208 Journal of Postgraduate Medicine July 2013 Vol 59 Issue 3

Introduction
T
he rapid spread of multidrug-resistant (MDR)
Gram-negative bacteria (GNB), such as Pseudomonas
aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae,
St enot r ophomonas mal t ophi l i a, and Ent er obact er
(especially in intensive care units (ICUs), burn units, and
immunocompromised patients) has been of concern.
[1]
Gram-
negative Enterobacteriaceae with resistance to carbapenems
(conferred by New Delhi metallo--lactamase 1 (NDM-1)) are
an emerging problem. Kumarasamy et al., (2009), while studying
the prevalence of multidrug resistant (MDR) Enterobacteriaceae
found that, 75 Escherichia coli, 60 Klebsiella spp, and six other
Enterobacteriaceae resistant to carbapenems were isolated
from 3,521 Enterobacteriaceae isolates (Chennai).
[2]
Of 141
carbapenem resistant organisms, 44 were NDM-1 positive.
[2]

During same period, 47 from 198 isolates (24%) were identified
as carbapenem-resistant from Haryana.
[2]
Of these, 26 (13%)
were K. pneumoniae positive for NDM-1.
[2]
These Indian
isolates were primarily from community acquired urinary tract
infections, pneumonia, and blood-stream infections and most
isolates were susceptible to Colistin and Tigecycline.
[2]
The slow rate of development of newer antimicrobials has led to
the re-discovery of the old and forgotten antibiotic-Colistin,
and it is increasingly being used as salvage therapy in patients
with MDR GNB infections.
[3]
Colistin was initially discovered
in Japan in 1949 and was more frequently used during the
1960s and early 1970s.
[1]
The use of Colistin was restricted
later because of concerns regarding its neurotoxicity and
nephrotoxicity; however in recent studies, Colistin has been
found to be efficacious with lower toxicity.
[1]
The aim of this
review is to discuss about the pharmacology and uses of Colistin
for treatment of MDR GNB infections.
History
Colistin belongs to polymyxin group of antibiotics, of which two
(polymyxin B and E) have been used.
[1]
The difference between
polymyxin B and Colistin lies in the amino-acid components.
[1,4]

Colistin is the more commonly used because of lesser toxicity.
[1]

Though Colistin has been available for use in GNB infections
since 1959, its use got limited when the potentially safer/
less-toxic aminoglycosides and anti-pseudomonal agents
Department of Pediatrics,
Seth Gordhandas
Sunderdas Medical
College and King Edward
Memorial Hospital,
Mumbai, Maharashtra,
India
Address for correspondence:
Dr. Milind S Tullu,
E-mail: milindtullu@yahoo.
com
Colistin: Re-emergence of the forgotten
antimicrobial agent
Dhariwal AK, Tullu MS
ABSTRACT
The treatment of the emerging multidrug resistant (MDR) gram-negative organisms is a challenge. The development
of newer antibiotics has recently slowed down. This has led to the re-emergence of the old forgotten antibiotic
Colistin, whose use had almost stopped (after 1970s) due to the high incidence of nephrotoxicity and
neurotoxicity. Colistin (polymyxin E) is a polypeptide antibiotic belonging to polymyxin group of antibiotics with
activity mainly against the gram-negative organisms. Use of colistin has been increasing in the recent past and
newer studies have shown lesser toxicity and good efficacy. Colistin acts on the bacterial cell membrane resulting
in increased cell permeability and cell lysis. Colistin can be administered orally, topically, by inhalational route,
intramuscularly, intrathecally, and also intravenously. Parenteral Colistin (in the form of colistimethate sodium)
has been used to treat ventilator-associated pneumonia (VAP) and bacteremia caused by MDR bacteria such
as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. Inhaled Colistin is used for
treating pneumonia/VAP due to MDR gram-negative organisms and also used prophylactically in patients with
cystic fibrosis. This manuscript is a brief review of Colistin and its clinical applications in the pediatric population.
KEY WORDS: Antibiotic, antibacterial, bacteremia, bacteria, colistin, drug-resistant, infections, nosocomial,
sepsis
Drug Review
Received : 17-03-2013
Review completed : 16-04-2013
Accepted : 08-05-2013
Access this article online
Quick Response Code: Website:
www.jpgmonline.com
DOI:
10.4103/0022-3859.118040
PubMed ID:
***
Dhariwal and Tullu: Colistin
Journal of Postgraduate Medicine July 2013 Vol 59 Issue 3 209
became available and thus, the use of Colistin declined from
1970s to the early 2000s.
[5]
Chemical Structure
Colistin is a multi-component polypeptide antibiotic
composed of Colistin A and Colistin B.
[3-5]
Colistin sulfate
and Colistimethate sodium (CMS) are the forms of Colistin.
Although CMS is the form administered parenterally, it
undergoes conversion (in vivo) to form Colistin (which has
antibacterial activity).
[3-6]
Mechanism of Action
The antibacterial activity of Colistin is concentration-dependent
(bacteriostatic in low concentrations and bactericidal in higher
concentrations).
[1,4]
CMS is characterized by a moderate and
prolonged post-antibiotic effect (at higher concentrations)
against MDR A. baumannii and P. aeruginosa strains.
[1,4]
Colistin
acts on the bacterial cell membrane. The cationic polypeptide
(Colistin) interacts with the anionic lipopolysaccharide (LPS)
molecules in the outer membrane of GNB (gram-negative
bacilli) and displaces magnesium and calcium, which are the
stabilizers of the LPS molecules of the outer membrane of the
GNB.
[1,4]
This process results in increased cell permeability,
leakage of cell-contents, lysis of cell, and finally, bacterial cell
death.
[1,4]
Colistin also has a potent action against endotoxin
it inhibits the elaboration of cytokines and neutralizes the
endotoxin.
[1,4]
Hydrophilic antibiotics (rifampicin, carbapenems,
glycopeptides, and tetracyclines) can work synergistically owing
to the disruption of membrane integrity by Colistin.
[5]
Modes of Administration and Antibacterial Activity
Colistin can be administered orally, topically (as otic solution
and skin powder as Colistin sulfate), intramuscularly, via
inhalation, intrathecally, and intravenously as CMS.
[4]
Colistin
is mostly active against Gram-negative clinical isolates including
Enterobacteriaceae.
[5]
The non-fermentative GNB-P. aeruginosa
and Acinetobacter species are naturally susceptible to
Colistin.
[5]
Colistin is also effective against-Haemophilus
influenzae, E. coli, Salmonella spp., Shigella spp., Klebsiella
spp., Legionella pneumophila, Aeromonas spp., Citrobacter
spp., Bordetella pertussis., and Campylobacter species (variable
susceptibility).
[4,5,7]
Pharmacokinetics-pharmacodynamics
The pharmacokinetics (PK) of Colistin appear to be complex.
[4]

