Accepted Manuscript

Title: In vitro activity of colistin against Stenotrophomonas

maltophilia

Author: Carlos Hernan Rodrı́guez Marcela Nastro Jimena

Lopez Calvo Maria Elisa Fariña Laura Dabos Angela
Famiglietti

PII: S2213-7165(14)00059-9
DOI: http://dx.doi.org/doi:10.1016/j.jgar.2014.04.004
Reference: JGAR 89

To appear in:

Received date: 10-3-2014

Revised date: 9-4-2014
Accepted date: 22-4-2014

Please cite this article as: Rodríguez CH, Nastro M, Calvo JL, Fariña
ME, Dabos L, Famiglietti A, In vitro activity of colistin against
Stenotrophomonas maltophilia, Journal of Global Antimicrobial Resistance (2010),
http://dx.doi.org/10.1016/j.jgar.2014.04.004

This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.
In vitro activity of colistin against Stenotrophomonas maltophilia

Carlos Hernan Rodríguez a,*, Marcela Nastro a, Jimena Lopez Calvo b, Maria Elisa

Fariña b, Laura Dabos a, Angela Famiglietti a

t
ip
cr
a
Laboratorio de Bacteriología, Departamento de Bioquímica Clínica, Hospital de

Clínicas José de San Martín, Facultad de Farmacia y Bioquímica, Universidad de

us
Buenos Aires, Buenos Aires, Argentina
b
Servicio de Farmacia, Hospital de Clínicas José de San Martín, Universidad de

Buenos Aires, Buenos Aires, Argentina

an
M
Article history:

Received 10 March 2014

d

Accepted 22 April 2014

p te

Keywords:
ce

Stenotrophomonas maltophilia

Colistin resistance
Ac

Colistin usage

* Corresponding author. Present address: Hospital de Clínicas José de San Martín,

Departamento de Bioquímica Clínica, Av. Córdoba 2351, 1120 Buenos Aires,

Argentina. Tel.: +54 11 4502 8597; fax: +54 11 5950 8694.

E-mail address: carlos_hernanrodriguez@hotmail.com (C.H. Rodríguez).

Page 1 of 9
ABSTRACT

Colistin is one of the few antimicrobials that retains activity against multidrug-

resistant Gram-negative bacteria. However, the emergence of colistin resistance has

been described recently. The aims of this study were to determine the activity of

t
colistin against isolates of Stenotrophomonas maltophilia. In total, 641 S. maltophilia

ip
clinical isolates were obtained from single patients admitted to a university hospital in

cr
Buenos Aires city, Argentina, between the years 1996 and 2013. Susceptibility to

us
colistin was determined by the agar dilution method. An increase in colistin

resistance from 8% in 1996 to 45% in 2013 was observed, which correlated with a

an
marked increase in colistin consumption of 11.4-fold during the same period.
M
d
p te
ce
Ac

Page 2 of 9
1. Introduction

The emergence of multiple mechanisms of resistance has renewed interest in the

use of polymyxins against multidrug-resistant Gram-negative pathogens [1].

t
Unfortunately, colistin resistance and heteroresistance have been described mainly

ip
in Acinetobacter baumannii and Klebsiella pneumoniae. However, the lack of activity

cr
of this antimicrobial agent against some other Gram-negative bacilli is less known

[2].

us
Here we report a decrease in the activity of colistin against Stenotrophomonas

an
maltophilia in the last 17 years that occurred simultaneously with an increase in the

use of colistin in a university hospital in Buenos Aires city, Argentina.

M
d

2. Methods
te

In total, 641 S. maltophilia clinical isolates were obtained from single patients
p

admitted to Hospital de Clínicas José de San Martín (Buenos Aires, Argentina),

ce

between the years 1996 and 2013. Isolates were identified using conventional

methodology, and susceptibility to trimethoprim/sulfamethoxazole (SXT), levofloxacin

Ac

and colistin was determined by the agar dilution method [3]. Concentrations used for

colistin were 2 mg/L and 4 mg/L. As the Clinical and Laboratory Standards Institute

(CLSI) has not established interpretative criteria for colistin in S. maltophilia, the

minimum inhibitory concentration (MIC) breakpoint for Acinetobacter spp. was

applied [4]. Colistin consumption in the hospital was measured from 2003–2013 and

Page 3 of 9
was expressed in vials containing 100 mg of colistin methanesulfonate. The daily

dose of colistin/1000 patients was calculated over 8 years.

3. Results and discussion

t
ip
In the period studied, S. maltophilia represented 2.1% of nosocomial isolates and

cr
55% were recovered from lower respiratory tract samples. No considerable changes

were observed regarding the number and demographic characteristics of the

us
patients attended. Resistance rates to SXT and levofloxacin were 10% and 12%,

respectively. However, the percentage of colistin resistance showed a marked

an
increase from 8% in 1996 to 45% in 2013, reaching 60% in 2010. During this period,

colistin consumption also increased from 500 vials/year in 2003 to 5700 vials/years
M
in 2013 (11.4-fold increase) (Table 1). Moreover, 80% of the patients from whom a

colistin-resistant S. maltophilia strain was isolated had previously received colistin.

d
te

Polymyxins have not been particularly used in Hospital de Clínicas José de San
p

Martín for the treatment of infections caused by S. maltophilia owing to the good
ce

activity shown by SXT and fluoroquinolones. Furthermore, exposure of S. maltophilia

to colistin is secondary to the treatment of infections caused by other multidrug-

Ac

resistant Gram-negative pathogens. Most studies examining S. maltophilia have

reported very high colistin susceptibility rates, reaching 90% [4,5]. It is worth

mentioning that the increasing colistin resistance rates in S. maltophilia may not be

detected by many laboratories owing to the fact that neither the CLSI nor the

European Committee on Antimicrobial Susceptibility Testing (EUCAST) have

published recommendations to test susceptibility to colistin in S. maltophilia.

