Colistin Breakpoints for Pseudomonas aeruginosa

and Acinetobacter spp.

CLSI rationale document MR01

September 2018

Romney M. Humphries, PhD, D(ABMM)

Accelerate Diagnostics, Inc.
USA

1 Foreword
The Clinical and Laboratory Standards institute (CLSI) is a not-for-profit membership organization that brings together the varied
perspectives and expertise of the worldwide laboratory community for the advancement of a common cause: to foster excellence
in laboratory medicine by developing and implementing medical laboratory standards and guidelines that help laboratories fulfill
their responsibilities with efficiency, effectiveness, and global applicability.

Using the CLSI voluntary consensus process, the Subcommittee on Antimicrobial Susceptibility Testing develops standards that
promote accurate antimicrobial susceptibility testing and appropriate reporting. The subcommittee reviews data from various
sources and studies (eg, in vitro, pharmacokinetic-pharmacodynamic [PK-PD], and clinical studies) to establish antimicrobial
susceptibility test methods, breakpoints, and quality control (QC) ranges.

The details of the necessary and recommended data for selecting appropriate breakpoints and QC ranges, and how the data are
presented for evaluation, are described in CLSI document M23.1 CLSI antibacterial breakpoints are provided in CLSI documents
M1002 and M45.3

Over time, a microorganism’s susceptibility to an antimicrobial agent may decrease, resulting in a lack of clinical efficacy and/
or safety. In addition, microbiological methods, QC parameters, and the manner in which breakpoints are established may be
refined to ensure more accurate results. Because of these types of changes, CLSI continually monitors and updates information
in its documents. Although CLSI standards and guidelines are developed using the most current information available at the time,
the field of science and medicine is always changing; therefore, standards and guidelines should always be used in conjunction
with clinical judgment, current knowledge, and clinically relevant laboratory test results to guide patient treatment. For more
information, visit www.clsi.org.

This CLSI rationale document is based on CLSI agenda items submitted by the CLSI-EUCAST Joint Colistin Ad Hoc Working Group.

© Clinical and Laboratory Standards Institute. All rights reserved. 1

 Colistin Breakpoints for Pseudomonas aeruginosa and Acinetobacter spp.

2 Introduction
Colistin (polymyxin E) is a member of the polymyxin group of antimicrobial agents. The polymyxins are composed of large
amphipathic cyclic lipopeptides that are positively charged at physiological pH.4 Their mode of action is through electrostatic
interaction with the lipopolysaccharide (LPS) component of the gram-negative cell wall. This interaction leads to a competitive
displacement of the divalent cations that normally stabilize the LPS. This disruption of the outer membrane integrity leads to
cytoplasmic leakage and cell death.4,5 The polymyxins, including colistin, are active against most gram-negative bacilli, including
Enterobacteriaceae (excluding Proteae and Serratia spp.), Pseudomonas aeruginosa, and Acinetobacter spp. Neisseria spp., Brucella
and Burkholderia55spp.
Enterobacteriaceae.
spp.,
Enterobacteriaceae. There is
is complete
are intrinsically
There cross-resistance
completeresistant between
to the polymyxins.
cross-resistance the
the polymyxins.
betweenPolymyxin For
resistance
polymyxins. current
current and
is primarily
For past
the result
and past of modification
colistin
of the breakpoints,
polymyxin LPS see Tables
target. A 1 and 2,
transmissible respectively.
form of
colistin breakpoints, see Tables 1 and 2, respectively. resistance, mediated by plasmid-borne mcr genes, has been described among
the Enterobacteriaceae. There is complete cross-resistance between the polymyxins. For current and past colistin breakpoints, see
5

Colistin
Colistin
Tables is
is approved
1 and approved by
by the
the US
2, respectively. US Food
Food and
and Drug
Drug Administration
Administration (FDA)
(FDA) for
for the
the treatment
treatment ofof acute
acute or
or chronic
chronic
infections
infections due
due to
to susceptible
susceptible strains
strains of
of gram-negative
gram-negative bacilli,
bacilli, particularly
particularly those
those caused
caused by
by susceptible
susceptible strains
strains
6
of
of P.
Colistin is approved6 In
P. aeruginosa.
aeruginosa. by practice,
In practice, colistin
colistin
the US Food use
use is
and Drug typically
typically relegated
isAdministration
relegated to
to salvage
(FDA) for salvage therapy
of for
therapy
the treatment for infections
infections
acute caused
caused
or chronic by
by due to
infections
multidrug-resistant
multidrug-resistant
susceptible (MDR)
strains of gram-negativeP.
(MDR) P. bacilli,aeruginosa,
aeruginosa, Acinetobacter
Acinetobacter
particularly baumannii,
those caused bybaumannii, or carbapenem-resistant
or carbapenem-resistant
susceptible strains of P. aeruginosa. In practice, colistin
6

