VA Class:AM900
Polymyxin B is a polymyxin antibiotic that is structurally and pharmacologically related to colistin.14, 105
Polymyxin B sulfate is used for the treatment of serious infections, including infections of the urinary tract, meninges, or bloodstream, caused by susceptible gram-negative bacteria (e.g., Pseudomonas aeruginosa , Escherichia coli , Enterobacter aerogenes , Klebsiella pneumoniae , Haemophilus influenzae ).100, 101, 102, 105, 112 The drug also is used in the treatment of respiratory tract infections† caused by susceptible gram-negative bacteria (e.g., Ps. aeruginosa , Acinetobacter baumannii †).107, 115, 122, 126 Although other less toxic anti-infectives (e.g., fluoroquinolones, aminoglycosides, third generation cephalosporins, extended-spectrum penicillins, carbapenems) usually are the drugs of choice for most gram-negative bacterial infections,105, 106, 107 polymyxin B may be indicated when these drugs are ineffective or contraindicated, especially for serious infections caused by multidrug-resistant Ps. aeruginosa or A. baumannii .100, 101, 102, 105, 106, 109, 112, 115, 116, 117, 121, 122, 128, 134, 136, 144
Meningitis and Other CNS Infections
Polymyxin B sulfate is used intrathecally100, 101, 102, 136 or intraventricularly†113, 136 for the treatment of meningeal infections caused by susceptible gram-negative bacteria, including Ps. aeruginosa , E. coli †, K. pneumoniae †, and H. influenzae . In some cases, intrathecal polymyxin B has been effective when used alone for the treatment of these infections; however, intrathecal or intraventricular polymyxin B usually has been used in conjunction with a parenteral anti-infective (e.g., IV or IM polymyxin B, IV meropenem, IV penicillin, IV cephalosporin).113, 136 Because polymyxin B penetrates poorly into CSF following IM or IV administration,100, 101, 102 parenteral therapy with the drug should not be used alone for the treatment of meningitis or other CNS infections.146
Treatment of meningitis caused by Ps. aeruginosa should be guided by results of in vitro susceptibility tests.114 The usual regimen of choice for these infections is parenteral therapy with an antipseudomonal cephalosporin (ceftazidime, cefepime) or carbapenem (meropenem) with or without an aminoglycoside (amikacin, gentamicin, tobramycin).106, 114, 132 Intrathecal or intraventricular polymyxin B may be indicated for infections caused by multidrug-resistant Ps. aeruginosa that are resistant to or do not respond to the usual regimens of choice.136
Polymyxin B has been used intraventricularly† in conjunction with IV meropenem for the treatment of ventriculitis caused by ceftazidime-resistant K. pneumoniae †.113
Intrathecal polymyxin B is considered an alternative for the treatment of meningitis caused by susceptible H. influenzae .100, 101, 102 The usual drug of choice for the treatment of these infections is a parenteral third-generation cephalosporin (e.g., cefotaxime, ceftriaxone),106, 114, 132 although parenteral ampicillin can be used if the infection is caused by β-lactamase-negative strains.114
IV polymyxin B sulfate is used as an alternative for the 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 A. baumannii ).115, 117, 122 Polymyxin B is not usually considered a drug of choice for initial empiric therapy of respiratory tract infections,106, 107 and generally is used in these infections only when other less toxic anti-infectives are ineffective or contraindicated.100, 101, 102, 105, 117, 121, 122
In some patients, IV polymyxin B has been used alone or in conjunction with IV aztreonam for the treatment of nosocomial pneumonia caused by multidrug-resistant Ps. aeruginosa 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 have not been identified to date.126
Polymyxin B has been administered by oral inhalation via nebulization† for the treatment of respiratory tract infections† caused by susceptible gram-negative bacteria (e.g., Ps. aeruginosa , A. baumannii ).105, 109, 112, 116, 117, 122, 127 In patients with pneumonia, polymyxin B administered by oral inhalation generally has been used in conjunction with a parenteral anti-infective (e.g., IV polymyxin B);116, 117, 122 however, the drug 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 have not been established and additional study is needed, the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) and other clinicians suggest that adjunctive use of aerosolized polymyxin B can be considered for the 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
Polymyxin B also has been administered by oral inhalation for prophylaxis in an attempt to prevent nosocomial pneumonia† in seriously ill patients;105, 112, 127 however, such prophylaxis appears to promote development of polymyxin B-resistant bacteria.105, 112
