Update on infections caused by Stenotrophomonas maltophilia with particular attention to resistance mechanisms and therapeutic options

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doi: 10.3389/fmicb.2015.00893

Edited by:

Giovanni Di Bonaventura, Università degli Studi “G. d’Annunzio” Chieti e Pescara, Italy

Reviewed by:

Deborah R. Yoder-Himes, University of Louisville, USA Ronald Paul Rabinowitz, University of Maryland School of Medicine, USA Malgorzata Anna Mikaszewska-Sokolewicz, The Medical University of Warsaw, Poland

*Correspondence:

Yen-Hsu Chen, Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100, Tzyou 1st Road, Kaohsiung 807, Taiwan infchen@gmail.com; Po-Ren Hsueh, Departments of Laboratory Medicine and Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, No. 7, Chung-Shan South Road, Taipei 100, Taiwan hsporen@ntu.edu.tw

Specialty section:

This article was submitted to Infectious Diseases, a section of the journal Frontiers in Microbiology

Received: 03 March 2015 Accepted: 17 August 2015 Published: 02 September 2015 Citation:

Chang Y-T, Lin C-Y, Chen Y-H and Hsueh P-R (2015) Update on infections caused by Stenotrophomonas maltophilia with particular attention to resistance mechanisms and therapeutic options. Front. Microbiol. 6:893. doi: 10.3389/fmicb.2015.00893

Update on infections caused by

Stenotrophomonas maltophilia

with

particular attention to resistance

mechanisms and therapeutic options

Ya-Ting Chang

1, 2

_{, Chun-Yu Lin}

2, 3

_{, Yen-Hsu Chen}

2, 3, 4

_{* and Po-Ren Hsueh}

5

_*

1_{Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Municipal HsiaoKang Hospital, Kaohsiung,}

Taiwan,2_{Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung}

Medical University, Kaohsiung, Taiwan,3_{School of Medicine, Graduate Institute of Medicine, Sepsis Research Center,}

College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan,4_{Department of Biological Science and Technology,}

College of Biological Science and Technology, National Chiao Tung University, HsinChu, Taiwan,5_{Departments of Laboratory}

Medicine and Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan

Stenotrophomonas maltophilia

is a Gram-negative, biofilm-forming bacterium. Although

generally regarded as an organism of low virulence, S. maltophilia is an emerging

multi-drug resistant opportunistic pathogen in hospital and community settings,

especially among immunocompromised hosts. Risk factors associated with S.

maltophilia

infection include underlying malignancy, cystic fibrosis, corticosteroid or

immunosuppressant therapy, the presence of an indwelling central venous catheter

and exposure to broad spectrum antibiotics. In this review, we provide a synthesis of

information on current global trends in S. maltophilia pathogenicity as well as updated

information on the molecular mechanisms contributing to its resistance to an array of

antimicrobial agents. The prevalence of S. maltophilia infection in the general population

increased from 0.8–1.4% during 1997–2003 to 1.3–1.68% during 2007–2012. The

most important molecular mechanisms contributing to its resistance to antibiotics

include β-lactamase production, the expression of Qnr genes, and the presence of

class 1 integrons and efflux pumps. Trimethoprim/sulfamethoxazole (TMP/SMX) is the

antimicrobial drug of choice. Although a few studies have reported increased resistance

to TMP/SMX, the majority of studies worldwide show that S. maltophilia continues

to be highly susceptible. Drugs with historically good susceptibility results include

ceftazidime, ticarcillin-clavulanate, and fluoroquinolones; however, a number of studies

show an alarming trend in resistance to those agents. Tetracyclines such as tigecycline,

minocycline, and doxycycline are also effective agents and consistently display good

activity against S. maltophilia in various geographic regions and across different time

periods. Combination therapies, novel agents, and aerosolized forms of antimicrobial

drugs are currently being tested for their ability to treat infections caused by this

multi-drug resistant organism.

(2)

Stenotrophomonas maltophilia is a Gram-negative, aerobic,

glucose non-fermenting, motile bacillus. S. maltophilia was first

isolated from pleural effusion in 1943 and initially named

Bacterium bookeri. The organism was reclassified as a member

of the genus Pseudomonas in 1961, Xanthomonas in 1983,

and then Stenotrophomonas in 1993 (

Al-Anazi and Al-Jasser,

2014

). It survives on almost any humid surface and has

been isolated from a wide variety of aquatic sources, such as

suction tubing, nebulizers, endoscopes, hemodialysis dialysate

samples, plant rhizosphere, faucets, sink drains, and shower

heads (

Brooke, 2012

). S. maltophilia is characterized by its

ability to form biofilms on various abiotic and biotic surfaces,

including lung cells (

de Oliveira-Garcia et al., 2003; Pompilio

et al., 2010

), and by its resistance to a broad array of

antimicrobial agents. The World Health Organization recently

classified S. maltophilia as one of the leading multidrug

resistant organisms (MDROs) in hospital settings (

Brooke,

2014

).

S. maltophilia is generally regarded as an organism of low

virulence and therefore an opportunistic pathogen, especially

in immunocompromised hosts. The risk factors associated

with acquiring S. maltophilia infections are well-known

and include underlying malignancy (especially hematologic

malignancy), organ transplantation, human immunodeficiency

virus (HIV) infection, cystic fibrosis, prolonged hospitalization,

intensive care unit (ICU) admission, mechanical ventilation,

indwelling catheters (vascular, urinary, biliary), corticosteroid or

immunosuppressant therapy, and recent antibiotics treatment

(

Al-Anazi and Al-Jasser, 2014

). These risk factors reflect

specific features of S. maltophilia, such as its ability to survive

on almost any humid surface, its propensity to form biofilm

and colonize humid surfaces, and its employment of several

mechanisms that confer resistance to a number of antimicrobial

agents.

