hours, those with Clcr 5–20 mL/minute receive 50% of the usual daily dose in 2 divided doses every 12 hours, and those with Clcr <5 mL/minute receive 30% of the usual daily dose every 12–18 hours.105 Some have used 75% of the usual daily dose in those with Clcr 20–50 mL/minute and 33% of the usual daily dose in those with Clcr <20 mL/minute.115

Cautions for Polymyxin B Sulfate

Contraindications

  • Polymyxin B: History of hypersensitivity to polymyxins.100 101 102

  • Fixed combination solution for irrigation containing polymyxin B and neomycin solution: Hypersensitivity to polymyxins, neomycin, or any ingredient in the formulation.103 104 History of hypersensitivity or serious toxic reaction to an aminoglycoside.103 104

Warnings/Precautions

Warnings

Nephrotoxicity

Can cause potentially serious nephrotoxicity.100 101 102 105 111 112 115 117 122

Polymyxin B-associated nephrotoxicity is considered to be dose-dependent,111 112 has been reported in 6–25% of patients receiving usual dosages,111 112 115 117 122 and generally is reversible after the drug is discontinued.112

Nephrotoxicity usually is manifested by albuminuria or proteinuria,100 101 102 105 111 cylindruria,100 101 102 111 azotemia,100 101 102 increasing blood concentrations of the drug (not related to an increase in dosage),100 101 102 and an increase in serum creatinine concentration and decrease in Clcr.111 Acute tubular necrosis,111 oliguria,111 hematuria,105 111 leukocyturia,a and excessive excretion of electrolytes may occur.a

Determine baseline renal function prior to initiation of polymyxin B therapy; monitor renal function frequently during therapy using blood tests and urinalysis.100 101 102 146 The manufacturers also recommend that serum concentrations of the drug be monitored frequently during therapy.100 101 102 Use reduced dosage in patients with impaired renal function or renal damage and nitrogen retention.100 101 102 (See Renal Impairment under Dosage and Administration.)

Discontinue polymyxin B if urine output diminishes or BUN concentration increases.100 101 102

Avoid concurrent or sequential use of other nephrotoxic drugs.100 101 102 111 112 (See Interactions.)

Neurotoxicity

Can cause potentially serious neurotoxicity.100 101 102 105 111 112 117 135

Polymyxin B-associated neurotoxicity is considered to be dose-dependent111 112 and generally subsides after the drug is discontinued.105 111 135

Neurotoxicity may manifest as facial flushing,100 101 102 dizziness100 101 102 111 that may progress to ataxia,100 101 102 105 altered mental status or mental confusion,105 117 irritability,100 101 102 nystagmus,a muscle weakness,105 111 122 drowsiness,100 101 102 giddiness,105 and peripheral paresthesia (circumoral and stocking glove).100 101 102 105 111 117 135

Numbness,105 a blurring of vision100 101 102 or vision disturbances,111 112 slurred speech,a coma,105 and seizures105 111 122 also can occur.

Avoid concurrent or sequential use of other neurotoxic drugs.100 101 102 111 112 (See Interactions.)

Neuromuscular Blockade

Respiratory paralysis resulting in respiratory failure or apnea may occur as a result of neuromuscular blockade,100 101 102 105 111 112 especially in patients with neuromuscular disease such as myasthenia gravis or in patients who are receiving neuromuscular blocking agents or general anesthetics.100 101 102 111 112 (See Interactions.)

Polymyxin B-induced neuromuscular blockade is not easily reversed and is resistant to neostigmine105 and edrophonium;a calcium chloride has been used successfully in some cases.105

If signs of respiratory paralysis occur, assist respiration and discontinue polymyxin B.100 101 102 111 Neuromuscular blockade usually improves within 24 hours after polymyxin B is discontinued.105

Sensitivity Reactions

Hypersensitivity

Fever,100 101 102 105 111 rash,105 111 pruritus,105 111 urticaria,100 101 102 111 skin exanthemata,a eosinophilia,a and anaphylactoid reactions with dyspnea and tachycardiaa reported rarely during parenteral polymyxin B therapy.

