Colistimethate (Colistin)

Pharmacologic Category

Antibiotic, Miscellaneous

Dosing: Adult

Note: Dosage expressed in terms of mg of colistin base activity (CBA). CBA 1 mg is defined to be equivalent to colistimethate sodium (CMS) 30,000 units which is equivalent to ~2.4 mg CMS (see table below) (EMA 2014; ESCMID/EUCAST [Tsuji 2019]; Falagas 2006; Kassamali 2013; Nation 2014; Nation 2017).

Bronchiectasis, pulmonary colonization/infection with susceptible organisms in cystic fibrosis and noncystic fibrosis patients (off-label use/route): Inhalation: 30 to 150 mg CBA via nebulizer 1 to 2 times daily (maximum dose: 150 mg CBA 2 times daily) (Haworth 2014; Le 2010; Sabuda 2008; Steinfort 2007). Note: An optimal dosing regimen has not been determined and varies widely among studies; lower doses have been used in noncystic fibrosis patients with bronchiectasis (Steinfort 2007). Use in addition to systemic antibiotics (ESCMID/EUCAST [Tsuji 2019]).

Meningitis and ventriculitis (susceptible gram-negative organisms; adjunct to systemic therapy) (use a preservative-free preparation): Intrathecal/intraventricular (off-label route): 4.2 mg CBA/day (equivalent to 10 mg CMS/day) (ESCMID/EUCAST [Tsuji 2019]; IDSA [Tunkel 2017]; Imberti 2012; Ziaka 2013). Note: Dose in clinical reports has ranged from 0.7 to 8.3 mg CBA/day in 1 or 2 divided doses (administered with concomitant systemic antimicrobial therapy) (Benifla 2004; De Bonis 2016; Falagas 2007; Fotakopoulos 2016; Imberti 2012; Katragkou 2005; Rodríguez Guardado 2008). When intraventricular colistimethate is administered via a ventricular drain, clamp drain for 15 to 60 minutes after administration (allows solution to equilibrate in CSF) (IDSA [Tunkel 2004]; IDSA [Tunkel 2017]). Intraventricular administration is generally reserved for use in patients who fail parenteral therapy despite removal of CSF shunt or when CSF shunt cannot be removed (Baddour 2018).

Pneumonia, hospital-acquired or ventilator-associated due to susceptible multidrug-resistant gram-negative bacilli (eg, Pseudomonas aeruginosa, Acinetobacter spp) (off label): Note: When used for empiric treatment, use in combination with other agent(s) when appropriate (IDSA/ATS [Kalil 2016]).

Nebulization (via ventilator circuit): 150 mg CBA every 8 hours delivered over 60 minutes for 14 days or until successful wean from mechanical ventilation (treatment duration range: 7 to 19 days) (Lu 2012). May consider using as an adjunct in patients receiving IV colistin; may improve clinical outcomes (Doshi 2013; ESCMID/EUCAST [Tsuji 2019]; Tumbarello 2013; Valachis 2015).

IV: Loading dose: 300 mg CBA followed by 300 to 360 mg CBA/day in divided doses twice daily. Begin maintenance dose 12 hours after the loading dose. Adjunctive inhaled colistin is also recommended (ESCMID/EUCAST [Tsuji 2019]). Note: This dosing should achieve a target average colistin steady-state plasma concentration of 2 mg/L and is derived from analysis of pharmacokinetic data in critically ill patients (Nation 2017).

Severe infections (due to multidrug-resistant organisms susceptible to colistin) (off-label dosing): IV: Loading dose: 300 mg CBA followed by 300 to 360 mg CBA/day in divided doses twice daily (Dalfino 2012; ESCMID/EUCAST [Tsuji 2019]; Plachouras 2009). Begin maintenance dose 12 hours after the loading dose (ESCMID/EUCAST [Tsuji 2019]). Note: This dosing should achieve a target average colistin steady-state plasma concentration of 2 mg/L and is derived from analysis of pharmacokinetic data in critically ill patients. Attainment rates for the target colistin concentration of 2 mg/L using these calculations in patients with CrCl ≥80 mL/minute were ~40%; consider combination therapy with other antibacterials for these patients, especially for treatment of respiratory tract infection and/or for organisms with colistin MIC ≥1 mg/L (Nation 2017). Do not exceed a loading dose of 300 mg CBA or a total daily dose of 360 mg CBA due to risk of nephrotoxicity (Nation 2016; Nation 2017).