IV or IM polymyxin B sulfate is used for the treatment of septicemia or bacteremia caused by susceptible Ps. aeruginosa , E. aerogenes , or K. pneumoniae .100, 101, 102, 124 The drug also has been used IV for the treatment of bloodstream infections caused by multidrug-resistant A. baumannii †.117 Polymyxin B generally is used in the treatment of septicemia or bacteremia only when other less toxic anti-infectives are ineffective or contraindicated.100, 101, 102, 105, 121, 124
Polymyxin B may be a drug of choice for the treatment of septicemia or bacteremia caused by Ps. aeruginosa 100, 101, 102 and 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 have not been identified to date.124
IV or IM polymyxin B sulfate is used for the treatment of serious urinary tract infections caused by susceptible Ps. aeruginosa or E. coli .100, 101, 102 Polymyxin B generally is used in these infections only when other less toxic anti-infectives are ineffective or contraindicated.100, 101, 102, 105, 121
Bacteriuria and Bacteremia Associated with Indwelling Catheters
The fixed-combination solution for irrigation containing polymyxin B sulfate and neomycin sulfate is used in abacteriuric patients for short-term (up to 10 days) irrigation or rinse of the urinary bladder to help prevent bacteriuria and gram-negative rod septicemia associated with the use of indwelling catheters.103, 104
Bacteria can gain entrance to the bladder by way of, through, and around indwelling catheters and clinically significant bacteriuria may be induced by bacterial multiplication in bladder urine, the mucoid film that may be present between the catheter and urethra, and in other sites.103, 104 Urinary tract infection may result from the repeated presence of large numbers of pathogenic bacteria in the urine,103, 104 and the use of closed systems with indwelling catheters has been shown to reduce the risk of infection.103, 104 The manufacturers state that use of a 3-way closed catheter system and bladder rinse with the fixed-combination solution for irrigation containing polymyxin B sulfate and neomycin sulfate may help prevent development of infection in patients with indwelling catheters.103, 104 However, 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
In a randomized, double-blind study in adults 19-82 years of age with spinal cord injury and neurogenic bladder dysfunction who had indwelling urinary catheters and existing bacteriuria (at least 100,000 colony-forming units per mL [cfu/mL]), bladder irrigation (30 mL twice daily for 8 weeks) with neomycin sulfate and polymyxin B sulfate solution for irrigation, 0.25% acetic acid, or normal saline did not reduce the degree of bacteriuria or inflammation.137 Culture data obtained prior to, during, and after the 8-week irrigation regimen indicated no substantial change in colony count (counts remained at least 100,000 cfu/mL in almost all individuals).137 Although there was an increase in the number of patients harboring Enterococcus , the variety of other bacteria present in the urine generally remained the same.137 In addition, there was no evidence of an increased incidence of resistant bacteria, including multidrug-resistant strains.137
For information on use of topical fixed-combination preparations containing polymyxin B sulfate and other anti-infectives for the prevention or treatment of superficial skin infections, see Bacitracin 84:04.04 and see Neomycin Sulfate 84:04.04.
For information on use of topical or subconjunctival polymyxin B sulfate for the treatment of ophthalmic infections or use of topical fixed-combination preparations containing polymyxin B sulfate and other anti-infectives for the treatment of ophthalmic or otic infections, see Polymyxin B Sulfate 52:04.04.
Reconstitution and Administration
Polymyxin B sulfate usually is administered IV.100, 101, 102 Although polymyxin B sulfate may also be given by IM injection, IM administration of the drug is not routinely recommended because severe pain occurs at the injection site, especially in infants and children.100, 101, 102
For the treatment of meningitis, polymyxin B sulfate is administered intrathecally100, 101, 102, 136 or intraventricularly†.113, 114, 136 Polymyxin B should not be given IV or IM alone for the treatment of meningitis or other CNS infections since distribution of the drug into CNS is expected to be low following these routes.100, 101, 102, 136
Although safety and efficacy have not been established, polymyxin B sulfate has been administered by oral inhalation via nebulization† for the adjunctive treatment of respiratory tract infections†.105, 107, 112, 116, 117, 127 (See Uses: Respiratory Tract Infections.)
The fixed-combination solution for irrigation containing polymyxin B sulfate and neomycin sulfate is administered by continuous irrigation of the urinary bladder.103, 104
For IV administration, polymyxin B sulfate powder for injection is reconstituted 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.