General Precautions

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of polymyxin B and other antibacterials, use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.100 101 102

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.100 101 102 In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.100 101 102

Superinfection

As with other anti-infectives, use of polymyxin B may result in overgrowth of nonsusceptible organisms, including fungi.100 101 102 Institute appropriate therapy if superinfection occurs.100 101 102

Precautions Related to Fixed-combination Solution for Bladder Irrigation

Consider the precautions and contraindications related to both polymyxin B and neomycin.103 104

Should be used only for irrigation of the bladder; do not use for irrigation of other areas.103 104

Do not use for prophylactic bladder care if there is a possibility of systemic absorption.103 104 The likelihood of toxicity following topical irrigation of the intact urinary bladder is low since appreciable amounts of polymyxin B or neomycin do not enter systemic circulation if the duration of irrigation is ≤10 days.103 104 However, absorption of neomycin from the denuded bladder surface has been reported.103 104 Systemic absorption after topical application of neomycin to open wounds, burns, and granulating surfaces is clinically significant, and serum concentrations comparable to or higher than those attained following oral and parenteral therapy have been reported.103 104

Use only for continuous prophylactic irrigation (maximum of 10 days) of the lumen of the intact urinary bladder of patients with indwelling catheters who are under constant supervision by a clinician.103 104 Because of the risk of toxicity due to systemic absorption following diffusion into absorptive tissues and spaces, avoid use if there are defects in bladder mucosa or bladder wall, such as vesical rupture, or in association with operative procedures on the bladder wall.103 104

If absorption occurs, consider that both polymyxin B and neomycin are nephrotoxic and neurotoxic and that the effects of the drugs may be additive.103 104

Collect urine specimens for urinalysis, culture, and susceptibility testing during prophylactic bladder care;103 104 positive cultures suggest the presence of organisms resistant to polymyxin B and neomycin.103 104

Take appropriate measures if overgrowth of nonsusceptible organisms, including fungi, occurs.103 104

Specific Populations

Pregnancy

Polymyxin B: Safety not established in pregnant women.100 101 102

Some clinicians state that polymyxin B should not be used during pregnancy, except in rare situations when other appropriate anti-infectives cannot be used.146

Fixed-combination solution for irrigation containing polymyxin B and neomycin: If use is being considered for a pregnant woman, inform the woman of the potential hazard to the fetus.103 104 Aminoglycosides cross the placenta and there have been reports of complete, irreversible, bilateral congenital deafness in children whose mothers received an aminoglycoside (i.e., streptomycin) during pregnancy.103 104

Pediatric Use

Polymyxin B: Used IV in infants and children.100 101 102 IM route not routinely used in infants and children because severe pain occurs at the injection site, especially in this age group.100 101 102

Fixed-combination solution for irrigation containing polymyxin B and neomycin: Safety and efficacy not established in children.103 104

Renal Impairment

Risk of nephrotoxicity and neurotoxicity may be increased in patients with renal impairment;105 112 use reduced dosage.14 100 101 102 105 112 125 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

IV or IM: Nephrotoxicity,100 101 102 105 111 112 115 117 122 neurotoxicity,100 101 102 105 111 117 112 135 fever,100 101 102 105 111 rash,105 111 pruritus,105 111 urticaria.100 101 102 111 Severe pain at IM injection site;100 101 102 105 thrombophlebitis at IV site.100 101 102

Intrathecal: Meningeal irritation,100 101 102 136 headache,100 101 102 fever,100 101 102 stiff neck,100 101 102 increased leukocytes and protein in the CSF.100 101 102

Oral inhalation via nebulization: Bronchial irritation,105 cough,116 bronchospasm,105 116 acute airway obstruction.112

Bladder irrigation with fixed-combination solution containing polymyxin B and neomycin: Irritation of bladder mucosa.103 104