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment: Adult

Note: Dosage expressed in terms of colistin base activity (CBA); although reported conversions have varied slightly in the literature, CBA 1 mg is defined to be equivalent to colistimethate sodium 30,000 units (EMA 2014; Falagas 2006; Kassamali 2013; Nation 2014; Nation 2017). These dosing recommendations should achieve a target average colistin steady-state plasma concentration of 2 mg/L and are derived from analysis of pharmacokinetic data in critically ill patients (Nation 2017).

IV:

Loading dose: 300 mg CBA, followed by a maintenance dose based on CrCl (ESCMID/EUCAST [Tsuji 2019]; Nation 2017), calculated using the Cockcroft-Gault equation with an adjusted body weight (ideal body weight [IBW] + 0.4 [total body weight – IBW]) (ESCMID/EUCAST [Tsuji 2019]; Nation 2017; Winter 2012).

Maintenance dose: The following total daily maintenance doses (administered in 2 divided doses) are recommended (ESCMID/EUCAST [Tsuji 2019]; Nation 2017):

CrCl ≥90 mL/minute: 360 mg CBA/day.

CrCl 80 to <90 mL/minute: 340 mg CBA/day.

CrCl 70 to <80 mL/minute: 300 mg CBA/day.

CrCl 60 to <70 mL/minute: 275 mg CBA/day.

CrCl 50 to <60 mL/minute: 245 mg CBA/day.

CrCl 40 to <50 mL/minute: 220 mg CBA/day.

CrCl 30 to <40 mL/minute: 195 mg CBA/day.

CrCl 20 to <30 mL/minute: 175 mg CBA/day.

CrCl 10 to <20 mL/minute: 160 mg CBA/day.

CrCl 5 to <10 mL/minute: 145 mg CBA/day.

CrCl <5 mL/minute: 130 mg CBA/day.

Alternative renal dosing strategy (EMA 2014; Nation 2016):

IV:

For critically ill patients, a loading dose of 300 mg CBA should be administered followed by a maintenance dose based on CrCl. The following total daily maintenance doses (administered in 2 or 3 divided doses) are recommended:

CrCl ≥50 mL/minute: 300 mg CBA/day; some patients with good renal function may require higher daily doses.

CrCl 30 to <50 mL/minute: 183 to 250 mg CBA/day.

CrCl 10 to <30 mL/minute: 150 to 183 mg CBA/day.

CrCl <10 mL/minute: 117 mg CBA/day.

Intermittent hemodialysis (administer after hemodialysis on dialysis days): IV: Loading dose: 300 mg CBA followed by 130 mg CBA once daily. On dialysis days, a supplemental dose of 40 mg CBA or 50 mg CBA for a 3- or 4-hour intermittent hemodialysis (IHD) session, respectively, should be added to the daily maintenance dose. The dialysis session should occur toward the end of the dosing interval, and the supplement to the baseline (nonhemodialysis) daily dose should be administered with the next regular dose, after the dialysis session has ended (ESCMID/EUCAST [Tsuji 2019]; Nation 2017). Note: Dosing dependent on the assumption of 3 times/week, complete IHD sessions.

CVVH/CVVHD/CVVHDF: IV: Loading dose: 300 mg CBA followed by 220 mg CBA every 12 hours (ESCMID/EUCAST [Tsuji 2019]). Note: These are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 to 2 L/hour and minimal residual renal function) and should not supersede clinical judgment. More recent data among patients receiving CVVHDF suggest that the daily dose at least equal or even exceed that of patients with normal renal function (ESCMID/EUCAST [Tsuji 2019]; Karvanen 2013).

Sustained low-efficiency dialysis: IV: Loading dose: 300 mg CBA followed by maintenance dose based on renal function and duration of sustained low-efficiency dialysis (SLED) session. Add 10% per 1 hour of SLED replacement to the recommended baseline daily dose for renal function (eg, CrCl <5 mL/minute, 130 mg CBA/day); administer in 2 divided doses administered 12 hours apart. For example, in a patient with a CrCl of <5 mL/minute receiving 10 hours nocturnal SLED session each day, the suggested CBA dose is: 130 mg + (10 hours × 13) = 260 mg CBA/day, administered as 130 mg every 12 hours. SLED session should begin 1 to 2 hours after the afternoon/evening dose (ESCMID/EUCAST [Tsuji 2019]; Nation 2017).

