By Emily Mui, PharmD, BCPS

Infectious Disease Pharmacist, Stanford Health Care

Dr. Mui reports no financial relationships relevant to this field of study.

SYNOPSIS: Based on their kinetics and toxicity profiles, polymyxin B may be the preferred agent for treatment of systemic infections, while colistin is preferred for infections limited to the urinary tract.

Polymyxins are a group of polypeptide antibacterials that include polymyxin A, B, C, D, E, etc. The two polymyxins that are used clinically are polymyxin B and polymyxin E (also known as colistin). These compounds, which were originally isolated in 1947 from a Bacillus polymyxa, became obsolete due to their toxicities, but now have generated interest due to the predominance of infections caused by multidrug-resistant organisms. Due to their similarities in structure, polmyxin B and colistin have been regarded as being equivalent, but differences in their pharmacokinetics have significant clinical implications for their use.


Polymyxin B and colistin are almost identical in structure, with the exception of an amino acid in the L-Dab peptide ring.1 Although similar in structure, there are distinct differences between both formulations. Polymyxin B is administered intravenously as a sulfate salt, which is the active antibacterial compound, whereas colistin is administered as a pro-drug in the form of colistin methanesulfonate (also known as CMS or colistimethate). CMS lacks antibacterial activity and requires conversion in vivo to its active form, colistin, to exert an antibacterial effect.


Polymyxin B and colistin both are rapidly bactericidal against susceptible organisms, binding to the lipopolysaccharides and phospholipids in the outer cell membrane of Gram-negative bacteria. This displaces calcium and magnesium from the phosphate group of membrane lipids, which leads to disruption of the outer cell membrane, resulting in leakage of intracellular contents, and finally bacterial death.2,3 Polymyxins also have been reported to bind and neutralize lipopolysaccharides in a dose-dependent manner, thus mitigating the damaging effects of endotoxins.


Polymyxin B and colistin have basically identical antibacterial activity. Both have activity against most Gram-negative organisms such as Acinetobacter spp, Pseudomonas aeruginosa, Klebsiella spp, Enterobacter spp, Salmonella spp, Shigella spp, Escherichia coli, and Citrobacter spp, but lack activity against Gram-positive and anaerobic bacteria. The Clinical and Laboratory Standards Institute (CLSI) indicates that the breakpoint for both polymyxin B and colistin is 2 mcg/mL against a few clinically important pathogens such as P. aeruginosa, Enterobacteriaceae, and Acinetobacter spp. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) only reports breakpoints for colistin, likely because polmyxin B is unavailable for systemic administration in Europe. The EUCAST breakpoint for colistin against Enterobacteriaceae is ≤ 2 mcg/kg, and is set at ≤ 4 mcg/mL for P. aeruginosa. Of note, because CMS is the inactive prodrug of colistin, susceptibility testing must be performed with colistin sulfate. Due to variable results in MIC estimations with colistin, CLSI will soon stop reporting breakpoints for colistin and only provide them for polymyxin B.


Both Polymyxin B and colistin are not well absorbed after oral administration.4 Intravenous polymyxin B is administered directly as active drug, whereas CMS is administered as the pro-drug that converts into the active moiety colistin.5 The prodrug CMS is cleared predominately by renal excretion via tubular secretion and its other non-renal excretion is conversion to active colistin. Studies suggest that the extent of conversion of CMS to colistin is low, especially in those with normal renal function.6 With normal renal function, prodrug CMS is more efficiently eliminated via renal excretion; it is estimated that only 20-25% of a dose of CMS is converted to colistin.6 As a result, larger doses of CMS are required to achieve therapeutic concentrations of colistin. After conversion to active drug, both colistin and polymyxin B are minimally excreted in the urine and are primarily eliminated by non-renal clearance. Although minimally excreted, therapeutic concentrations of colistin can be found in the urine as a result of the highly excreted prodrug CMS undergoing conversion to colistin within the urinary tract.6 Urinary recovery of polymyxin B is less than 1%.7 These pharmacokinetic differences make CMS/colistin the preferred formulation for infections that require a high urinary concentration. The kinetics of polymyxin B are preferable for systemic infections due to the rapid and reliable active drug concentration achieved in the serum, compared to the variable rate and extent of conversion with CMS to colistin.


In vitro pharmacodynamics data on polymyxin B and colistin show concentration-dependent killing against multidrug-resistant P. aeruginosa and A. baumanii.8-11 When comparing different dosing regimens with the same total daily dose of polymyxin B, altering the dosing schedule did not appear to influence the killing or resistance suppression against the isolates.12 This suggests that the PK/PD index that best characterizes polmyxin B activity is the ratio of the area under the concentration-time curve to MIC (fAUC/MIC).