Interactions for Polymyxin B Sulfate

Nephrotoxic and Neurotoxic Drugs

Since nephrotoxic and neurotoxic effects may be additive, concurrent or sequential use of polymyxin B and other nephrotoxic and/or neurotoxic drugs, particularly bacitracin, aminoglycosides (amikacin, gentamicin, kanamycin, neomycin, paromomycin, streptomycin, tobramycin), colistimethate/colistin, and viomycin (not commercially available in the US) should be avoided.100 101 102 111 112 145

Specific Drugs

Drug

Interaction

Comments

Aminoglycosides (amikacin, gentamicin, kanamycin, neomycin, paromomycin, streptomycin, tobramycin)

Possible potentiation of nephrotoxic and/or neurotoxic effects100 101 102 111 112

Avoid concomitant or sequential use100 101 102 111 112

Azithromycin

In vitro evidence of synergistic antibacterial effects between polymyxin B and azithromycin against some strains of multidrug-resistant Ps. aeruginosa; the combination has been bactericidal against some strains, but bacteriostatic against other strains143

Clinical importance of in vitro studies evaluating combination of polymyxin B and azithromycin against gram-negative bacteria is unclear143

Carbapenems (imipenem, meropenem)

In vitro evidence of synergistic antibacterial effects between polymyxin B and imipenem against Ps. aeruginosa;143 indifferent antibacterial effects in vitro when combined with meropenem142

Conflicting in vitro results reported with imipenem or meropenem against A. baumannii;118 119 125 133 142 143 in vitro antibacterial effects have been synergistic, partially synergistic, additive, or indifferent118 125 133 142

Clinical importance of in vitro studies evaluating combinations of polymyxin B and carbapenems against gram-negative bacteria is unclear119 143

Colistimethate/colistin

Possible potentiation of nephrotoxic effects100 101 102 111 112 145

Possible potentiation of neuromuscular blockade145

Avoid concomitant use; use caution145

Neuromuscular blocking agents and general anesthetics (ether, succinylcholine, tubocurarine, gallamine, decamethonium)

Possible potentiation of neuromuscular blockade which may precipitate respiratory depression, especially if polymyxin B is given soon after anesthesia and/or muscle relaxants100 101 102 111

Avoid concomitant use100 101 102

If signs of respiratory paralysis occur, assist respiration and discontinue polymyxin B100 101 102 111

Rifampin

In vitro evidence of synergistic antibacterial effects between polymyxin B and rifampin against multidrug-resistant Ps. aeruginosa; a 3-drug combination of polymyxin B, rifampin, and imipenem was more consistently bactericidal against these strains143

In some in vitro studies, combination of polymyxin B and rifampin (with or without imipenem) was synergistic or additive against A. baumannii118 125 133

Combination of polymyxin B and rifampin was synergistic in vitro against K. pneumoniae125

Clinical importance of in vitro studies evaluating combinations of polymyxin B and rifampin against gram-negative bacteria is unclear143

Sodium citrate

May precipitate respiratory depression100 101 102

Avoid concomitant use100 101 102

Polymyxin B Sulfate Pharmacokinetics

Absorption

Bioavailability

Not absorbed from GI tract.14 100 101 102 105 144

Not absorbed to an appreciable extent from mucous membranes14 or intact or denuded skin.14 a

After IM administration of a single dose of 20,000–40,000 units/kg (2–4 mg/kg) in adults, peak serum concentrations of 1–8 mcg/mL are obtained144 within approximately 2 hours.a Drug may be detectable in serum for up to 12 hours.a

Serum concentrations are higher in infants and children than in adults.100 101 102

In critically ill adults who received doses of 0.5–1.5 mg/kg by IV infusion over 60 minutes, peak plasma concentrations at completion of the infusion ranged from 2.38–13.9 mcg/mL and concentrations of polymyxin B1 were fourfold higher than concentrations of polymyxin B2.123 (See Actions.)

Special Populations

Serum concentrations are higher and more prolonged in patients with renal impairment.105 (See Actions.)