Dosing: Hepatic Impairment: Adult

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

Dosing: Adjustment for Toxicity: Adult

CNS toxicity: Dose reduction may reduce neurologic symptoms.

Nephrotoxicity: Withhold treatment if signs of renal impairment occur during treatment.

Dosing: Pediatric

Note: Doses should be based on ideal body weight in obese patients; dosage primarily expressed in terms of colistin base activity (CBA). CBA 1 mg is defined to be equivalent to colistimethate sodium (CMS) 30,000 units which is equivalent to ~2.4 mg CMS (EMA 2014; Falagas 2006; Kassamali 2013; Nation 2017).

General dosing, susceptible infection: Infants, Children, and Adolescents: Colistin base: IM, IV: 2.5 to 5 mg CBA/kg/day divided every 6 to 12 hours

CNS infection (VP-shunt infection, ventriculitis, meningitis), multidrug resistant: Limited data available; variable doses reported; optimal dose not defined.

Infants and Children: Very limited data available: Intraventricular/Intrathecal: Colistin base: Reported range: 1 to 4.2 mg CBA/dose once daily in combination with systemic antibiotics (Dalgic 2009; IDSA [Tunkel 2017]; Ng 2006; Ozdemir 2010). Doses should be individualized based on culture/sensitivity, MIC, and tolerability while ensuring that patient size and CSF volume are considered. In one case report, a 4-year old with multidrug resistant Acinetobacter baumannii received an intraventricular dose of 1 mg CBA on Day 1, followed by 2 mg CBA once daily for 2 days, then 4 mg CBA once daily; after 13 days, a dose reduction to 2 mg CBA once daily was necessary due to CSF leukocytosis (Ng 2006). A similar protocol was described in a 2-month old with multidrug resistant Acinetobacter baumannii; the initial dose on Day 1 was 1 mg CBA followed by 2 mg CBA once daily for 2 days, then 4 mg CBA once daily; due to failure to sterilize the CSF, the dose was slowly titrated up to 10 mg CBA/day for a total of 20 days (Dalgic 2009). In a case report of a 3-year old with multidrug resistant Acinetobacter baumannii, intrathecal colistin was administered without titration at a dose of 4.2 mg CBA/day (Ozdemir 2010).

Adolescents: Very limited data available: Intraventricular/Intrathecal: Colistin base: 4.2 mg CBA/day (equivalent to 10 mg CMS/day) (IDSA [Tunkel 2017]; Yagmur 2006); Note: Dose in clinical reports in adults has ranged from 0.7 to 8.3 mg CBA/day in 1 or 2 divided doses (administered with concomitant systemic antimicrobial therapy) (Benifla 2004; Falagas 2007; Imberti 2012; Katragkou 2005)

Cystic fibrosis, pulmonary infection: Limited data available: Children ≥5 years and Adolescents: Colistin base: IV: Usual reported range: 3 to 5 mg CBA/kg/day divided every 8 hours; maximum dose: 100 mg CBA/dose (Bosso 1991; Reed 2001; Young 2013); doses >5 mg CBA/kg/day (up to 8 mg CBA/kg/day) may be required in some situations; however, higher doses are associated with more severe toxicity (Bosso 1991; Reed 2001).

Pulmonary infection: Limited data available: Infants, Children, and Adolescents: Colistin base: Inhalation: Usual dose: 75 to 150 mg CBA in 3 mL of NS (4 mL total volume) via nebulizer twice daily is most frequently reported in clinical practice; reported range: 30 to 150 mg CBA/dose (Le 2010; Tramper-Stranders 2010)

Dosing adjustment for toxicity: Infants, Children, and Adolescents: Based on experience with other aminoglycosides, the following should be considered:

CNS toxicity: Dose reduction may reduce neurologic symptoms.

Nephrotoxicity: Withhold treatment if signs of renal impairment occur during treatment.