Enterobacteriaceae.
Enterobacteriaceae.
use In
is typically relegated these
In to
these scenarios,
therapycolistin
scenarios,
salvage colistin is
is primarily
causedused
primarily
for infections used as
as part
part of
of combination
combination
by multidrug-resistant (MDR) P.therapy.
therapy. Inhaled
Inhaled
aeruginosa, Acinetobacter
formulations
formulations of
of colistin
colistin are
are also
also available.
available. NOTE:
NOTE: The
The breakpoints
breakpoints in
in this
this document
document do
do not
not apply
apply to
to inhaled
inhaled
baumannii, or carbapenem-resistant Enterobacteriaceae. In these scenarios, colistin is primarily used as part of combination
use.
use.
therapy. Inhaled formulations of colistin are also available. NOTE: The breakpoints in this document do not apply to inhaled use.
Table
Table 1.
1. Current
Current CLSI
CLSI Colistin Breakpoints
Breakpoints*
*

Organism Group
Organism Group S SDD
SDD II R
R
P. aeruginosa
P. aeruginosa  2 g/mL
 2 g/mL –– –– 
44 g/mL
g/mL
Acinetobacter spp.
Acinetobacter spp. 
22 g/mL
g/mL –– –– 
44 g/mL
g/mL
*
** Last
Last reviewed
reviewed June 2016; first
June 2016; first published
published in
in CLSI
CLSI document
document M100,
M100, 27th
27th ed.
ed.
Abbreviations:
Abbreviations: I,
I, intermediate;
intermediate; R,R, resistant;
resistant; S,
S, susceptible;
susceptible; SDD,
SDD, susceptible-dose
susceptible-dose dependent.
dependent.

Table
Table 2.
2. Historical
Historical CLSI
CLSI Colistin Breakpoints
Breakpoints Replaced
Replaced by
by Current
Current Colistin
*
Colistin Breakpoints*
Organism Group S SDD I R
R
P. aeruginosa
P. aeruginosa 
 2
2 g/mL
g/mL –
– 4
4 
 8
8 g/mL
g/mL
*
** Last
Last published
published in
in CLSI
CLSI document
document M100,
M100, 26th
26th ed.
ed.
Abbreviations:
Abbreviations: I,I, intermediate;
intermediate; R,
R, resistant;
resistant; S,
S, susceptible;
susceptible; SDD,
SDD, susceptible-dose
susceptible-dose dependent.
dependent.

3 Standard
3 Standard
Standard Dosages
andand
Dosages
Dosages and Pharmacokinetic
DataData
Pharmacokinetic
Pharmacokinetic Data
Table
Table 3.
3. Current
Current FDA
FDA Dosing
Dosing Recommendations
Recommendations According
According to
to Creatinine
Creatinine Clearance
6
Clearance6
Renal
Renal Function
Function Group,
Group, mL/minute
mL/minute Daily Dose,** mg/kg
mg/kg
≥
≥ 80
80 2.5–5
2.5–5
50
50 –– <
< 80
80 2.5–3.8
2.5–3.8
30 – < 50
30 – < 50 2.5
2.5
10 – < 30
30 1
1
**
Colistin
Colistin base
* base activity.
activity.
Abbreviation: FDA,
Abbreviation: FDA, US
US Food
Food and
and Drug
Drug Administration.
Administration.

