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Polymyxin B

Pronunciation

(pol i MIKS in bee)

Index Terms

  • Polymyxin B Sulfate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Injection:

Generic: 500,000 units (1 ea)

Solution Reconstituted, Injection [preservative free]:

Generic: 500,000 units (1 ea)

Pharmacologic Category

  • Antibiotic, Irrigation
  • Antibiotic, Miscellaneous

Pharmacology

Binds to phospholipids, alters permeability, and damages the bacterial cytoplasmic membrane permitting leakage of intracellular constituents

Absorption

Not absorbed from GI tract.

Distribution

Tissue diffusion is poor; critically ill patients: Central Vd: ~0.09 L/kg; peripheral Vd: 0.33 L/kg (Sandri 2013a); does not cross blood brain barrier into CSF or into the eye (Hoeprich 1970)

Excretion

Urine (<1% as unchanged drug within first 12 hours; as therapy continues, up to 60% as unchanged drug in the urine [Evans 1999]); Critically ill adults: Urine (median: 4% [range: 0.98% to 17.4%] as unchanged drug) (Sandri 2013a)

Time to Peak

Serum: IM: Within 2 hours (Hoeprich 1970)

Half-Life Elimination

6 hours, increased with reduced renal function (Evans 1999)

Protein Binding

~60% (Kassamali 2015); 79% to 92% (critically ill patients) (Zavascki, 2008)

Use: Labeled Indications

Infections, acute:

Pseudomonal infections: Treatment of infections of the urinary tract, meninges, and bloodstream caused by susceptible strains of Pseudomonas aeruginosa

Serious infections: Treatment of serious infections caused by susceptible strains of the following organisms, when less potentially toxic drugs are ineffective or contraindicated: H. influenzae, specifically meningeal infections; Escherichia coli, specifically urinary tract infections; Aerobacter aerogenes, specifically bacteremia; Klebsiella pneumoniae, specifically bacteremia

In meningeal infections, polymyxin B sulfate should be administered only by the intrathecal route.

Contraindications

Hypersensitivity to polymyxin B or any component of the formulation

Dosing: Adult

Note: Dosing presented as units; 10,000 units = 1 mg

CNS infections: Intrathecal:

Manufacturer’s labeling: 50,000 units once daily for 3 to 4 days, then every other day for at least 2 weeks after cultures of the CSF are negative

Alternate dosing (off-label regimen): Intrathecal, Intraventricular: 50,000 units once daily for 7 days; used in combination with other IV antibiotics (eg, meropenem) (IDSA [Tunkel 2004]; Segal-Maurer 1999)

Ocular infections: Ophthalmic: A concentration of 0.1% to 0.25% (10,000 to 25,000 units/mL) is administered as 1 to 3 drops every hour, then increasing the interval as response indicates. A subconjunctival injection of up to 100,000 units/day may be used for P. aeruginosa corneal and conjunctival infections. Note: Avoid total systemic and ophthalmic doses of >25,000 units/kg/day.

Systemic infections: Note: Most of the available limited data evaluating polymyxin B for multidrug resistant pathogens cite manufacturer’s labeling dosing of 15,000 to 25,000 units/kg/day IV divided every 12 hours (Furtado 2007; Ouderkirk 2003). More recent publications have cited alternate dosing regimens based on pharmacokinetics/pharmacodynamics data (eg, Monte Carlo simulations) (Sandri 2013a), which support using a loading dose to rapidly achieve target serum concentrations and higher dosing regimens particularly for severe infections (pathogens with an MIC ≤2 mcg/mL); however, actual clinical data employing these higher dosing regimens remain extremely limited. Monitor closely for nephrotoxicity. Dosing based on actual body weight has been suggested for patients within a normal weight range for their height (Kassamali 2015; Pai 2013; Sandri 2013a).

Manufacturer’s labeling:

IM: 25,000 to 30,000 units/kg/day in divided doses every 4 to 6 hours. Note: Routine IM administration not recommended due to severe pain at injection site.

