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Polymyxin B: Similarities to and differences from colistin (polymyxin E)

Article  in  Expert Review of Anti-infective Therapy · November 2007

DOI: 10.1586/14787210.5.5.811 · Source: PubMed

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Polymyxin B: similarities to and

CONTENTS
Chemistry, structure &
mechanism of action
of polymyxins
Formulations & potency
Modes of administration &
antimicrobial spectrum
Susceptibility testing,
breakpoints & resistance
differences from colistin
(polymyxin E)
Andrea Kwa, Sofia K Kasiakou, Vincent H Tam and Matthew E Falagas†
Hospital-acquired infections due to multidrug-resistant Gram-negative bacteria constitute
major health problems, since the medical community is continuously running out of
available effective antibiotics and no new agents are in the pipeline. Polymyxins, a group
of antibacterials that were discovered during the late 1940s, represent some of the last
treatment options for these infections. Only two polymyxins are available commercially,
polymyxin E (colistin) and polymyxin B. Although several reviews have been published
recently regarding colistin, no review has focused on the similarities and differences
between polymyxin B and colistin. These two medications have many similarities with
respect to mechanism of action, antimicrobial spectrum, clinical uses and toxicity.
However, they also differ in several aspects, including chemical structure, formulation,
potency, dosage and pharmacokinetic properties.

Dosage Expert Rev. Anti Infect. Ther. 5(5), 811–821 (2007)

Pharmacokinetics
Pharmacodynamics
Toxicity
Clinical uses
Expert commentary
Five-year view
Financial & competing
interests disclosure
Key issues
References
Affiliations
†
Author for correspondence
Alfa Institute of Biomedical
Sciences (AIBS), 9 Neapoleos Str.,
151 23 Marousi, Athens, Greece
Tel.: +30 210 683 9604
Fax: +30 210 683 9605
m.falagas@aibs.gr;
matthew.falagas@tufts.edu
KEYWORDS:
Acinetobacter baumannii,
multidrug-resistant
microorganisms, nosocomial
infections, polypeptide
antibiotics, Pseudomonas
aeruginosa, resistance
Polymyxin B and polymyxin E (colistin) are
old antibiotics belonging to a group of
polypeptide antibacterials known as poly-
myxins. Although these medications were
obsolete for many decades, they have attracted
great interest recently because of the predomi-
nance of infections caused by multidrug-resist-
ant Gram-negative bacteria that are often sus-
ceptible only to this class of antibiotics [1–3].
Polymyxin B was produced by the growth of
Bacillus polymyxa in 1947, whereas colistin was
produced by the growth of B. polymyxa subsp.
colistinus in 1949 [4]. While the recent litera-
ture contains many papers dealing with the
characteristics and chemical properties of colis-
tin, as well as data on its safety and efficacy, less
attention has been given to polymyxin B [4–7].
In this review, we aim to summarize the similar-
ities and differences of these two compounds,
focusing primarily on polymyxin B.
Chemistry, structure & mechanism of action
of polymyxins
The only differences between the structure of
polymyxin B and colistin are in the amino acid
components. Both polymyxins contain a mix-
ture of D- and L-amino acids arranged as a
cyclic heptapeptide ring with a tripeptide side
chain. The side chain is covalently bound to a
fatty acid via an acyl group. The presence of
D-leucine (highlighted in bold in FIGURE 1B) in
the molecule of colistin distinguishes colistin
from polymyxin B. D-phenylalanine replaces
leucine in polymyxin B (FIGURE 1A).
The degradation of polymyxin B is most rapid
at pH 7.4. Colistin sulfate is more stable in
acidic media; it is less stable in solutions of pH
greater than 5 and in water of pH above 6 [8–10].
Colistin base is resistant to pepsin (pH range
2.2–4.8), trypsin (pH 4.4–7.5), pancreatin
(pH 4.4–7.5) and erepsin (pH 6.1–7.8), but is
inactivated by lipase [11].
Polymyxin B is amphipathic, having a
hydrophobic fatty acid moiety and a polar
moiety of five unmasked γ-amino groups,
which contribute to its basic property of a pKa
of approximately 10. Thus, polymyxin B is
able to distribute well in polar and nonpolar
environments, as does colistin. Both poly-
myxins share the same mechanism of action
against bacteria. Specifically, the polycationic
peptide ring interacts with the lipid A of
lipopolysaccharide (LPS), allowing penetration
through the outer membrane by displacing

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Kwa, Kasiakou, Tam & Falagas