Page 4 of 9
The occurrence of several types of infections as well as differences in the

susceptibility testing methods used have been previously suggested as possible

causes of variation in the activity of colistin in S. maltophilia [6–8]. However, the role

t
played by the increasing use of colistin in the resistance rates has not been reported.

ip
cr
Therapeutic options are often limited, particularly after the emergence of SXT-

us
resistant isolates. Resistance rates to this antimicrobial agent ranged from 3.8% to

26% in different surveillance studies [9]. Some authors reported the use of colistin as

an
an alternative treatment, mainly as part of combination regimens. Milne and Gould

determined that the combination of colistin with ticarcillin/clavulanic acid produced

M
synergistic activity in 40% of the isolates studied [10]. Similar results were observed

in other studies that combined colistin with rifampicin or SXT [11].

d
te

According to this study, colistin cannot be considered a new therapeutic option

against S. maltophilia. It is still necessary to know whether the ability of colistin to

p

produce synergy in S. maltophilia is maintained even when the colistin MIC reaches
ce

≥8 mg/L.
Ac

In conclusion, we report a marked increase in the rate of resistance to colistin in S.

maltophilia, which rose from 8% to 45% during the period 1996–2013 and correlated

with a rise in the use of colistin in this teaching hospital.

Funding: This work was supported by grants from the Secretaría de Ciencia y

Técnica de la Universidad de Buenos Aires [UBACyT 01/W296]) to AF.

5

Page 5 of 9
Competing interests: None declared.

Ethical approval: Not required.

t
ip
cr
us
an
M
d
p te
ce
Ac

Page 6 of 9
References

[1] Falagas ME, Bliziotis I. Pandrug-resistant Gram-negative bacteria: the dawn

of the post-antibiotic era? Int J Antimicrob Agents 2007;29:630–6.

t
[2] Coi Y, Chai D, Wang R, Liang B, Bai N. Colistin resistance of Acinetobacter

ip
baumannii: clinical reports, mechanisms and antimicrobials strategies. J

cr
Antimicrob Chemother 2012;67:1607–15.

[3] Marcenac FM, Fernandez AJ, Herran IL, Civalero TR. Semi-quantitative

us
determination of resistance in agar [in German]. Arzneimittelforschung

1978;28:582–5.

an
[4] Clinical and Laboratory Standards Institute. Performance standards for

antimicrobial susceptibility testing; twentieth informational supplement.

M
Document M100-S20. Wayne, PA: CLSI; 2010.

[5] Fedler KA, Biedenbach DJ, Jones RN. Assessment of pathogen frequency
d

and resistance patterns among pediatric patient isolates: report from the 2004
te

SENTRY Antimicrobial Surveillance Program on 3 continents. Diagn Microbiol

p

Infect Dis 2006;56:427–36.

ce

[6] Samonis G, Karageorgopoulos DE, Maraki S, Levis P, Dimopoulou D,

Spernovasilis NA, et al. Stenotrophomonas maltophilia infections in a general

Ac

hospital: patient characteristics, antimicrobial susceptibility, and treatment

outcome. PLoS One 2012;7:e37375.

[7] Goncalvez-Vidigal P, Grosse Onebrink J, Buer J, Rath PM, Steinmann J.

Stenotrophomonas maltophilia in cystic fibrosis: improved detection by the

use of selective agar and evaluation of antimicrobial resistance. J Cyst Fibros

2011;10:422–7.

Page 7 of 9
[8] Galani I, Kontopidou F, Souli M, Rekatsina PD, Koratzanis E, Deliolanis J, et

al. Colistin susceptibility testing by Etest and disk diffusion methods. Int J

Antimicrob Agents 2008;31:541–4.

[9] Denton M, Kerr KG. Microbiological and clinical aspects of infection

t
associated with Stenotrophomonas maltophilia. Clin Microbiol Rev

ip
1998;11:57–80.

cr
[10] Milne KE, Gould IM. Combination antimicrobial susceptibility testing of

us
multidrug-resistant Stenotrophomonas maltophilia from cystic fibrosis patients.

Antimicrob Agents Chemother 2012;56:4071–7.

an
[11] Giamarellos-Bourboulis EJ, Karnesis L, Giamarellou H. Synergy of

colistin with rifampin and trimethoprim/sulfamethoxazole on multidrug-

M
resistant Stenotrophomonas maltophilia. Diagn Microbiol Infect Dis

2002;44:259–63.
d
p te
ce
Ac

Page 8 of 9
Table 1

Evolution of resistance to colistin (COL) in Stenotrophomonas maltophilia and its

relation to COL consumption in a university hospital in Buenos Aires city, Argentina

Year n Resistance to COL COL consumption (no. of DDD COL/1000

t
a
(%) vials) patients

ip
1996– 42 8 N/D N/D
2000

cr
2001– 71 22.3 N/D N/D
2002

us
2003 62 37 500 5
2004 61 39 1400 16

an
2005 50 48 2300 24
2006 53 49 2700 25
2007 55 54 2100 31
M
2008 51 51 3900 N/D
2009 43 57 4600 N/D
2010 37 60 4600 21
d

2011 35 53 4100 19
te

2012 40 50 4800 21
2013 41 45 5700 N/D
p

N/D, not determined; DDD, defined daily doses.

ce

a
Vials containing 100 mg of colistin methanesulfonate.
Ac

Page 9 of 9