IV infusions of polymyxin B usually are given over a period of 60-90 minutes.105 An infusion period less than 30 minutes should not be used.105 Because of the risk of neuromuscular blockade, rapid IV injections should be avoided.105
For IM administration, polymyxin B sulfate powder for injection is reconstituted by adding 2 mL of sterile water for injection, 0.9% sodium chloride injection, or 1% procaine hydrochloride injection to a vial labeled as containing 500,000 units of polymyxin B100, 101, 102 to provide a solution containing approximately 250,000 units/mL.
IM injections should be given deeply into the upper outer quadrant of the gluteal muscle and injection sites should be alternated.146 The fact that IM injections may cause severe injection site pain should be considered.100, 101, 102
For intrathecal administration, polymyxin B sulfate powder for injection is reconstituted by adding 10 mL of 0.9% sodium chloride injection to a vial labeled as containing 500,000 units of the drug to provide a solution containing approximately 50,000 units/mL.100, 101, 102 Procaine hydrochloride solutions should not be used to prepare intrathecal injections of polymyxin B.146
For oral inhalation via nebulization†, 0.5% solutions of polymyxin B sulfate have been prepared using 0.9% sodium chloride.112 Polymyxin B concentrations higher than 10 mg/mL should not be used for administration by oral inhalation since the drug may cause bronchial irritation.105
For continuous irrigation of the urinary bladder, the commercially available fixed-combination solution for irrigation containing 200,000 units of polymyxin B and 40 mg of neomycin should be diluted by adding the contents of the 1-mL ampul containing the irrigation solution to 1 L of 0.9% sodium chloride solution.103, 104
The diluted solution for irrigation should be administered via a 3-way catheter at a rate of 1 L every 24 hours (approximately 40 mL/hour).103, 104 If the patient's urine output exceeds 2 L/day, the inflow rate should be adjusted to deliver 2 L every 24 hours.103, 104 If not used immediately, the diluted solution should be stored at 4°C and used within 48 hours.103, 104
It is important that the bladder irrigation be given continuously for up to 10 days; the inflow or rinse solution should not be interrupted for more than a few minutes.103, 104
Dosage of polymyxin B sulfate usually is expressed in terms of polymyxin B activity (units of polymyxin B).100, 101, 102, 105 Dosage of the drug also may be expressed as 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
Meningitis and Other CNS Infections
For the treatment of meningitis caused by susceptible gram-negative bacteria, the manufacturers recommend that adults receive an intrathecal dosage of polymyxin B of 50,000 units once daily for 3 or 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 content is normal.100, 101, 102
For the treatment of ventriculitis† in an adult caused by ceftazidime-resistant Klebsiella pneumoniae , polymyxin B has been given intraventricularly† in a dosage of 50,000 units once daily for 7 days in conjunction with IV meropenem continued for 21 days after the first negative CSF culture.113
Although safety and efficacy have not been 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 for the treatment of meningitis caused by susceptible gram-negative bacteria.136
Although safety and efficacy of polymyxin B administered by oral inhalation via nebulization† have not been established, adults have received the drug by oral inhalation in a dosage of 2.5 mg/kg daily in divided doses every 6 hours for adjunctive treatment of respiratory tract infections caused by susceptible Pseudomonas 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
In a study in adults who had respiratory tract infections caused by multidrug-resistant gram-negative bacilli that had not responded to parenteral anti-infectives alone, polymyxin B was given by oral inhalation in a dosage of 500,000 units twice daily given approximately 20 minutes after an oral inhalation dose of a β2-adrenergic agonist.116 Patients with pneumonia received polymyxin B administered by oral inhalation in conjunction with IV polymyxin B therapy; those with tracheobronchitis caused by Ps. adrenergic received the drug by oral inhalation alone.116 Treatment was continued for an average of 14 days (range: 4-25 days).116
The total daily dosage administered by oral inhalation should not exceed that recommended for parenteral administration.105
Septicemia or Urinary Tract Infections
The usual IV dosage of polymyxin B for the treatment of septicemia or urinary tract infections caused by susceptible gram-negative bacteria in adults with normal renal function is 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 The total daily IV dosage in these patients should not exceed 25,000 units/kg.100, 101, 102
The usual IM dosage of polymyxin B for the treatment of septicemia or urinary tract infections caused by susceptible gram-negative bacteria in adults with normal renal function is 25,000-30,000 units/kg daily (2.5-3 mg/kg daily); the daily dosage may be divided and given at 4- to 6-hour intervals.100, 101, 102 The total daily IM dosage in these patients should not exceed 30,000 units/kg.100, 101, 102
Bacteriuria and Bacteremia Associated with Indwelling Catheters
