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Journal of Clinical Microbiology, January 2001, p. 183-190, Vol. 39, No. 1
0095-1137/01/$04.00+0 DOI: 10.1128/JCM.39.1.183-190.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Contemporary Assessment of Antimicrobial
Susceptibility Testing Methods for Polymyxin B and Colistin: Review of
Available Interpretative Criteria and Quality Control
Guidelines
Ana C.
Gales,1,2
Adriana O.
Reis,2 and
Ronald N.
Jones1,*
Department of Pathology, University of Iowa
College of Medicine, Iowa City, Iowa 52242,1 and
Disciplina de Doenças Infecciosas e Parasitàrias,
Universidade Federal de São Paulo, São Paulo,
Brazil2
Received 29 June 2000/Returned for modification 4 September
2000/Accepted 16 October 2000
 |
ABSTRACT |
The emergence of infections caused by multidrug-resistant
Pseudomonas aeruginosa and Acinetobacter spp.
has necessitated the search for alternative parenteral agents such as
the polymyxins. The National Committee for Clinical Laboratory
Standards (NCCLS) documents do not currently provide interpretative
criteria for the testing of the polymyxins, colistin and polymyxin B. Therefore, an evaluation of the antimicrobial activity of colistin and
polymyxin B was initiated using 200 bloodstream infection pathogens
collected through the SENTRY Antimicrobial Surveillance Program. All
susceptibility tests were performed according to the NCCLS
recommendations. Polymyxin B and colistin displayed a nearly identical
spectrum of activity, exhibiting excellent potency against P. aeruginosa (MIC90, 2 µg/ml) and
Acinetobacter sp. (MIC90, 2 µg/ml). In
contrast, they showed limited activity against some other
nonfermentative bacilli such as Burkholderia cepacia
(MIC90, 
128 µg/ml). Excellent correlation was achieved
between broth microdilution and agar dilution tests (r = 0.96 to 0.98); 94.3% of the results were ±1 log2
dilution between the methods used for both compounds. At a resistance
breakpoint of 4 µg/ml for both agents, unacceptable
false-susceptible or very major errors were noted for colistin (5%)
and polymyxin B (6%). Modified zone criteria for colistin (
11 and
14 mm) and polymyxin B (10 and 14 mm) were suggested, but some
degree of error persisted (3.5%). It is recommended that all
susceptible disk diffusion results be confirmed by MIC tests using the
preferred reference NCCLS method. The quality control (QC) ranges
listed in the product package insert require an adjusted range by
approximately 3 mm for both NCCLS gram-negative quality control
strains. This evaluation of in vitro susceptibility test methods for
the polymyxin class drugs confirmed continued serious testing error
with the disk diffusion method, the possible need for breakpoint
adjustments, and the recalculation of disk diffusion QC ranges.
Clinical laboratories should exclusively use MIC methods to assist the
therapeutic application of colistin or polymyxin B until disk diffusion
test modifications are sanctioned and published by the NCCLS.
| |
INTRODUCTION |
Polymyxins are a group of
polycationic peptides naturally synthesized by Bacillus
polymyxa, a nonactinomycete bacterium (7). Members of
this class (colistin and polymyxin B) act primarily on the
gram-negative bacterial cell wall, leading to rapid permeability changes in the cytoplasmic membrane and ultimately to cell death. These
drugs cross the bacterial outer membrane (self-promoted pathway) by
competitive divalent cation displacement by the bulky polycations,
which noncovalently cross the bridge adjacent to the polysaccharide
component. Consequently, the bacterial outer membrane becomes distorted
and more permeable, permitting increased uptake of the permeabilizing
compounds (10, 19). Of the five recognized polymyxins (A
to E), only polymyxins B and E (colistin) have advanced to therapeutic use.