Distribution

Extent

Diffuses poorly in tissues.100 101 102 Does not distribute into synovial fluid or aqueous humor following systemic administration.a

Following IV or IM administration, not distributed into CSF100 101 102 105 (even when meninges are inflamed).a

Does not cross the placenta.a

Plasma Protein Binding

In an in vitro study using plasma from critically ill adults, polymyxin B was 78.5–92.4% bound to plasma proteins; however, mean protein binding was only 55.9% when testing was done using pooled plasma from healthy individuals.123

Elimination

Elimination Route

Eliminated in urine principally by glomerular filtration.144 Some studies indicate only low amounts of the dose eliminated in urine within the first 12 hours after a dose, but eventually approximately 60% of a dose excreted in urine.105 Other studies suggest that <1% of a dose eliminated unchanged in urine over 3 days.123

Half-life

4.3-6 hours in adults with normal renal function.a

Special Populations

Adults with Clcr <10 mL/minute: half-life increases to 2–3 days.a

Not removed to an appreciable extent by hemodialysis or peritoneal dialysis.105 111 112

Stability

Storage

Parenteral

Powder for Injection

15–30°C or 20–25°C, depending on the manufacturer;100 101 102 protect from light.100 101 102 Following reconstitution, store at 2–8°C and discard any unused portions after 72 hours.100 101 102

Solution for Bladder Irrigation

Fixed-combination Solution Containing Polymyxin B and Neomycin

2-8°C.103 104 Following dilution in 0.9% sodium chloride solution, store at 4°C and use within 48 hours.103 104

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Dextrose 5% in water100 101 102

Sodium chloride 0.9%HID

Drug CompatibilityHID
Admixture Compatibility

Compatible

Amikacin sulfate

Ascorbic acid injection

Colistimethate sodium

Diphenhydramine HCl

Erythromycin lactobionate

Hydrocortisone sodium succinate

Lincomycin HCl

Penicillin G potassium

Penicillin G sodium

Phenobarbital sodium

Ranitidine HCl

Incompatible

Amphotericin B

Chloramphenicol sodium succinate

Chlorothiazide sodium

Heparin sodium

Magnesium sulfate

Y-Site CompatibilityHID

Compatible

Esmolol HCl

Actions

  • Structurally and pharmacologically related to colistin.14 105 Commercially available polymyxin B sulfate is a mixture of the sulfate salts of polymyxins B1 and B2.14 100 101 102 103 104

  • Usually bactericidal in action.100 101 102 105 109 125 131

  • Acts like a cationic detergent and binds to and damages bacterial cytoplasmic membrane of susceptible bacteria causing alteration of the osmotic barrier and leakage of essential intracellular components.14 105 112 125 144

  • Spectrum of activity is similar to that of colistin.14 105 125 140

  • Active in vitro against many gram-negative aerobic bacteria, but inactive against gram-positive bacteria, anaerobic bacteria, fungi, and viruses.105 112 125 144

  • Active in vitro against most strains of Pseudomonas aeruginosa, including many multidrug-resistant strains105 107 108 112 115 122 125 129 130 131 140 141 144 (e.g., those that produce metallo-β-lactamase).108 126 130 Also active in vitro against many strains of Acinetobacter baumannii, including multidrug-resistant strains.105 115 122 125 140 141

  • Active in vitro against most Enterobacteriaceae, including most strains of Citrobacter,125 141 Escherichia coli,105 112 125 141 Klebsiella pneumoniae,105 125 140 141 Salmonella,105 112 125 141 and Shigella,105 112 125 141 and some strains of Enterobacter.105 125 141 Generally inactive against Proteus,105 112 125 140 141 Providencia,112 125 Morganella,125 and Serratia marcescens.105 112 125 140 141

  • Has some activity against Haemophilus influenzae,105 125 Bordetella pertussis,105 125 and Legionella pneumophila,105 125 but inactive against Moraxella catarrhalis,125 Neisseria,105 125 and Brucella.125

  • May be active against some strains of Stenotrophomonas maltophilia,125 140 141 but inactive against Burkholderia cepacia (formerly Ps. cepacia).105 125 140 141

  • Resistance to polymyxin B has been reported rarely in Ps. aeruginosa105 125 131 140 141 143 and A. baumannii.125 138 140 141