PK
PK data
PKdata from
fromaaamultinational,
datafrom multinational,
multinational, multicenter
multicenter
multicenter study
study
study focusing
focusing
focusing on
on the
on the the PK-PD
PK-PD
PK-PD properties
properties
properties of
of colistin
colistin
of colistin (administered
(administered
(administered intravenously as
intravenously
intravenously
colistin as colistin methanesulfonate
as colistin[CMS])
methanesulfonate methanesulfonate [CMS])
[CMS])with
in critically ill patients in critically
in critically ill patients
ill patients
multiresistant with multiresistant
infections weregram-
with multiresistant
gram-negative gram-
analyzed.7 PK data
77
negative
negative
for infections
infections
162 patients were analyzed.
were analyzed.
not receiving PK data
PK data for
renal replacement for 162 patients
162 patients
therapy, not receiving
not receiving
with a broad renal
range of renal replacement
replacement
creatinine therapy,
therapy,
clearances with
with
(minimum = 5.6 mL/minute,
aa broad
broad range
range of
of creatinine
creatinine clearances
clearances (minimum
(minimum =
= 5.6
5.6 mL/minute,
mL/minute, maximum
maximum =
= 211.2
211.2 mL/minute)
mL/minute) were
were
maximum = 211.2 mL/minute) were reviewed. The apparent clearance of formed colistin also ranged widely (minimum = 1.85 L/h,
reviewed.
reviewed. The
The apparent
apparent clearance
clearance of
of formed
formed colistin
colistin also
also ranged
ranged widely
widely (minimum
(minimum == 1.85
1.85 L/h,
L/h, maximum
maximum = =
41.3 L/h). With the physician-selected daily doses of CMS, the steady-state average concentrations
L/h). With the physician-selected daily doses of CMS, the steady-state average concentrations
(Css,avg)
(Css,avg) of
of formed
formed colistin
colistin ranged
ranged from
from 0.24
0.24 to
to 9.81
9.81 mg/L
mg/L (median
(median =
= 2.2
2.2 mg/L).
mg/L).

Protein
Protein binding
binding waswas determined
determined by by twotwo independent
independent methods:
methods: ultracentrifugation
ultracentrifugation and
and rapid
rapid equilibrium
equilibrium
dialysis
dialysis in in polytetrafluoroethylene
polytetrafluoroethylene cells. cells. Protein
Protein binding
binding of
of colistin
colistin was
was concentration
concentration independent
independent over
over the
the
observable
observable ranges
ranges of
of concentration
concentration found
found in
in mice
mice and
and humans
humans (see
(see Figure
Figure 1).
1). The
The average
average unbound
unbound fraction
fraction
© Clinical and Laboratory Standards Institute. All rights reserved. 2
of
of colistin
colistin forfor the
the healthy
healthy human
human (QC)(QC) plasma
plasma samples
samples was
was 0.49
0.49 ±± 0.03.
0.03. For
For plasma
plasma of
of neutropenic
neutropenic infected
infected
mice, the average (±
mice, the average (± standard deviation [SD]) percentage bound for all colistin concentrations presented
standard deviation [SD]) percentage bound for all colistin concentrations presented in
in
Figure
Figure 11 was was 92.9%
92.9% ± ± 3.3%
3.3% when
when binding
binding was was measured
measured by
by ultracentrifugation,
ultracentrifugation, and
and 90.4%
90.4% ±± 1.1%
1.1% byby
 Colistin Breakpoints for Pseudomonas aeruginosa and Acinetobacter spp.

maximum = 41.3 L/h). With the physician-selected daily doses of CMS, the steady-state average concentrations (Css,avg) of
formed colistin ranged from 0.24 to 9.81 mg/L (median = 2.2 mg/L).
Protein binding was determined by two independent methods: ultracentrifugation and rapid equilibrium dialysis in
polytetrafluoroethylene cells. Protein binding of colistin was concentration independent over the observable ranges of
concentration found in mice and humans (see Figure 1). The average unbound fraction of colistin for the healthy human (QC)
plasma samples was 0.49 ± 0.03. For plasma of neutropenic infected mice, the average (± standard deviation [SD]) percentage
bound for all colistin concentrations presented in Figure 1 was 92.9% ± 3.3% when binding was measured by ultracentrifugation,
and 90.4% ± 1.1%
equilibrium by equilibrium
dialysis. dialysis.
The average Thetwo
of the average of thewas
methods two91.6%.
methods wasthe
Thus, 91.6%. Thus, unbound
average the average unbound
fraction for fraction for
colistin
colistinininplasma
plasmaofof
neutropenic infected
neutropenic mice
infected waswas
mice 0.084.
0.084.