S. maltophilia causes a wide range of infections including

respiratory tract infections (RTI), blood stream infections

(BSI) and, less commonly, skin and soft tissue infections

(SSTI), bone and joint infections, biliary tract infections,

urinary tract infections, endophthalmitis, endocarditis, and

meningitis (

Falagas et al., 2009a; Looney et al., 2009

). The

correlations between S. maltophilia infection and structural

abnormalities with or without obstruction or procedural

manipulation are well documented. Biliary tract infections

caused by obstruction due to hepatobiliary neoplasms (

Papadakis

et al., 1995; Chang et al., 2014

) or post-operative anastomotic

strictures of the gastrointestinal tract (

Perez et al., 2014

) have

been reported in patients with biliary S. maltophilia sepsis.

Pleural infections caused by post-surgical/tube thoracostomy

or fistula (broncho-/esophageal-/bilio-) (

Lee et al., 2014

),

post-neurosurgical meningitis (

Sood et al., 2013; Lai et al., 2014b

),

complicated urinary tract infections (

Vartivarian et al., 1996

),

and obstructive lung cancer (

Fujita et al., 1996; Vartivarian

et al., 2000

) have all been reported to create a milieu for S.

maltophilia infection. In addition, although commonly perceived

as nosocomial pathogens, community-acquired infections appear

to be on the rise (

Falagas et al., 2009a; Chang et al.,

2014

).

Prevalence

There were few data before 1970 regarding the prevalence or

clinical characteristics of S. maltophilia (previously Pseudomonas

maltophilia or Xanthomonas maltophilia) because of its rarity

and relative clinical insignificance. It was in the 1980s when S.

maltophilia became more frequently reported as an emerging

nosocomial pathogen (

Jang et al., 1992; Victor et al., 1994

),

especially in patients with post-chemotherapy neutropenia (

Kerr

et al., 1990; Labarca et al., 2000

) and in those with indwelling

central venous catheters (CVC) (

Victor et al., 1994; Lai et al.,

2006; Chen et al., 2014

). Beginning in the late 1990s worldwide

surveillance programs and multi-center studies began to provide

more comprehensive information about the pathogenicity of S.

maltophilia. Of the global surveillance programs, the SENTRY

Antimicrobial Surveillance Program initiated in 1997 and the

Study for Monitoring Antimicrobial Resistance Trends (SMART)

initiated in 2002 are the most well-known (

Jean et al., 2015

). A

number of nationwide and antimicrobial agent-targeted projects

were also launched during the late 1990s, including the Canadian

Ward Surveillance Study (CANWARD), the Surveillance and

Control of Pathogens of Epidemiologic Importance (SCOPE)

study, the British Society for Antimicrobial Chemotherapy

(BSAC) Resistance Surveillance Project, the Taiwan Surveillance

of Antimicrobial Resistance (TSAR) study, and the Tigecycline

Evaluation Surveillance Trial (TEST).

Despite the massive scale of these surveillance studies,

there are still limited integrated data on the prevalence and

susceptibility patterns of S. maltophilia. The heterogeneity

among the studies stems from the diverse patient demographics,

geographic differences, and the ratio of the isolates collected from

different sources, making inter-literature comparison difficult.

To add to the complexity, there are no worldwide guidelines

on susceptibility testing methodology and breakpoints for S.

maltophilia (

Nicodemo et al., 2004; Hombach et al., 2012

), which

results in different or absence of susceptibility breakpoints for

some antibiotics. The lack of universal references for evaluating

resistance of S. maltophilia to antimicrobial agents leads to

confusion and complications when interpreting clinical data.

Table 1

_{shows the prevalence rates of infection due to S.}

maltophilia, categorized by sources of infection, reported by

worldwide and nationwide surveillance projects as well as

multi-center studies. Specific patient groups such as the critically ill

in intensive care units (ICUs) and the pediatric population are

presented separately in Table 1. By comparing data gathered by

large surveillance studies over time we can estimate longitudinal

change in prevalence of S. maltophilia infection in the general

population. The frequency of occurrence among isolates from

all sources ranged from 0.8 to 1.4% in five SENTRY studies

during 1997∼2003 (

Fluit et al., 2001a; Gales et al., 2001a; Sader

et al., 2004; Sader and Jones, 2005; Fedler et al., 2006b

). During

2007–2012, the CANWARD surveillance study (

Zhanel et al.,

2011, 2013; Walkty et al., 2014

) and the SENTRY antimicrobial

surveillance program (

Farrell et al., 2010b; Sader et al., 2013

)

reported prevalence rates ranging from 1.3 to 1.68%. These data

indicate that there is an increasing trend in infections due to S.

maltophilia in the general population.

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TABLE 1 | Prevalence of S. maltophilia in worldwide surveillance and multicenter studies.

Countrya Studyb Year Number of isolates Prevalence and/or ranking References

All regionsc _SENTRY _1997–1999 _{Total isolates:70067} SMd_{isolates: 842}

Among:

all pathogens: 1.2%

Gales et al., 2001a

EU SENTRY 1997–1998 Total/SM isolates in:

BSIe_{: 9194/82} RTI: 2052/54 SSTI: 2320/13 UTI: 2138/3 Among: all pathogens: 1.0% BSI: 0.89%, ranking: 19th RTI: 2.63%, ranking: 9th SSTI: 0.56%, ranking: 19th UTI: 0.14%, ranking: 25th

Fluit et al., 2001a

LA SENTRY 1997–2001 Total isolates: 19547

SM isolates: 166

Among:

all pathogens: 0.8%

Sader et al., 2004

All regions SENTRY 1997–2001 NFGNBf_{isolates: 18569}

SM isolates: 1488

Among: NFGNB: 8%

Jones et al., 2003

All regions SENTRY 1997–2003 Total isolates: 221084

NFGNBfisolates: 25305 Uncommon NFGNBg: 3509 SM isolates: 2076 Among: all pathogens: 0.94% NFGNB: 8.20% Uncommon NFGNB: 59.16%