Most formulations contain CMS, which is hydrolyzed to various
partial derivatives and Colistin in vivo.
[4]
Various pharmaceutical
formulations often describe their contents differently, and
thus, uniform and rational dosing of Colistin is challenging.
[4]

Both forms (Colistin sulfate and CMS) are not absorbed by
the gastrointestinal (GI) tract.
[1]
After administration of CMS,
Colistin appears rapidly in the plasma.
[6]
The serum half-life of
this medication is 4.5-6 hours.
[1]
CMS is predominantly cleared
by the renal route, and a fraction of the dose is converted
in vivo to Colistin.
[3]
The Colistin formed is mainly cleared
by non-renal mechanisms. In renal impairment, elimination
of colistimethate (by the kidney) would be decreased and
a greater fraction of colistimethate would be converted to
Colistin; thus the need to decrease the dose of colistimethate in
renal-impaired patients.
[3]
Following parenteral administration
of CMS, the overall disposition of formed Colistin is rate
limited by its elimination (rather than formation) as indicated
by the substantially longer terminal half-life of formed Colistin
(compared with that of the administered CMS).
[8]
The general
minimum inhibitory concentration (MIC) breakpoint to
identify bacteria susceptible to CMS is up to 4 mg/l based on
the British Society for Antimicrobial Chemotherapy Guidelines
(if MIC 8mg/l, the GNB are resistant).
[1]
Many authorities
consider susceptibility to Colistin if the respective MIC
90
of
Colistin is a maximum of 2 microg/ml (against a variety of GNB
including E. coli, Klebsiella spp., Enterobacter spp., A. baumannii,
and P. aeruginosa).
[1]
Colistin concentrations in the vicinity of
MICs or above result in extremely rapid initial killing, with large
decreases in colony forming units per mL (cfu/mL) occurring
as early as 5 minutes following exposure.
[8]
Dosage and Formulation
There are two forms of Colistin available commercially: Colistin
sulfate (tablets or syrup for oral use and powder for topical use),
which is also available as an aqueous suspension solution for
topical use in eyes and ears and CMS for parenteral use.
[4,7]
Both
these forms can be delivered by inhalation route. Colistimethate
sodium is administered parenterally (less toxic than Colistin
sulfate).
[9]
The doses of Colistin through the various routes
of administration are given in Table 1.
[4,5,10-12]
The dosage of
intravenous CMS (as recommended by the manufacturers
in the USA) is 2.5-5 mg/kg (31,250-62,500 IU/kg) per day,
Table 1: Doses of various routes of administration of
colistin
[4,5,10-12]
Route of administration Weight Dose
Intravenous/Intramuscular
CMS (UK manufacturers)
Children and
adults<60 kg
4-6 mg/kg (50,000-
75,000 IU/kg)
per day, in three
divided doses
Adults>60 kg 80-160 mg
(1-2 million IU)
every 8 h
Inhalational CMS
[10]
Body
weight<40 kg
40 mg (500,000 IU)
every 12 h
Body
weight>40 kg
80 mg (1,000,000 IU)
every 12 h
Intrathecal/intraventricular
CMS. Guidelines published
by the infectious diseases
society of America in
2004
[11]
10 mg
Oral Colistin sulfate (for
bowel sterilization/GI
infections)
[12]
Children:
<15 kg
0.25-0.5 million IU
8 hourly
15-30 kg 0.75-1.5 million IU
8 hourly
Adults 1.5-3 million IU
8 hourly
CMS Colistimethate sodium; GI Gastrointestinal; IU International Units
Dhariwal and Tullu: Colistin
210 Journal of Postgraduate Medicine July 2013 Vol 59 Issue 3
divided into two to four equal doses.
[5,13]
Dosage adjustments
are recommended for patients with mild-to-moderate renal
dysfunction as shown in Table 2.
[5,14]
For patients with renal
failure, the recommended intravenous dosages of CMS are
2-3 mg/kg after each hemodialysis treatment and 2 mg/kg daily
during peritoneal dialysis.
[5,15,16]
In India, parenteral colistin is available in two brands:
Xylistin
TM
by Cipla pharmaceuticals [available as 1 million IU
(International Units) and 2 million IU vials)] and Colinem
TM
by
Macleods pharmaceuticals (available as 1 million IU per vial); the
dosage being similar to that being used in United Kingdom.
[17,18]

There is a substantial difference in the recommended doses of
the European and US products. However, according to recent
clinical experience, higher daily doses of intravenous Colistin,
up-to 720 mg (9 million IU) per day, administered in large
series of patients did not exhibit higher toxicity.
[1,19-21]
Colistin
base has been assigned a potency of 30,000 IU/mg and CMS
has a potency of 12,500 IU/mg. Hence, the recommendations
regarding dosing should clearly refer to Colistin base and CMS
to avoid possible confusion.
[5,22]
The recommended dose of Colistin when given by inhalation
is given in Table 1. For recurrent or severe pulmonary
infections, the dose can be doubled to 160 mg (2,000,000 IU)
administered every 8 hours.
[10]
The recommended dose for
spontaneously breathing patients is 80 mg (1,000,000 IU).
[10]

Colistin is added to 4 ml of normal saline or sterile water
and the solution is nebulized with 8 L/min oxygen flow and
inhaled via a face mask.
[10,13]
The optimal nebulized dosing
remains unclear. Colistin is not approved by the Food and Drug
Administration (FDA) to be inhaled via a nebulizer.
[10]
CMS is mostly administered for 10-14 days.
[5]
Dose regimens
vary considerably and should be adjusted for renal function
depending on serum creatinine levels or creatinine clearance.
[5]