100

90

80

70
Colistin Bound in Plasma, %

60

50

40

30

20
Infected neutropenic mice UC
10 Human UC
Infected neutropenic mice ED
0
0.00 10.00 20.00 30.00 40.00 50.00 60.00
Plasma Colistin Concentration, mg/L
Abbreviations: ED, equilibrium dialysis; UC, ultracentrifugation.
Figure 1. Protein Binding of Colistin in Infected Neutropenic Mice (by UC and ED) and in
Normal Human Plasma (by UC)

Protein
Proteinbinding
bindingwas also
was determined
also in plasma
determined from from
in plasma 66 critically ill patients
66 critically ill who werewho
patients receiving
were CMS intravenously
receiving CMS for the
intravenously
treatment for thecaused
of infection treatment
by anofMDR
infection caused by
gram-negative an MDR
organism. gram-negative
Binding organism.
was determined by UC,Binding wasof healthy
and samples
determined by UC, and samples of healthy human plasma were included in each of the 11 UC runs in which
human plasma were included in each of the 11 UC runs in which the binding in the patient samples was measured. Table 4
8
the binding
provides in the patient
a summary samples
of the results.8 was measured. Table 4 provides a summary of the results.

© Clinical and Laboratory Standards Institute. All rights reserved. 3

 Colistin Breakpoints for Pseudomonas aeruginosa and Acinetobacter spp.

Table 4. Unbound Fraction of Colistin in Plasma of Critically Ill Patients and Healthy Humans
(Reprinted from Int J Antimicrob Agents, Vol 35 / No 2, Falagas ME, Rafailidis PI, Ioannidou E, et al., Colistin therapy
for microbiologically documented multi-drug resistant gram-negative bacterial infections: a retrospective cohort
study of 258 patients, pp. 194-199, © 2010, with permission from Elsevier.)
Unbound Fraction
Critically Ill Patients Healthy Humans
Number of patients* 66 11
Average 0.49 0.48
SD 0.11 0.06
10th percentile 0.36 0.41
25th percentile 0.42 0.42
50th percentile (median) 0.48 0.47
75th percentile 0.56 0.51
90th percentile 0.63 0.59
* Number of individual critically ill patients or number of ultracentrifugation runs in which those samples were

analyzed along with samples of plasma from healthy humans.

Abbreviation: SD, standard deviation.

44 Minimal Inhibitory
Minimal Concentration
Inhibitory Distribution
Concentration Data Data
Distribution
Minimal inhibitory concentration (MIC) distribution data from the European Committee on Antimicrobial Susceptibility Testing
Minimal databases
(EUCAST) inhibitory were
concentration (MIC)
reviewed and are distribution
presented in data from
Figures the3.European
2 and 9 Committee on Antimicrobial
Susceptibility Testing (EUCAST) databases were reviewed and are presented in Figures 2 and 3.9

60

50

40
Microorganisms, %

30

20

10

0
0.5

16

32

64
1

8
 0.002

0.004

0.008

0.015

0.03

0.06

0.12

0.25

128

256

 512

MIC, mg/L
Abbreviation: MIC, minimal inhibitory concentration.
Figure 2. International MIC Distributions for P. aeruginosa and Colistin.*,9 4208 observations
from eight data sources were used to determine the epidemiological cutoff value of 4 mg/L.
The wild-type organism epidemiological cutoff values are ≤ 4 mg/L.
*MIC distributions include collated data from multiple sources, geographical areas, and time periods and can never
be used to infer rates of resistance.

© Clinical and Laboratory Standards Institute. All rights reserved. 4

 Colistin Breakpoints for Pseudomonas aeruginosa and Acinetobacter spp.

60

50

40
Microorganisms, %

30

20

10

0
0.5

16

32

64
1

8
 0.002

0.004

0.008

0.015

0.03

0.06

0.12

0.25

128

256

 512
MIC, mg/L
Abbreviation: MIC, minimal inhibitory concentration.
Figure 3. International MIC Distributions for A. baumannii and Colistin.*,9 251 observations
from eight data sources were used to determine the epidemiological cutoff value of 2 mg/L.
The wild-type organism epidemiological cutoff values are 2 mg/L.
* MIC distributions include collated data from multiple sources, geographical areas, and time periods and can never

be used to infer rates of resistance.

55 Pharmacodynamic
Pharmacodynamic Data
Data
Pharmacodynamic
Pharmacodynamicdata
datafor
forcolistin and
colistin various
and microorganisms
various are shown
microorganisms in Table
are shown 5.
in Table 5.