Polymyxin B and colistin have been demonstrated to be active against
Pseudomonas aeruginosa. Four decades ago, polymyxins were
among the few treatments available for serious P. aeruginosa infections. Since 1980 other, less-toxic antimicrobial agents have
become available, and the clinical use of polymyxins has been limited
to topical formulations for the treatment of skin, ear, and
ocular diseases. Polymyxin B topical formulations also have
been used prophylatically for the prevention of infection in
neutropenic or cystic fibrosis patients (6, 11). Recently, the emergence of multidrug-resistant P. aeruginosa and
Acinetobacter spp. isolates causing life-threatening
infections has restored the potential therapeutic indication for the
parenteral use of polymyxins (1, 12, 20), usually colistin
in North American medical centers. Consequently, clinical microbiology
laboratories should be able to perform reliable susceptibility testing
for drugs in this class.
The National Committee on Clinical Laboratory Standards (NCCLS) does
not provide guidance for the testing of polymyxins. In fact, the
resistance breakpoint criteria for polymyxins were last available
in the 1981 NCCLS Approved Standard M2-A2 S2 (15); however, with the very restricted use of polymyxins, the published information was later withdrawn.
In this study, the antimicrobial activities of the polymyxins were
evaluated against selected contemporary bacterial pathogens. The
correlation of the broth microdilution, disk diffusion, and agar
dilution methods was performed to determine the susceptibility criteria
for polymyxins. Disk diffusion quality controls for Escherichia coli ATCC 25922 and P. aeruginosa ATCC 27853 were also
carried out to validate method control and the interpretation criteria only found in the disk product package insert.
| |
MATERIALS AND METHODS |
Bacterial strains.
Bloodstream isolates collected from
distinct geographic areas during 1998 through the SENTRY Antimicrobial
Surveillance Program were evaluated in this study. Only one isolate per
patient was included. The distribution of species was as follows:
Acinetobacter spp. (60), Burkholderia cepacia
(12), Enterobacter spp. (5), Klebsiella pneumoniae (9), Morganella morganii (2), Proteus
mirabilis (2), Providencia rettgeri (2),
Pseudomonas aeruginosa (80), Serratia marcescens (5), and Stenotrophomonas maltophilia
(23). The bacterial identifications were confirmed by routine
laboratory methods in laboratories at the University of Iowa College of
Medicine (Iowa City, Iowa). The isolates were selected at random, but
nearly 20% of the P. aeruginosa and
Acinetobacter spp. isolates were chosen to be resistant to
carbapenems (imipenem, meropenem), and all K. pneumoniae
were extended-spectrum 
-lactamases (ESBL)-producing strains.
Antimicrobial agents.
Polymyxin B and colistin sulfate
powders were obtained from Sigma Chemical (St. Louis, Mo.). Other
tested drugs were obtained commercially or provided by their respective manufacturers.
Susceptibility testing.
Antimicrobial susceptibility testing
was performed as recommended by the NCCLS (16, 17). All
bacterial isolates were tested by broth microdilution and disk
diffusion tests, while only 35 isolates representing all the species
were tested by agar dilution to provide a comparison to its broth
microdilution test results. These organisms were selected to provide a
wide range of polymyxin MICs (Fig. 1).
The susceptibility test medium was Mueller-Hinton agar or broth
according to the test performed. Microdilution broth trays were
prepared by PML Microbiologics (Wilsonville, Oreg.) and stored at
70°C until used. E. coli ATCC 25922 and P. aeruginosa ATCC 27853 were used as quality control (QC) strains.
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FIG. 1.
Scattergram results for colistin comparing broth
microdilution MICs with the reference agar dilution method against 35 recent clinical isolates selected to possess a wide range of MIC
values. The diagonal line represents complete agreement, and the
numbers represent the occurrences observed at each point. The broken
lines represent ±1-log2 MIC agreement limits between test
results. Horizontal and vertical broken lines indicate the resistant
MIC breakpoints (4 µg/ml).
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QC study.