IV: 15,000 to 25,000 units/kg/day in divided doses every 12 hours (maximum: 25,000 units/kg/day)

Alternate dosing: Infections (eg, intraabdominal infections, pneumonia [hospital-acquired or ventilator-associated], sepsis), due to susceptible multidrug-resistant gram-negative bacilli (eg, Pseudomonas aeruginosa, Acinetobacter spp) (off-label dose):

IV:

Severe infections (MIC ≤2 mcg/mL): 25,000 units/kg/dose infused over 2 hours as a one-time loading dose, followed by a maintenance dose of 30,000 units/kg/day divided every 12 hours (Kassamali 2015; Sandri 2013a) or 25,000 to 30,000 units/kg/day in 2 divided doses without a loading dose (IDSA [Kalil 2016])

Moderate infections: (MIC ≤1 mcg/mL): 25,000 units/kg/day divided every 12 hours (Sandri 2013a)

Note: Safety data for single doses >30,000 units/kg/dose or for daily doses >2,000,000 units/day are extremely limited. To minimize bacterial regrowth and heteroresistance, consider use in combination with other antibiotics depending on infection site and susceptibilities (Bergen 2015, Kassamali 2015, Rigatto 2015). Monotherapy should only be considered for infections due to carbapenem-resistant organisms (Kassamali 2015)

Obesity: Due to minimal data in morbidly obese patients, consider dosing based on adjusted body weight in these patients (Kassamali 2015; Pai 2013; Sandri 2013a).

Inhalation (off-label route): 500,000 units every 12 hours; an aerosolized beta-2 agonist should be given ~20 minutes prior to polymyxin B (Pereira 2007). Note: Colistimethate sodium is preferred in patients with hospital or ventilator-associated pneumonia (IDSA [Kalil 2016]). In the treatment of pneumonia, concomitant IV administration may also be necessary (Pereira 2007).

Selective gastrointestinal tract decontamination (off-label use): Oral: 1,000,000 units orally 4 times daily for 2 days prior to surgery through post-operative day 3 in combination with oral tobramycin and oral amphotericin B (Roos 2011). Note: To minimize resistance development and preserve polymyxin effectiveness for severe systemic infections, use for selective decontamination is strongly discouraged (Nation 2015)

Obesity: Due to minimal data in morbidly obese patients, consider dosing based on adjusted body weight in these patients (Kassamali 2015; Pai 2013; Sandri 2013a).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Dosing presented as units; 10,000 units = 1 mg. Use extra caution with prescribing and/or dispensing. Multiple routes of administration available for use (eg, IV, IM, intrathecal, ophthalmic) and dosing is different based upon route; use extra precaution to verify dose and route of administration.

Severe, life-threatening, multidrug resistant infection (excluding meningitis): Note: From experience in adult patients, safety data for single doses >30,000 units/kg/dose or total daily doses >2,000,000 units/day are extremely limited (Kassamali 2015).

Infants:

IM: 25,000 to 40,000 units/kg/day divided every 4 to 6 hours; Note: Routine IM administration not recommended due to severe pain at injection site.

IV: 15,000 to 40,000 units/kg/day divided every 12 hours

Children and Adolescents:

IM: 25,000 to 30,000 units/kg/day divided every 4 to 6 hours; Note: Routine IM administration not recommended due to severe pain at injection site.

IV:

Manufacturer's labeling: 15,000 to 25,000 units/kg/day divided every 12 hours

Alternate dosing: Children ≥2 years and Adolescents: Very limited data available: Dosing based on previous recommendations (Hoeprich 1970) and extrapolations from adult pharmacokinetic modeling (Sandri 2013a) which assumes that dosing for pediatric patients ≥2 years and adults is the same (per current manufacturer's labeling); some centers have used the following:

Loading dose: 25,000 units/kg

Maintenance dose: 25,000 to 30,000 units/kg/day divided every 12 hours; consider higher doses for organisms with higher MIC

Meningitis, Pseudomonas aeruginosa or Haemophilus influenzae:

Infants and Children <2 years: Intrathecal: 20,000 units once daily for 3 to 4 days or 25,000 units once every other day; continue 25,000 units once every other day for at least 2 weeks after cultures of the CSF are negative

Children ≥2 years and Adolescents: Intrathecal: 50,000 units daily as a single dose for 3 to 4 days, then every other day for at least 2 weeks after cultures of CSF are negative

CNS infection (VP-shunt infection, ventriculitis): Limited data available: Children and Adolescents: Intraventricular/intrathecal: 20,000 to 50,000 units/day; lower doses should be used in smaller patients (Hoeprich, 1970; IDSA [Tunkel 2004])

Ocular infection, Pseudomonas aeruginosa: Infants, Children, and Adolescents: Ophthalmic: Refer to adult dosing.