For continuous irrigation of the urinary bladder, the diluted solution of neomycin sulfate and polymyxin B sulfate irrigation solution should be administered via a 3-way catheter at a rate of 1 L every 24 hours (approximately 40 mL/hour).103, 104 The solution should be administered at a rate of 2 L every 24 hours if the patient's urine output exceeds 2 L/day.103, 104
The duration of irrigation therapy should not exceed 10 days.103, 104
Meningitis and Other CNS Infections
For the treatment of meningitis caused by susceptible gram-negative bacteria in children younger than 2 years of age, the manufacturers recommend an initial intrathecal dosage of polymyxin B of 20,000 units once daily for 3 or 4 days or 25,000 units once every other day.100, 101, 102 With either regimen, treatment should be continued with 25,000 units once every other day given for at least 2 weeks after CSF cultures are negative and CSF glucose content is normal.100, 101, 102
For the treatment of meningitis caused by susceptible gram-negative bacteria in children older than 2 years of age, the manufacturers recommend an intrathecal dosage of polymyxin B of 50,000 units once daily for 3 or 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 content is normal.100, 101, 102
Although safety and efficacy have not been 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 for the treatment of meningitis caused by susceptible gram-negative bacteria.136
Septicemia or Urinary Tract Infections
The usual IV dosage of polymyxin B for the treatment of septicemia or urinary tract infections caused by susceptible gram-negative bacteria in children with normal renal function is 15,000-25,000 units/kg daily (1.5-2.5 mg/kg daily).100, 101, 102 Daily dosage may be administered in 2 divided doses every 12 hours.100, 101, 102 The manufacturers state that the total daily IV dosage in children should not exceed 25,000 units/kg,100, 101, 102 but that infants with normal renal function may receive an IV dosage of up to 40,000 units/kg daily (4 mg/kg daily) without adverse effects.100, 101, 102
Clinicians should consider that IM administration of polymyxin B is not routinely recommended in children and infants because severe pain occurs at the injection site.100, 101, 102 If the drug is given IM for the treatment of septicemia or urinary tract infections caused by susceptible gram-negative bacteria in children with normal renal function, the usual IM dosage is 25,000-30,000 units/kg daily (2.5-3 mg/kg daily); daily dosage may be divided and given at 4- to 6-hour intervals.100, 101, 102 The manufacturers state that the total daily IM dosage in children should not exceed 30,000 units/kg,100, 101, 102 but that infants with normal renal function may receive an IM dosage of up to 40,000 units/kg daily (4 mg/kg daily) without adverse effects.100, 101, 102 A dosage as high as 45,000 units/kg daily (4.5 mg/kg daily) has been used in limited clinical studies in premature and full-term neonates for the treatment of sepsis caused by Ps. aeruginosa .100, 101, 102
Dosage of polymyxin B should be decreased in patients with renal impairment.14, 100, 101, 102, 105, 112, 125 Serum polymyxin B concentrations should be monitored and IV or IM dosage adjusted to maintain desired serum concentrations of the drug.105, 146
Various dosage regimens have been recommended for use of polymyxin B in patients with renal impairment; however, these regimens are not well established and are not based on pharmacokinetic data from patients with renal impairment.105, 109, 115, 125, 134
It has been recommended that patients with creatinine clearances of 30-80 mL/minute receive an IV loading dose of polymyxin B of 2.5 mg/kg on the first day of treatment followed by 1-1.5 mg/kg daily and that those with creatinine clearances less than 25-30 mL/minute receive these doses once every 2-3 days.134 For anuric patients, some clinicians have recommended an IV loading dose of 2.5 mg/kg followed by 1-1.5 mg/kg given once every 5-7 days.112, 134
Alternatively, it has been suggested that patients with creatinine clearances greater than 20 mL/minute receive 75-100% of the usual daily dose in 2 divided doses every 12 hours, those with creatinine clearances of 5-20 mL/minute receive 50% of the usual daily dose in 2 divided doses every 12 hours, and those with creatinine clearances less than 5 mL/minute receive 30% of the usual daily dose every 12-18 hours.105, 112 Some clinicians have used 75% of the usual daily dose in those with creatinine clearances 20-50 mL/minute and 33% of the usual daily dose in those with creatinine clearances less than 20 mL/minute.115
Adverse effects reported with polymyxin B sulfate are similar to those reported with colistimethate sodium and colistin sulfate (not commercially available in the US).105, 109, 111 Nephrotoxicity and neurotoxicity are the most serious adverse effects of polymyxin B and are most likely to occur when the drug is used in higher than recommended dosages or in patients with renal impairment.105, 112
Polymyxin B can cause nephrotoxicity.100, 101, 102, 105, 111, 112, 115, 117, 122 Polymyxin B-associated nephrotoxicity is considered to be dose-dependent111, 112 and has been reported in 6-25% of patients receiving usual dosages of the drug.111, 112, 115, 117, 122 Nephrotoxicity 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 creatinine clearance.111 Acute tubular necrosis,111 oliguria,111 hematuria,105, 111 leukocyturia, and excessive excretion of electrolytes may occur.