Dosing: Renal Impairment: Pediatric

There are no pediatric specific recommendations in the manufacturer’s labeling; in adult patients, dosage adjustment is suggested.

Dosing: Hepatic Impairment: Pediatric

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

Use: Labeled Indications

Treatment of acute or chronic infections due to sensitive strains of certain gram-negative bacilli (particularly Pseudomonas aeruginosa) which are resistant to other antibacterials or in patients allergic to other antibacterials

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Bronchiectasis, pulmonary colonization/infection with susceptible organisms in cystic fibrosis and noncystic fibrosis patients (nebulized)Level of Evidence [C]

Data from a small number of patients with bronchiectasis and severe chronic obstructive pulmonary disease with recurrent gram-negative infections demonstrated that colistimethate may improve quality of life and slow decline in FEV1 and FVC Ref. A subsequent study suggested a longer time to exacerbation and improved quality of life compared to placebo Ref. Among patients with cystic fibrosis and early Pseudomonas aeruginosa infection, the use of nebulized antibiotics, including colistin, may eradicate the organism for up to 2 years Ref. Additional data are necessary to further define the role of nebulized colistimethate for this indication.

Cystic fibrosisLevel of Evidence [C]

Based on three studies Ref, only one of which was randomized and controlled Ref, the use of intravenous colistimethate has demonstrated efficacy alone or in combination with an additional antipseudomonal antibiotic for the treatment of acute exacerbations of cystic fibrosis. Additional data are necessary to further define the role and dose of intravenous colistimethate for patients with cystic fibrosis.

Pneumonia, hospital-acquired or ventilator-associated due to multidrug-resistant gram-negative bacilli (eg, Pseudomonas aeruginosa or Acinetobacter baumannii [nebulized]) (alternative agent)Level of Evidence [B, G]

Based on the Infectious Diseases Society of America and the American Thoracic Society guidelines for the management of hospital-acquired and ventilator-associated pneumonia, inhaled colistimethate may be considered as an alternative adjunctive agent for patients with hospital-acquired or ventilator-associated pneumonia (VAP) caused by susceptible, multidrug-resistant (including carbapenem-resistant) gram-negative bacilli (eg, P. aeruginosa, Acinetobacter species) Ref. Data from a prospective, observational, comparative study in patients with VAP caused by A. baumannii and P. aeruginosa demonstrated that the use of nebulized colistimethate was noninferior to IV beta-lactams/aminoglycosides or quinolones in patients with a sensitive strain Ref. In addition, a meta-analysis among patients with VAP, found that adjunctive aerosolized colistimethate was associated with improved clinical cure Ref.

Level of Evidence Definitions

Level of Evidence Scale

Clinical Practice Guidelines

Meningitis, Bacterial:

IDSA, “Practice Guidelines for the Management of Bacterial Meningitis,” November 2004

Meningitis and Ventriculitis, Healthcare-Associated:

IDSA, "Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis," February 2017.

Pneumonia, Hospital-Acquired and Ventilator-Associated:

IDSA/ATS, "Management of Adults with Hospital-Acquired and Ventilator-Associated Pneumonia," July 2016.

Polymyxins:

ACCP/ESCMID/IDSA/ISAP/SCCM/SIDP, “International Consensus Guidelines for the Optimal Use of the Polymyxins,” January 2019.

Skin and Soft-tissue Infection:

IDSA, “Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections,” June 2014.

Administration: IV

Infuse over 30 minutes to 1 hour (ESCMID/EUCAST [Tsuji 2019]).

Administration: Inhalation

Off-label route: Administer solution via nebulizer (vibrating plate nebulizer may be preferred [Lu 2012]) promptly following preparation to decrease possibility of high concentrations of colistin from forming which may lead to potentially life-threatening lung toxicity. Consider use of a bronchodilator (eg, albuterol) within 15 minutes prior to administration (Le 2010). If patient is on a ventilator, place medicine in a T-piece at the midinspiratory circuit of the ventilator. One study in adult patients with VAP administered colistimethate over 60 minutes using a vibrating plate nebulizer positioned on the inspiratory limb 10 cm proximal to the Y-piece (Lu 2012).