Ca2+ and Mg2+. Insertion between the phospholipids of the Polymyxin B sulfate, which is essentially a mixture of the
cytoplasmic membrane leads to a loss of membrane integrity sulfates of polypeptides produced by the growth of B. poly-
and to bacterial cell death [12]. myxa, or obtained by other means, contains two major com-
Both colistin and polymyxin B have potent antiendotoxin ponents: polymyxin B1 (C56H98N16O13) and polymyxin B2
activity due to their binding to endotoxin, specifically the lipid A (C55H96N16O13) that contain 6-methyloctanoic acid and
portion of LPS molecules of Gram-negative bacteria. The pre- 6-methylheptanoic acid, respectively (FIGURE 1A). TABLE 1 illus-
vention of septic shock through the release of cytokines, however, trates the different molecular formulae of the polypeptides
is unclear [4,12]. In terms of potency, polymyxin B sulfate is the that are contained in polymyxin B. This is also similar in col-
most potent compound, followed by colistin sulfate and then istin sulfate and colistimethate sodium. Specifically, both
colistimethate sodium. medications also contain two major components: colistin A
and colistin B (FIGURE 1B). TABLE 2 illustrates the different
Formulations & potency molecular formulae of the polypeptides that are contained in
Commercially, colistin is formulated as colistin sulfate and colistin sulfate, which is essentially a mixture of sulfates of
colistimethate sodium, while polymyxin B is only formulated as polypeptides produced by B. polymyxa subsp. colistinus or
polymyxin B sulfate. Each milligram of pure polymyxin B base obtained by any other means.
has an equivalency of 10,000 IU of polymyxin B. Conversely, Recent studies have indicated that colistimethate is a non-
each milligram of pure colistin base in colistin sulfate and colis- active prodrug of colistin and has to be hydrolyzed to a series
timethate sodium is equivalent to 30,000 and 12,500 IU of of methanesulfonated derivatives plus colistin (the active drug)
colistin, respectively. in human plasma [13]. Hence, the terms colistin and colisti-
methate are not interchangeable and for-
mulations of colistin should be described
fully in all future reports, particularly
γ-NH2 clinical studies, as either colistin sulfate or
A
CH3 L-Dab D-Phe L-Leu
colistimethate sodium. Since only one
formulation is available commercially,
RCH2CH(CH2)4CO L-Dab L-Thr L-Dab L-Dab
this confusion regarding the formulation
γ-NH2 γ-NH2
L -Thr L -Dab L -Dab as well as the daily dosage of colistin that
exists in the medical community does not
γ-NH2 γ-NH2
apply to polymyxin B.
B γ-NH2
Modes of administration &
L-Dab D-Leu L-Leu
antimicrobial spectrum
Fatty acid L-Dab L-Thr L-Dab L-Dab
The only difference between polymyxin
γ-NH2 γ-NH2 L-Thr L-Dab L-Dab B and the two commercially available for-
mulations of colistin (colistin sulfate and
γ-NH2 γ-NH2
colistimethate sodium) is that
polymyxin B is not indicated for oral use.
C SO3H Otherwise, polymyxin B sulfate can be
CH2 administered via intravenous, intra-
muscular, inhalational, intrathecal or top-
γ-NH ical routes (as ophthalmic, otic and irriga-
L-Dab D-Leu L-Leu tion solution, ointment or powder).
Colistin can be administered orally, topi-
Fatty acid L-Dab L-Thr L-Dab L-Dab
cally (as otic solution and skin powder as
γ-NH γ-NH L-Thr L-Dab L-Dab colistin sulfate), intramuscularly, via
γ-NH γ-NH
inhalation, intrathecally, and with
CH2 CH2 increasing frequency, intravenously (as
CH2 CH2 colistimethate sodium) [14–17].
SO3H SO3H
SO3H SO3H
Polymyxin B possesses the same antimi-
crobial activity with colistin. Their spec-
Figure 1. Structures of polymyxin B, colistin and colistimethate. (A) Structures of polymyxin B1 and trum includes most Gram-negative aero-
B2. (B) Structures of colistin A and B. (C) Structures of colistimethate A and B. bic bacilli, such as Acinetobacter
Fatty acid: 6-methyloctanoic acid for colistin A and colistimethate A and 6-methylheptanoic acid for baumannii, Pseudomonas aeruginosa,
colistin B and colistimethate B. Dab: a,g-diaminobutyric acid; Leu: Leucine; Thr: Threonine; a and γ indicate Escherichia coli and Klebsiella spp., while all
the respective amino group involved in the peptide linkage.
Proteus spp., Neisseria spp., Burkholderia