Renal function should be assessed prior to initiation of polymyxin B therapy and monitored frequently during therapy.100, 101, 102 If signs of renal impairment develop, the drug should be discontinued.100, 101, 102, 111 (See Cautions: Precautions and Contraindications.)
Polymyxin B can cause neurotoxicity.100, 101, 102, 105, 111, 112, 117, 135 Neurotoxicity is considered to be dose-dependent111, 112 and 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, 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 blurring of vision100, 101, 102 or vision disturbances,111, 112 slurred speech, coma,105 or seizures105, 111, 122 also can occur. These adverse effects generally subside after the drug is discontinued.105, 111, 135
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 Drug Interactions.) Polymyxin B-induced neuromuscular blockade is not easily reversed and is resistant to neostigmine105 and edrophonium; calcium chloride has been used successfully in some cases.105 Neuromuscular blockade usually improves within 24 hours after polymyxin B is discontinued.105
Intrathecal administration of polymyxin B sulfate may cause meningeal irritation,100, 101, 102, 136 such as headache, fever, stiff neck, and increased leukocytes and protein in the CSF.100, 101, 102 In addition, nerve root irritation may occur causing neuritic pain and urine retention. High doses given intrathecally or intraventricularly† may lead to seizures and signs of meningismus.111
Fever,100, 101, 102, 105, 111 rash,105, 111 pruritus,105, 111 urticaria,100, 101, 102, 111 skin exanthemata, eosinophilia, and anaphylactoid reactions with dyspnea and tachycardia have been reported rarely during parenteral polymyxin B therapy.
Cough,116 bronchospasm,105, 116 and acute airway obstruction112 have been reported when polymyxin B was administered by oral inhalation via nebulization†. Bronchospasm may have been the result of an allergic reaction or bronchial irritation.105
Severe pain may occur at IM injection sites,100, 101, 102, 105 especially in infants and children.100, 101, 102 Thrombophlebitis has been reported at IV injection sites.100, 101, 102
Precautions and Contraindications
Polymyxin B sulfate is contraindicated in individuals with a history of hypersensitivity to polymyxins.100, 101, 102
Polymyxin B can cause potentially serious nephrotoxicity and/or neurotoxicity.100, 101, 102 The drug should be given IV, IM, and/or intrathecally only to hospitalized patients who are under constant supervision by a clinician.100, 101, 102
Baseline renal function should be determined prior to initiation of polymyxin B therapy and renal function should be monitored 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 Dosage of polymyxin B should be reduced in patients with impaired renal function or renal damage and nitrogen retention.100, 101, 102 (See Dosage and Administration: Dosage in Renal Impairment.) If urine output diminishes or BUN concentration increases during polymyxin B therapy, the drug should be discontinued.100, 101, 102
Polymyxin B-associated neurotoxicity may be manifested by irritability, weakness, drowsiness, ataxia, perioral paresthesia, numbness of the extremities, and blurred vision.100, 101, 102 These symptoms usually are associated with high serum polymyxin B concentrations found in patients with impaired renal function and/or nephrotoxicity.100, 101, 102 Neurotoxicity can result in respiratory paralysis from neuromuscular blockade, especially if polymyxin B is given soon after anesthesia and/or muscle relaxants.100, 101, 102 (See Drug Interactions.) If signs of respiratory paralysis occur, respiration should be assisted as required and the drug discontinued.100, 101, 102
Concurrent or sequential use of other nephrotoxic and/or neurotoxic drugs should be avoided.100, 101, 102, 111, 112 (See Drug Interactions.)