Note: A case report of fatal lung toxicity implicated in vitro colistin formation from an inhalation solution as a potential etiology, but data regarding the concentration, formulation and storage of the inhaled colistin administered to the patient were not reported (FDA 2007; McCoy 2007; Wallace 2008). An acceptable limit of in vitro colistin formation to prevent potential toxicity is unknown. Limited stability data are available regarding the storage of colistin solution for inhaled administration (Healan 2012; Wallace 2008). Storing for >24 hours may increase the risk for potential lung toxicity; preparation immediately prior to administration is recommended (FDA 2007; Le 2010, Wallace 2008).

Administration: Intrathecal

Intrathecal/intraventricular (off-label route): Administer only preservative-free solutions via intrathecal/intraventricular routes. Administer promptly after preparation. Discard unused portion of vial. When administered through a ventricular drain, clamp drain for 15 to 60 minutes before opening the drain to allow colistimethate solution to equilibrate in the CSF (IDSA [Tunkel 2004]; IDSA [Tunkel 2017]).

Administration: Pediatric

Parenteral:

IM: Administer deep into a large muscle mass (eg, gluteal muscle or lateral part of the thigh).

IV push: Administer over 3 to 5 minutes.

Intermittent IV infusion: Administer over 30 minutes.

Continuous IV infusion: Initially, one-half of the total daily dose is administered by direct IV injection over 3 to 5 minutes followed 1 to 2 hours later by the remaining one-half of the total daily dose diluted in a compatible IV solution infused over 22 to 23 hours. Infusion should be completed within 24 hours of preparation.

Inhalation: Administer solution via nebulizer promptly following preparation of solution to decrease possibility of high concentrations of colistin from forming which may lead to potentially life-threatening lung toxicity. Consider use of a bronchodilator (eg, albuterol) within 15 minutes prior to administration (Le 2010).

Note: A case report of fatal lung toxicity implicated in vitro colistin formation from an inhalation solution as a potential etiology, but data regarding the concentration, formulation, and storage of the inhaled colistin administered to the patient were not reported (FDA 2007; McCoy 2007; Wallace 2008). An acceptable limit of in vitro colistin formation to prevent potential toxicity is unknown. Limited stability data are available regarding the storage of colistin solution for inhaled administration (Healan 2012; Wallace 2008). Storing for >24 hours may increase the risk for potential lung toxicity; preparation immediately prior to administration is recommended (FDA 2007; Le 2010; Wallace 2008).

Intraventricular/Intrathecal: Administer only preservative-free solutions via intrathecal/intraventricular routes. Administer promptly after preparation. Discard unused portion of vial. When administering via a ventricular drain, experts recommend the drain be clamped for 15 to 60 minutes to allow equilibration of colistin with CSF prior to opening the drain (Tunkel [IDSA 2017).

Storage/Stability

Store intact vials (prior to reconstitution) at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Reconstituted vials may be refrigerated at 2°C to 8°C (36°F to 46°F) or stored at 20°C to 25°C (68°F to 77°F) for up to 7 days. Solutions for infusion should be freshly prepared in D51/4NS, D51/2NS, D5NS, D5W, LR, or NS; do not use beyond 24 hours.

Preparation for Administration: Adult

IV use: Reconstitute each vial containing 150 mg of colistin base activity with 2 mL of SWFI resulting in a concentration of 75 mg colistin base activity/mL; swirl gently to avoid frothing. May further dilute in D5W or NS for IV infusion.

Intrathecal/intraventricular use (off-label route): Reconstitute with preservative-free diluent (SWFI or NS) only; use promptly after preparation; discard unused portion of vial (Quinn 2005).

Inhalation (via nebulizer; off-label route): Reconstitute vial containing 150 mg of colistin base activity with NS; further dilute dose with NS to a final concentration between 3 to 30 mg colistin base activity/mL (Maskin 2015; Yapa 2014). Optimal dosing regimens have not been determined and final concentrations used in studies vary widely; the nebulizer reservoir volume may also determine the final concentration (Berlana 2005). Storing for >24 hours may increase the risk for potential lung toxicity; preparation immediately prior to administration is recommended (FDA 2007; Le 2010, Wallace 2008); see Warnings/Precautions, Appropriate Use and Safety.