Sader and Jones, 2005

All regions SENTRY 2001–2004 GNB isolates: 54731

NFGNB isolates: 13808 SM isolates: 1256 Among: GNB: 2.29% NFGNB: 9.10% Gales et al., 2006

Canada CANWARD 2007–2009 Total isolates: 18538

GNB isolates: 8949h SM isolates: 245

Among:

all pathogens: 1.3%, ranking: 17th GNB: 2.7%

Zhanel et al., 2011

AP SENTRY 2008 Total isolates: 5759

SM isolates: 97

Among:

all pathogens: 1.68%

Farrell et al., 2010b

Canada CANWARD 2008 Total isolates: 5282

SM isolates: 57

Among:

all pathogens: 1.1%, ranking: 17th

Zhanel et al., 2010

France MTC 2008–2009 Total isolates: 46400

Uncommon NFGNB isolates: 158 SM isolates: 61 Among: all pathogens: 0.13% Uncommon NFGNB: 39% Fihman et al., 2012

SM isolates: 378

Among:

all pathogens: 1.4%, ranking 16th

Zhanel et al., 2013

All regions SENTRY 2011 Total isolates: 22005

SM isolates: 362

Among: all pathogens: 1.6% Sader et al., 2013

SM isolates: 104

Among:

all pathogens: 1.6%

Walkty et al., 2014 BSI

USA SCOPE 1995–1996 NFGNB isolates: 270

SM isolates: 18

Among: NFGNB: 6.7%

Jones et al., 1997

USA, Canada SENTRY 1997 Total isolates:5058

SM isolates: 40

Among:

all pathogens: 0.8%, ranking: 15th In USA: 0.7%, in Canada: 1.1%

Pfaller et al., 1998

NA, LA SENTRY 1997 Total isolates: 9519

GNB isolates: 4267 SM isolates: 69 Among: all pathogens: 0.7% GNB: 1.6% Diekema et al., 1999 (Continued)

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TABLE 1 | Continued

EU SENTRY 1997–1998 Total isolates: 9194

SM isolates: 82

Among:

Fluit et al., 2001a

All regions SENTRY 1997–1999 Among all pathogens in:

AP: 0.9%, Canada: 0.6% EU: 0.9%, LA: 0.8%, USA: 0.7%

Gales et al., 2001a

LA SENTRY 1997–2000 NA Among:

all pathogens: 0.7%

1997: 0.9%, 1998: 0.8%, 1999: 0.6%, 2000: 0.3%

SM isolates: 86

Among:

Sader et al., 2004

Worldwide MTC 2000–2004 All isolates: 26474

SM isolates: 203

Among:

all pathogens: 0.8%

Sader et al., 2005b RTI

NA SENTRY 1997 Total isolates: 2757

SM isolates: 99

Among:

Jones et al., 2000

LA SENTRY 1997 Total isolates: 556

SM isolates: 13

Among:

Sader et al., 1998

SM isolates: 114

Among:

Mathai et al., 2001

SM isolates: 54

Among:

Fluit et al., 2001a

Gales et al., 2001a

SM isolates: 41

Among:

all pathogens: 1.6%

Gales et al., 2002

SM isolates: 60

Among:

all pathogens: 1.8%

Sader et al., 2004

NA SENTRY 2000 SM isolates: 94 Among:

all pathogens: 3.5%

Hoban et al., 2003

NA, LA, EU SENTRY 2004–2008 Isolates from HABP and

VABPi

Total cases: 31436

Regional incidence: all regions: 3.1%

USA: 3.3%, LA: 2.3%, EU: 3.2%

Jones, 2010

Canada CANWARD 2008 Total isolates: 1612

SM isolates: 42

Among:

Zhanel et al., 2010

USA and EU SENTRY 2009–2012 Total isolates: 12851

GNB isolates: 8201

Among all pathogens in: USA: 4.4%, ranking: 6th EU: 3.2%, ranking:9th GNB: 6.02%

Sader et al., 2014a

USA and EU MTC 2012 Total isolates: 2968

SM isolates: 186

Among:

all pathogens:6.3%

Farrell et al., 2014 UTI

GNB isolates: 80% SM isolates: 6 Among: all pathogens: 0.35% GNB: 0.44% Jones et al., 1999b (Continued)

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TABLE 1 | Continued

SM isolates: 3

Among:

Fluit et al., 2001a

Gales et al., 2001a

SM isolates: 0

Among: all pathogens: 0%

Sader et al., 2004

AP region SMARTj _2009–2010 _{Total GNB isolates: 1762} _{Among all GNB in:}

China: 1.3%, Thailand: 3.3%

Lu et al., 2012

USA SMART 2009–2011 Total GNB isolates: 2135

SM isolates: 6

Among: all GNB: 0.28%

Bouchillon et al., 2013 IAI

China SMART 2002–2009 Total GNB isolates: 3420

SM isolates: 50

Among: all GNB: 1.5% NFGNB: ranking: 3rd

Yang et al., 2010

AP region SMART 2003–2010 Total GNB isolates: 20710

NFGNB isolates: 2252 SM isolates: 204 Among: all GNB: 1.0% NFGNB: 9.1% Liu et al., 2012

Taiwan SMART 2006–2010 Total GNB isolates: 2417

SM isolates: 28

Among: all GNB: 1.2%

Lee et al., 2012

Africa and middle east

TEST 2007–2012 Total isolates of cSSSI14 and IAI from TEST: 1990 and 255

GNB isolates from IAI: 225 SM isolates rom IAI: 16

Among:

all pathogens in IAI: 6.3% GNB in IAI: 7.3%

Renteria et al., 2014

SSTI

SM isolates: 15

Among:

Doern et al., 1999

SM isolates: 13

Among:

Fluit et al., 2001a

USA: 1.0%, Canada: 1.1% AP: 0.1%, EU: 0.6%, LA: 0.4%,

Gales et al., 2001a

SM isolates: 7

Among:

Sader et al., 2004 ICU

EU SENTRY 1997–1998 Total isolates from ICU:

3981

Among:

all pathogens: 1.6%, ranking: 14th BSI: 1.1%, ranking: 15th RTI: 3.0%, ranking: 8th UTI: 0.0%

Fluit et al., 2001b

SM isolates: 166

Among all pathogens in: ICU: 2.77%

Sader et al., 2004

NA SENTRY 2001 Total isolates from ICU:

1321 SM isolates: 40

Respiratory source: 89.0%

Among:

Streit et al., 2004

NA, LA, EU, Asia-Australia area

MTC 2000–2004 Isolates from ICU patients Total isolates: 9093 SM isolates: 131

Among:

all pathogens: 1.4%

Sader et al., 2005a

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TABLE 1 | Continued

German SARI 2003–2004 Isolates collected from 39

German ICUs Total isolates:28266 GNB isolates: 12234

Among all pathogens: Median percentage: 1.7%

Meyer et al., 2006

Canada CAN-ICU 2005–2006 Isolates from ICU patients

Total isolates:4180 SM isolates: 108

Among:

all pathogens: 2.6%

Zhanel et al., 2008

Korea MTC 2008–2009 Respiratory tract isolates

from patient with HABP in ICUs Total isolates: 372 CRGNB isolates: 82 SM isolates: 10 Among: all pathogens: 2.7% CRGNBk: 11.6% Kim et al., 2014 EU MTC(27) 9 countries

Published in 2011 Respiratory tract isolates from patient with HABP in ICUs Total isolates: 495 SM isolates: 13 Among: all pathogens: 2.6% Magret et al., 2011 PEDIATRIC POPULATION

NA SENTRY 1998–2003 Total isolates: 59826

Total isolates from pediatric patients <7 years: 4641 SM isolates: 166

Among: all pathogens in:

all ages: 1.4%, pediatric: 1.2%, both ranking: 10th

Fedler et al., 2006b

NA, LA, EU SENTRY 2004 Total isolates from pediatric

patients ≤18 years: 3537 SM isolates: 53

Among:

all pathogens: 1.5%, ranking: 15th all regions combined

Fedler et al., 2006a

COMMUNITY-ACQUIRED

USA, Canada, LA SENTRY 1997 BSI

SM isolates: 69

CAl_{/N/unknown: 23/28/18} CA: 33.3%

Diekema et al., 1999

UK and Ireland BSAC 2001–2006 BSI

SM isolates: 165

C/N: 31/66 CA: 33%

Livermore et al., 2008

AP region SMART 2003–2010 IAI

SM isolates: 204

CA/N: 26/125 CA: 17.2%

Liu et al., 2012

France MTC 2008–2009 All sources

SM isolates: 61

CA/N: 9/29 CA: 23.7%

Fihman et al., 2012

Taiwan SMART 2006–2010 IAI

SM isolates: 28

CA/Ni: 3/18 CA: 14.3%

Lee et al., 2012

a_{NA, North America; LA, Latin America; EU, Europe; USA, the United States of America; UK, United Kingdom; AP, Asia-Pacific.}

b_{SENTRY, The SENTRY Antimicrobial Surveillance Program; SMART, Study for Monitoring Antimicrobial Resistance Trends; CAN-ICU, The Canadian Intensive Care Unit Surveillance}

Study; CANWARD, The Canadian Ward Surveillance Study; SARI, Surveillance of Antibiotic Use and Bacterial Resistance in ICUs(German); BSAC, The British Society for Antimicrobial Chemotherapy Resistance Surveillance Project; TEST, Tigecycline Evaluation Surveillance Trial; TIST, Tigecycline In Vitro Surveillance in Taiwan; TSAR, Taiwan Surveillance of Antimicrobial Resistance; SCOPE, Surveillance and Control of Pathogens of Epidemiologic Importance (USA); MTC, multicenter studies.

c_{The SENTRY Antimicrobial Surveillance Program has monitored the predominant pathogens and antimicrobial resistance in 5 geographic regions: Asia-Pacific, Europe, Latin America,}

Canada, and the United States (Gales et al., 2001a).

d_{SM, Stenotrophomonans maltophilia.}

e_{BSI, bloodstream infection; RTI, respiratory tract infection; IAI, intra-abdominal infection; UTI, urinary tract infection; SSTI, skin and soft tissue infection.} f_{NFGNB, non-fermentative Gram-negative bacilli}

g_{Uncommon NFGNB, Acinetobacter spp. and Pseudomonas aeruginosa excluded.}

h_{Of the 18538 organisms collected, the 20 most common represented 16780 (90.5%) of the isolates and underwent susceptibility testing, which included 8949 (53.3%) Gram-negative}

bacilli.

i_{HABP, hospital-acquired bacterial pneumonia; VABP, ventilator-associated bacterial pneumonia.}

j_{SMART is a global surveillance program that has monitored the in vitro susceptibility patterns of clinical Gram-negative bacilli to antimicrobial agents collected worldwide from}

intra-abdominal infections since 2002 and urinary tract infections since 2009 (Morrissey et al., 2013).

k_{CRGNB, carbapenem-resistant Gram-negative bacteria.}

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It has been observed in the general population (

Gales et al.,

2001a

) and in ICUs (

Fluit et al., 2001b

) alike that S. maltophilia

is most frequently associated with respiratory tract infections

(RTIs), followed by bloodstream infections (BSIs), and, rarely,

skin and soft tissue infections (SSTIs) and urinary tract infections

(UTI) (

Gales et al., 2001a

). The prevalence of RTIs due to S.

maltophilia is generally higher than that of other infections

caused by that pathogen, but varies widely among countries and

continents, ranging from 1.6 to 6.3% during the period 1997–

2012 (

Sader et al., 1998, 2004, 2014a; Jones et al., 2000; Fluit et al.,

2001a; Gales et al., 2001a, 2002; Mathai et al., 2001; Hoban et al.,

2003; Jones, 2010; Zhanel et al., 2010; Farrell et al., 2014

). The

United States has the most consecutive records regarding RTI

isolates collected by the SENTRY program. Based on data from

four SENTRY studies (

Gales et al., 2001a; Hoban et al., 2003;

Jones, 2010; Sader et al., 2014a

), the prevalence rates increased

from 3.3–3.5% during 1997–2004 to 4.4% during 2009–2012.