Nephrotoxicity and neurotoxicity are the most common side effects associated with polymyxin B and colistin. It was long believed that polymyxins were associated with a high incidence of nephrotoxicity; however, recent data suggest it may not be as toxic as previously thought.13 The rate of nephrotoxicity has been described for polymyxin B and colistin in several small, retrospective, case-series with varying rates of nephrotoxicity. Two recent comparative studies involving a large number of patients reported lower rates of nephrotoxicity with polymyxin B than colistin, possibly due to higher exposure of colistin in the kidneys from CMS excretion compared to polymyxin B, which is not renally cleared.14,15

The incidence of neurotoxicity is reported less compared to nephrotoxicity. Neurotoxicity manifests as dizziness, muscles weakness, paresthesia, headache, visual disturbances, partial deafness, vertigo, confusion, hallucinations, seizures, ataxia, and neuromuscular blockade.


Polymyxin B and colistin have re-emerged as important antimicrobial agents as a result of infections due to multidrug-resistant Gram-negative bacteria. Polymyxin B has more predictable systemic drug exposure compared to colistin; however, colistin is preferred for the treatment of urinary infections as the prodrug CMS is renally excreted. In terms of toxicities, recently published studies have shown comparable and possibly less nephrotoxicity with polmyxin B.

Table 1. Clinical Trials/Evidence Summary

Conversions2: 1 mg colistin base activity = 30,000 IU colistin; 1 mg CMS = 12,500 IU colistin; 10,000 IU polymyxin B = 1 mg polymyxin B





Renal Impairment

Other Comments

Oliveira MS, 200919

Retrospective study of CMS vs. polymyxin B

N = 82 (41 vs. 41) patients with serious infection caused by carbapenem-resistant Acinetobacter spp.

Median daily dose:

  • CMS 6 MIU (1-9 MIU)
  • Polymyxin B 1.0 MIU (0.4-1.5 MIU)

Treatment (P = 0.48):

  • Success 39% vs. 39%
  • Failure colistin 41% vs. PolyB 32%

30-day mortality

  • Colistin 56% vs. PolyB 61% (P = 0.66)
  • Criteria: 2-fold increase in Scr at any time during the treatment or an increase by 1 mg/dL if initial Scr was > 1.4 mg/dL
  • Colistin 26% vs. PolyB 27% (P = 0.92)

Both polymyxins are comparable in efficacy with similar renal toxicity

Groups treated with colistimethate had more surgical site infections, especially CNS infections than the polymyxin B group

Akajagbor DS, 201314

Retrospective study of colistin vs. polymyxin B

N = 173 (106 vs. 67) patients

  • Colistin base activity 5 mg/kg/day of ideal BW or actual BW or 150 mg q12h
  • Polymyxin B 15,000-25,000 units/kg/day as continuous infusion over 24 hrs

Not reported

  • RIFLE criteria
  • PolyB 60.4% vs. Colistin 41.8% (P = 0.02)

Colistin had higher incidence of nephrotoxicity vs. polymyxin B.

Colistin nephrotoxicity increases with dose (> 5 mg/kg/day)

Tuon FF, 201320

Retrospective study of colistin vs. polymyxin B

N = 132 (36 vs. 96) patients

Median daily dose:

  • CMS 2 MIU
  • Polymyxin B 9 MIU

Not reported

  • AKIN criteria
  • Colistin 38.9% vs. PolyB 20.8% (P = 0.06)

Trend, but not statistically significant difference in nephrotoxicity between CMS and polymyxin B

Only variable associated with AKI was doses ≥ 2 MIU polymyxin B or ≥ 9 MIU CMS

Phe K, 201415

Retrospective study of CMS vs. polymyxin B

N = 225 (121 vs. 104) patients

Median daily dose:

  • CMS 4.6 mg/kg/day in IBW
  • Polymyxin B 1.8 mg/kg/day in IBW

Not reported

  • RIFLE criteria
  • ITT: Colistin 33.9% vs. PolyB 23.1% (P = 0.08)
  • Matched pairs: Colistin 55.3% vs. PolyB 21.1% (P = 0.003)

Polymyxin B was not found to be more nephrotoxic than colistin

Cystic fibrosis was found to be protective against the development of nephrotoxicity in patients who received CMS


Table 2. Dosage



≥ 80 mL/min

50-79 mL/min

30-49 mL/min

10-29 mL/min



a. Of note, polmyxin B is eliminated through nonrenal clearance. Therefore, renal impairment should not affect drug concentrations. A single case report suggests that polmyxin B may not require dose adjustment in the renally impaired.16

b. More experience with inhaled CMS use in cystic fibrosis patients.17,18

Polymyxin B3

Use actual body weight; adjusted body wt for obese


15,000 – 25,000 units/kg/day (in divided doses)

Renal impairment: 15,000 units/kg/day

No Data


Use ideal body weight

Doses expressed in colistin base activity


5 mg/kg/day in 2-3 divided doses

1.25–1.9 mg/kg Q12H

2.5 mg/kg Q24H


1.25 mg/kg Q12h

1.5 mg/kg Q36H

1.5 mg/kg Q24-48h

2.5 mg/kg Q12-24H


150 mg inhalation Q12H


Table 3. Cost


How Supplied



Cost/day (70 kg)

Polymyxin B

500,000 unit vial

$13.50 per vial

12.5 units/kg q12h



150 mg vial

$33.60 per vial

2.5 mg/kg q12h



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