Colistimethate

Dosage Forms

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)

Pharmacology

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

Pharmacokinetics/Pharmacodynamics

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: V_d: 8.92 L; Colistin: V_d: 12.4 L (Couet 2012)

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

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

Metabolism

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

Excretion

Primarily urine (as unchanged drug)

Time to Peak

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

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

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: ~3.5 hours (Li 2003)

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

Protein Binding

50%

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

Use: Off Label

Bronchiectasis, pulmonary colonization/infection with susceptible organisms in cystic fibrosis and noncystic fibrosis patients (nebulized)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 Steinfort 2007. A subsequent study suggested a longer time to exacerbation and improved quality of life compared to placebo Haworth 2014. 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 Langton Hewer 2017. Additional data are necessary to further define the role of nebulized colistimethate for this indication.

Cystic fibrosisc

Based on three studies Conway 1997, Conway 2000, Ledson 1998, only one of which was randomized and controlled Conway 1997, 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)byes

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) IDSA [Kalil 2016. 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 Lu 2012. In addition, a meta-analysis among patients with VAP, found that adjunctive aerosolized colistimethate was associated with improved clinical cure Valachis 2015.

Contraindications

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

Dosage and Administration

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).

Table has been converted to the following text.

Colistimethate Sodium Conversion (EMA 2014):

Colistimethate sodium 12,500 units equals

Colistimethate sodium 1 mg and equals

Colistin-base activity (CBA) 0.4 mg

Colistimethate sodium 150,000 units equals

Colistimethate sodium 12 mg and equals

Colistin-base activity (CBA) 5 mg

Colistimethate sodium 1,000,000 units equals

Colistimethate sodium 80 mg and equals

Colistin-base activity (CBA) 34 mg

Colistimethate sodium 4,500,000 units equals

Colistimethate sodium 360 mg and equals

Colistin-base activity (CBA) 150 mg

Colistimethate sodium 9,000,000 units equals

Colistimethate sodium 720 mg and equals

Colistin-base activity (CBA) 300 mg

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 2019 [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).

Dosing: Geriatric

Refer to adult dosing.

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: Adjustment for Toxicity

CNS toxicity: Dose reduction may reduce neurologic symptoms.

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

Reconstitution

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).

Administration

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

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).

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]).

Storage

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.

Drug Interactions

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

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

Bacitracin (Systemic): Colistimethate 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 Colistimethate. Monitor therapy

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

Cephalothin: May enhance the nephrotoxic effect of Colistimethate. 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. Avoid combination

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

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

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

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

Polymyxin B: May enhance the neuromuscular-blocking effect of Colistimethate. 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. 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. Consider therapy modification

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

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

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.

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]).

Pregnancy

Pregnancy Risk Factor

C

Pregnancy Considerations

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

Patient Education

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.