During that 15-year period, S. maltophilia went from being the

eighth to the sixth most common cause of RTI. In a large study

on 2968 RTI isolates collected from 59 medical centers in the

USA and 15 centers in European countries in 2012, 6.3% of

the pathogens were S. maltophilia (

Farrell et al., 2014

). These

observations suggest an increasing frequency of occurrence of

respiratory tract infections due to S. maltophilia.

S. maltophilia is less frequently isolated from patients with

BSIs, UTIs, or SSTIs than from patients with RTIs, with reported

isolation rates ranging from 0.7 to 1.1% for BSIs (

Jones et al.,

1997; Pfaller et al., 1998; Diekema et al., 1999; Fluit et al.,

2001a; Gales et al., 2001a; Sader et al., 2004, 2005b

), 0–0.3%

for UTIs (

Pfaller et al., 1998; Jones et al., 1999b; Fluit et al.,

2001a; Gales et al., 2001a; Sader et al., 2004, 2005b

), and 0.39–

0.96% for SSTIs (

Diekema et al., 1999; Fluit et al., 2001a; Gales

et al., 2001a; Sader et al., 2004

). SMART studies have also shown

that isolation of S. maltophilia from intra-abdominal infections

(IAIs) is also fairly uncommon, with rates ranging from 1 to

1.7% (2002–2010) (

Guembe et al., 2008; Yang et al., 2010; Lee

et al., 2012; Liu et al., 2012

). However, data from African and

Middle Eastern countries collected as part of the Tigecycline

Evaluation Surveillance Trial during 2007–2012 (

Renteria et al.,

2014

) revealed an uncommonly high rate of isolation (6.3%) of

S. maltophilia from patients with IAIs. In addition, the results

from a SMART study surveying UTIs in the Asian-Pacific region

during 2009–2010 disclosed higher rates of S. maltophilia isolated

from patients with UTIs in China (1.3%) and Thailand (3.3%)

than in other countries (

Lu et al., 2012

), although the rates were

not as high as those in certain countries in Africa and the Middle

East.

Gram-negative Bacilli (GNB) and

Non-fermenting Gram-negative Bacilli

(NFGNB)

The worldwide rate of isolation of S. maltophilia among GNB

pathogens ranges from 2.29 to 2.7% according to a SENTRY

study (2001–2004) (

Gales et al., 2006

) and a CANWARD

surveillance study (2007–2009) (

Zhanel et al., 2011

). In the US

state of Texas, however, a study at the M. D. Anderson Cancer

Center revealed an increasing trend in the ratio of S. maltophilia

among GNB isolates obtained from cancer patients during 1986–

2002 (from 2% in 1986 to 7% in 2002) (

Safdar and Rolston,

2007

).

Among NFGNB, S. maltophilia has been reported to be

the third most commonly isolated pathogen after Pseudomonas

aeruginosa and Acinetobacter baumannii. In a large survey

conducted as a part of the SENTRY program, 221,084 GNB

isolates were collected worldwide, including 25,305 (11.5%)

NFGNB isolates, of which Acinetobacter spp. and P. aeruginosa

accounted for the vast majority (87.7%). The remaining 3509

isolates were deemed unusual NFGNB species. Of them, S.

maltophilia was the most frequently isolated (n = 2076, 59.16%)

(

Sader and Jones, 2005

). A similar finding was reported in a

prospective multi-center study involving nine teaching hospitals

in France, in which S. maltophilia was the most commonly

isolated NFGNB among all unusual NFGNB species (39%)

(

Fihman et al., 2012

). Other surveillance studies, namely SCOPE

(

Jones et al., 1997

), SENTRY (

Jones et al., 2003; Gales et al.,

2006

), and SMART (

Liu et al., 2012

) showed a steady increase in

isolation of S. maltophilia among all NFGNB pathogens during

the period 1995–2010 (6.7% in 1995–1996, 8.0% in 1997–2001,

and 9.1% in 2001–2010). These findings show that S. maltophilia

is not an insignificant pathogen among disease-causing GNB and

NFGNB species.

Intensive Care Units, Pediatric Population,

and Community-acquired Infections

As expected, the prevalence of infections due to S. maltophilia

is higher in intensive care units (1.4–3.0%) than in the general

population (

Fluit et al., 2001b; Sader et al., 2004; Streit et al., 2004;

Sader et al., 2005a; Meyer et al., 2006; Zhanel et al., 2008; Magret

et al., 2011; Kim et al., 2014

).

There is limited information on the worldwide prevalence

of S. maltophilia infections in the general pediatric population.

SENTRY studies conducted during 1998–2003 (

Fedler et al.,

2006b

) and in 2004 (

Fedler et al., 2006a

) showed that the

prevalence of infections due to S. maltophilia was 1.2% among

children ≤ 7 years and 1.4% among children ≤ 18 years

old. The rates are similar to those in the adult population.

A comparison of two single-center studies in China and the

USA revealed markedly different incidence rates of

ventilator-associated pneumonia due to S. maltophilia among pediatric

patients in ICUs. Ning et al. reported a rate of 20.3% among

patients aged 2 months to 16 years in a pediatric ICU in China

(

Ning et al., 2013

) whereas Arthur et al. found that the rate of

infection due to S. maltophilia among infants aged 0–6 months

in a cardiac ICU in the USA was only 0.8% (

Arthur et al., 2015

).