  • Two types of resistance to polymyxin B have been identified in Ps. aeruginosa, including low-level, transmissible mutations and high-level, stepwise resistance.140

  • Complete cross-resistance occurs between polymyxin B and colistin; cross-resistance with other anti-infectives not reported to date.105 125 131 140 144

Advice to Patients

  • Advise patients that antibacterials (including polymyxin B) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).100 101 102

  • Importance of completing full course of therapy, even if feeling better after a few days.100 101 102

  • Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with polymyxin B or other antibacterials in the future.100 101 102

  • Importance of informing clinicians of existing concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., renal impairment, neuromuscular disease).100 101 102

  • Importance of women informing their clinician if they are or plan to become pregnant.100 101 102

  • Importance of informing patients of other important precautionary information.100 101 102 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Polymyxin B Sulfate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Bulk

Powder*

100 million units (of polymyxin B)

Poly-Rx

X-Gen

Parenteral

For injection

500,000 units (of polymyxin B)*

Polymyxin B Sulfate For Injection

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Neomycin and Polymyxin B Sulfates

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Urogenital

Solution, for irrigation

Neosporin Sulfate (40 mg of neomycin) per mL and Polymyxin B Sulfate 200,000 units (of polymyxin B) per mL*

Neomycin and Polymyxin B Sulfates Solution for Irrigation

Neosporin G.U. Irrigant

Monarch

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 4, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

14. Bruton LL, Lazo JS, Parker KL, eds. Goodman and Gilman's pharmacological basis of therapeutics. 11th ed. New York, NY: McGraw-Hill; 2005: 1193-4.

100. X-Gen Pharmaceuticals. Polymyxin B for injection USP prescribing information. Northport, NY; 2006 May.

101. Bedford Laboratories. Polymyxin B for injection prescribing information. Bedford, OH; 2004 Feb

102. Abraxis. Polymyxin B for injection, USP prescribing information. Schaumburg, IL. 2007 Jan.

103. Watson Laboratories. Neomycin and polymyxin B sulfates solution for irrigation USP prescribing information. Corona, CA; 2005 Dec.

104. Monarch Pharmaceuticals. Neosporin G.U. irrigant sterile (neomycin sulfate-polymyxin B sulfate solution for irrigation) prescribing information. Bristol, TN; 2003 May.

105. Kucers A, Crowe S, Grayson ML et al, eds. The use of antibiotics. A clinical review of antibacterial, antifungal, and antiviral drugs. 5th ed. Jordan Hill, Oxford: Butterworth-Heinemann; 1997: 667-75.

106. Anon. Choice of antibacterial drugs. Med Lett Treat Guid. 2007; 5:33-50.

107. American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005; 171:388-416. [PubMed 15699079]

108. Miyajima Y, Hiramatsu K, Mizukami E et al. In vitro and in vivo potency of polymyxin B against IMP-type metallo-beta-lactamase-producing Pseudomonas aeruginosa. Int J Antimicrob Agents. 2008; 32:437-40. [PubMed 18715759]

109. Michalopoulos A, Falagas ME. Colistin and polymyxin B in critical care. Crit Care Clin. 2008; 24:377-91, x. [PubMed 18361952]

110. Falagas ME, Kasiakou SK, Michalopoulos A. Polymyxins: a word of caution for prudent use of valuable “old antibiotics”. Infect Control Hosp Epidemiol. 2006; 27:995. [PubMed 16941333]

111. Falagas ME, Kasiakou SK. Toxicity of polymyxins: a systematic review of the evidence from old and recent studies. Crit Care. 2006; 10:R27. [PubMed 16507149]

112. Evans ME, Feola DJ, Rapp RP. Polymyxin B sulfate and colistin: old antibiotics for emerging multiresistant gram-negative bacteria. Ann Pharmacother. 1999; 33:960-7. [PubMed 10492501]

113. Segal-Maurer S, Mariano N, Qavi A et al. Successful treatment of ceftazidime-resistant Klebsiella pneumoniae ventriculitis with intravenous meropenem and intraventricular polymyxin B: case report and review. Clin Infect Dis. 1999; 28:1134-8. [PubMed 10452648]

