POLYMIXIN E (COLISTIN)

Spectrum of activity

Colistin has excellent bactericidal activity against most gram-negative aerobic bacilli, including: Acinetobacterspecies (MIC90 ≤ 2 mg/L) P. aeruginosa (MIC90 ≤ 4 mg/L) K. pneumoniae (MIC90 ≤ 1 mg/L) E. coli(MIC90 ≤ 2 mg/L) Enterobacter spp (MIC50 ≤ 1 mg/L).

It also may be active against: Salmonella spp (MIC90 ≤ 1 mg/L) Shigella spp (MIC90 ≤ 0.5 mg/L) Citrobacter spp (MIC90 ≤ 1 mg/L) Yersinia pseudotuberculosis Haemophilus influenzae

Resistance

Pseudomonas mallei, Burkholderia cepacia, Proteus species, Providencia species, Serratia species, Edwardsiella species, and Brucella species are all resistant to colistin. In addition, colistin is not active against gram-negative and gram-positive aerobic cocci, gram-positive aerobic bacilli, all anaerobes, fungi, and parasites

Polymyxin use in a critical care setting

Polymyxin E is currently considered for the treatment of MDR gram-negative infections confirmed by in vitro susceptibility testing.

Ventilator-associated pneumonia (VAP)Most research work has been done to check the efficacy of colistin. The usefulness of colistin as a treatment option in ventilator-associated pneumonia has been done in many studies.

Garnacho-Montero, et al. administered CMS intravenously to 21 of 35 patients with VAP due to MDRA. baumanii strains and reported a cure in 57% of the patients.

Reina, et al. examined the effectiveness and safety profile of colistin in infections caused by A. baumanii and P. aeruginosa in the ICU. There was no significant difference in cure rates and the adverse effect profile when compared with the carbepenem group.

Studies by Levin, Linden, and Markou in patients with VAP due to A. baumanii and P. aeruginosa confirmed the equal efficacy of intravenous colistin with carbepenems.

Michalopoulus, et al.used aerosolized colistin for the treatment of MDR gram-negative nosocomial pneumonia in patients without cystic fibrosis. All the patients also received

intravenous therapy concomitantly. A total of 7 out of 8 patients recovered, thus they concluded that aerosolised colistin can be used as a beneficial adjunctive therapy in the treatment of MDR VAP.

Bacteremia/sepsis

Markou, et al. administered colistin intravenously to patients with sepsis due to multiple causes. He observed a clinical response rate of 73% with 14.4% of the patients showing some deterioration in renal functions.

Michalopoulus, et al. studied the effect of colistin in sepsis due to MDR gram-negative organisms. He showed a clinical cure rate of 70%.

Meningitis Bukhary, et al. treated a case of nosocomial MDR A. baumanii meningitis by

administering 125,000 IU every 12 hrs in 5 ml normal saline intrathecally. There were no apparent side-effects.

Berlana, et al. treated 92% of patients with meningitis by administering colistin intravenously, intramuscularly, intrathecally, or inhaled.

Kasiakou, et al. treated an isolated case of MDR meningitis by intraventricular administration of colistin.

Combination therapy with colistinThere are very few studies that report the efficacy of combination therapy of colistin with other antimicrobials. A few studies have shown the synergistic activity of colistin with other antipseudomonal antibiotics like carbepenems, piperacillin/tazobactam, ceftazidime, or ciprofloxacin. Colistin and rifampicin have shown some synergistic activity against MDR strains of A. baumanii.

DosageAdult: 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 (9 MU) followed by 135 mg (4.5 MU) 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 in NS (3 to 4 mL total) via nebulizer 1 to 3 times daily (maximum dose: 150 mg 2 times daily) (Le 2010; Sabuda 2008; Steinfort 2007). Note: Lower doses have been used in noncystic fibrosis patients with bronchiectasis (Steinfort 2007); the most commonly used dose is 150 mg twice daily (Le 2010).

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: PediatricNote: 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: Geriatric Refer to adult dosing.

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.

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).

CrCl >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 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). 

Dosing: Hepatic Impairment No dosage adjustment provided in manufacturer’s labeling.

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

Dosing: Adjustment for ToxicityCNS toxicity: Dose reduction may reduce neurologic symptoms.Nephrotoxicity: Withhold treatment if signs of renal impairment occur during treatment.

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).

o 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 (150 mg colistin base activity/10 mL SWFI) using a vibrating plate nebulizer over 60 minutes (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).

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 D5

1/4NS, D51/2NS, D5NS, D5W, LR, NS.

Y-site administration: Variable (consult detailed reference): Telavancin.