Dosing: Renal Impairment

Note: Manufacturer labeling recommends a dosage reduction in renal impairment however some clinical data suggest that total body clearance of polymyxin B is not altered in renal impairment and that dose adjustment is not necessary (Sandri 2013a; Thamlikitkul 2016). Decreasing daily doses in renal impairment may lead to suboptimal plasma exposure, adverse clinical outcomes and resistance development (Nelson 2015; Sandri 2013a; Zavascki 2008). Some data suggest that non-renal pathways are primarily responsible for elimination. These authors suggest that renal dosage adjustment recommendations should await further data from larger clinical trials (Zavascki 2008). However, use is associated with nephrotoxicity. Recent data suggests polymyxin B undergoes a selective uptake process into renal cells, which plays a primary role in nephrotoxicity potential (Abdelraouf 2014). One small study in patients receiving polymyxin B with a normal baseline renal function observed an overall prevalence rate of nephrotoxicity of 46% with a median onset of 9 days (Dubrovskaya 2015).

Manufacturer’s labeling: IV: For individuals with renal impairment, reduce to dose to <15,000 units/kg/day. More specific dosage reduction not provided.

Alternate recommendations: Adults:

CrCl ≥80 mL/minute: IV: 15,000 to 25,000 units/kg/day in divided doses every 12 hours (Evans 1999)

CrCl 30 to 80 mL/minute: IV: Loading dose: 25,000 units/kg on day 1, followed by 10,000 to 15,000 units/kg/day thereafter (Evans 1999)

CrCl <30 mL/minute: IV: Loading dose: 25,000 units/kg on day 1, followed by 10,000 to 15,000 units/kg every 2 to 3 days thereafter (Evans 1999)

Anuric patients: IV: Loading dose: 25,000 units/kg on day 1, followed by 10,000 units/kg every 5 to 7 days thereafter (Evans 1999)

Hemodialysis, peritoneal dialysis: IM: 250,000 units every 24 hours; no supplemental dose necessary (Cunha 1988)

CVVHD: No dosage adjustment necessary (Sandri 2013b).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Obesity

Refer to indication-specific dosing for obesity-related information (may not be available for all indications).

Reconstitution

IV infusion: Dissolve 500,000 units in 300 to 500 mL D5W

IM injection: Dissolve 500,000 units in 2 mL NS, or 1% procaine HCl

Intrathecal: Dissolve 500,000 units in 10 mL NS (preservative free) (concentration: 50,000 units/mL)

Ophthalmic: Dissolve 500,000 units in 20 to 50 mL SWFI or NS (concentration: 10,000 to 25,000 units/mL [0.1 to 0.25%])

Administration

IM: The IM route is not routinely recommended due to severe pain at injection site. Intramuscular injections should only be administered in a hospital.

IV: Administer as a continuous IV infusion or in divided doses every 12 hours. Administration over 60 to 120 minutes as an intermittent infusion has been reported (Teng 2008; Zavascki 2008).

Inhalation for nebulization (off-label use/route): Use with standard jet nebulizer connected to an air compressor; an aerosolized beta-2 agonist should be given ~20 minutes prior to polymyxin (Pereira 2007).

Intrathecal: May be administered intrathecally; intrathecal injections should only be administered in a hospital.

Ophthalmic: May be administered as a subconjunctival injection or as topical ophthalmic drops.

Compatibility

See Trissel’s IV Compatibility Database

Storage

Store intact vials at room temperature of 20°C to 25°C (68°F to 77°F) and protect from light. After reconstitution, store at 2°C to 8°C (36°F to 46°F). Discard any unused solution after 72 hours.

Drug Interactions

Bacitracin (Systemic): Polymyxin B may enhance the nephrotoxic effect of Bacitracin (Systemic). Avoid combination

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Capreomycin: May enhance the neuromuscular-blocking effect of Polymyxin B. Monitor therapy

Cefazedone: May enhance the nephrotoxic effect of Polymyxin B. Monitor therapy

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Avoid combination

Colistimethate: Polymyxin B may enhance the neuromuscular-blocking effect of Colistimethate. Monitor therapy

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

Mecamylamine: Polymyxin B may enhance the neuromuscular-blocking effect of Mecamylamine. Avoid combination

Methoxyflurane: May enhance the nephrotoxic effect of Polymyxin B. Avoid combination

Neuromuscular-Blocking Agents: Polymyxin B may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Consider therapy modification

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification

Adverse Reactions

Frequency not defined.

Cardiovascular: Facial flushing

Central nervous system: Neurotoxicity (includes ataxia, blurred vision, drowsiness, irritability, numbness of extremities oral paresthesia), dizziness, drug fever, meningitis (intrathecal administration)

Dermatologic: Urticaria

Endocrine & metabolic: Hypocalcemia, hypochloremia, hypokalemia, hyponatremia

Genitourinary: Nephrotoxicity

Hypersensitivity: Anaphylactoid reaction

Local: Pain at injection site

Neuromuscular & skeletal: Neuromuscular blockade, weakness

ALERT: U.S. Boxed Warning

Appropriate use:

When this drug is given IM, IV, or intrathecally, it should be given only to hospitalized patients, so as to provide constant supervision by a physician.