114. Tunkel AR, Hartman BJ, Kaplan SL et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004; 39:1267-84. [IDIS 537717] [PubMed 15494903]

115. Ouderkirk JP, Nord JA, Turett GS et al. Polymyxin B nephrotoxicity and efficacy against nosocomial infections caused by multiresistant gram-negative bacteria. Antimicrob Agents Chemother. 2003; 47:2659-62. [PubMed 12878536]

116. Pereira GH, Muller PR, Levin AS. Salvage treatment of pneumonia and initial treatment of tracheobronchitis caused by multidrug-resistant Gram-negative bacilli with inhaled polymyxin B. Diagn Microbiol Infect Dis. 2007; 58:235-40. [PubMed 17350201]

117. Holloway KP, Rouphael NG, Wells JB et al. Polymyxin B and doxycycline use in patients with multidrug-resistant Acinetobacter baumannii infections in the intensive care unit. Ann Pharmacother. 2006; 40:1939-45. [PubMed 17018688]

118. Wareham DW, Bean DC. In-vitro activity of polymyxin B in combination with imipenem, rifampicin and azithromycin versus multidrug resistant strains of Acinetobacter baumannii producing OXA-23 carbapenemases. Ann Clin Microbiol Antimicrob. 2006; 5:10. [PubMed 16630352]

119. Wareham DW, Bean DC. In vitro activities of polymyxin B, imipenem, and rifampin against multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2006; 50:825; author reply 825-6.

120. Ostronoff M, Ostronoff F, Sucupira A et al. Multidrug-resistant Pseudomonas aeruginosa infection in neutropenic patients successfully treated with a combination of polymyxin B and rifampin. Int J Infect Dis. 2006; 10:339-40. [PubMed 16412679]

121. Obritsch MD, Fish DN, MacLaren R et al. Nosocomial infections due to multidrug-resistant Pseudomonas aeruginosa: epidemiology and treatment options. Pharmacotherapy. 2005; 25:1353-64. [PubMed 16185180]

122. Sobieszczyk ME, Furuya EY, Hay CM et al. Combination therapy with polymyxin B for the treatment of multidrug-resistant Gram-negative respiratory tract infections. J Antimicrob Chemother. 2004; 54:566-9. [PubMed 15269195]

123. Zavascki AP, Goldani LZ, Cao G et al. Pharmacokinetics of intravenous polymyxin B in critically ill patients. Clin Infect Dis. 2008; 47:1298-304. [PubMed 18840079]

124. Zavascki AP, Barth AL, Goldani LZ. Nosocomial bloodstream infections due to metallo-beta-lactamase-producing Pseudomonas aeruginosa. J Antimicrob Chemother. 2008; 61:1183-5. [PubMed 18319237]

125. Zavascki AP, Goldani LZ, Li J et al. Polymyxin B for the treatment of multidrug-resistant pathogens: a critical review. J Antimicrob Chemother. 2007; 60:1206-15. [PubMed 17878146]

126. Zavascki AP, Barth AL, Fernandes JF et al. Reappraisal of Pseudomonas aeruginosa hospital-acquired pneumonia mortality in the era of metallo-beta-lactamase-mediated multidrug resistance: a prospective observational study. Crit Care. 2006; 10:R114. [PubMed 16882337]

127. Falagas ME, Kasiakou SK. Local administration of polymyxins into the respiratory tract for the prevention and treatment of pulmonary infections in patients without cystic fibrosis. Infection. 2007; 35:3-10. [PubMed 17297582]

128. Falagas ME, Kasiakou SK, Tsiodras S et al. The use of intravenous and aerosolized polymyxins for the treatment of infections in critically ill patients: a review of the recent literature. Clin Med Res. 2006; 4:138-46. [PubMed 16809407]

129. Raja NS, Singh NN. Antimicrobial susceptibility pattern of clinical isolates of Pseudomonas aeruginosa in a tertiary care hospital. J Microbiol Immunol Infect. 2007; 40:45-9. [PubMed 17332906]