Use 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 Non-ventilator associated pneumonia (non-VAP) infections (nebulized; off-label route) Ventilator-associated pneumonia (VAP) due to multidrug-resistant Pseudomonas aeruginosa or

Acinetobacter baumannii (nebulized; off-label route) Bronchiectasis, pulmonary colonization/infection with susceptible organisms in patients with cystic

fibrosis and noncystic fibrosis Prevention of Pseudomonas aeruginosa respiratory tract infections in immunocompromised patients

(nebulized inhalation) Adjunct agent (nebulized inhalation) for the treatment of P. aeruginosa infections in patients with cystic

fibrosis and other seriously ill or chronically ill patients

Adverse Reactions  Central nervous system: Neurotoxicity (7%; higher incidence with high-dose IV use in cystic fibrosis,

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%) proteinuria Neuromuscular & skeletal: Lower extremity weakness Renal: Acute renal failure (33% to 60%), 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)

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

Warnings/PrecautionsConcerns 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.

Pregnancy Risk Factor: C

Clinical Studies

Patients and study design:

This was an open-label population PK study conducted at two sites in the United States and one in Thailand. Patients were eligible for enrollment in the study if they were 18 years or older, receiving CMS as part of their clinical care for treatment of bloodstream infection or pneumonia due to a Gram-negative bacillus lacking susceptibility to all of the antibiotics cefepime or ceftazidime, imipenem or eropenem, piperacillin/tazobactam, and ciprofloxacin or levofloxacin, and had adequate venous access to enable collection of blood for determination of CMS and formed colistin in plasma.

CMS administration:

CMS and colistimethate for injection was administered intravenously as a short-term infusion (range of infusion durations, 9 to 180 min) every 8 to 24 h according to a dosage regimen determined by the respective treating physician. The dose of CMS was expressed as colistin base activity (CBA); 150 mg CBA is equivalent to approximately 5 million units (MU) of CMS and approximately 400 mg CMS sodium.

METHODS:

All patients who had sepsis due to COS gram-negative bacteria or minimally susceptible gram-negative bacteria and received intravenous colistimethate sodium (CMS) were prospectively enrolled. The CMS dosing schedule was based on a loading dose of 9 MU (270mg) and a 9-MU twice-daily fractioned maintenance dose, titrated on renal function. For each CMS course, clinical cure, bacteriological clearance, daily serum creatinine clearance, and estimated creatinine clearance were recorded.

RESULTS:

Twenty-eight infectious episodes due to Acinetobacter baumannii (46.4%), Klebsiella pneumoniae (46.4%), and Pseudomonas aeruginosa (7.2%) were analyzed. The main types of infection were bloodstream infection (64.3%) and ventilator-associated pneumonia (35.7%). Clinical cure was observed in 23 cases (82.1%). Acute kidney injury developed during 5 treatment courses (17.8%), did not require renal replacement therapy, and subsided within 10 days from CMS discontinuation. No correlation was found between variation in serum creatinine level (from baseline to peak) and daily and cumulative doses of CMS, and between variation in serum creatinine level (from baseline to peak) and duration of CMS treatment.

CONCLUSIONS:

Our study shows that in severe infections due to COS gram-negative bacteria, the high-dose, extended-interval CMS regimen has a high efficacy, without significant renal toxicity. This study shows that a 9-MU twice daily fractioned dosing regimen of colistin, along with a 9-MU loading dose, can be used with satisfactory efficacy and relatively low nephrotoxicity in life-threatening infections caused by COS gram-negative bacteria, provided that an ongoing adaption of dosing regimen to renal function is ensured.

DOSING SCHEDULE RECOMMENDED:

Increasing the daily dose from 2 MU to 9 MU improves clinical cure rates from 51% to 70%, respectively. However, not only daily dose, but also fractioning may affect efficacy.

A fractioned CMS regimen of 9 MU 3 times daily, currently prescribed in ICU practice, has been associated with suboptimal and delayed steady-state concentrations. Therefore, a loading dose to rapidly achieve target drug concentration and a dosing schedule that uses high single doses at longer intervals has been proposed. On the basis of this pharmacokinetic/pharmacodynamic background and severity of infection, a CMS dosing schedule was adopted that involved a loading dose of 9 MU and a maintenance dose of 4.5 MU every 12 hours.

This regimen is consistent with data by Garonzik et al., who, on the basis of pharmacokinetic analysis of CMS and colistin in critically ill patients, suggest that to obtain a colistin steady state plasma concentration of 2.5 mg/L, a 70-kg patient with a creatinine clearance rate of 80 mL/minutes needs to receive a CMS loading dose of 10 MU, followed by a maintenance CMS daily dose of 10 MU.

Dosing regimen resulted in a clinical cure rate of 82%.