Determination of the disk diffusion QC results for
E. coli ATCC 25922 and P. aeruginosa ATCC 27853 was done by testing two or three 300-U polymyxin B disks from two
different lots (BD Microbiology Systems, Cockeysville, Md.; Difco
Laboratories, Detroit, Mich.). Three 10-µg colistin disks were tested
from a single lot (BD Microbiology Systems). The tests were replicated
10 times and read by four different observers. This study produced at
least 20 replicate zone diameters for each disk and 200 and 120 zones
overall for polymyxin B and colistin, respectively.
Statistical methods.
The MIC results of the broth
microdilution and agar dilution methods were compared by regression
analysis. Essential agreement was defined to be when the broth
microdilution results agreed within ±1-log2 dilution of
the reference agar dilution test. A result was determined to be
discrepant if there was a 2-log2 dilution difference
between test results. Broth microdilution results were also compared to
the zones of inhibition produced by the polymyxin disk diffusion tests
also using the method of least squares as applied to computers.
Categorical agreement was defined if the test results were
within the same susceptibility category, and errors were determined
by
methods published in NCCLS M23-A2 (
18) and ranked as
follows:
very major error, false-susceptible result by the disk
diffusion
test; major error, false-resistant result produced by the
disk
diffusion test; and minor error, intermediate result by the disk
diffusion method and a resistant or susceptible category for the
dilution test (only two categories have been
suggested).
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RESULTS |
Polymyxin antimicrobial activity.
Tables
1 and
2 (colistin only) summarize the
activities of the polymyxins against 200 contemporary gram-negative
clinical isolates. Polymyxin B and colistin displayed nearly identical spectrums of activity, exhibiting usable potency against P. aeruginosa (MIC90, 2 µg/ml) and
Acinetobacter sp. (MIC90, 2 µg/ml). In
contrast, they showed no activity against some other nonfermentative
bacilli such as B. cepacia (MIC90, 128
µg/ml). Nearly three-quarters of the S. maltophilia
isolates were inhibited at 4 µg/ml of both compounds. The polymyxins
(MIC50, 1 µg/ml) were eightfold more potent than
ceftazidime (MIC50, 8 µg/ml) and cefepime
(MIC50, 8 µg/ml) and showed similar activity to that
displayed by the carbapenems against Acinetobacter sp.
strains. Only three carbapenem-resistant Acinetobacter sp.
isolates were not inhibited at polymyxin MICs of 2 µg/ml. Although
levofloxacin and doxycycline exhibited similar potency against
Acinetobacter sp., only doxycycline showed a susceptibility rate greater than 90.0%.
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TABLE 1.
Antimicrobial activity of colistin and polymyxin B
compared to other antimicrobial agents against 200 contemporary
bacterial isolates
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Against
P. aeruginosa, colistin and polymyxin B were at
least twofold more potent than ceftazidime, cefepime, and amikacin
(MICs, 2 µg/ml). In contrast, polymyxin B and colistin were not
active against
B. cepacia (MICs,
128 µg/ml). Against
this pathogen,
the most active compounds based on potency and
susceptibility
rate were: trimethoprim-sulfamethoxazole
(MIC
50, 1 µg/ml), 100.0%
susceptible) > meropenem = levofloxacin (MIC
50, 1 µg/ml, 75.0%).
Ceftazidime and meropenem were fourfold more potent than comparative
drugs in their classes, cefepime and imipenem, respectively. The
aminoglycosides showed very poor activity against these
isolates.
Among the selected
S. maltophilia isolates, 26.2% isolates
were resistant to polymyxins. Doxycycline showed the highest
susceptibility
rate (95.7%) for
S. maltophilia, followed by
levofloxacin (87.0%),
and the usual "drug of choice"
trimethoprim-sulfamethoxazole (73.9%).
Carbapenems and aminoglycosides
were not active against this
pathogen.