Colistin pharmacokinetics are different in critically ill patients
as they have frequent fluctuations in renal clearance. Many
authors reported the administration of CMS at a dose of 3 MIU
every 8 hours, especially in critically ill patients with normal
renal function.
[16,23,24]
There is inadequate data available on the
safety of Colistin during pregnancy and in patients with liver
function impairment.
[17,18]
Adverse Effects
The adverse effects of Colistin are-nephrotoxicity (acute tubular
necrosis in up to 20% of patients), neurotoxicity (0-7% of
patients), dizziness, weakness, facial and peripheral paresthesia,
vertigo, confusion, ataxia, and neuromuscular blockade (can
lead to respiratory failure or apnea).
[1,5]
Recent studies have
reported significantly lower nephrotoxicity rates associated
with Colistin administration (especially CMS).
[19]
The toxicity
is dose-dependent and reversible on discontinuation of the
treatment.
[1,5]
Concomitant administration of other potential
nephrotoxic agents (such as diuretics, aminoglycosides or
vancomycin) increases the likelihood of nephrotoxicity.
[1]

Other adverse reactions include-hypersensitivity reactions, rash,
urticaria, generalized itching, fever, gastro-intestinal disorders,
and pseudomembranous colitis.
[17,18]
The incidence of allergic
reactions due to Colistin use has been reported to be about
2%.
[1,25]
Bronchoconstriction and chest tightness are reported as
rare complications when Colistin is used by inhalation route.
[1]
Drug Interactions
Concomitant use of Colistin with other drugs of neurotoxic
and/or nephrotoxic potential (diuretics, aminoglycosides or
vancomycin) should be avoided.
[1]
Neuromuscular blocking
drugs and ether should be used with extreme caution in patients
receiving CMS.
[17,18]
Contraindications
It is contraindicated in patients with known hypersensitivity
to Colistin or polymyxin B and in patients with myasthenia
gravis.
[17,18]
Colistin should be used with extreme caution in
patients with porphyria.
Resistance
Colistin has been shown to be active (even) in the presence of
extended spectrum -lactamases and metallo--lactamases.
[1]

Still, relatively high Colistin resistance rates in GNB (such as
Acinetobacter spp., P. aeruginosa strains, and Enterobacteriaceae
produced carbapenemases) have been recently reported
worldwide.
[1]
Although the mechanisms of Colistin resistance
have not been completely understood, alteration of the
outer membrane of the (bacterial) cell, the reduction in
cell envelope Mg
2+
and Ca
2+
contents and efflux pumps or
production of enzyme(s) could be possible mechanisms.
[1,4,26]

The emergence of MDR or pandrug-resistant Gram-negative
isolates, and especially, the emergence of Colistin resistance, are
of concern.
[1,27]
Colistin-resistant K. pneumoniae, A. baumannii,
and P. aeruginosa pathogens may be encountered in clinical
practice.
[1]
Hence, Colistin should be used judiciously (as
treatment options for Colistin-resistant GNB are very
limited).
[1,28]
In a recent study on the emergence of MDR
A. baumanii in patients with complicated urinary tract infections
(North India); out of the total 224 isolates studied, 3.5% of
total and 16% of the carbapenem-resistant MDR strains were
found to be resistant to both Colistin and Tigecycline.
[29]
The
pathogenic Neisseria spp., M. catarrhalis, H. pylori, P. mirabilis,
S. marcescens, Morganella morganii, Chromobacterium, and
Brucella species are naturally resistant to Colistin.
[5,30-34]
Also,
isolates of Inquilinus, Pandoraea, and Burkholderia associated
with cystic fibrosis are intrinsically resistant to Colistin.
[5,35-38]

In P. mirabilis, Burkholderia cepacia, and Chromobacterium
violaceum, polymyxin resistance has been associated with the
changes in the lipid A.
[5,34,39]
Table 2: Dosage adjustment in renal impairment
[5,14]
Serum creatinine levels (mg/dl) Dose in adults>60 kg
1.3-1.5 2 million IU every 12 hrs
1.6-2.5 2 million IU every 24 hrs
2.6 2 million IU every 36 hrs
Dhariwal and Tullu: Colistin
Journal of Postgraduate Medicine July 2013 Vol 59 Issue 3 211
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e
u
r
o
t
o
x
i
c
i
t
y

(
4

p
a
t
i
e
n
t
s
)
;

C
l
o
s
t
r
i
d
i
u
m

d
i
f
f
i
c
i
l
e

i
n
f
e
c
t
i
o
n

(
1
.
1
%
)
;

G
a
s
t
r
o
i
n
t
e
s
t
i
n
a
l

c
o
m
p
l
a
i
n
t
s

(
2
.
2
%
)
;

R
a
s
h

(
1
.
1
%
)
;

R
e
s
p
i
r
a
t
o
r
y

(
2
.
2
%
)
P
a
k
s
u

e
t

a
l
.
,

2
0
1
2
[
5
8
]
R
e
t
r
o
s
p
e
c
t
i
v
e

s
t
u
d
y
.

7
9

c
a
s
e
s

b
e
t
w
e
e
n

J
u
n
e

2
0
0
8

t
o

J
a
n

2
0
1
1

(
r
a
n
g
e
:

3

t
o

2
1
6

m
o
n
t
h
s
,

m
e
d
i
a
n
-
3
0

m
o
n
t
h
s
)
C
h
r
o
n
i
c

n
e
u
r
o
l
o
g
i
c
a
l

o
r

n
e
u
r
o
-
m
u
s
c
u
l
a
r

d
i
s
e
a
s
e
-
2
6
;

C
o
n
g
e
n
i
t
a
l

h
e
a
r
t

d
i
s
e
a
s
e
-
1
0
;

P
r
i
m
a
r
y

i
m
m
u
n
e

d
e
f
i
c
i
e
n
c
y
-
8
;

I
n
h
e
r
i
t
e
d

m
e
t
a
b
o
l
i
c

d
i
s
o
r
d
e
r
s
-
7
;

M
a
l
i
g
n
a
n
c
y
-
2
;