To reduce development of drug-resistant bacteria and maintain effectiveness of polymyxin B and other antibacterials, the drug should be used only for the 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, results of culture and in vitro susceptibility testing should be used.100, 101, 102 In the absence of such data, local epidemiology and susceptibility patterns should be considered when selecting anti-infectives for empiric therapy.100, 101, 102
Patients should be advised 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 Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing 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
As with other anti-infectives, use of polymyxin B may result in overgrowth of nonsusceptible organisms, including fungi.100, 101, 102 Appropriate therapy should be instituted if superinfection occurs.100, 101, 102
Precautions Related to Fixed-combination Solution for Bladder Irrigation
When the fixed-combination solution for bladder irrigation containing polymyxin B sulfate and neomycin sulfate solution is used, the precautions and contraindications related to both polymyxin B and neomycin should be considered.103, 104
The fixed-combination solution for irrigation is contraindicated in individuals hypersensitive to polymyxins, neomycin, or any ingredient in the solution.103, 104 Because cross-sensitivity can occur among aminoglycosides, a history of hypersensitivity or serious toxic reaction to an aminoglycoside may also contraindicate use of any other aminoglycoside.103, 104
The fixed-combination solution for irrigation should be used only for irrigation of the bladder and should not be used for irrigation of other areas.103, 104
The fixed-combination solution for irrigation should not be used 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 with the fixed-combination solution is low since appreciable amounts of polymyxin B or neomycin do not enter systemic circulation if the duration of irrigation does not exceed 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 and often higher than those attained following oral and parenteral therapy have been reported.103, 104
The fixed-combination solution for irrigation is intended 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, irrigation should be avoided in patients with 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, the fact that both polymyxin B and neomycin are nephrotoxic and neurotoxic and that the effects of these drugs may be additive should be considered.103, 104
Irrigation of the bladder with the fixed-combination solution containing polymyxin B and neomycin may result in overgrowth of nonsusceptible organisms, including fungi, and appropriate measures should be taken if this occurs.103, 104
Urine specimens for urinalysis, culture, and susceptibility testing should be collected during prophylactic bladder care.103, 104 Positive cultures suggest the presence of organisms resistant to polymyxin B and neomycin.103, 104
IV polymyxin B sulfate is used in infants and children.100, 101, 102 IM polymyxin B sulfate is not routinely recommended in infants and children because severe pain occurs at the injection site, especially in this age group.100, 101, 102
Safety and efficacy of the fixed-combination solution for irrigation containing polymyxin B sulfate and neomycin sulfate have not been established in children.103, 104
The safety of polymyxin B sulfate in pregnant women has not been established.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
If use of the fixed-combination solution for irrigation containing polymyxin B sulfate and neomycin sulfate is being considered for a pregnant woman, the woman should be informed of the potential hazard to the fetus.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
Nephrotoxic and Neurotoxic Drugs
Since nephrotoxic and neurotoxic effects may be additive, concurrent or sequential use of polymyxin B sulfate and other nephrotoxic and/or neurotoxic drugs, particularly aminoglycosides (amikacin, gentamicin, kanamycin, neomycin, paromomycin, streptomycin, tobramycin), bacitracin, colistimethate/colistin, and viomycin (not commercially available in the US) should be avoided.100, 101, 102, 111, 112, 145
In vitro, the antibacterial effects of polymyxin B and imipenem have been synergistic against some strains of Pseudomonas aeruginosa , but were indifferent against other strains.143 In one study, the combination of polymyxin B and meropenem was indifferent against Ps. aeruginosa .142
In vitro studies evaluating the antibacterial effects of combinations of polymyxin B and imipenem or meropenem against Acinetobacter baumannii have provided conflicting results.118, 119, 125, 133, 142, 143 In some in vitro studies, these combinations had synergistic, partially synergistic, or additive antibacterial effects against A. baumannii ;125, 133, 142, 143 however, there was no evidence of synergism in other in vitro studies.118, 125
The clinical importance of in vitro studies evaluating combinations of polymyxin B and carbapenems against gram-negative bacteria is unclear.119, 143
In an in vitro study, the antibacterial effects of polymyxin B and rifampin were synergistic against only 1 out of 10 strains of multidrug-resistant Ps. aeruginosa ; however, a 3-drug combination of polymyxin B, rifampin, and imipenem was bactericidal against all strains.143
In some in vitro studies, the combination of polymyxin B and rifampin (with or without imipenem) was synergistic or additive against A. baumannii .118, 125, 133
The combination of polymyxin B and rifampin has been synergistic in vitro against Klebsiella pneumoniae .125
The clinical importance of in vitro studies evaluating combinations of polymyxin B and rifampin against gram-negative bacteria is unclear.143
A synergistic antibacterial effect has been reported between polymyxin B and some other anti-infectives (e.g., tetracyclines, chloramphenicol, azithromycin, erythromycin, sulfonamides).