Nephrotoxicity:

Renal function should be carefully determined, and patients with renal damage and nitrogen retention should have reduced dosage. Patients with nephrotoxicity due to polymyxin B sulfate usually show albuminuria, cellular casts, and azotemia. Diminishing urine output and a rising blood urea nitrogen (BUN) are indications for discontinuing therapy with this drug.

Neurotoxicity:

Neurotoxic reactions may be manifested by irritability, weakness, drowsiness, ataxia, perioral paresthesia, numbness of the extremities, and blurring of vision. These are usually associated with high serum levels found in patients with impaired renal function and/or nephrotoxicity.

Concurrent therapy:

The concurrent or sequential use of other neurotoxic or nephrotoxic drugs with polymyxin B sulfate, particularly bacitracin, streptomycin, neomycin, kanamycin, gentamicin, tobramycin, amikacin, cephaloridine, paromomycin, viomycin, and colistin should be avoided.

Neuromuscular blockade:

The neurotoxicity of polymyxin B sulfate can result in respiratory paralysis from neuromuscular blockade, especially when the drug is given soon after anesthesia or muscle relaxants.

Use in pregnancy:

The safety of this drug in human pregnancy has not been established.

Warnings/Precautions

Concerns related to adverse effects:

• Local reactions: May cause severe pain at IM injection site or thrombophlebitis at IV infusion site.

• Nephrotoxicity: [US Boxed Warning]: May cause nephrotoxicity; avoid concurrent or sequential use of other nephrotoxic drugs. Usual risk factors include preexisting renal impairment, advanced age and dehydration. Polymyxin B-induced nephrotoxicity may be manifested by albuminuria, cellular casts, and azotemia; monitor BUN, serum creatinine, and urinary analysis at baseline and as clinically indicated. Discontinue therapy with decreasing urinary output and increasing BUN. Data suggest polymyxin B undergoes a selective uptake process into renal cells, which plays a primary role in nephrotoxicity potential (Abdelraouf 2014). One small study in patients receiving polymyxin B with a normal baseline renal function observed an overall prevalence rate of nephrotoxicity of 46% with a median onset of 9 days (Dubrovaskaya 2015).

• Neurotoxicity: [US Boxed Warning]: May cause neurotoxicity, which can also result in respiratory paralysis from neuromuscular blockade especially when the drug is given soon after anesthesia or muscle relaxants. Avoid concurrent or sequential use of other neurotoxic drugs. Avoid concurrent use of curariform muscle relaxants and other neurotoxic drugs (eg, ether, tubocurarine, succinylcholine, gallamine, decamethonium, sodium citrate), which may cause respiratory depression.

• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Renal impairment: Use with caution in patients with impaired renal function; manufacturer’s prescribing information states dosage reduction required, however, recent pharmacokinetic/pharmacodynamic and clinical studies suggest daily dose requirement is not affected by renal function (Sandri 2013a; Nelson 2015; Thamlikitkul 2016).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information

Special populations:

• Pregnancy: [US Boxed Warning]: Safety in pregnant women not established.

Other warnings/precautions:

• IM/Intrathecal/IV administration: [US Boxed Warning]: Intramuscular/intrathecal/intravenous administration only to hospitalized patients.

• Parenteral administration: Polymyxin B sulfate is most toxic when given parenterally; avoid parenteral use whenever possible.

Monitoring Parameters

Neurologic symptoms and signs of superinfection; renal function (decreasing urine output and increasing BUN may require discontinuance of therapy)

Pregnancy Considerations

[US Boxed Warning]: Safety in pregnant women has not been established. Animal reproduction studies are lacking. A teratogenic potential has not been identified for polymyxin b, but very limited data is available (Heinonen 1977; Kazy 2005). Based on the relative toxicity compared to other antibiotics, systemic use in pregnancy is not recommended (Knothe 1985). Due to poor tissue diffusion, topical use would be expected to have only minimal risk to the mother or fetus (Leachman 2006).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea. Have patient report immediately to prescriber signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain), signs of nerve problems (sensitivity to heat or cold; decreased sense of touch; burning, numbness, or tingling; pain; or weakness in the arms, hands, legs, or feet), difficulty breathing, change in balance, severe fatigue, vision changes, flushing, dizziness, headache, stiff neck, or signs of Clostridium difficile (C. diff)-associated diarrhea (stomach pain or cramps, very loose or watery stools, or bloody stools) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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