Colistin

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; Falagas 2006; Kassamali 2013; Nation 2014; Nation 2017).

Colistimethate Sodium Conversion (EMA 2014)

Colistimethate Sodium	Colistimethate Sodium	Colistin-Base Activity (CBA)
12,500 units	1 mg	0.4 mg
150,000 units	12 mg	5 mg
1,000,000 units	80 mg	34 mg
4,500,000 units	360 mg	150 mg
9,000,000 units	720 mg	300 mg

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

Severe infections (due to multidrug-resistant organisms susceptible to colistin in the critically ill) (off-label dosing): IV: Loading dose: 300 mg CBA followed by 150 mg CBA 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. Attainment rates for the desirable target colistin concentration (2 mg/L) using these calculations in patients with creatinine clearance ≥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):

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. Application of these equations has not been evaluated in obese patients.

Daily maintenance dose of colistin base activity (mg) = Target average colistin steady-state plasma concentration (in mg/L) x 10(0.0048 x CrCl [mL/minute] + 1.825) in 2 divided doses. Administer twice daily beginning 12 hours after loading dose. See Dosing: Renal Impairment: Adult for frequency of administration based on CrCl.

Note: Do not exceed a loading dose of 300 mg CBA or a total daily dose of 360 mg CBA due to risk of nephrotoxicity (according to this algorithm). Target Css,avg is typically 2 mg/L and should be based on MIC, site, and severity of infection. CrCl is expressed in mL/minute (Nation 2016; 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).

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

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) (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):

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; Tumbarello 2013; Valachis 2015).

IV: Loading dose: Target average colistin steady-state plasma concentration (in mg/L) x 2 x weight (in kg); use the lower of ideal or actual body weight, followed by a maintenance dose beginning 12 hours after the loading dose; the daily maintenance dose (in mg) may be calculated with the following equation: Target average colistin steady-state plasma concentration (in mg/L) x 10(0.0048 x CrCl [mL/minute] + 1.825) and administered in 2 divided doses every 12 hours based on CrCl (see Dosing: Renal Impairment: Adult) (Nation 2017). Caution is advised when administering loading doses >300 mg CBA or daily doses >360 mg CBA. Attainment rates for the desirable target colistin concentration (2 mg/L) using these calculations in patients with creatinine clearance ≥80 mL/minute were ~40%; consider combination therapy with other antibacterials for these patients with CrCl ≥80 mL/minute especially for organisms with colistin MIC ≥1 mg/L (Nation 2017). Also consider using adjunctive inhaled colistin. When used for empiric treatment of ventilator-associated pneumonia, use in combination with an agent with MRSA activity (or MSSA activity, if appropriate), with or without an additional antipseudomonal agent (dependent on risk factors) (IDSA [Kalil 2016]).

Administration: Adult

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. 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]).