© Clinical and Laboratory Standards Institute. All rights reserved. 5

 Table 5. Target Values of Colistin fAUC/MIC for Colistin
Stasis Breakpoints
and 1- and 2-log10 Kill
for Pseudomonas P.Acinetobacter spp.
Againstand
aeruginosa
aeruginosa and A. baumannii in Mouse Thigh and Lung Models of Infection (Modified from
10

Cheah SE, Wang J, Nguyen VT, Turnidge JD, Li J, Nation RL, New pharmacokinetic/pharmacodynamic studies of
Table 5. Target
systemically Values
administered of against
colistin Colistin fAUC/MICaeruginosa
Pseudomonas for Stasis and 1- andbaumannii
and Acinetobacter 2-log10 Kill Against
in mouse P.
thigh and
aeruginosa and A.smaller
lung infection models: baumannii
responseinin Mouse ThighJ and
lung infection, LungChemother.,
Antimicrob Models of2015,
Infection
Vol 70 10
/ No 12, pp. 3291-
(Modified from
3297, by
Cheah SE,permission of Oxford
Wang J, Nguyen VT,University
Turnidge Press.)
JD, Li J, Nation RL, New pharmacokinetic/pharmacodynamic studies of
Target
systemically administered colistin against Pseudomonas aeruginosa andValue of Colistin
Acinetobacter fAUC/MIC
baumannii in mouse thigh and
lung infection
Model models: smaller response
Species/Strainin lung infection, J Antimicrob
Stasis Chemother., 2015,
1-log10 Kill Vol 70 /2-log
No 12, pp. 3291-
10 Kill
3297, by permission of Oxford University Press.)
Thigh infection P. aeruginosa
Target Value of Colistin fAUC/MIC
ATCC® 27853 9.94 12.4 15.8
Model Species/Strain Stasis 1-log10 Kill 2-log10 Kill
PAO1 6.01 6.53 7.34
Thigh infection P. aeruginosa
19056 6.41 8.56 11.3
ATCC® 27853 9.94 12.4 15.8
Mean 7.5 9.2 11.5
PAO1 6.01 6.53 7.34
A. baumannii
19056® 6.41 8.56 11.3
ATCC 19606 1.47 3.45 9.13
Mean 7.5 9.2 11.5
248-01-C.248 3.91 6.11 7.44
A. baumannii
N-16870.213 9.47 13.9 17.6
ATCC® 19606 1.47 3.45 9.13
Mean 5.0 78 11.4
248-01-C.248 3.91 6.11 7.44
Lung infection P. aeruginosa
N-16870.213 9.47 13.9 17.6
ATCC® 27853 34.1 43.3 51.8
Mean 5.0 78 11.4
PAO1 15.2 44.8 –*
Lung infection P. aeruginosa
19056 38.6 57.9 105
ATCC® 27853 34.1 43.3 51.8
Mean 29.3 48.7 78.4
PAO1 15.2 44.8 –*
A. baumannii
19056® 38.6 57.9 105
ATCC 19606 –† –† –†
Mean 29.3 48.7 78.4
248-01-C.248 11.6 20.8 36.8
A. baumannii
N-16870.213 – † – † –††
ATCC
* Unable to determine, because
® 19606 –† – † –
highest bacterial kill was ≈ 1 log10, even at fAUC/MIC values resulting from highest
tolerated dosage regimens of248-01-C.248
colistin. 11.6 20.8 36.8
N-16870.213 –† at fAUC/MIC values
† Unable to determine, because stasis was not achieved, even
–† resulting from highest
–† tolerated
*dosage
Unableregimens of colistin.
to determine, because highest bacterial kill was ≈ 1 log10, even at fAUC/MIC values resulting from highest
Abbreviation:
tolerated dosage regimensratio
fAUC/MIC, of the area under the unbound concentration–time curve to the minimal inhibitory
of colistin.
†concentration.
Unable to determine, because stasis was not achieved, even at fAUC/MIC values resulting from highest tolerated
dosage regimens of colistin.
Abbreviation:
Because of the ratio of the
wide variations
fAUC/MIC, in area under the
creatinine andunbound
colistin concentration–time
clearance among curve to the
patients minimal
in the inhibitory
multinational,
concentration. 7 variations in creatinine and colistin clearance among patients in the multinational, multicenter study7
multicenter study (see Section 3), target attainment estimation using a population PK model and Monte
Because of the wide
Carlo
(see simulation
Section wasattainment
3), target not used estimation
in this breakpoint assessment.
using a population PKRather,
model andtheMonte
patientCarlo
population studied
simulation wasused in this
was not
Because of the
divided into six wide
renal variations
function in creatinine
groups (see and6).
Table colistin clearance among patients in the multinational,
breakpoint assessment.
7 Rather, the patient population studied was divided into six renal function groups (see Table 6).
multicenter study (see Section 3), target attainment estimation using a population PK model and Monte
Carlo
Tablesimulation
6. Renal was not used
Function in this breakpoint assessment. Rather, the patient population studied was
Groups
divided into six renal function groups (see Table 6).
Creatinine Clearance (Uncorrected) Range,
Group Number of Patients mL/minute
Table 6. Renal Function Groups
1 27 5.4–26.9
Creatinine Clearance (Uncorrected) Range,
2 27 27.0–40.7
Group Number of Patients mL/minute
3 27 41.6–57.0
1 27 5.4–26.9
4 27 57.8–76.0
2 27 27.0–40.7
5 27 77.2–117.3
3 27 41.6–57.0
6 27 121.1–211.2
4 27 57.8–76.0
5 27 77.2–117.3
TheCss,avg
The Css,avgofof formed
formed colistin
colistin was
was27 calculated
calculated for each
for each patient
patient basedbased on individual
on individual pharmacokinetics,
pharmacokinetics, with
with each patient receiving
6 121.1–211.2
daily maintenance doses of colistin base activity (see Table 3), as opposed to the physician-selected doses usedthe
each patient receiving daily maintenance doses of colistin base activity (see Table 3), as opposed to in the study.
A body
The weightofofformed
Css,avg 70 kg was assumed,
colistin and calculations
was calculated for the
for each two based
patient patients
onwith a creatinine
individual clearance < 10 mL/minute
pharmacokinetics, with were
each patient receiving daily maintenance doses of colistin base activity (see Table 3), as opposed to the