812 Expert Rev. Anti Infect. Ther. 5(5), (2007)


Table 1. Molecular formula of the polypeptides
contained in polymyxin B.
Polymyxin Molecular formula
B1 C56H98N16O13
B2 C55H96N16O13
B3 C55H96N16O13
B1-I C56H98N16O13
Sum of polymyxins B1, B2, B3 and B1-I: constitutes minimum 80.0%.
Adapted from [81].
cepaciae, Brucella spp., Bacteroides fragilis, Serratia marcescens,
some Vibrio cholerae strains, Gram-positive microorganisms,
fungi and parasites are resistant [4].
Susceptibility testing, breakpoints & resistance
The susceptibility testing methods and standards for both poly-
myxins have already been developed in Europe and the UK for a
good period of time but have been published only recently by the
Clinical and Laboratory Standards Institute (CLSI) in the USA.
Polymyxin B sulfate is the adopted testing agent. In the
Kirby–Bauer method or disc susceptibility testing, a 300-unit
(or 30 µg) disc of polymyxin B is used. The resistance break-
point for polymyxin B sulfate of at least 4 mg/l was last availa-
ble in the Approved Standard M2-A2 S2 document provided
by the CLSI (formerly the National Committee on Clinical
Laboratory Standards) in 1981 [18]; however, with the very
limited use of polymyxins, the published information was
subsequently withdrawn until recently.
On the other hand, colistin sulfate is the commonly adopted
testing agent, despite the fact that it is more potent and is used
less often clinically than colistimethate sodium. It is not known
whether the data from in vitro testing with the sulfate formula-
tion are predictive of in vivo activity of colistimethate sodium,
but it should be noted that colistimethate sodium is converted
in part to colistin base following administration [8,19]. In the
Kirby–Bauer method or disc susceptibility testing, a 10-µg disc
of colistin sulfate is used.
With respect to the breakpoints (for systemic use only) for
susceptibility based on colistin sulfate, the British Society for
Antimicrobial Chemotherapy has adopted 4 mg/l or less and at
least 8 mg/l for susceptible and resistant strains, respectively. By
contrast, the Société Francaise de Microbiologie and the latest
CLSI guidelines in 2007 have advocated 2 mg/l or less and at
least 4 mg/l as the susceptibility and resistance breakpoints,
respectively. The German Deutsches Institut für Normung
adopts breakpoints that vary considerably with the rest: suscep-
tible 0.5 mg/l or less, intermediate 1–2 mg/l and resistant at
least 4 mg/l.
Bacteria can develop resistance to polymyxin B through the
same mechanisms as those to colistin. These mechanisms
mainly involve alterations of the outer membrane of the bacte-
rial cell via reduction in LPS, reduced expression of specific
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Polymyxin B: similarities to and differences from colistin
outer membrane proteins, reduction in cell envelope Mg2+ and
Ca2+ contents and lipid alterations [20–22]. An efflux pump/K+
system in Yersinia spp. has also been reported as a possible way to
Mr develop resistance to polymyxin B [23]. While a strain of colisti-
nase (an enzyme that inactivates colistin) producing B. polymyxa
1204 (subsp. colistinus) has been reported, no enzymatic resistance to
1190 polymyxin B has been mentioned in the literature [24].
1190
Dosage
1204 The dosage of polymyxin B and colistimethate sodium that is
used widely in clinical practice is described in BOX 1. The availa-
ble data concerning the specific dosage adjustments of colisti-
methate sodium in the presence of renal impairment are sum-
marized in TABLE 3 & 4. As for polymyxin B, the available dosage
recommendations for patients with renal dysfunction were pub-
lished in 1970 (TABLE 5) [25]. However, in an updated form of the
package insert of polymyxin B, no specific recommendations
are included.
Pharmacokinetics
The pharmacokinetics of colistin appear to be complex and
have been reviewed in detail previously [4,7,26]. Most pharma-
ceutical formulations contain colistimethate sodium, which is
hydrolyzed to various partial derivatives and colistin in vivo (at
different rates depending on physical conditions, such as pH
and temperature), but the dispositions and antimicrobial activ-
ity of colistimethate sodium and colistin are different [19,27].
Furthermore, various pharmaceutical formulations often
describe their contents differently [28]. Consequently, uniform
and rational dosing design of colistin may be challenging, if at
all possible.
In healthy subjects, serum half-life of colistimethate sodium
is approximately 1.5 h following intravenous administration
and 2.75–3 h following intramuscular administration [29]. Peak
serum levels after intravenous administration occur within
10 min and are higher but decline more rapidly than those
achieved after intramuscular administration [29]. However, in
this study, a microbiological assay was used that was unable to
distinguish the relative contribution of antimicrobial activity by
the parent compound (colistimethate sodium) administered,
any of the partial derivatives or colistin.
Table 2. Molecular formula of the polypeptides
contained in colistin.
Polymyxin Molecular formula Mr
E1 C53H100N16O13 1170
E2 C52H98N16O13 1155
E3 C52H98N16O13 1155
E1-I C53H100N16O13 1170
E1–7MOA C53H100N16O13 1170
Sum of E1, E2, E3, E1-I and E1–7MOA: constitutes minimum 77.0%.
Adapted from [82].
813
Kwa, Kasiakou, Tam & Falagas

Box 1. Dosage of polymyxin B and colistimethate sodium.