130. Ribeiro J, Mendes RE, Domingos R et al. Microbiological and epidemiological characterization of imipenem-resistant Pseudomonas aeruginosa strains from a Brazilian tertiary hospital: report from the SENTRY Antimicrobial Surveillance Program. J Chemother. 2006; 18:461-7. [PubMed 17127220]

131. Tam VH, Schilling AN, Vo G et al. Pharmacodynamics of polymyxin B against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2005; 49:3624-30. [PubMed 16127031]

132. Chaudhuri A, Martinez-Martin P, Martin PM et al. EFNS guideline on the management of community-acquired bacterial meningitis: report of an EFNS Task Force on acute bacterial meningitis in older children and adults. Eur J Neurol. 2008; 15:649-59. [PubMed 18582342]

133. Yoon J, Urban C, Terzian C et al. In vitro double and triple synergistic activities of Polymyxin B, imipenem, and rifampin against multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2004; 48:753-7. [PubMed 14982760]

134. Arnold TM, Forrest GN, Messmer KJ. Polymyxin antibiotics for gram-negative infections. Am J Health Syst Pharm. 2007; 64:819-26. [PubMed 17420197]

135. Weinstein L, Doan TL, Smith MA. Neurotoxicity in patients treated with intravenous polymyxin B: Two case reports. Am J Health Syst Pharm. 2009; 66:345-7. [PubMed 19202043]

136. Falagas ME, Bliziotis IA, Tam VH. Intraventricular or intrathecal use of polymyxins in patients with Gram-negative meningitis: a systematic review of the available evidence. Int J Antimicrob Agents. 2007; 29:9-25. [PubMed 17126534]

137. Waites KB, Canupp KC, Roper JF et al. Evaluation of 3 methods of bladder irrigation to treat bacteriuria in persons with neurogenic bladder. J Spinal Cord Med. 2006; 29:217-26. [PubMed 16859225]

138. Urban C, Mariano N, Rahal JJ et al. Polymyxin B-Resistant Acinetobacter baumannii Clinical Isolate Susceptible to Recombinant BPI and Cecropin P1. Antimicrob Agents Chemother. 2001; 45:994-995. [PubMed 16557680]

139. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; sixteenth informational supplement. CLSI document M100-S16. Wayne, PA; 2006.

140. Gales AC, Reis AO, Jones RN. Contemporary assessment of antimicrobial susceptibility testing methods for polymyxin B and colistin: review of available interpretative criteria and quality control guidelines. J Clin Microbiol. 2001; 39:183-90. [PubMed 11136768]

141. Gales AC, Jones RN, Sader HS. Global assessment of the antimicrobial activity of polymyxin B against 54 731 clinical isolates of Gram-negative bacilli: report from the SENTRY antimicrobial surveillance programme (2001-2004). Clin Microbiol Infect. 2006; 12:315-21. [PubMed 16524407]

142. Guelfi KC, Tognim MC, Cardoso CL et al. In vitro evaluation of the antimicrobial activity of meropenem in combination with polymyxin B and gatifloxacin against Pseudomonas aeruginosa and Acinetobacter baumannii. J Chemother. 2008; 20:180-5. [PubMed 18467243]

143. Landman D, Bratu S, Alam M et al. Citywide emergence of Pseudomonas aeruginosa strains with reduced susceptibility to polymyxin B. J Antimicrob Chemother. 2005; 55:954-7. [PubMed 15883174]

144. Kaye KS, Kaye D. Polymyxins (polymyxin B and colistin). In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 6th ed. New York: Churchill Livingstone; 2005.

145. JHP Pharmaceuticals. Coly-Mycin M parenteral (colistimethate) for injection, USP prescribing information. Rochester, MI; 2007 Dec.

146. Reviewers’ comments (personal observations).

a. AHFS drug information 2009. McEvoy GK, ed. Polymyxin B Sulfate. Bethesda, MD: American Society of Health-System Pharmacists; 2009:502-4.

HID. Trissel LA. Handbook on injectable drugs. 17th ed. Bethesda, MD. American Society of Health-System Pharmacists; 2013:954-6.

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