© Clinical and Laboratory Standards Institute. All rights reserved. 6

physician-selected doses used in the study. A body weight of 70 kg was assumed, and calculations for the
two patients with a creatinine clearance < 10 mL/minute were conducted using a daily dose of colistin base
activity of 1 mg/kg. Target attainment rates in each of the six renal function categories were then determined
with the following parameters: Colistin Breakpoints for Pseudomonas aeruginosa and Acinetobacter spp.

 Plasmausing
conducted protein binding
a daily in colistin
dose of critically ill activity
base patientsofand healthyTarget
1 mg/kg. humans of ≈ 50%
attainment (ie, in
rates unbound fraction
each of the of ≈function
six renal
0.5; see
categories Table
were then4)determined with the following parameters:

 • A Plasma
target protein
fAUC24binding
/MIC of in critically ill patients and healthy humans of ≈ 50% (ie, unbound fraction of ≈ 0.5; see Table 4)
12 (the approximate mean 2-log10 kill target for P. aeruginosa and
• A target fAUC24/MIC of 12 (theinfection
A. baumannii in mouse thigh approximate and mean
the approximate highest
2-log10 kill target for P.1-log 10 kill and
aeruginosa target for the three
A. baumannii in mouse thigh
strains of each
infection andspecies in the same
the approximate infection
highest 1-logmodel
10
kill (see
target Table
for the 5) corresponds
three strains of to a
eachfCss,avg/MIC
species in the of 0.5.
same infection model
This corresponds to a Css,avg/MIC of 1 in human patients (plasma protein binding ≈ 50% as shown
(see Table 5) corresponds to a fCss,avg/MIC of 0.5. This corresponds to a Css,avg/MIC of 1 in human patients (plasma in
Figure 4 and
protein Table≈ 50%
binding 7). as shown in Figure 4 and Table 7).

Thus,
Thus,with
withthese
theseparameters,
parameters, thethe
target attainment
target rate
attainment at each
rate MICMIC
at each is equivalent to theto
is equivalent target attainment
the target rate for Css,avg (ie, for
attainment
rate for
total Css,avg
colistin (ie, for total colistin in plasma).
in plasma).