Polymyxin B
• For adults and children older than 2 years with normal renal function:
– iv.: 15,000–25,000 IU/kg (1.5–2.5 mg/kg) daily in two divided doses
– i.m.: 25,000–30,000 IU/kg (2,5–3,0 mg/kg) daily in four or six divided doses
– Intrathecal/intraventricular: 50,000 IU (5 mg) once daily for 3–4 days, then 50,000 IU (5 mg) once every other day for at least 2
weeks, after cultures of cerebrospinal fluid are negative and/or glucose normal
Colistimethate sodium
• For patients who are 60 kg or less and with normal renal function:
– iv. or im.: 4–6 mg per kg/day CMS in three divided doses
• For patients who are more than 60 kg and with normal renal function:
– iv. or im.: 240–480 mg/day (UK) or up to 720 mg/day (USA) CMS in three divided doses
• Inhalation:
– 40 mg (500,000 IU) every 12 h for patients who are 40 kg or less
– 80 mg (1,000,000 units) every 12 h for patients who are more than 40 kg
– For recurrent pulmonary infections, the dosage of aerosolized CMS can be increased to 160 mg (2 million IU) every 8 h
• Intrathecal/intraventricular:
– Guidelines published by the Infectious Diseases Society of America in 2004 suggest that the intraventricular dosage of CMS should
be 10 mg [83]
CMS: Colistimethate sodium; im.: Intramuscularly; iv.: Intravenously.

In another study involving cystic fibrosis patients, the phar-
macokinetics of colistimethate sodium and colistin were deter-
mined specifically. Mean elimination half-life and volume of dis-
tribution of colistimethate sodium were reported to be 2.1 h and
0.34 l/kg, respectively. By contrast, the mean elimination half-
life of colistin was 4.2 h. In a patient undergoing continuous
venovenous hemodiafiltration, conversion of colistimethate
sodium to colistin was rapid and the terminal half-lifes of colisti-
methate sodium and colistin were 6.8 and 7.5 h, respectively
[30]. Colistin is not expected to penetrate very well into the CNS
(15–25%); relevant data have been reviewed recently [31]. The
protein binding of colistin sulfate in human plasma is unknown
but it was reported to be approximately 55% in rat plasma [32].
Relatively speaking, there is much less information available
on the pharmacokinetics of polymyxin B but it appears to be
less complex. Most pharmaceutical formulations contain poly-
myxin B sulfate. There are no published modern pharmaco-
kinetic studies of polymyxin B [12]. The data cited most often
were reported previously after intramuscular administration;
following a 50-mg (500,000 IU) dose, peak concentration of
8 µg/ml was achieved in approximately 2 h and serum half-life
was approximately 6 h [12]. However, details of the original
study design, such as patient characteristics (general vs criti-
cally-ill versus cystic fibrosis patients), single versus multiple
doses, sample size, sampling schedule, assay methodology and
pharmacokinetic analysis could not be retrieved from
PubMed. Several clinical studies are ongoing, examining the
pharmacokinetics of polymyxin B (including serum protein
binding) resulting from intravenous administration in the gen-
eral patient population and critically ill patients undergoing
continuous renal replacement therapy. Preliminary results sug-
gest that the pharmacokinetics of polymyxin B resulting from
intravenous administration in the general patient population
may be significantly different from those most often cited in
the literature.
Pharmacodynamics
Both colistin and polymyxin B have been shown to exhibit rapid
and concentration-dependent killing against P. aeruginosa, and
colistin has been shown to display concentration-dependent kill-
ing against A. baumannii in time–kill studies [27,33,34]. The kill-
ing activity of colistimethate sodium appeared to be slower and
exhibited a shorter postantibiotic effect compared with colistin
[27]. There are also recent data to suggest that colistimethate
sodium may not even be active on its own; the observed activity
was due to hydrolysis to colistin [13]. In in vitro-infection model
studies in which the concentration of polymyxin fluctuates over
time with linear elimination and repeated dosing, regrowth was
readily observed after an initial decline in bacterial burden with
both colistin and polymyxin B monotherapy [33,35–37]. Synergis-
tic killing was observed when colistin was used in combination
with ceftazidime given at a constant infusion (at 50 µg/ml) [35,37].
A dose fractionation study design (using an identical daily dose
but once-, twice- or three-times-daily administration) was used to
explore whether the frequency of dosing has an impact on the
bactericidal activity of colistin and polymyxin B [36]. Elevated