O
t
h
e
r
s

(
c
o
l
l
a
g
e
n

t
i
s
s
u
e

d
i
s
e
a
s
e
,

c
h
r
o
n
i
c

r
e
n
a
l

f
a
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l
u
r
e
,

C
h
r
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n
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c

l
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g

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i
s
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a
s
e
,

e
t
c
.
)
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9
V
e
n
t
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l
a
t
o
r
-
a
s
s
o
c
i
a
t
e
d

p
n
e
u
m
o
n
i
a

(
V
A
P
)

(
5
6
.
3
%
)
;

B
l
o
o
d
s
t
r
e
a
m

i
n
f
e
c
t
i
o
n

(
B
S
I
)

(
1
0
.
3
%
)
;

V
A
P
+
B
S
I

(
2
0
.
7
%
)
;

C
l
i
n
i
c
a
l

s
e
p
s
i
s

(
9
.
2
%
)
;

O
t
h
e
r
s

(
c
e
n
t
r
a
l

n
e
r
v
o
u
s

s
y
s
t
e
m

i
n
f
e
c
t
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o
n
,

s
o
f
t

t
i
s
s
u
e

i
n
f
e
c
t
i
o
n
,

p
e
r
i
t
o
n
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t
i
s

(
3
.
4
%
)
A
c
i
n
e
t
o
b
a
c
t
e
r

b
a
u
m
a
n
n
i
i

(
5
9
.
8
%
)
;

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s
e
u
d
o
m
o
n
a
s

a
e
r
u
g
i
n
o
s
a

(
1
8
.
4
%
)
;

K
l
e
b
s
i
e
l
l
a

p
n
e
u
m
o
n
i
a
e

(
1
.
1
%
)
;

A
.

b
a
u
m
a
n
n
i
i
+

P
.

a
e
r
u
g
i
n
o
s
a

o
r

K
.

p
n
e
u
m
o
n
i
a
e

(
8
.
0
%
)
I
n
t
r
a
v
e
n
o
u
s

5
.
4

0
.
6

m
g
/
k
g
/
d
a
y
.

M
e
a
n

d
u
r
a
t
i
o
n
:

1
7
.
2

8
.
4

d
a
y
s
.

C
o
n
c
o
m
i
t
a
n
t
l
y

i
n
t
r
a
v
e
n
t
r
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c
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l
a
r
l
y

t
o

o
n
e

p
a
t
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e
n
t

a
t

a

d
o
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e

o
f

1
0

m
g
/
d
a
y

f
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r

2
1

d
a
y
s
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l
y
c
o
p
e
p
t
i
d
e
s

(
4
1
.
4
%
)

A
n
t
i
f
u
n
g
a
l

a
g
e
n
t
s

(
f
l
u
c
o
n
a
z
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l
e
,

a
m
p
h
o
t
e
r
i
c
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n

B
,

a
n
d

c
a
s
p
o
f
u
n
g
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n
)

(
3
6
.
8
%
)

C
a
r
b
a
p
e
n
e
m
s

(
3
2
.
2
%
)

A
m
i
n
o
g
l
y
c
o
s
i
d
e
s

(
3
1
.
0
%
)

F
l
u
o
r
o
q
u
i
n
o
l
o
n
e
s

(
1
3
.
8
%
)
;

L
i
n
e
z
o
l
i
d

(
1
3
.
8
%
)
;

C
e
f
o
p
e
r
a
z
o
n
e
/
s
u
l
b
a
c
t
a
m

(
9
.
2
%
)
;

P
i
p
e
r
a
c
i
l
l
i
n
/
t
a
z
o
b
a
c
t
a
m

(
6
.
9
%
)
;

A
n
t
i
v
i
r
a
l

a
g
e
n
t
s

(
a
c
y
c
l
o
v
i
r
,

g
a
n
c
i
c
l
o
v
i
r
)

(
5
.
7
%
)

O
t
h
e
r
s

(
c
e
f
t
a
z
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d
i
m
e
,

t
r
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m
e
t
h
o
p
r
i
m
/
s
u
l
f
a
m
e
t
h
o
x
a
z
o
l
e
,

m
e
t
r
o
n
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d
a
z
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l
e
,

c
l
a
r
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t
h
r
o
m
y
c
i
n
,

a
m
p
i
c
i
l
l
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n
/
s
u
l
b
a
c
t
a
m
)

(
9
.
2
%
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C
l
i
n
i
c
a
l

a
n
d

m
i
c
r
o
b
i
o
l
o
g
i
c
a
l

r
e
s
p
o
n
s
e
-

6
5

(
7
4
.
7
%
)
;

C
l
i
n
i
c
a
l

r
e
s
p
o
n
s
e
-
o
n
l
y

5

(
5
.
8
%
)
;

M
i
c
r
o
b
i
o
l
o
g
i
c
a
l

r
e
s
p
o
n
s
e
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o
n
l
y

3

(
3
.
4
%
)

D
i
s
c
o
n
t
i
n
u
a
t
i
o
n

o
f

t
r
e
a
t
m
e
n
t

o
w
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n
g

t
o

s
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d
e

e
f
f
e
c
t
-

1

(
1
.
1
%
)

C
h
a
n
g
e

o
f

t
r
e
a
t
m
e
n
t

o
w
i
n
g

t
o

c
l
i
n
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c
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l

u
n
r
e
s
p
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n
s
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v
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n
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s
s
-

1

(
1
.
1
%
)

D
e
a
t
h
s
-
1
2

(
1
3
.
8
%
)
N
e
u
r
o
t
o
x
i
c
i
t
y

(
2
.
3
%
)
;

R
e
n
a
l

t
o
x
i
c
i
t
y

(
2
.
3
%
)
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a
j
o
o

e
t

a
l
.
,

2
0
1
1
[
5
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]
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e
t
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o
s
p
e
c
t
i
v
e

d
e
s
c
r
i
p
t
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v
e

s
t
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d
y
.

1
8

n
e
o
n
a
t
e
s

r
e
c
e
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v
e
d

2
1

c
o
u
r
s
e
s

b
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t
w
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n

J
a
n

2
0
0
9

a
n
d

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e
c

2
0
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9

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t
e
r
m

a
n
d

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p
r
e
t
e
r
m
.