Several recent studies have shown that S. maltophilia is also

an emerging opportunistic pathogen in community settings

(

Falagas et al., 2009a; Chang et al., 2014

). Results of a worldwide

SENTRY study in 1997 (

Diekema et al., 1999

) and the British

Society for Antimicrobial Chemotherapy Resistance surveillance

project conducted during 2001–2006 (

Livermore et al., 2008

)

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showed that 33.3 and 32%, respectively, of S. maltophilia

isolates were collected within 48 h after admission (defined

as community-acquired in these studies) from patients with

bloodstream infections. The results from two recent SMART

studies revealed that 14.3–17.2% of isolates from patients with

community-acquired IAI (also defined by a 48-h time frame

within admission) during 2003–2010 were S. maltophilia (

Lee

et al., 2012; Liu et al., 2012

). Another recent study on the

prevalence of community-acquired S. maltophilia BSI in Taiwan,

which specifically divided the patients into three categories

based on whether they had community-acquired (excluding

patients hospitalized within 90 days before admission, cared

in a nursing facility, etc.), healthcare-associated or

hospital-acquired infections, reported that 17.6% of all

community-acquired bloodstream infections were due to S. maltophilia

(

Chang et al., 2014

). A similar study in France revealed that

23.7% of all community-acquired BSIs were due to S. maltophilia

(

Fihman et al., 2012

). These studies show that

community-acquired S. maltophilia infections are far less rare than previously

thought.

Risk Factors of Mortalty

A number of risk factors for death due to S. maltophilia

infections have been reported. Paez et al. (

Paez and Costa,

2008

) reviewed the literature from 1985 to 2008 and found

that BSI and pneumonia, shock, thrombocytopenia, and

Acute Physiological Assessment and Chronic Health Evaluation

(APACHE) score >15 are independent risk factors associated

with outcome. In addition, underlying hematological malignancy

and admission to ICU are independent risk factors for cancer

patients. The impact of appropriate antimicrobial treatment and

removal of CVC on mortality were concluded to require further

clinical studies (

Paez and Costa, 2008

). The conclusion of the

review corresponds to the aforementioned studies. Falagas et al.

analyzed 15 articles for attributable mortality of S. maltophilia

infections. Only four studies provided relevant data regarding

inappropriate antibiotic treatment, and three out of the four

studies found significantly higher mortality when compared with

initial appropriate therapy (

Falagas et al., 2009b

).

Antimicrobial Susceptibility

There

are

limited

antimicrobial

options

for

infections

due to S. maltophilia because of its extensive resistance

to

most

antibiotics,

including

β

-lactam

antibiotics,

cephalosporins, macrolides, aminoglycosides, and carbapenems.

Interpretive

breakpoints

for

susceptibility

are

available

only

for

ticarcillin/clavulanate,

ceftazidime,

minocycline,

levofloxacin,

trimethoprim/sulfamethoxazole

(TMP/SMX),

and chloramphenicol (

CLSI, 2015

). Table 2 shows the rates of

susceptibility of S. maltophilia to antimicrobial agents reported

in the studies presented in Table 1. TMP/SMX is recognized

as the drug of choice (

Wang et al., 2014a

). Resistance rates

vary geographically but are generally less than 10% (

Chung

et al., 2013

). However, high and various rates of resistance

to TMP/SMX have been reported in patients with cancer

(

Vartivarian et al., 1994; Micozzi et al., 2000

), cystic fibrosis

(

Saiman et al., 2002; Cantón et al., 2003; San Gabriel et al., 2004;

Valenza et al., 2008

), and in several countries, including Taiwan,

Japan, Korea, Thailand, Spain, Mexico, Saudi Arabia, Turkey,

and Canada (16–78.8%) (

Valdezate et al., 2001; del Toro et al.,

2002; Lai et al., 2004; Gülmez and Hasçelik, 2005; Memish et al.,

2012; Wu et al., 2012; Rattanaumpawan et al., 2013; Rhee et al.,

2013; Zhanel et al., 2013; Flores-Treviño et al., 2014; Hotta

et al., 2014; Walkty et al., 2014; Wang et al., 2014a

). In the

present review, global surveillance data for the period 1997–2012

show that S. maltophilia continues to be highly susceptible to

TMP/SMX (Table 2). Over that 15-year period, the susceptibility

rates reported in worldwide SENRTY studies (

Gales et al., 2001a;

Jones et al., 2003; Gales et al., 2006; Sader et al., 2013, 2014a

),

a BSAC surveillance study (

Livermore et al., 2008

), and three

large-scale multi-national studies (

Sader et al., 2005b; Farrell

et al., 2010a, 2014

) ranged from 90 to 100%.

Ceftazidime and ticarcillin/clavulanate used to be the most

effective among β-lactam drugs against S. maltophilia. However,

recent studies have demonstrated resistance rates of more than

30% and a trend in decreasing susceptibility with ceftazidime

(47–75% during 1997–1999 to 30.5–36.8% during 2009–2012)

(Table 2) (

Gales et al., 2001a; Farrell et al., 2010a; Sader et al.,

2014b

). The same is true for ticarcillin/clavulanate. During

1997–1998, the rates of susceptibility of S. maltophilia to that

combination ranged from 71–90% but dropped to 27–46.1%

during 2003–2008.