814 Expert Rev. Anti Infect. Ther. 5(5), (2007)

 Polymyxin B: similarities to and differences from colistin

colistimethate sodium. However, it was demonstrated that

Table 3. Modification of dosage schedules of larger doses of colistimethate sodium are required for effective-
colistimethate sodium for adults with impaired ness, and thus the rate of nephrotoxicity equals that of poly-
renal function. myxin B [38]. The mechanisms by which polymyxin B induces
Degree of Renal function acute renal failure and neuromuscular blockade, the two major
impairment adverse events, are the same as those of colistin and have
Creatinine Dosage (over 60 kg recently been reviewed extensively elsewhere [39].
clearance bodyweight) In a recent study in which polymyxin B was used for the
(ml/min)
treatment of multidrug-resistant Gram-negative infections in
Mild 20–50 1–2 million IU every 60 patients in New York, microbiological eradication was
8h achieved in 88% of the patients, and 14% of those with nor-
Moderate 10–20 1 million IU every mal baseline renal function developed renal failure. The inci-
12–18 h dence of nephrotoxicity was lower than previous reports that
Severe <10 1 million IU every ranged from 17 to 100% [40–42]. The authors also admitted
18–24 h that the 14% nephrotoxicity rate that they had observed was
most probably an overestimate of the true rate of polymyxin
Reproduced with permission from [84].
B-related nephrotoxicity as numerous other nephrotoxic
dosing of polymyxin B (at eight-times the most commonly used agents were administered. We previously reported a poly-
clinical dose) was also attempted; regrowth was suppressed with myxin B-related nephrotoxicity rate of 0% in 26 patients who
a wild-type strain, but not with a clinical multidrug-resistant received polymyxin B for multidrug-resistant Gram-negative
strain of P. aeruginosa [33]. It was reported that the daily dose infections in Singapore general hospital [43]. Another similar
(but not dosing frequency) was the most important factor deter- study reported a polymyxin B-related nephrotoxicity rate of
mining the antimicrobial activity of colistin and polymyxin B, 10% [44].
and AUC:MIC ratio appeared to be the pharmacodynamic These rates of nephrotoxicity are comparable to those
parameter linked most closely to killing. reported in recent studies of critically ill patients who received
Collectively, the pharmacodynamic properties of both pol- intravenous colistimethate sodium. Suggestively, Michalopolos
ymyxins appear to be similar, and available data seem to et al. and Markou et al. reported incidences of nephrotoxicity
imply that commonly used dosing regimens (which are often of 18.6 and 14.3%, respectively, in their intensive care unit
based on convention, rather than supported by pharmacoki- (ICU) studies, which utilized 9 million units of colistimethate
netics/pharmacodynamics) may be suboptimal as mono- sodium (CMS) per day [2,45]. Kasiakou et al. reported on inci-
therapy in immunosuppressed patients. With an improved dence of nephrotoxicity of 8% in their medical ICU study that
understanding of these agents, it is anticipated that optimal utilized a dose of 4.5 million IU CMS per day [46].
dosing regimens could be designed to maximize (prolong) The incidence of neurotoxicity (mainly paresthesia) related
their clinical utilities. to the use of intravenous polymyxin B has been reported to be
approximately 7% in recent studies [44]. We reported a possi-
Toxicity ble case of paresthesia in our case study of 26 patients and no
The use of polymyxin B is associated with the likelihood of cases of neuromuscular blockade leading to respiratory paraly-
developing nephrotoxic and neurotoxic adverse events, similar sis [43]. The use of polymyxin B via inhalation has also been
to colistin. Originally, polymyxin B was thought to be the most associated with higher incidence of brochoconstriction com-
nephrotoxic compound compared with colistin sulfate and pared with colistimethate sodium. This could probably be

Table 4. Dosage adjustments of colistimethate sodium for adults in the presence of renal dysfunction.
Degree of impairment Renal function
Plasma creatinine Urea clearance Unit dose Frequency Total daily Approximate daily
(mg/100 ml) (% of normal) colistin (mg) (times/day) dose (mg) dose (mg/kg/day)
Normal 0.7–1.2 80–100 100–150 Four to two 300 5.0
Mild 1.3–1.5 40–70 75–115 Two 150–230 2.5–3.8
Moderate 1.6–2.5 25–40 66–150 One or two 133–150 2.5
Considerable 2.6–4.0 10–25 100–150 Every 36 h 100 1.5
Note: the suggested unit dose is 2.5–5 mg/kg; however, the time interval between injections should be increased in the presence of impaired renal function.
Reproduced with permission from [85].