100

90
Patients Who Achieve Css,avg, %

80

70

60
Css,avg
50 > 4 mg/L
40 > 2 mg/L
> 1 mg/L
30
> 0.5 mg/L
20

10

0
1 2 3 4 5 6
Renal Function Group

*
Daily dose is adjusted according to the 2013 FDA-approved product label.
Abbreviation: FDA, US Food and Drug Administration.
Figure 4. Probability of Colistin Target Attainment*,11

Table 7. Percentage Target Attainment for Colistin*,11

Css,avg
Renal Creatinine (Summary Stats) Percentage Attainment
Function Clearance Css,avg Css,avg Css,avg Css,avg
Group Range Average SD >4 >2 >1 > 0.5
1 5.4–26.9 1.53 0.56 0.0% 22.2% 88.9% 100.0%
2 27.040.7 2.69 1.30 14.8% 70.4% 88.9% 96.3%
3 41.657.0 2.97 1.52 18.5% 66.7% 100.0% 100.0%
4 57.876.0 2.80 0.94 3.7% 77.8% 96.3% 100.0%
5 77.2117.3 2.25 1.35 11.1% 48.1% 92.6% 100.0%
6 121.1211.2 1.50 0.93 0.0% 22.2% 59.3% 100.0%
* Daily dose is adjusted according to the 2013 FDA-approved product label.

Abbreviation: SD, standard deviation.

6 Clinical Efficacy
No clinical efficacy data are available.

7 Committee Rationale for the Breakpoint

© Clinical and Laboratory Standards Institute. All rights reserved. 7
At the time of breakpoint selection, it was noted that PD target attainment rates using maximum
recommended doses were not optimal in patients with normal or supranormal renal function. As such,
* Daily dose is adjusted according to the 2013 FDA-approved product label.

Abbreviation: SD, standard deviation.

6 Clinical Efficacy Colistin Breakpoints for Pseudomonas aeruginosa and Acinetobacter spp.

6NoClinical
clinical efficacy data are available.
Efficacy
7 clinical
No Committee Rationale
efficacy data for
are available. the Breakpoint
7AtCommittee
the time ofRationale
breakpoint for the Breakpoint
selection, it was noted that PD target attainment rates using maximum
recommended
At doses were
the time of breakpoint not optimal
selection, in patients
it was noted with
that PD normal
target or supranormal
attainment rates using renal function.
maximum As such, doses were
recommended
breakpoints need to be accompanied with language warning of this issue and providing advice about
not optimal in patients with normal or supranormal renal function. As such, breakpoints need to be accompanied with language
management: “Colistin (methanesulfonate) should generally be administered with a loading dose and at the
warning of this issue and providing advice about management: “Colistin (methanesulfonate) should generally be administered
maximum recommended doses, in combination with other agents.”
with a loading dose and at the maximum recommended doses, in combination with other agents.”
8 Final Table Entry
8  Final Table Entry
2
Tables88and
Tables and9 9include
include
thethe final
final table
table entries
entries from
from CLSICLSI document
document M100.M100.
2

Table 8. Excerpt From CLSI document M1002 Table 2B-1, Zone Diameter and MIC
Breakpoints for Pseudomonas aeruginosa
Interpretive Categories and
Test/Report Antimicrobial MIC Breakpoints, g/mL
Group Agent S I R Comments
O Colistin 2 – 4 (16) Colistin (methanesulfonate)
should generally be administered
with a loading dose and at the
maximum recommended doses, in
combination with other agents.

(17) The only approved MIC

method for testing is broth
microdilution. Disk diffusion and
gradient diffusion methods should
not be performed.
Abbreviations: I, intermediate; MIC, minimal inhibitory concentration; R, resistant; S, susceptible.

Table 9. Excerpt From CLSI document M1002 Table 2B-2, Zone Diameter and MIC
Breakpoints for Acinetobacter spp.
Interpretive Categories and
Test/Report Antimicrobial MIC Breakpoints, g/mL
Group Agent S I R Comments
O Colistin 2 – 4 (5) Colistin (methanesulfonate)
should generally be given with a
loading dose and at maximum
recommended doses and used in
combination with other agents.

(6) Applies to A. baumannii

complex only.

(7) The only approved MIC method

for testing is broth microdilution.
Disk diffusion and gradient
diffusion methods should not be
performed.
Abbreviations: I, intermediate; MIC, minimal inhibitory concentration; R, resistant; S, susceptible.
 