Polymyxin B and colistin also demonstrated excellent activity against
the ESBL-producing
K. pneumoniae isolates
(MIC
50,
1
µg/ml). Although many ESBL-producing isolates
show resistance
to fluoroquinolones, the isolates tested in this study
were very
susceptible to this class of agents. Carbapenems were also
potent,
exhibiting 100.0% susceptibility
rates.
Against AmpC-cephalosporinase producers, the activities of polymyxin B
and colistin varied from excellent (
Enterobacter aerogenes and
M. morganii MICs,
1 µg/ml) to poor (
S. marcescens and
P. rettgeri MICs,
128 µg/ml).
Carbapenems and cefepime were the
only agents with complete activity
and spectrum versus these
Enterobacteriaceae (except one
S. marcescens isolate with a cefepime MIC of
32
µg/ml).
Comparisons of broth microdilution and agar dilution methods.
Figure 1 shows the comparative analysis between the reference dilution
tests for colistin using a subset of 35 strains having a wide range of
polymyxins MICs. Polymyxin B (data not shown) and colistin broth
microdilution MICs showed excellent correlation with agar dilution test
results, exhibiting an essential agreement of 94.3%
(±1-log2 dilution) for both compounds (r = 0.96 to 0.98). Only two organisms showed agar dilution MIC values at
fourfold higher than broth microdilution MICs for each compound. A
trend toward higher MIC results with the agar method was
observed. The discrepant results between the reference MIC tests would
result in a single change in the susceptibility category (one dilution variation; Fig. 1), if the resistance breakpoint of 4 µg/ml was applied.
Comparison of disk diffusion zones to reference broth microdilution
MICs.
Figures 2 and
3 present the scattergram for 200 bacterial strains tested by broth microdilution and standardized disk
diffusion methods against colistin and polymyxin B, respectively. For
both polymyxins, two distinct large bacterial populations exhibiting MICs of 2 and 128 µg/ml were detected. When the previously
suggested interpretative resistance criteria for colistin (MICs, 4
µg/ml; zone, 8 mm) were applied to these data, 1 and 5% of minor
and very major errors (false susceptible) were detected. Modifying the
colistin disk diffusion resistant and susceptible zone diameters to
10 and 14 mm slightly improved error rates by decreasing very major
errors to 3.5% but increased the minor error rate to 1.5%. All but
one error observed occurred among Acinetobacter spp. (two)
and S. maltophilia isolates (seven).
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FIG. 2.
Scattergram comparing broth microdilution MICs and
10-µg disk zone diameters for colistin tested against 200 contemporary clinical isolates. The solid lines represent the
breakpoint values contained in reference 15, while the broken lines
show the proposed new breakpoint values for colistin.
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FIG. 3.
Scattergram comparing broth microdilution MICs and 300-U
disk zone diameters for polymyxin B tested against 200 contemporary
clinical isolates. The solid lines represent the breakpoint values
contained in reference 15, while the broken lines show the proposed new
breakpoint values for colistin (see Fig. 2).
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Based on the long-established polymyxin B susceptibility interpretative
criteria (MICs,
4 µg/ml; zones,
8 mm), 12 strains
would present
discrepant results between test methods (Fig.
3).
All errors
represented false-susceptible results (6.0%; very major
errors). Most
errors occurred with
S. maltophilia (seven) and
Acinetobacter spp. (three). Even if the zone diameters were
modified
as suggested for colistin, the percentage of false-susceptible
results would not be
diminished.
Determination of polymyxin QC.
The disk diffusion QC results
for the colistin and polymyxin B disks tested against E. coli ATCC 25922 and P. aeruginosa ATCC 27853 are shown
in Table 3. The number of occurrences at
each zone diameter determined by various readers were compared and demonstrated minimal variation between technologists. For the 120 colistin zone diameters produced (three disks, four observers, and 10 replicates), the modal zone diameters were 18 and 17 mm for E. coli ATCC 25922 and P. aeruginosa ATCC 27853, respectively. The interval derived from calculating the two standard
deviations above and below the mean (17.8 mm) contains 95% of the
results, and the modified QC ranges of zones suggested would be 16 to
20 mm and 15 to 19 mm for the E. coli ATCC 25922 and
P. aeruginosa ATCC 27853 strains, respectively.
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TABLE 3.