www.future-drugs.com 815
Kwa, Kasiakou, Tam & Falagas
Table 5. Modification of dosage schedules of
polymyxin B for adults with impaired renal function.
Renal function Dosage
Creatinine clearance 1.5–2.5 mg/kg/day divided into two
≥80 ml/min equal doses
Creatinine clearance Loading dose 2.5 mg/kg on day 1,
30–80 ml/min then 1.0–1.5 mg/kg/day thereafter
Creatinine clearance Loading dose 2.5 mg/kg on day 1,
<30 ml/min then 1.0–1.5 mg/kg given every
2–3 days thereafter
Anuric patients Loading dose 2.5 mg/kg on day 1,
then 1.0 mg/kg given every
5–7 days thereafter
explained by the fact that polymyxin B induces degranulation
of mast cells, release of histamine, or IgE-mediated allergic
reactions [39]. In earlier reports, polymyxin B was also found to
cause electrolyte abnormalities, such as hypokalemia,
hyponatremia, hypochloremia and a negative anion gap [47,48].
Clinical uses
In terms of clinical use, polymyxin B has many similarities with
colistimethate sodium and colistin sulfate. Specifically, poly-
myxin B and colistin sulfate have both been used widely for the
treatment of otic, ophthalmic and skin infections [49–53]. In
addition, intravenous polymyxin B and colistimethate sodium
have also been used for the treatment of critically ill patients
with nosocomial infections caused by multidrug-resistant or
polymyxin-only-sensitive Gram-negative bacteria [44,54–58]. In
TABLE 6 we summarize the existing experience from recent clini-
cal studies that evaluated the efficacy and safety of parenteral
polymyxin B for the treatment of these infections. It is evident
that polymyxin B targets the same types of infection (including
bacteremia, pneumonia, abdominal infections and urinary tract
infections) as colistimethate sodium.
The observed clinical outcomes in nosocomial infections
(mainly in the ICU) resulting from the intravenous use of poly-
myxin B have been encouraging. Clinical response rate and
mortality reported in these studies were ranging from 76 to
95% and 20 to 48%, respectively. These results are comparable
with those reported in the majority of trials that used intrave-
nous colistimethate sodium in a similar cohort [2,41,45,46,59,60].
Of note, there is less experience and data available with the use
of polymyxin B for combating multidrug-resistant nosocomial
infections than with colistimethate sodium. There is no appar-
ent reason except perhaps the fact that earlier studies reported a
higher incidence of toxicity compared with colistimethate
sodium [25,61].
Similar to colistimethate sodium, clinical experience with
the use of inhaled polymyxin B is limited. Polymyxin B has
been administered directly to the respiratory tract in order to
either prevent colonization in the lungs or diminish the inci-
dence of pulmonary infections in critically ill patients. Most
816
studies were reported in the early 1970s and yielded conflict-
ing results [62–65]. Additionally, there are also few reported tri-
als that assessed the effectiveness and safety of aerosolized pol-
ymyxin B for the treatment of pneumonia, including
ventilator-associated pneumonia due to multidrug-resistant
Gram-negative microorganisms [44,57,66–68].
The largest report included 14 patients with pneumonia and
five patients with tracheobronchitis caused mainly by P. aerugi-
nosa (84% of patients). Most patients (89%) were in the ICU
with underlying diseases. In pneumonia cases, intravenous
polymyxin B was used in addition to the inhaled route of
administration, while in tracheobronchitis cases, only inhaled
polymyxin B was used. Dosage of inhaled polymyxin B was
500,000 IU twice a day for a mean duration of 14 days (range
4–25 days). Clinical response (cure and improvement) occurred
in 93 and 100% of the patients with pneumonia and tracheo-
bronchitis, respectively. No serious adverse events requiring dis-
continuation of treatment were observed. Mortality occurred in
64% of episodes of nosocomial pneumonia [68]. In contrast to
colistimethate sodium and colistin sulfate, polymyxin B has not
been examined in exacerbations of pulmonary infections in
cystic fibrosis patients. The intrathecal and intraventricular use
of polymyxin B for the treatment of CNS infections has been
reviewed extensively recently [31,69].
A major difference between the two polymyxins regarding
their clinical applications is the use of polymyxin B immobi-
lized fiber column (PMX-F) in sepsis and septic shock. This is
a medical device first produced in Japan, in which polymyxin B
is bound and immobilized to polystyrene fibers [70–72]. The aim
of this intervention is to disrupt the inflammatory response
cascade leading to sepsis by the absorption of the circulating
bacterial endotoxin (LPS of Gram-negative and lipoteichoic
acid of Gram-positive bacteria) [73–75]. Direct hemoperfusion
with the PMX-F in patients with sepsis has been found to exert
an effect via various mechanisms. Some of these include the
inhibition of neutrophil reactive oxygen species, the absorption
of anandamide (an intrisinc cannabinoid that induces hypo-
tension in septic shock), the reduction of circulating neutrophil
elastase, the improvement in pulmonary oxygenation, the
decrease in mediators, such as TNF-α, IL-6, IL-8, IL-10 and
plasminogen activator inhibitor-1 [71,76–79]. However, the exact
mechanism of action is not clearly understood. A recent system-
atic review of the available published literature suggested that
direct hemoperfusion with PMX-F may be beneficial in
patients with sepsis, compared with conventional treatment.
However, the quality of the clinical trials included for analysis was
relatively low. The investigators demonstrated a statistically sig-
nificant increase in mean arterial pressure and mean PaO2/FiO2,
a decrease in dopamine/dobutamine dose requirement and a
positive effect on mortality [80].
In conclusion, polymyxin B (as colistin [polymyxin E]) con-
stitutes a valuable therapeutic option for the management of
nosocomial infections due to multidrug-resistant Gram-
negative bacteria. Polymyxin B shares many similarities with
colistin regarding mechanism of action, spectrum of activity,
Expert Rev. Anti Infect. Ther. 5(5), (2007)
 Table 6. Characteristics and clinical outcomes of recently published studies of patients who received polymyxin B for infections due to multidrug-resistant
Gram-negative bacteria (parenteral administration).
Author Setting Patients Drug Dosage/duration of Site of Pathogen Mortality Clinical cure or Toxicity Ref.
(year) (n) administration polymyxin B infection improvement