In an in vitro study, the antibacterial effects of polymyxin B and azithromycin were synergistic against 6 out of 10 strains of multidrug-resistant Ps. aeruginosa ; the combination was bactericidal against some strains, but bacteriostatic against other strains.143 The clinical importance of in vitro studies evaluating combinations of polymyxin B and azithromycin against gram-negative bacteria is unclear.143
Neuromuscular Blocking Agents and Anesthetics
Polymyxin B can cause respiratory paralysis from neuromuscular blockade, especially if the drug is given soon after anesthesia and/or muscle relaxants.100, 101, 102, 111 Concurrent use of polymyxin B and neuromuscular blocking agents (e.g., succinylcholine, ether, gallamine [not commercially available in the US], tubocurarine [not commercially available in the US], decamethonium [not commercially available in the US]) and other neurotoxic drugs (e.g., sodium citrate) should be avoided since these agents may precipitate respiratory paralysis.100, 101, 102, 111 If signs of respiratory paralysis occur, respiration should be assisted as required and the drug discontinued.100, 101, 102, 111
Polymyxin B usually is bactericidal in action.100, 101, 102, 105, 109, 125, 131 The bactericidal activity of the drug is concentration dependent.112, 131
Polymyxin B binds to phosphate groups in the lipids of the bacterial cytoplasmic membrane of susceptible bacteria and acts as a cationic detergent, thereby altering the osmotic barrier of the membrane and causing leakage of essential intracellular components.14, 105, 112, 125, 144
Polymyxin B has a spectrum of activity that is similar to that of colistin.14, 105, 125, 140 Polymyxin B is active in vitro against many gram-negative aerobic bacteria; however, the drug is inactive against gram-positive bacteria, anaerobic bacteria, fungi, and viruses.105, 112, 125, 144
Polymyxin B generally is active in vitro against Pseudomonas aeruginosa and is active against many multidrug-resistant strains,105, 107, 108, 112, 115, 122, 125, 129, 130, 131, 140, 141, 144 including metallo-β-lactamase-producing Ps. aeruginosa .108, 126, 130 The drug also is active against many strains of Acinetobacter baumannii , including multidrug-resistant strains.105, 115, 122, 125, 140, 141 Although polymyxin B is active against some strains of Stenotrophomonas maltophilia ,125, 140, 141 it is inactive against Burkholderia cepacia (formerly Ps. cepacia ).105, 125, 140, 141
Polymyxin B is 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 Polymyxin B generally is inactive against Proteus ,105, 112, 125, 140, 141 Providencia ,112, 125 Morganella ,125 and Serratia marcescens .105, 112, 125, 140, 141
Polymyxin B has some activity against Haemophilus influenzae ,105, 125 Bordetella pertussis ,105, 125 and Legionella pneumophila ,105, 125 but is inactive against Moraxella catarrhalis ,125 Neisseria ,105, 125 and Brucella .125
When broth or agar dilution susceptibility tests are used to test in vitro susceptibility of Ps. aeruginosa to polymyxin B, the Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards [NCCLS]) states that strains with minimum inhibitory concentrations (MICs) of 2 mcg/mL or less are susceptible to polymyxin B, those with MICs of 4 mcg/mL have intermediate susceptibility, and those with MICs of 8 mcg/mL or greater are resistant to the drug.125
When broth or agar dilution susceptibility tests are used to test in vitro susceptibility of Acinetobacter to polymyxin B, CLSI states that strains with MICs of 2 mcg/mL or less are susceptible to polymyxin B and those with MICs of 4 mcg/mL or greater are resistant to the drug.125, 139
If a disk diffusion procedure is used to test susceptibility to polymyxin B, a 300-unit polymyxin B disk is used and organisms with growth inhibition zones 12 mm or greater are considered susceptible to polymyxin B.100, 101, 102, 112, 115, 125 However, the disk diffusion method usually is not recommended for testing susceptibility to polymyxin B since the drug diffuses poorly in agar and false-susceptible results may occur.125, 140 If a disk diffusion procedure is used, results indicating susceptibility to polymyxin B should be confirmed using a broth or agar dilution method.125, 140
Resistance to polymyxin B has been reported rarely in Pseudomonas aeruginosa 105, 125, 131, 140, 141, 143 and Acinetobacter baumannii .125, 138, 140, 141 Surveillance data based on clinical isolates obtained from North America, Latin America, Europe, and the Asia-Pacific region during 2001-2004 indicated that 1.1-2.9% of Ps. aeruginosa isolates and 1.7-2.7% of Acinetobacter isolates were resistant to polymyxin B.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,105, 112, 125, 131, 140, 144 but there is no evidence to date of cross-resistance between these polymyxins and other anti-infectives.131
Polymyxin B sulfate is not absorbed from the GI tract.14, 100, 101, 102, 105, 144
After IM administration of a single polymyxin B 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. Serum concentrations are higher in infants and children.100, 101, 102 Following IM administration of polymyxin B to adults with normal renal function, detectable amounts of the drug are present in serum for up to 12 hours.