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g
e
:

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a
n
g
e
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0
-
2
4

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y
s
,

m
a
l
e
s
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5
0
%
)
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a
j
o
r

s
u
r
g
e
r
y

b
e
c
a
u
s
e

o
f

m
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c
o
n
g
e
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A
n
o
m
a
l
i
e
s
-
9
,

r
e
s
p
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r
a
t
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r
y

d
i
s
t
r
e
s
s

s
y
n
d
r
o
m
e
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5
,

B
i
r
t
h

A
s
p
h
y
x
i
a
-

4
,

a
n
d

m
e
c
o
n
i
u
m

a
s
p
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r
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t
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o
n

s
y
n
d
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o
m
e

w
i
t
h

p
e
r
s
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s
t
e
n
t

p
u
l
m
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h
y
p
e
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t
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n
s
i
o
n
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1
P
n
e
u
m
o
n
i
a
-
9

(
5
0
%
)
,

B
l
o
o
d

s
t
r
e
a
m

i
n
f
e
c
t
i
o
n
-
1
0

(
5
5
%
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,

c
a
t
h
e
t
e
r
-
r
e
l
a
t
e
d

b
l
o
o
d

s
t
r
e
a
m

i
n
f
e
c
t
i
o
n
-
2

(
1
1
%
)
,

m
e
n
i
n
g
i
t
i
s

i
n

2

(
1
1
%
)
,

a
n
d

e
m
p
y
e
m
a

t
h
o
r
a
c
i
s
-
2

(
1
1
%
)
A
.

b
a
u
m
a
n
n
i
i

1
4

(
5
6
%
)
,

K
.

p
n
e
u
m
o
n
i
a
e

5

(
2
4
%
)
,

P
.

a
e
r
u
g
i
n
o
s
a

3

(
1
2
%
)
,

a
n
d

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n
t
e
r
o
b
a
c
t
e
r

3

(
1
2
%
)
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n
t
r
a
v
e
n
o
u
s

C
M
S

5
0
,
0
0
0

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U

t
o

7
5
,
0
0
0

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U
/
k
g
/
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i
n

3

d
i
v
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d
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d

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o
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s
.

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e
a
n

d
u
r
a
t
i
o
n
:

1
3
.
1

d
a
y
s
/
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r
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e

(
r
a
n
g
e
:

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2
1

d
a
y
s
)
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r
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p
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m

1
4
/
2
1

c
o
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r
s
e
s
,

n
e
t
i
l
m
i
c
i
n

6
/
2
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,

p
i
p
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r
a
c
i
l
l
i
n
-

t
a
z
o
b
a
c
t
a
m

3
/
2
1
,

f
l
u
c
o
n
a
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o
l
e

2
/
2
1
,

a
n
d

a
m
p
h
o
t
e
r
i
c
i
n

B

1
/
2
1
F
a
v
o
r
a
b
l
e

c
l
i
n
i
c
a
l

o
u
t
c
o
m
e

1
6
/
2
1

(
7
6
%
)

c
o
u
r
s
e
s
.

5

p
a
t
i
e
n
t
s

d
i
e
d
.

M
i
c
r
o
b
i
o
l
o
g
i
c
a
l

c
l
e
a
r
a
n
c
e

1
7
/
2
1
N
e
p
h
r
o
t
o
x
i
c
i
t
y

i
n

2

n
e
o
n
a
t
e
s
,

n
o

n
e
u
r
o
t
o
x
i
c
i
t
y
C
o
n
t
d
.
.
.
Dhariwal and Tullu: Colistin
212 Journal of Postgraduate Medicine July 2013 Vol 59 Issue 3
T
a
b
l
e

3
:

C
o
n
t
d
.
.
.
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f
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d
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p
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r
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2
0
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[
6
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R
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p
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1
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c
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e
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y
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Dhariwal and Tullu: Colistin
Journal of Postgraduate Medicine July 2013 Vol 59 Issue 3 213
Clinical Uses
Oral and topical route
Colistin sulfate is used orally for bowel decontamination and
topically (as a powder) for the treatment of skin infections.
[1]
Intravenous or intramuscular route
CMS has been used to treat ventilator-associated pneumonia
(VAP) and bacteremia caused by MDR bacteria, such
as P. aeruginosa, K. pneumoniae and A. baumannii.
[30,40]

Intramuscular route is avoided as it is very painful and local
irritation at the site of injection may occur.
[17,18]
Inhalational route
Prophylactic use
Colistin has been administered for the eradication of pathogens
from the respiratory tract in cystic fibrosis (CF) patients in
combination with ciprofloxacin administered orally for at least
3 weeks (or, even better, for 3 months) or by means of inhaled
tobramycin as monotherapy for 4 weeks or longer. The therapeutic
results of this preventive strategy have been successful.
[10,41]
Therapeutic use
Recent data in (critically ill) patients receiving Colistin by
nebulization for management of pneumonia/VAP due to MDR
GNB show favorable results.
[10]
High drug concentrations are
usually achieved in sputum and bronchial secretions, maintained
for 8-12 hours in the majority of patients.
[16]
However, further
controlled trials are required in this regards.
[1]
Intraventricular or intrathecal route
Colistin is usually administered intravenously, although adequate
concentrations may not be achieved in the cerebrospinal fluid due
to poor penetration of Colistin across the blood-brain barrier.
[1,3]

Hence, Colistin can also be administered by the intraventricular
or intrathecal route (considered if the ventriculitis is refractory
to systemic antimicrobial therapy).
[1,3]
Direct instillation of
Colistin into the central nervous system (CNS) may cause
chemical meningitis or ventriculitis.
[1]
Toxicity (probably or
possibly) related to the topical administration of Colistin is seen
in about 15% of patients.
[1,42]
Administration of Colistin directly
into the CNS appears to be successful and well tolerated.
[1]