99 Voting Record
Voting Record
Approved in January 2016 (8 approved, 2 opposed, 0 abstained, 1 absent).
Approved in January 2016 (8 approved, 2 opposed, 0 abstained, 1 absent).
© Clinical and Laboratory Standards Institute. All rights reserved. 8
 Colistin Breakpoints for Pseudomonas aeruginosa and Acinetobacter spp.

10 References
1 CLSI. Development of In Vitro Susceptibility Testing Criteria and Quality Control Parameters. 5th ed. CLSI guideline M23.
Wayne, PA: Clinical and Laboratory Standards Institute; 2018.

2 CLSI. Performance Standards for Antimicrobial Susceptibility Testing. 28th ed. CLSI supplement M100. Wayne, PA: Clinical and
Laboratory Standards Institute; 2018.

3 CLSI. Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria. 3rd ed.
CLSI guideline M45. Wayne, PA: Clinical and Laboratory Standards Institute; 2016.

4 Kassamali Z, Rotschafer JC, Jones RN, Prince RA, Danziger LH. Polymyxins: wisdom does not always come with age. Clin
Infect Dis. 2013;57(6):877-883.

5 Poirel L, Jayol A, Nordmann P. Polymyxins: antibacterial activity, susceptibility testing, and resistance mechanisms encoded
by plasmids or chromosomes. Clin Microbiol Rev. 2017;30(2):557-596.

6 Monarch Pharmaceuticals. Coly-Mycin M parenteral (colistimethate for injection, USP).

https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050108s026lbl.pdf. Accessed July 12, 2018.

7 NIH. Optimizing dosing of colistin for infections resistant to all other antibiotics, approved NIH protocol dated 12.06.07
(DMID protocol #07-0036). https://clinicaltrials.gov/ct2/show/NCT00235690. Accessed July 12, 2018.

8 Falagas ME, Rafailidis PI, Ioannidou E, et al. Colistin therapy for microbiologically documented multi-drug resistant
gram-negative bacterial infections: a retrospective cohort study of 258 patients. Int J Antimicrob Agents.
2010;35(2):194-199.

9 European Committee on Antimicrobial Susceptibility Testing. Data from the EUCAST MIC distribution website.
https://mic.eucast.org/Eucast2/. Accessed July 12, 2018.

10 Cheah SE, Wang J, Nguyen VT, Turnidge JD, Li J, Nation RL. New pharmacokinetic/pharmacodynamic studies of systemically
administered colistin against Pseudomonas aeruginosa and Acinetobacter baumannii in mouse thigh and lung infection
models: smaller response in lung infection. J Antimicrob Chemother. 2015;70(12):3291-3297.

11 JHP Pharmaceuticals. Coly-Mycin M parenteral (colistimethate for injection, USP).

https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050108s030lbl.pdf. Accessed July 12, 2018.

© Clinical and Laboratory Standards Institute. All rights reserved. 9

 Colistin Breakpoints for Pseudomonas aeruginosa and Acinetobacter spp.

The findings, recommendations, and conclusions in this rationale document are those of the authors and
have not been reviewed through the CLSI consensus process. They do not necessarily reflect the views of
any single individual or organization.

Copyright ©2018 Clinical and Laboratory Standards Institute. Except as stated below, any reproduction
of content from a CLSI copyrighted standard, guideline, derivative product, or other material requires
express written consent from CLSI. All rights reserved. Interested parties may send permission requests to
permissions@clsi.org.
CLSI hereby grants permission to each individual user to make a single reproduction of this publication for use
in its laboratory procedures manual at a single site. To request permission to use this publication in any other
manner, e-mail permissions@clsi.org.

Suggested Citation
CLSI. Colistin Breakpoints for Pseudomonas aeruginosa and Acinetobacter spp. 1st ed. CLSI rationale document
MR01. Wayne, PA: Clinical and Laboratory Standards Institute; 2018.

ISBN 978-1-68440-018-8
ISSN 2162-2914

For additional information on activities of the CLSI Subcommittee on Antimicrobial Susceptibility Testing or to
submit comments, contact CLSI.

Clinical and Laboratory Standards Institute

950 West Valley Road, Suite 2500
Wayne, PA 19087 USA
P: +1.610.688.0100
F: +1.610.688.0700
www.clsi.org
standard@clsi.org

© Clinical and Laboratory Standards Institute. All rights reserved. 10