www.future-drugs.com
Pereira et al. ICU (89%) 19 iv. and inhaled: Inhaled: 500,000 IU every Pneumonia 74% Pseudomonas 47% of 93% of Cough/ [68]
(2007) 14 pts 12 h Tracheobronchitis aeruginosa 84% pneumonia cases pneumonia cases bronchospasm
Inhaled only: Mean duration of inhaled: 26% Klebsiella 0% of 100% of 21%
5 pts 14 days (4–25 days) pneumoniae, tracheobronchitis tracheobronchitis
Alcaligenes cases cases
xylosoxidans,
Burkholderia spp.
one case each
Ostronoff Hematology 2 iv. 1 mg/kg every 12 h Bacteremia 1 pt P. aeruginosa 0% Both pts cured No [56]
et al. (2006) department for 19 and 21 days Cellulitis 1 pt
Holloway ICU 33 28 pts iv. Median daily dose (iv.): VAP 50% Acinetobacter 27% 76% Nephrotoxicity [57]
et al. (2006) 2 pts by 1.3 MIU BSI 43% baumannii 21%
nebulization Median daily dose (by Neurotoxicity
3 pts both iv. and nebulization): 2 MIU (27 of 2%
by nebulization the 33 pts monotherapy)
Parchuri CAPD 1 iv. 150,000 IU every 12 h CAPD-associated K. pneumoniae Pt was No [55]
et al. (2005) for 10 days (meropenem, peritonitis discharged
amikacin)
Sobieszczyk ICU 25/29 29 courses: (iv.) loading dose Respiratory tract A. baumannii 55% Overall mortality 76% Nephrotoxicity [44]
et al. (2004) courses 21 iv. 2.5–3 mg/kg and then P. aeruginosa 41% 48% 10%
6 aerosol according to estimated Clcr End-of- Neurotoxicity
2 combination (aerosolized) approximately treatment 7%
2.5 mg/kg/day mortality 21%
Mean duration: 19 days
(2–57 days)
Sarria et al. ICU 1 with iv. Loading dose 2.5–3 mg/kg Catheter-related A. baumannii Pt was No [58]
(2004) septic followed by two doses of bacteremia discharged
shock 1 mg/kg on days 4 and 8,
receiving then 0.8 mg/kg daily
CVVHD Duration 24 days
Ouderkirk Critically ill 60 Parenterally Mean daily dose: 1.1 MIU Lung 65% A. baumannii 77% Overall mortality Microbiological Nephrotoxicity [54]
et al. (2003) Mean duration: 13.5 days Blood 8% P. aeruginosa 3% 20% cure 88% 14%
Abdomen 5% Both isolates 3%
Urine 3%
Bone 3%
BSI: Bloodstream infection; CAPD: Continuous ambulatory peritoneal dialysis; Clcr: Creatine clearance; CVVHD: Continuous venovenous hemodialysis; ICU: Intensive care unit; iv.: Intravenously; MIU: Million international units;
Pt: Patient; VAP: Ventilator-associated pneumonia.
Polymyxin B: similarities to and differences from colistin