Intra-ventricular and intrathecal administration of Colistin is an
effective (and safe) option for treatment of post-neurosurgical
meningitis (or ventriculitis) due to MDR GNB (especially when
the intravenous route is not feasible/available).
[1]
Combination therapy
Colistin can be used as combination therapy to improve its
antibacterial activity.
[5]
A synergistic effect has been reported in
different studies as regards the combination of Colistin with other
antibiotics.
[5,40,43,44]
Combination therapy with rifampicin and
polymixin is one of the alternatives for treatment of MDR-GNB
infections.
[5,45-49]
Synergistic effect was detected in most of
the studies that examined the combination of Colistin and
rifampicin, whereas carbapenems exhibited a synergistic effect
in a few studies.
[5,43]
Sulbactam may be considered an option in
association with Colistin, in the treatment of MDR A. baumannii
infections.
[5,50,51]
Combinations of Colistin/Meropenem, Colistin/
Rifampicin, and Colistin/Minocycline are synergistic in vitro
against extensive drug-resistant A. baumannii.
[5,52]
Wareham et al.,
have documented a synergistic effect of Colistin in combination
with teicoplanin against MDR A. baumannii strains.
[53]

Glycopeptides have also shown synergy with polymyxin.
[5,44,54]
Colistin-uses in Children
Colistin is permitted for use in all children including infants.
[55]

