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Colistimethate

Pronunciation

(koe lis ti METH ate)

Index Terms

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

Dosage Forms

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

Solution Reconstituted, Injection [strength expressed as base]:

Coly-Mycin M: 150 mg (1 ea)

Generic: 150 mg (1 ea)

Solution Reconstituted, Injection [strength expressed as base, preservative free]:

Generic: 150 mg (1 ea)

Brand Names: U.S.

  • Coly-Mycin M

Pharmacologic Category

  • Antibiotic, Miscellaneous

Pharmacology

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

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)

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: Unlabeled

Used as nebulized inhalation in the prevention of Pseudomonas aeruginosa respiratory tract infections in immunocompromised patients; used as nebulized inhalation adjunct agent for the treatment of P. aeruginosa infections in patients with cystic fibrosis and other seriously ill or chronically ill patients; used as nebulized inhalation in the treatment of ventilator-associated pneumonia (VAP) due to multidrug-resistant P. aeruginosa or Acinetobacter baumannii

Contraindications

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

Dosing: Adult

Note: Dosage expressed in terms of colistin base activity. Colistimethate sodium 1 mg is equivalent to ~12,500 units of colistimethate sodium; Colistimethate sodium ~2.67 mg is equivalent to 1 mg of colistin base activity (Li 2006; Nation 2014).

Susceptible infections: IM, IV: 2.5 to 5 mg/kg/day in 2 to 4 divided doses; maximum: 5 mg/kg/day

Severe infections (due to multidrug-resistant organisms susceptible to colistin in the critically ill) (off-label dosing): IV: Loading dose: 270 mg followed by 135 mg twice daily (Dalfino 2012; Plachouras 2009). Additional trials may be necessary to further evaluate the use of this dosing in critically ill patients with this condition.

May also consider using the following calculations; however, although derived from critically ill patients, the use of this algorithm has not been prospectively evaluated in the critically ill (Garonzik 2011):

Loading dose of colistin base activity (mg) = Target average colistin steady-state plasma concentration (in mg/L) x 2 x weight (in kg). For patient weight, use the lower of ideal or actual body weight expressed in kg. In obese patients, application of these equations has not been evaluated.

Daily maintenance dose of colistin base activity (mg) = Target average colistin steady-state plasma concentration (in mg/L) x ([1.5 x CrCl] + 30). See dosing in renal impairment for frequency of administration based on CrCl.

Note: Do not exceed a total daily dose of 300 mg (according to this algorithm). Unless it is appropriate to target a low colistin steady-state plasma concentration (Css,avg), the authors do not recommended the use of these calculations in patients with CrCl >70 mL/minute/1.73 m2, in which case the loading dose or the daily maintenance dose may be substantially greater than 300 mg. Use caution with loading doses >300 mg. Target Css,avg is typically 2.5 mg/L (range: 2 to 4 mg/L [Couet 2012]) and should be based on MIC, site, and severity of infection. Crcl is expresssed in mL/minute/1.73 m2.

Bronchiectasis, pulmonary colonization/infection with susceptible organisms in patients with cystic fibrosis and noncystic fibrosis (off-label use/route): Inhalation: 30 to 150 mg via nebulizer 1 to 3 times daily (maximum dose: 150 mg 2 times daily) (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).

Meningitis (susceptible gram-negative organisms): Intrathecal/Intraventricular (off-label route): 10 mg/day (IDSA 2004); Note: Dosage in clinical reports has ranged from 1.6 to 20 mg/day in 1 or 2 divided doses (maximum single dose: 10 mg) (administered with concomitant systemic antimicrobial therapy) (Guardado 2008; Kasiakou 2005; Katragkou 2005)

Cystic fibrosis (off-label use): IV: 3 mg/kg/day in 3 divided doses (Young 2013)

Ventilator-associated pneumonia due to susceptible multidrug-resistant Pseudomonas aeruginosa, Acinetobacter baumannii, or Klebsiella pneumoniae (off-label use/route): Nebulization (via ventilator circuit): 150 mg 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; Tumbarello 2013; Valachis 2015).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Dosage expressed in terms of colistin base activity. Colistimethate sodium 1 mg is equivalent to ~12,500 units of colistimethate sodium; Colistimethate sodium ~2.67 mg is equivalent to 1 mg of colistin base activity (Li 2006; Nation 2014).

Susceptible infections: IM, IV: 2.5 to 5 mg/kg/day in 2 to 4 divided doses; maximum: 5 mg/kg/day

Dosing: Renal Impairment

Note: Dosage expressed in terms of colistin base activity.

IM, IV: Adults:

Manufacturer's labeling:

CrCl ≥80 mL/minute: No dosage adjustment necessary; maximum: 5 mg/kg/day

CrCl 50 to 79 mL/minute: 2.5 to 3.8 mg/kg/day in 2 divided doses

CrCl 30 to 49 mL/minute: 2.5 mg/kg/day once daily or in 2 divided doses

CrCl 10 to 29 mL/minute: 1.5 mg/kg every 36 hours

Alternative recommendations:

Severe infections (due to multidrug-resistant organisms susceptible to colistin in the critically ill) (Dalfino 2012): Note: CrCl calculated using the Cockcroft-Gault equation. IV:

CrCl ≥50 mL/minute: Loading dose of 270 mg followed by 135 mg twice daily.

CrCl 20 to 50 mL/minute: Loading dose of 270 mg followed by 135 mg once daily.