Mechanically ventilated patients: Dilute 150 mg colistin base activity with SWFI; further dilute dose with 10 mL SWFI to a final concentration of 15 mg colistin base activity/mL (Lu 2012).

Preparation for Administration: Pediatric

Parenteral:

IV or IM use: Reconstitute vial containing 150 mg of colistin base activity with 2 mL of SWFI resulting in a concentration of 75 mg colistin base/mL; swirl gently to avoid frothing. May further dilute in D5W or NS for IV infusion.

Continuous IV infusion: The final concentration for continuous infusion should be based on the patient's fluid needs; infusion should be completed within 24 hours of preparation.

Nebulized inhalation: Reconstitute vial containing 150 mg of colistin base activity with 2 mL SWFI, resulting in a concentration of 75 mg colistin base activity/mL; further dilute dose to a total volume of 4 mL in NS (Le 2010; Tramper 2010). Storing for >24 hours may increase the risk for potential lung toxicity; preparation immediately prior to administration is recommended (FDA 2007; Le 2010; Wallace 2008).

Intrathecal/Intraventricular: Very limited data available; case reports in infants and children describe mixing the dose with 1 to 2 mL of preservative-free NS (Dalgic 2009; Ng 2006)

Compatibility

See Trissel’s IV Compatibility Database

Open Trissel's IV Compatibility

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to treat bacterial infections.

Frequently reported side effects of this drug

• Diarrhea

• Nausea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.

• Burning or numbness feeling

• Slurred speech

• Dizziness

• Passing out

• Seizures

• Muscle weakness

• Difficulty breathing

• Slow breathing

• Shallow breathing

• Clostridioides (formerly Clostridium) difficile-associated diarrhea like abdominal pain or cramps, severe diarrhea or watery stools, or bloody stools.

• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Other safety concerns:

Contraindications

Hypersensitivity to colistimethate, colistin, or any component of the formulation

Warnings/Precautions

Concerns related to adverse effects:

• Bronchoconstriction: Use of inhaled colistimethate (off-label route) may result in bronchoconstriction. Use with caution in patients with hyperactive airways; consider administration of a bronchodilator (eg, albuterol) within 15 minutes prior to administration (Le 2010).

• CNS toxicity: Transient, reversible neurological disturbances (eg, dizziness, numbness, paresthesia, generalized pruritus, slurred speech, tingling, vertigo) may occur. Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Dose reduction may reduce neurologic symptoms; monitor closely.

• Renal toxicity: Dose-dependent nephrotoxicity has been reported, generally reversible upon discontinuation of treatment. Withhold treatment if signs of renal impairment occur during treatment.

• Respiratory arrest: Respiratory arrest has been reported with use; impaired renal function may increase the risk for neuromuscular blockade and apnea.

• 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 preexisting renal impairment; dosage adjustments are recommended. Impaired renal function may increase the risk for respiratory arrest.

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.

Other warnings/precautions:

• Appropriate use: Inhalation (off-label route): Once mixed, colistimethate begins conversion to bioactive colistin, a component of which may result in severe pulmonary toxicity (Le 2010). Solutions for inhalation must be mixed immediately prior to administration and used within 24 hours to reduce the incidence of pulmonary toxicity.

• Appropriate use: IV: Use only to prevent or treat infections strongly suspected or proven to be caused by susceptible bacteria to minimize development of bacterial drug resistance.

• Safety: Potential for dosing errors due to lack of standardization in literature when referring to product and dose; colistimethate (inactive prodrug) and colistin base strengths are not interchangeable; verify prescribed dose is expressed in terms of colistin base activity prior to dispensing.

* See Cautions in AHFS Essentials for additional information.

Warnings: Additional Pediatric Considerations

Nephrotoxicity is dose dependent and reversible upon discontinuation and has been observed to occur within the first 4 days of therapy in patients with cystic fibrosis (Bosso 1991). The Cystic Fibrosis Foundation recommends that patients not use colistimethate for inhalation premixed by pharmacies; patients should prepare their colistimethate nebulizer inhalation solutions immediately prior to use. Colistin is comprised of two components: Colistin A (polymyxin E1) and colistin B (polymyxin E2). Polymyxin E1 has been shown to cause localized airway inflammation in animal studies and may result in lung toxicity in humans. Clinicians who continue to prescribe colistimethate for inhalation should be aware of this potentially life-threatening effect and should administer solutions for inhalation promptly following preparation of solution.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Colistimethate crosses the placenta in humans.