Colistin and polymyxin disk diffusion QC results for
E. coli ATCC 25922 and P. aeruginosa ATCC 27853 (120 to 200 observations)
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The 300-U polymyxin B disk zone diameters ranged from 17 to 20 mm
for the
E. coli ATCC 25922, with a mean and mode at 19 mm.
Although the polymyxin B zones varied from 17 to 22 mm for
P. aeruginosa ATCC 27853, the mean and mode was the same as that
observed for the
E. coli strain (19 mm). Using the same
statistical
method applied to the colistin disk tests, the modified QC
ranges
suggested would be 17 to 20 mm (4 mm) for
E. coli
ATCC 25922 and
17 to 21 mm (5 mm) for
P. aeruginosa ATCC
27853. The proposed
ranges would include nearly all (
99.5%) values
obtained within
the limits. These ranges were significantly larger than
those
listed in the disk product package
insert.
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DISCUSSION |
Emerging resistance in gram-negative bacilli has produced the
necessity for the parenteral use of polymyxins associated with the need
for reliable susceptibility methods to predict the clinical response.
In the 1970s, the NCCLS published the breakpoints of susceptibility for
colistin and polymyxin B (15). However, at that time the
procedures for standardization of susceptibility testing, the
establishment of interpretative breakpoints, and the definition of QC
strains guidelines were less rigorous (18). With the
introduction of aminoglycosides and broad-spectrum -lactams into
clinical practice for the treatment of gram-negative infections, the
use of polymyxins became very uncommon and was generally restricted to
topical indications. This led to the NCCLS removal of these agents from
the list of drugs suggested for testing and reporting (16).
The activity of polymyxins against P. aeruginosa isolates
has been widely known. One of the objectives of this study; however, was to observe if the polymyxins remain effective against routine contemporary clinical isolates of P. aeruginosa and also
against multiresistant nonfermentative isolates such as
Acinetobacter spp. and S. maltophilia. Results
proved that both polymyxin B and colistin were very active against
recent P. aeruginosa and Acinetobacter spp.
isolates, and our observations agreed with other published reports
(1, 4, 13). All P. aeruginosa isolates,
including the carbapenem nonsusceptible isolates, were inhibited at 2
µg/ml concentrations of colistin and polymyxin B. Although the
polymyxins had also been very active against Acinetobacter spp., with nearly 95.0% of isolates being inhibited by MICs of 2
µg/ml, three carbapenem-resistant Acinetobacter isolates
also showed reduced susceptibility to colistin and polymyxin B (MICs of
4 for colistin and polymyxin B). These isolates were obtained from
infected patients in the United States and Brazil. The clinical significance of the reduced susceptibility to polymyxins observed among
these isolates is currently under investigation. If the reduced
susceptibility to polymyxins correlates with a poor clinical response,
the situation will be disastrous, leaving no efficacious drug for the
treatment of serious infections caused by multidrug-resistant Acinetobacter spp. strains.
Although P. aeruginosa strains resistant to polymyxins were
not detected in this study, polymyxin-resistant isolates have been
described (9, 14). Polymyxin B and colistin show
near-complete cross-resistance (6, 7), and two types of
resistance to polymyxin B have been observed in P. aeruginosa: low-level, transmissible mutations and high-level
stepwise resistance, that is unstable without the presence of polymyxin
(9, 14). Nikas and Hancock proposed that the P. aeruginosa outer membrane protein OprH blocks the self-promoted
uptake pathway. Thus, the overexpression of OprH caused by mutation or
as a result of adaptation to an Mg2+-deficient medium can
be associated with resistance to polymyxin B, aminoglycosides, and EDTA
(19, 20).