817
Kwa, Kasiakou, Tam & Falagas

mechanisms of resistance and clinical uses. However, it also has
several differences in chemical structure, potency and pharma-
cokinetic properties. A major difference between the two anti-
biotics is the use of polymyxin B in a medical device for the
treatment of sepsis. However, more comparative studies are
needed to clarify further the characteristics and properties of
both polymyxins. Despite the fact that these antibiotics were
discovered many years ago, there is still much to be learned,
since their use was practically abandoned for approximately
two decades.
Expert commentary
Most recent information on the use of polymyxins is related to
colistin; however, there are also reports on the effectiveness and
toxicity of polymyxin B. Direct comparison of these two anti-
biotics reveals more similarities than differences. They have the
same mechanism of action as well as antimicrobial spectrum.
Their structure differs only in one amino acid: colistin contains
D-leucine while polymyxin B contains D-phenylalanine. Colis-
tin is formulated as colistin sulfate and colistimethate sodium,
while polymyxin B is only formulated as polymyxin B sulfate.
1 mg of polymyxin B is equivalent to 10,000 IU, whereas 1 mg
of colistin sulfate and colistimethate sodium is equal to 30,000
and 12,500 IU, respectively. Both antibiotics can be adminis-
tered intravenously, intramuscularly, intrathecally, inhalationally
and topically. Colistin can also be administered orally, unlike
polymyxin B. In terms of clinical indications, both polymyxins
are used in patients with nosocomial infections due to multid-
rug-resistant Gram-negative bacteria. However, colistin has
been used more widely in cystic fibrosis patients, either intrave-
nously or in a nebulized formulation. Furthermore, only poly-
myxin B has been used for the treatment of patients with sepsis
or septic shock through PMX-F.
Five-year view
In the forthcoming years, well-designed randomized, control-
led trials, as well as other comparative studies, are needed to
further elucidate the various characteristics of polymyxin B
and colistin, especially their pharmacokinetic/pharmaco-
dynamic properties, optimal dosing strategy, effectiveness and
safety in the treatment of patients with nosocomial infections
caused by multidrug-resistant bacteria. Finally, the use of
PMX-F deserves thorough assessment as an adjunct to the
conventional therapeutic option for patients with sepsis.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involve-
ment with any organization or entity with a financial interest in
or financial conflict with the subject matter or materials discussed
in the manuscript. This includes employment, consultancies, hon-
oraria, stock ownership or options, expert testimony, grants or
patents received or pending, or royalties.
No writing assistance was utilized in the production of this
manuscript.

Key issues

• Multidrug-resistant Gram-negative infections are a major cause of morbidity and mortality, especially among critically ill patients.
• Polymyxins represent potentially effective treatment approaches.
• Only polymyxin B and polymyxin E (colistin) have been used in clinical practice.
• Polymyxin B is active against specific Gram-negative bacteria including Acinetobacter baumannii, Pseudomonas aeruginosa,
Klebsiella spp. and Enterobacter spp., similar to colistin.
• The safety and efficacy of polymyxin B for the management of nosocomial infections due to multidrug-resistant Gram-negative
microorganisms have been evaluated in recent studies and resemble those of colistin.
• An extracorporeal device that contains polymyxin B immobilized fiber column has been used in patients with sepsis, with
promising results.

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Affiliations
• Andrea Kwa, PharmD, BCPS
Principle Research Pharmacist, Singapore
General Hospital, Outram Road, 169608,
Singapore
Tel.: +65 9650 6819
Fax: +65 6227 4330
andrea.kwa.l.h@sgh.com.sg
• Sofia K Kasiakou, MD
Alfa Institute of Biomedical Sciences (AIBS),
9 Neapoleos Str., 151 23 Marousi,
Athens, Greece
Tel.: +30 210 683 9604
Fax: +30 210 683 9605
skasiakou@yahoo.gr;
s.kasiakou@aibs.gr
• Vincent H Tam, PharmD, BCPS
(Infectious Diseases)
Assistant Professor, Dept of Clinical Sciences &
Administration, University of Houston College of
Pharmacy, 1441 Moursund Str., Houston,
TX 77030, USA
Tel.: +1 713 795 8316
Fax: +1 713 795 8383
vtam@uh.edu
• Matthew E Falagas, MD, MSc, DSc
Director, Alfa Institute of Biomedical Sciences
(AIBS), 9 Neapoleos Str., 151 23 Marousi,
Athens, Greece
and
Department of Medicine, Tufts University School
of Medicine, Boston, MA, USA
Tel.: +30 210 683 9604
Fax: +30 210 683 9605
m.falagas@aibs.gr; matthew.falagas@tufts.edu
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