Breast-Feeding Considerations

Colistin (the active form of colistimethate sodium) and colistin sulphate (another form of colistin) are excreted in human milk. The manufacturer recommends caution if giving colistimethate sodium to a breast-feeding woman. Nondose-related effects could include modification of bowel flora.

Lexicomp Pregnancy & Lactation, In-Depth

• Colistimethate

Briggs' Drugs in Pregnancy & Lactation

• Colistimethate

Adverse Reactions

>10%:

Genitourinary: Nephrotoxicity (18% to 26% [Dalfino 2012; Oliveira 2009])

Renal: Acute renal failure (33% to 60% [Akajagbor 2013; Deryke 2010])

1% to 10%:

Central nervous system: Neurotoxicity (7%; higher incidence with high-dose IV use in cystic fibrosis [Bosso 1991; Koch-Weser 1970])

Frequency not defined:

Central nervous system: Dizziness, oral paresthesia, paresthesia, peripheral paresthesia, seizures, slurred speech, vertigo

Dermatologic: Pruritus, skin rash, urticaria

Gastrointestinal: Clostridioides (formerly Clostridium) difficile-associated diarrhea, gastric distress

Genitourinary: Decreased urine output

Hypersensitivity: Anaphylaxis

Renal: Decreased creatinine clearance, increased blood urea nitrogen, increased serum creatinine

Respiratory: Apnea, respiratory distress

Miscellaneous: Fever

* See Cautions in AHFS Essentials for additional information.

Metabolism/Transport Effects

None known.

Drug Interactions Open Interactions

Aminoglycosides: May enhance the nephrotoxic effect of Colistimethate. Aminoglycosides may enhance the neuromuscular-blocking effect of Colistimethate. Risk D: Consider therapy modification

Amphotericin B: May enhance the nephrotoxic effect of Colistimethate. Risk D: Consider therapy modification

Bacitracin (Systemic): Colistimethate may enhance the nephrotoxic effect of Bacitracin (Systemic). Risk X: Avoid combination

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

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

Capreomycin: May enhance the neuromuscular-blocking effect of Colistimethate. Risk C: Monitor therapy

Cefazedone: May enhance the nephrotoxic effect of Colistimethate. Risk C: Monitor therapy

Cephalothin: May enhance the nephrotoxic effect of Colistimethate. Risk C: Monitor therapy

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Risk X: Avoid combination

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

Mecamylamine: Colistimethate may enhance the neuromuscular-blocking effect of Mecamylamine. Risk X: Avoid combination

Methoxyflurane: Colistimethate may enhance the nephrotoxic effect of Methoxyflurane. Risk X: Avoid combination

Neuromuscular-Blocking Agents: Colistimethate may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Risk D: Consider therapy modification

Polymyxin B: May enhance the neuromuscular-blocking effect of Colistimethate. Risk C: Monitor therapy

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. Risk D: Consider therapy modification

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Risk D: Consider therapy modification

Vancomycin: May enhance the nephrotoxic effect of Colistimethate. Risk D: Consider therapy modification

Monitoring Parameters

Serum creatinine, BUN; urine output; signs of neurotoxicity; signs of bronchospasm (inhalation [off-label route]); colistin serum concentrations (to ensure adequate drug exposure particularly early in therapy) (ESCMID/EUCAST [Tsuji 2019]).

Reference Range

Target serum concentration is 2 mg/L for susceptible organisms (irrespective of reported MIC) (ESCMID/EUCAST [Tsuji 2019]).

Advanced Practitioners Physical Assessment/Monitoring

Assess culture and sensitivity report and patient allergy history prior to starting therapy. Assess for nephrotoxicity at baseline and frequently during treatment (BUN, creatinine, urinary output) adjust accordingly, neurotoxicity, and pulmonary toxicity.