New fluoroquinolones exhibit better potency against S.

maltophilia than ceftazidime or ticarcillin/clavulanate and have

become reasonable alternatives. Nonetheless, a comparison of

data from worldwide SENTRY studies reveals a decrease in

sensitivity of S. maltophilia to levofloxacin, from 83.4% during

the period 2003–2008 (

Farrell et al., 2010a

) to 77.3% in 2011

(

Sader et al., 2013

). Low susceptibility rates ranging from 64–

69.6% have also been reported in Canada (

Zhanel et al., 2013

),

China (

Yang et al., 2010; Tan et al., 2014

), and Korea (

Chung

et al., 2013

). Few multi-center studies have investigated the

efficacy of fluoroquinolones against S. maltophilia in patients

with UTIs. In a SMART study conducted in the Asia-Pacific

region, isolates of S. maltophilia from patients with UTIs showed

exceptionally high rates of resistance to levofloxacin (33.3%) (

Lu

et al., 2012

). Two recent reports showed low MIC50

(minimum

inhibitory concentration)values (0.5 mg/L and 0.5 mg/L) and

low MIC90

values (8 and 4 mg/L) for moxifloxacin against S.

maltophilia (

Zhanel et al., 2008; Chung et al., 2013

), indicating

that moxifloxacin could be considered an effective alternative.

Data from a number of studies demonstrate that ciprofloxacin

has poor activity against S. maltophilia, with susceptibility rates

averaging lower than 50% (Table 2).

Minocycline, doxycycline, and tigecycline have consistently

displayed good potency against S. maltophilia in studies with

various time periods, sources of specimens, and geographic

regions (

Sader et al., 2005b, 2013, 2014b; Gales et al., 2008;

Chen et al., 2012; Wu et al., 2012; Chung et al., 2013

). A TSAR

surveillance study conducted in Taiwan tested 377 isolates of

S. maltophilia obtained over a 10-year period (1998–2008) and

revealed low MIC50

(0.25 mg/L) and MIC90

values (1 mg/L) for

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TABLE 2 | Susceptibility of S. maltophilia to various antimicrobial agents in worldwide surveillance and multicenter studies.

Country Study Year/

subgroups

TMP/SMXd _LEVOd _CIPd _CAZd _T/Cd _MCNd _TGCd _TGCMIC

50/90 PBd References

NA, LA SENTRY 1997 78.0 20.9 Jones et al., 1999a

All regions SENTRY 1997–1999 Gales et al., 2001a

AP 92 51 47 71

CAN 98 47 60 85

EU 90 79 72 86

LA 98 57 75 87

USA 95 55 67 90

LA SENTRY 1997–2001 Sader et al., 2004

2001 98 98.6 55.7 54.3 45.7 59.2

4 years 97.1 88 43.4 57.8 56 NA

BSI 95.3 88.4 50 73.3 64

RTI 100 90 38.3 46.7 51.7

All regions SENTRY 1997–2001 92 86 32 54 86 Jones et al., 2003

All regions SENTRY 1997–2003 95.3 86.1 30.9 52.9 55.7 67.6 Sader and Jones,

2005

All regions SENTRY 2001–2004 97 86.9 52.4 47.6 72.4 Gales et al., 2006

NA, LA, EU, AP MTC 2003–2008 Farrell et al., 2010a

NA 97.6 82.5 51.0 46.1 94.5a 0.5/2 73.2

EU 98.9 83.7 45.2 42.7 95.3 72.6

AP 90.8 78.0 32.6 27.0 96.1 33.4

LA 95.5 91.3 48.8 36.7 96.5 76.4

ALL 96.0 83.4 44.8 39.1 95.5 64.6

All regions SENTRY 2011 Sader et al., 2013

CLSI 94.5 77.3 36.7 92.3a _0.5/2

EUCAST 95 NA NA 79.8

BSI

NA, LA SENTRY 1997 90.9% 81.8 27.3 27.3 90.9 Diekema et al., 1999

NA SENTRY 1998 73.9 87.0 52.2 65.2 55.7 73.9c Gales et al., 2001b

All regions MTC 2000–2004 98.0 29.6 56.9 93.1a 1/2 84.6 Sader et al., 2005b

UK and Ireland BSAC 2001–2006 100 89b _{Livermore et al.,}

2008

a_{Tigecycline breakpoints of ≤2 µg/mL for susceptibility and ≥8 mg/L for resistance were used for comparison purposes only, as defined by the USFDA.} b_{Susceptibility to tigecycline at the breakpoint of 1 mg/L used for Enterobacteriaceae and Acinetobacter spp.}

c_{Resistant strains with colistin and polymyxin B MICs of ≥4 mg/L.}

d_{Antibiotics abbreviations: TMP/SMX, trimethoprim/sulfamethoxazole; LEVO, levofloxacin; CIP, ciprofloxacin; CAZ, ceftazidime; T/C, Ticarcillin/Clavulanate; PB, polymyxin B; TGC,}

tigecycline; MCN, minocycline.

tigecycline (

Wu et al., 2012

). Similar results were demonstrated

in several large-scale worldwide surveillance studies as well. A

recent SENTRY study conducted during 2009–2012 (494 isolates)

(

Sader et al., 2014a

) revealed a susceptibility of 96% and a

recent TEST study conducted during 2007–2012 (2245 isolates)

(

Renteria et al., 2014

) demonstrated low MIC50

(0.25 mg/L) and

MIC90

(1 mg/L) values.

Molecular Mechanisms in Antimicrobial

Resistance

S. maltophilia has several molecular mechanisms contributing

to its extensive antimicrobial resistance. The mechanisms are

summarized in Table 3. Detailed descriptions of the major

mechanisms are elaborated as follows.

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TABLE 3 | Molecular mechanisms of antimicrobial resistance in S. maltophilia.

Mechanisms Associated determinants Related antimicrobial resistance

β-lactamases

1. L1, L2 (chromosomally and plasmid encoded) 2. TEM-2 (on a Tn1-like transposon)

ampR-dependent

(involving ampR, ampN-ampG operon, ampD_Iand mrcA)

β-lactamases

Class 1 integrons and ISCR elements sul1, sul2, dfrA TMP/SMX

Multidrug efflux pump RND family: SmeABC, SmeDEF, SmeGH*, SmeIJK, SmeMN*, SmeOP, SmeVWX, and SmeYZ ABC family: SmrA, MacABCsm MFS family: EmrCABsm

Summarized in Table 4

Qnr Smqnr Quinolones and tetracycline

Antibiotic-modifying enzymes AAC(6′_{)-Iz, APH(3}′_{)-IIc, AAC(6}′_)-Iak _{Aminoglycoside}

Lipopolysaccharide (LPS) SpgM (phosphoglucomutase) Aminoglycosides, polymyxin B, ticarcillin/clavulanic acid and piperacillin/tazobactam

Mutations of bacterial topoisomerase and gyrase genes Reduction in outer membrane permeability

*not yet characterized.