CrCl <20 mL/minute: Loading dose of 270 mg followed by 135 mg every 48 hours.

May also consider using the following calculations; however, although derived from critically ill patients, the use of this algorithm has not been prospectively evaluated in the critically ill (Garonzik 2011):

Loading dose of colistin base activity (mg) = Target average colistin steady-state plasma concentration (in mg/L) x 2 x weight (in kg). For patient weight, use the lower of ideal or actual body weight expressed in kg. In obese patients, application of these equations has not been evaluated.

Daily maintenance dose of colistin base activity (mg) = Target average colistin steady-state plasma concentration (in mg/L) x ([1.5 x CrCl] + 30)

Note: Use caution with loading doses >300 mg. Do not exceed a total daily dose of 300 mg (according to this algorithm). Target Css,avg is typically 2.5 mg/L but may range from 2 to 4 mg/L (Couet 2012). Calculate CrCl using the Jellife method mL/minute/1.73 m2 or the Cockcroft-Gault method (normalized to BSA of 1.73 m2).

CrCl >70 mL/minute/1.73 m2: Administer calculated daily maintenance dose in 2 to 3 divided doses every 12 or 8 hours, respectively. Note: Unless it is appropriate to target a low colistin Css,avg, the authors do not recommended the use of these calculations in patients with CrCl >70 mL/minute/1.73 m2.

CrCl 10 to 70 mL/minute/1.73 m2: Administer calculated daily maintenance dose in 2 to 3 divided doses every 12 or 8 hours, respectively.

CrCl <10 mL/minute/1.73 m2: Administer calculated daily maintenance dose in divided doses every 12 hours.

Intermittent hemodialysis (IHD) (administer after hemodialysis on dialysis days): IV: 1.5 mg/kg every 24 to 48 hours (Heintz 2009). Note: Dosing dependent on the assumption of 3 times/week, complete IHD sessions. Alternatively, may administer a daily dose of 30 mg for every 1 mg/L colistin Css,avg target given in divided doses every 12 hours on nonhemodialysis days. For example, if the Css,avg target is 2.5 mg/L, then administer 37.5 mg every 12 hours on nonhemodialysis days. On hemodialysis days (ideally performed at the end of the colistin dosage interval), administer a supplemental dose of 50% of the total daily dose if the supplemental dose is administered during the last half hour of the hemodialysis session or 30% of the total daily dose if the supplemental dose is administered after the hemodialysis session. These recommendations, although derived from critically ill patients, have not been prospectively evaluated in the critically ill (Garonzik 2011).

Continuous renal replacement therapy (CRRT) (Heintz 2009; Trotman 2005): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate). The following 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:

CVVH/CVVHD/CVVHDF: IV: 2.5 mg/kg every 24 to 48 hours (frequency dependent upon site or severity of infection or susceptibility of pathogen). Alternatively, in patients receiving CVVH or CVVHD, may administer a daily dose of 192 mg for every 1 mg/L colistin Css,avg target given 2 to 3 equally divided doses every 12 or 8 hours, respectively (Garonzik 2011).

Note: A single case report has demonstrated that the use of 2.5 mg/kg every 48 hours with a dialysate flow rate of 1 L/hour may be inadequate and that dosing every 24 hours was well-tolerated. Based on pharmacokinetic analysis, the authors recommend dosing as frequent as every 12 hours in patients receiving CVVHDF (Li 2005).

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer’s labeling.

Dosing: Adjustment for Toxicity

CNS toxicity: Dose reduction may reduce neurologic symptoms.

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

Dosing: Obesity

Doses should be based on ideal body weight in obese patients.

Reconstitution

IV or IM 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

Parenteral: Administer by IM, direct IV injection over 3 to 5 minutes, intermittent infusion over 30 minutes (Beringer 2001; Conway, 1997), or by continuous IV infusion (according to the manufacturer). For continuous IV infusion, 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. The final concentration for continuous infusion administration should be based on the patient's fluid needs; infusion should be completed within 24 hours of preparation.

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.

Compatibility

Stable in D51/4NS, D51/2NS, D5NS, D5W, LR, NS.

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. 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

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

Frequency not always defined.

Central nervous system: Neurotoxicity (7%; higher incidence with high-dose IV use in cystic fibrosis [Boss 1991; Koch-Weser 1970]), dizziness, headache, oral paresthesia, peripheral paresthesia, slurred speech, vertigo

Dermatologic: Pruritus, skin rash, urticaria

Gastrointestinal: Gastric distress

Genitourinary: Decreased urine output, nephrotoxicity (18% to 26% [Dalfino 2012; Oliveira 2009]), proteinuria

Neuromuscular & skeletal: Lower extremity weakness

Renal: Acute renal failure (33% to 60% [Akajagbor 2013; Deryke 2010]), increased blood urea nitrogen, increased serum creatinine

Respiratory: Apnea, respiratory distress

Miscellaneous: Fever

<1% (Limited to important or life-threatening): Pulmonary toxicity (acute respiratory tract failure following inhalation, bronchoconstriction, bronchospasm, chest tightness, respiratory distress)

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])

Pregnancy Risk Factor

C

Pregnancy Considerations

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

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 itching or nausea. Have patient report immediately to prescriber signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), burning or numbness feeling, slurred speech, severe dizziness, or signs of Clostridium difficile (C. diff)-associated diarrhea (abdominal pain or cramps, severe diarrhea 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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