Nursing Physical Assessment/Monitoring

Check lab results and report abnormalities. Monitor for and instruct patients to report signs/symptoms of nephrotoxicity (decreased urine output, blood in urine, big weight gain), neurotoxicity (facial paresthesia, vertigo, vasomotor instability, slurred speech, visual disturbances, confusion, psychosis), and pulmonary toxicity (coughing, bronchospasm). Instruct patients to avoid operating machinery or driving during use.

Dosage Forms: US

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

Solution Reconstituted, Injection [preservative free]:

Coly-Mycin M: 150 mg (1 ea)

Generic: 150 mg (1 ea)

Dosage Forms: Canada

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

Solution Reconstituted, Injection:

Coly-Mycin M: 150 mg (1 ea)

Generic: 150 mg (1 ea)

Anatomic Therapeutic Chemical (ATC) Classification

• A07AA10
• J01XB01

Generic Available (US)

Yes

Pricing: US

Solution (reconstituted) (Colistimethate Sodium (CBA) Injection)

150 mg (per each): $28.80 - $35.00

Solution (reconstituted) (Coly-Mycin M Injection)

150 mg (per each): $33.60

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

Colistimethate (or the sodium salt [colistimethate sodium]) is the inactive prodrug that is hydrolyzed to colistin, which acts as a cationic detergent and damages the bacterial cytoplasmic membrane causing leaking of intracellular substances and cell death

Pharmacodynamics/Kinetics

Absorption: Not absorbed from the GI tract, mucous membranes, or intact skin (Note: GI absorption has been observed in infants).

Distribution: Distributes widely, except for CNS, synovial, pleural, and pericardial fluids

Healthy volunteer: IV: Colistimethate: Vd: 8.92 L; Colistin: Vd: 12.4 L (Couet 2012)

Critically ill: IV: Colistimethate: Vd: 5.3 to 13.5 L; Colistin: Vd: 7.2 to 189 L (Couet 2012)

Cystic fibrosis: Adolescents and Adults: IV: Colistimethate: Vdss: 0.09 ± 0.03 L/kg (Reed 2001)

Protein binding: 50%

Metabolism: Colistimethate sodium (inactive prodrug) is hydrolyzed to colistin (active form). Note: Only ~30% of colistimethate sodium is converted to colistin (Couet 2011)

Half-life elimination: IM, IV: Colistimethate: 2 to 3 hours

Critically ill: Infants (including premature infants), Children, Adolescents, and Adults: IV: Colistimethate: 2.3 hours; Colistin: 14.4 hours (Plachouras 2009)

Cystic fibrosis: IV: Colistin: ~4 hours (Li 2003)

ESRD patients receiving CAPD: IV: Colistin: 13.2 hours (Koomanachai 2014)

Time to peak:

Healthy volunteers: IV: Colistin: 2 hours (range: 1 to 4 hours) (Couet 2011)

Critically ill: IV: Colistin: ~7 hours (Plachouras 2009)

Excretion: Primarily urine (as unchanged drug)); most colistin recovered in the urine is from postexcretion hydrolysis of colistimethate sodium (Couet 2011).

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

No significant effects or complications reported

Effects on Bleeding

No information available to require special precautions

Index Terms

Colistimethate Sodium; Colistin Methanesulfonate; Colistin Methanesulphonate; Colistin Sulfomethate; Pentasodium Colistin Methanesulfonate; Polymyxin E

References

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Brand Names: International

Acostin (IN); Aldreb (JP); Alficetin (AR); Alveoxina (AR); Avagal (UY); Colfinair (ES); Colifin (CH, DE); Colimex (LI, SA); Colimicina (IT); Colimycin (CL); Colimycine (FR, SK); Coliracin (IL); Colis (KR); Colistate (TH); Colistin (CH, HK, NL, PL); Colistin Link (AU, NZ); Colistineb (BE); Colixin (PT); Colmesdant (CR, DO, GT, HN, NI, PA, SV); Colobreathe (BE, CZ, EE, ES, GB, HU, IE, LT, NL, PL, RO, SE); Colomycin (CZ, GB, GR, HK, HN, IE, MY, SG, SI, UA); Costim (TW); Damacol (LI); Eskcolis (BD); Kolneb (AT); Kolomycin (SK); Mellistin (TH); Promixin (DE, DK, ES, GB, IE, NO); Tadim (AU, GR, NL, SE); Xylistin (IN)

Last Updated 3/11/20