When the polymyxins were tested by dilution methods, two distinct
bacterial populations (very susceptible and resistant) could be easily
distinguished. Based on the bacterial population distribution, we
suggest that the long-used resistance breakpoint applied to colistin
and polymyxin B remain at 4 µg/ml, a level easily achievable in
serum following intravenous administration (6, 7, 11). The
agar dilution and broth microdilution methods showed excellent agreement for testing colistin and polymyxin B. Only three bacterial isolates showed discords (2-log2 dilutions) between the
dilution methods, but these differences resulted in very limited
one-dilution error.
The correlation between the MICs and disk diffusion zone diameters can
be expressed mathematically by a regression line analysis or compared
by error rate bounding. The regression line and acceptable correlation
coefficients can be misleading if applied from data that fails to
disperse evenly among the entire range of MIC values observed for the
colistin and polymyxin B data (2). Using previously published (15) or the modified (10- and 14-mm) disk
diffusion zones proposed here for the polymyxins, the percentages of
false-susceptible errors for colistin (5.0 or 3.5%) and polymyxin B
(6.0%) were clearly and reproducibly unacceptable. The majority of
false-susceptible errors occurred among S. maltophilia
isolates. These results were influenced in part by the fact that the
disk diffusion test has been determined to be an unreliable method for
S. maltophilia testing. Furthermore, false-susceptible
errors were also detected among other species such as
Acinetobacter spp. and, rarely, Enterobacter cloacae. Therefore, we suggest that results of the disk diffusion test should be confirmed with a dilution method, especially when polymyxin use is required for the treatment of serious systemic infections caused by species other than P. aeruginosa. The
disk testing problem was further complicated by erroneous QC zone
diameter ranges found in product package inserts for gram-negative
strains suggested by the NCCLS (16-18).
Due to its ability to bind strongly to the lipopolysaccharides of
gram-negative bacteria and membranes, formulations such as polymyxin
B-dextran 70 and covalent polymyxin B conjugated with human
immunoglobulin G have been used as an adjuvant therapy of septic shock
(3, 5, 8). These combination agents reduce the polymyxin
toxicity profiles. However, these "sepsis treatment" agents have
negligible antimicrobial activity, even against highly susceptible
gram-negative species such as P. aeruginosa.
Further studies evaluating contemporary pharmacokinetics and
pharmacodynamics, toxicity, and the clinical response of parenteral polymyxin regimens appear warranted. To perform such studies, the
restandardization of antimicrobial susceptibility methods for
polymyxins becomes essential (18). Meanwhile, the
parenteral use of polymyxins should be restricted to the treatment of
infections caused by P. aeruginosa or possibly
Acinetobacter spp. strains resistant to less-toxic
antimicrobial agents. It appears that the footnote warning found in
reference 15 still applies: "colistin and polymyxin B diffuse poorly
in agar, and the diffusion method is thus less accurate. Resistance is
always significant, but when treatment of infections caused by a
susceptible strain is being considered, results of a diffusion test
should be confirmed with a dilution method. MIC correlates cannot be
calculated reliably from regression analysis."
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ACKNOWLEDGMENTS |
We thank the following persons for their significant
contributions to the manuscript: K. Meyer, M. Stiwell, D. M. Johnson, and M. Barrett.
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FOOTNOTES |
*
Corresponding author. Present address: 345 Beaver Kreek
Centre, Suite A, North Liberty, IA 52317. Phone: (319) 665-3370. Fax: (319) 665-3371.
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36:2566-2568[Abstract/Free Full Text].
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Journal of Clinical Microbiology, January 2001, p. 183-190, Vol. 39, No. 1
0095-1137/01/$04.00+0 DOI: 10.1128/JCM.39.1.183-190.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