Few efficacy data from controlled trials of its systemic use
in infants and children are available because of the relative
non-use of Colistin during the past 30 years.
[55]
Data on
pharmacokinetic properties, drug behavior and dosing in
children are also inadequate.
[55]
Published reports on the use of
Colistin in children describe its use in case-series/case reports.
Most published clinical data in children describes Colistin use
in patients with cystic fibrosis.
[55]
Falagas et al., (2009) reviewed
the literature on the systemic use of Colistin in children without
cystic fibrosis.
[56]
Included in this review were 326 children from
10 case series and 15 case reports, of which only 17 children
were evaluated in reports published after 1977.
[56]
Of these
children, 271 were evaluable for clinical outcome-more than
90% were cured of infection or improved.
[56]
Nephrotoxicity
occurred in 2.8% and no neurotoxicity was reported. Indications
for use of colistin included sepsis, meningitis, pneumonia, and
pyelonephritis.
[56]
Table 3
[57-63]
gives a summary of the recent
case series and studies on systemic (intravenous) use of Colistin
in pediatric population in the last 3 years (2009-2012) and
includes only one Indian study (hence more data is required on
the efficacy and safety of Colistin in Indian children).
[59]
Recent
case series on the use of inhaled Colistin for the treatment
of VAP and tracheobronchitis due to MDR A. baumanii and
P. aeruginosa in critically-ill pediatric patients and neonates,
have found Colistin treatment to be effective, safe, and tolerable
without any adverse effects.
[64-66]
In conclusion, recent studies and case reports have found
Colistin to be safe and effective in the treatment of critically ill
children with MDR GNB infections (more studies are required
for confirming these findings).
[57-66]
Acknowledgment
The authors thank Dr. Sandhya Kamath, Dean of Seth G. S. Medical
College and K. E. M. Hospital for granting permission to publish this
manuscript.
References
1. Michalopoulos AS, Karatza DC. Multidrug-resistant gram-negative
infections: The use of colistin. Expert Rev Anti Infect Ther
2010;8:1009-17.
2. Kumarasamy KK, Toleman MA, Walsh TR, Bagaria J, Butt F,
Balakrishnan R, et al. Emergence of a new antibiotic resistance
mechanism in India, Pakistan, and the UK: A molecular, biological,
and epidemiological study. Lancet Infect Dis 2010;10:597-602.
3. Li J, Nation RL, Turnidge JD, Milne RW, Coulthard K, Rayner CR,
et al. Colistin: The re-emerging antibiotic for multidrug-resistant
Gram-negative bacterial infections. Lancet Infect Dis 2006;6:589-601.
4. Kwa A, Kasiakou SK, Tam VH, Falagas ME. Polymyxin B: Similarities
to and differences from colistin (polymyxin E). Expert Rev Anti Infect
Ther 2007;5:811-21.
Dhariwal and Tullu: Colistin
214 Journal of Postgraduate Medicine July 2013 Vol 59 Issue 3
5. Biswas S, Brunel JM, Dubus JC, Reynaud-Gaubert M, Rolain JM.
Colistin: An update on the antibiotic of the 21
st
century. Expert Rev
Anti Infect Ther 2012;10:917-34.
6. Bergen PJ, Li J, Rayner CR, Nation RL. Colistin methanesulfonate
is an inactive prodrug of colistin against Pseudomonas aeruginosa.
Antimicrob Agents Chemother 2006;50:1953-8.
7. Giamarellou H, Poulakou G. Multidrug-resistant Gram-negative
infections: What are the treatment options? Drugs 2009;69:1879-901.
8. Bergen PJ, Li J, Nation RL. Dosing of colistin-back to basic PK/PD.
Curr Opin Pharmacol 2011;11:464-9.
9. Barnett M, Bushby SR, Wilkinson S. Sodium sulphomethyl derivatives
of polymyxins. Br J Pharmacol Chemother 1964;23:552-74.
10. Michalopoulos A, Papadakis E. Inhaled anti-infective agents:
Emphasis on colistin. Infection 2010;38:81-8.
11. Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM,
et al. Practice guidelines for the management of bacterial meningitis.
Clin Infect Dis 2004;39:1267-84.
12. CIMS India. 2012 UBM Medica. Available from: www.mims.
com/India/drug/info/colistin%20sulfate?type=full [Last cited on
2013 Jan 5].
13. Falagas ME, Kasiakou SK. Colistin: The revival of polymyxins for
the management of multidrug-resistant gram-negative bacterial
infections. Clin Infect Dis 2005;40:1333-41.
14. Falagas ME, Kasiakou SK, Tsiodras S, Michalopoulos A. The use
of intravenous and aerosolized polymyxins for the treatment of
infections in critically ill patients: A review of the recent literature.
Clin Med Res 2006;4:138-46.
15. Curi ti s JR, Eastwood JB. Col i sti n sul phomethate sodi um
administration in the presence of severe renal failure and during
haemodialysis and peritoneal dialysis. Br Med J 1968;1:484-5.
16. Michalopoulos A, Falagas ME. Colistin and polymyxin B in critical
care. Crit Care Clin 2008;24:377-91.
17. Xylistin package insert information (updated Sept 2011). Xylistin
10,00,000 IU vial-Colistimethate Sodium BP. Cipla pharmaceuticals,
India; 2011.
18. Colinem package insert information. Colinem 1 million IU
vial-Colistimethate Sodium BP. Macleods Pharmaceuticals Ltd,
Mumbai, India.
19. Falagas ME, Rafailidis PI, Ioannidou E, Alexiou VG, Matthaiou DK,
Karageorgopoulos DE, et al. Colistin therapy for microbiologically
documented multidrug-resistant Gram-negative bacterial infections:
A retrospective cohort study of 258 patients. Int J Antimicrob Agents
2010;35:194-9.
20. Michalopoulos AS, Tsiodras S, Rellos K, Mentzelopoulos S,
Falagas ME. Colistin treatment in patients with ICU-acquired
infections caused by multiresistant Gram-negative bacteria: The
renaissance of an old antibiotic. Clin Microbiol Infect 2005;11:115-21.
21. Plachouras D, Karvanen M, Friberg LE, Papadomichelakis E,
Antoniadou A, Tsangaris I, et al. Population pharmacokinetic analysis of
colistin methane sulfonate and colistin after intravenous administration
in critically ill patients with infections caused by Gram-negative
bacteria. Antimicrob Agents Chemother 2009;53:3430-6.
22. Mi chal opoul os AS, Fal agas ME. Col i sti n: Recent data on
pharmacodynamics properties and clinical efficacy in critically ill
patients. Ann Intensive Care 2011;1:30.
23. Markou N, Markantonis SL, Dimitrakis E, Panidis D, Boutzouka E,
Karatzas S, et al. Colistin serum concentrations after intravenous
administration in critically ill patients with serious multidrug-resistant,
gram-negative bacilli infections: A prospective, open-label,
uncontrolled study. Clin Ther 2008;30:143-51.
24. Spapen H, Jacobs R, Van Gorp V, Troubleyn J, Honor PM. Renal
and neurological side effects of colistin in critically ill patients. Ann
Intensive Care 2011;1:14.
25. Papagelopoulos PJ, Mavrogenis AF, Giannitsioti E, Kikilas A,
Kanellakopoulou K, Soucacos PN. Management of a multidrug-resistant
Pseudomonas aeruginosa infected total knee arthroplasty using
colistin. A case report and review of the literature. J Arthroplasty
2007;22:457-63.
26. Evans ME, Feola DJ, Rapp RP. Polymyxin B sulfate and colistin: Old
antibiotics for emerging multiresistant Gram-negative bacteria. Ann
Pharmacother 1999;33:960-7.
27. Perez F, Hujer AM, Hujer KM, Decker BK, Rather PN, Bonomo RA.
Global challenge of multidrug-resistant Acinetobacter baumannii.
Antimicrob Agents Chemother 2007;51:3471-84.
28. Matthaiou DK, Michalopoulos A, Rafailidis PI, Karageorgopoulos DE,
Papaioannou V, Ntani G, et al. Risk factors associated with the
isolation of colistin-resistant Gram-negative bacteria: A matched
case-control study. Crit Care Med 2008;36:807-11.
29. Taneja N, Singh G, Singh M, Sharma M. Emergence of tigecycline
and colistin resistant Acinetobacter baumanii in patients with
complicated urinary tract infections in North India. Indian J Med Res
2011;133:681-4.