In a study in critically ill adults who received polymyxin B 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 Chemistry.)
Serum concentrations are higher and more prolonged in patients with renal impairment.105
Polymyxin B does not appear to be absorbed to an appreciable extent from mucous membranes14 or intact or denuded skin.14
In a study in critically ill adults, the volume of distribution of polymyxin B ranged from 71-194 mL/kg.123
Polymyxin B diffuses poorly in tissues.100, 101, 102
Following IV or IM administration, polymyxin B is not distributed into CSF100, 101, 102, 105 (even when meninges are inflamed) or synovial fluid. Systemically administered polymyxin B does not penetrate into the aqueous humor of the eye, even in the presence of inflammation.
Polymyxin B does not cross the placenta.
Animal studies indicate that following IV or IM administration, approximately 50% of a dose is reversibly bound to phospholipids of cell membranes in the liver, kidneys, heart, muscle, brain, and probably other tissues.
In an in vitro study using plasma from critically ill adults receiving polymyxin B, the drug 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
The serum half-life of polymyxin B is reported to be 4.3-6 hours in adults with normal renal function. In patients with creatinine clearances less than 10 mL/minute, the serum half-life of polymyxin B has been reported to be 2-3 days.
Polymyxin B is eliminated in urine principally by glomerular filtration.144 Some studies indicate only low amounts of the dose are eliminated in urine within the first 12 hours after a dose, but eventually approximately 60% of a dose of polymyxin B is excreted in urine.105 Other studies suggest that less than 1% of a dose is eliminated unchanged in urine over 3 days.123 In adults, there is a 12- to 24-hour time lag following the initial dose during which very little polymyxin B appears in the urine, possibly as a result of binding of the drug to phospholipids of kidney cell membranes. Excretion continues for 24-72 hours after the final dose is administered. In adults with normal renal function, urinary drug concentrations have averaged 20-100 mcg/mL following usual IM doses at 6-hour intervals over a period of a few days. Infants excrete polymyxin B faster than do adults; 40-60% of an administered dose is excreted within 8 hours in the urine.
In a study in critically ill adults who received polymyxin B doses by IV infusion over 60 minutes, total body clearance ranged from 0.27-0.81 mL/minute per kg and less than 1% of a dose was eliminated unchanged in urine.123
Polymyxin B is not removed to an appreciable extent by hemodialysis or peritoneal dialysis.105, 111, 112
Polymyxin B is a polymyxin antibiotic derived from Bacillus polymyxa .14, 100, 101, 102, 103, 104, 105 Polymyxin B is 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
Polymyxin B sulfate occurs as a white to buff-colored, hygroscopic powder that is odorless or has a faint odor. The drug is freely soluble in water and in 0.9% sodium chloride injection and slightly soluble in alcohol. Each mg of pure polymyxin B is equivalent to 10,000 units of polymyxin B activity.100, 101, 102, 105 Aqueous solutions of polymyxin B sulfate have a pH of 5-7.5.
Polymyxin B sulfate powder for injection should be stored at 15-30°C or 20-25°C, depending on the manufacturer, and should be protected from light.100, 101, 102 Following reconstitution, polymyxin B solutions should be stored at 2-8°C;100, 101, 102 any unused portions should be discarded after 72 hours.100, 101, 102
The commercially available fixed-combination solution for irrigation containing polymyxin B sulfate and neomycin sulfate should be stored at 2-8°C.103, 104 Following dilution in 0.9% sodium chloride solution, the solution for irrigation should be stored at 4°C and used within 48 hours.103, 104
Polymyxin B is inactivated by strong acidic or alkaline solutions. The drug is chemically incompatible with many drugs including amphotericin B, ampicillin, cefazolin, chloramphenicol sodium succinate, chlorothiazide sodium, and heparin sodium. Polymyxin B in solution is also incompatible with the salts of calcium and magnesium.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Bulk | Powder* | |||
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
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 |
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