30. Landman D, Georgescu C, Martin DA, Quale J. Polymyxins revisited.
Clin Microbiol Rev 2008;21:449-65.
31. Doern GV, Morse SA. Branhamella (Neisseria) catarrhalis: Criteria for
laboratory identification. J Clin Microbiol 1980;11:193-5.
32. Glupczynski Y, Delmee M, Bruck C, Labbe M, Avesani V, Burette A.
Susceptibility of clinical isolates of Campylobacter pylori to 24
antimicrobial and anti-ulcer agents. Eur J Epidemiol 1988;4:154-7.
33. Garca-Rodrguez JA, Garca- Garca MI, Garca- Snchez E,
Garca-Snchez JE, Muoz Bellido JL. In vitro activity of 16
antimicrobial agents against Helicobacter (Campylobacter) pylori.
Enferm Infecc Microbiol Clin 1989;7:544-6.
34. Sidorczyk Z, Zhringer U, Rietschel ET. Chemical structure of the
lipid A component of the lipopolysaccharide from a Proteus mirabilis
re-mutant. Eur J Biochem 1983;137:15-22.
35. Schmoldt S, Latzin P, Heesemann J, Griese M, Imhof A, Hogardt M.
Clonal analysis of Inquilinus limosus isolates from six cystic fibrosis
patients and specific serum antibody response. J Med Microbiol
2006;55:1425-33.
36. Daneshvar MI, Hollis DG, Steigerwalt AG, Whitney AM, Spangler L,
Douglas MP, et al. Assignment of CDC weak oxidizer group 2 (WO-2)
to the genus Pandoraea and characterization of three new Pandoraea
genomospecies. J Clin Microbiol 2001;39:1819-26.
37. Denton M, Kerr KG. Microbiological and clinical aspects of infection
associated with Stenotrophomonas maltophilia. Clin Microbiol Rev
1998;11:57-80.
38. Al onso A, Mart nez JL. Mul ti pl e anti bi oti c resi stance i n
Stenotrophomonas maltophilia. Antimicrob Agents Chemother
1997;41:1140-2.
39. Hase S, Reitschel ET. The chemical structure of the lipid A component
of lipopolysaccharides from Chromobacterium violaceum NCTC 9694.
Eur J Biochem 1977;75:23-34.
40. Nation RL, Li J. Colistin in the 21
st
century. Curr Opin Infect Dis
2009;22:535-43.
41. Hoiby N, Frederiksen B, Pressler T. Eradication of early Pseudomonas
aeruginosa infection. J Cyst Fibros 2005;4:49-54.
42. Cascio A, Conti A, Sinardi L, Iaria C, Angileri FF, Stassi G, et al.
Post-neurosurgical multidrug-resistant Acinetobacter baumannii
meningitis successfully treated with intrathecal colistin. A new
case and a systematic review of the literature. Int J Infect Dis
2010;14:e572-9.
43. Petrosillo N, Ioannidou E, Falagas ME. Colistin monotherapy vs.
combination therapy: Evidence from microbiological, animal and
clinical studies. Clin Microbiol Infect 2008;14:816-27.
44. Gordon NC, Png K, Wareham DW. Potent synergy and sustained
bactericidal activity of a vancomycin-colistin combination versus
multidrug-resistant strains of Acinetobacter baumannii. Antimicrob
Agents Chemother 2010;54:5316-22.
45. Giamarellos-Bourboulis EJ, Xirouchaki E, Giamarellou H. Interactions
of colistin and rifampin on multidrug-resistant Acinetobacter
baumannii. Diagn Microbiol Infect Dis 2001;40:117-20.
46. Giamarellos-Bourboulis EJ, Sambatakou H, Galani I, Giamarellou H.
In vitro interaction of colistin and rifampin on multidrug-resistant
Pseudomonas aeruginosa. J Chemother 2003;15:235-8.
47. Hogg GM, Barr JG, Webb CH. In vitro activity of the combination
of colistin and rifampicin against multidrug-resistant strains of
Acinetobacter baumannii. J Antimicrob Chemother 1998;41:494-5.
48. Motaouakkil S, Charra B, Hachimi A, Nejmi H, Benslama A,
Elmdaghri N, et al. Colistin and rifampicin in the treatment of
nosocomial infections from multiresistant acinetobacter baumannii.
J Infect 2006;53:274-8.
49. Bassetti M, Repetto E, Righi E, Boni S, Diverio M, Molinari MP,
et al. Colistin and rifampicin in the treatment of multidrug-resistant
Acinetobacter baumannii infections. J Antimicrob Chemother
2008;61:417-20.
50. Kempf M, Rolain JM. Emergence of resistance to carbapenems in
Acinetobacter baumannii in Europe: Clinical impact and therapeutic
Dhariwal and Tullu: Colistin
Journal of Postgraduate Medicine July 2013 Vol 59 Issue 3 215
options. Int J Antimicrob Agents 2012;39:105-14.
51. Kempf M, Djouhri-Bouktab L, Brunel JM, Raoult D, Rolain JM.
Synergistic activity of sulbactam combined with colistin against
colistin-resistant Acinetobacter baumannii. Int J Antimicrob Agents
2012;39:180-1.
52. Liang W, Liu XF, Huang J, Zhu DM, Li J, Zhang J. Activities of
colistin- and minocycline-based combinations against extensive drug
resistant Acinetobacter baumannii isolates from intensive care unit
patients. BMC Infect Dis 2011;11:109.
53. Wareham DW, Gordon NC, Hornsey M. In vitro activity of teicoplanin
combined with colistin versus multidrug-resistant strains of
Acinetobacter baumannii. J Antimicrob Chemother 2011;66:1047-51.
54. Elemam A, Rahimian J, Doymaz M. In vitro evaluation of antibiotic
synergy for polymyxin B-resistant carbapenemase-producing
Klebsiella pneumoniae. J Clin Microbiol 2010;48:3558-62.
55. Bell EA. Colistin: Its role in pediatrics. [pharmacology consult]
Infectious diseases in children. July 2012. [p-18.Healio.com/
Pediatrics]. Available from: http://www.healio.com/Pediatrics/
Vaccine-Preventable%20Diseases/News [Last accessed on
2013 Jan 8].
56. Falagas ME, Vouloumanou EK, Rafailidis PI. Systemic colistin use in
children without cystic fibrosis: A systematic review of the literature.
Int J Antimicrob Agents 2009;33:503.e1-503.e13.
57. Tamma PD, Newland JG, Pannaraj PS, Metjian TA, Banerjee R,
Gerber JS, et al. The use of intravenous colistin among children in
the united states: Results from a multicenter, case series. Pediatr
Infect Dis J 2013;32:17-22.
58. Paksu MS, Paksu S, Karadag A, Sensoy G, Asilioglu N, Yildizdas D,
et al. Old agent, new experience: Colistin use in the paediatric
Intensive Care Unit: A multicentre study. Int J Antimicrob Agents
2012;40:140-4.
59. Jajoo M, Kumar V, Jain M, Kumari S, Manchanda V. Intravenous colistin
administration in Neonates. Pediatr Infect Dis J 2011;30:218-21.
60. Iosifidis E, Antachopoulos C, Ioannidou M, Mitroudi M, Sdougka M,
Drossou-Agakidou V, et al. Colistin administration to pediatric and
neonatal patients. Eur J Pediatr 2010;169:867-74.
61. Celebi S, Hacimustafaoglu M, Koksal N, Ozkan H, etinkaya M.
Colistimethate sodium therapy for multidrug-resistant isolates in
pediatric patients. Pediatr Int 2010;52:410-4.
62. Rosanova M, Epelbaum C, Noman A, Villasboas M, Alvarez V,
Berberian G, et al. Use of colistin in a pediatric burn unit in Argentina.
J Burn Care Res 2009;30:612-5.
63. Falagas ME, Sideri G, Vouloumanou EK, Papadatos JH, Kafetzis DA.
Intravenous colistimethate (colistin) use in critically ill children without
cystic fibrosis. Pediatr Infect Dis J 2009;28:123-7.
64. Nakwan N, Wannaro J, Thongmak T, Pornladnum P, Saksawad R,
Nakwan N, et al. Safety in treatment of ventilator-associated
pneumonia due to extensive drug-resistant Acinetobacter baumannii
with aerosolized colistin in neonates: A preliminary report. Pediatr
Pulmonol 2011;46:60-6.
65. Falagas ME, Sideri G, Korbila IP, Vouloumanou EK, Papadatos JH,
Kafetzis DA. Inhaled colistin for the treatment of tracheobronchitis
and pneumonia in critically ill children without cystic fibrosis. Pediatr
Pulmonol 2010;45:1135-40.
66. Celik IH, Oguz SS, Demirel G, Erdeve O, Dilmen U. Outcome
of ventilator-associated pneumonia due to multidrug-resistant
Acinetobacter baumannii and Pseudomonas aeruginosa treated with
aerosolized colistin in neonates: A retrospective chart review. Eur J
Pediatr 2012;171:311-6.
How to cite this article: Dhariwal AK, Tullu MS. Colistin: Re-emergence of
the 'forgotten' antimicrobial agent. J Postgrad Med 2013;59:208-15.
Source of Support: Nil, Confict of Interest: None declared.
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