β-Lactamases

S. maltophilia has two chromosomal-mediated inducible

β-lactamases, namely L1 and L2. L1 is a molecular class B

Zn

2+

-dependent metallo-β-lactamase and L2 is a molecular

class A clavulanic acid-sensitive cephalosporinase. The L1 and

L2 β-lactamases are simultaneously regulated by AmpR, a

transcriptional regulator in the L2 upstream region (

Okazaki

and Avison, 2008

). The ampR-L2 module is homologous to

the ampR-ampC systems, which are widely distributed in some

members of the family Enterobacteriaceae and in P. aeruginosa

(

Lodge et al., 1990

). The regulation of chromosomal ampR-ampC

systems has been well studied in Citrobacter freundii, where

the AmpC β-lactamase induction is linked to peptidoglycan

recycling and involves several regulatory genes, such as as

ampR, ampG, and ampD (

Lindberg et al., 1985

). A similar

induction mechanism was proposed for the ampR-ampC and

the ampR-L2 modules (

Okazaki and Avison, 2008

). But unlike

P. aeruginosa, the permease system in S. maltophilia requires

an intact ampN-ampG operon for the induction of β-lactamase

(

Huang et al., 2010

). Two ampD homologs, ampDI

and

ampDII

, were found in S. maltophilia, but only ampDIappears

to be relevant to the regulation of β-lactamase (

Yang et al.,

2009

).

Penicillin-binding

proteins

(PBPs)

participate

in

peptidoglycan biosynthesis and the inactivation of PBP4 in

P. aeruginosa has been shown to confer AmpC overexpression

and β-lactam resistance (

Moya et al., 2009

). The inactivation

of a putative PBP1a gene, mrcA, recently was found to

cause basal-level L1/L2 β-lactamase hyperproduction in S.

maltophilia KJ. The inactivation of mrcA only affects basal

L1/L2 production β-lactamase, which is ampR- and

ampN-ampG-dependent, and does not augment their induction (

Lin

et al., 2011

). The universality of disruption of ampDI

or mrcA

in β-lactamase-hyperproducing S. maltophilia mutants and

clinical isolates has been proved by the existence of wild-type

ampDI

and mrcA genes. The result implicates mutation of

at least one additional gene in this phenotype (

Talfan et al.,

2013

).

Efflux Pumps

Efflux pumps in microorganisms mediate the extrusion of drugs

and are classified into five families, namely the

resistance-nodulation-cell-division (RND) family, the major facilitator

superfamily (MFS), the small multidrug resistance (SMR) family,

the ATP binding cassette (ABC) family, and the multidrug

and toxic compound extrusion (MATE) family (

Putman et al.,

2000

). Two ABC-type (SmrA, MacABCsm), one MFS-type

(EmrCABsm), a fusaric acid extrusion efflux pump (FuaABC),

and six out of the eight postulated RND-type efflux systems

have been characterized in S. maltophilia (

Alonso and Martinez,

2000; Li et al., 2002; Crossman et al., 2008; Al-Hamad et al.,

2009; Chen et al., 2011; Hu et al., 2012; Gould et al., 2013;

Huang et al., 2013a; Lin et al., 2014a,b

). The six characterized

RND-type efflux pumps in the S. maltophilia genome are

SmeABC, SmeEF, SmeIJK, SmeOP, SmeVWX, and SmeYZ

(including SmeGH and SmeMN). Table 4 provides a summary

of antimicrobial resistance associated with the abovementioned

efflux pumps.

SmeABC

The overexpression of smeABC genes confers resistance to

aminoglycosides, β-lactams, and fluoroquinolones. SmeC was

identified to function independently of SmeAB, while deletions

in smeC but not smeB compromised the antimicrobial resistance

(

Li et al., 2002

).

(11)

TABLE 4 | Genetic determinants of efflux pumps.

Efflux pumps Associated antibiotic resistance

RND FAMILY

SmeABC Quinolones, ß-lactams and aminoglycosides

SmeDEF Quinolones, tetracyclines, macrolides, chloramphenicol, novobiocin and trimethoprim/sulfamethoxazole

SmeIJK Ciproxin, levofloxacin, tetracycline and minocycline

SmeOP-TolCsm Trimethoprim/sulfamethoxazole, aminoglycosides, macrolides, doxycycline, chloramphenicol, and nalidixic acid

SmeVWX Quinolones, chloramphenicol and tetracyclines

SmeYZ Trimethoprim/sulfamethoxazole and aminoglycosides ABC FAMILY

SmrA Fluoroquinolones and tetracycline

MacABCsm Aminoglycosides, macrolides and polymyxins MFS FAMILY

EmrCABsm Nalidixic acid and erythromycin FUSARIC ACID TRIPARTITE EFFLUX PUMP

FuaABC fusaric acid

SmeDEF

SmeDEF is a complex formed by an efflux pump located on the

inner membrane (SmeE), an outer membrane protein (SmeF)

and a periplasmic membrane fusion protein (SmeD). It is

involved in resistance to quinolones, tetracyclines, macrolides,

chloramphenicol and novobiocin (

Alonso and Martinez, 2000

).

Expression of the smeDEF operon is regulated by the SmeT

repressor (

Hernandez et al., 2009

). A recent study showed

that the SmeDEF efflux pump is associated with plant root

colonization by S. maltophilia, and that deletion of the smeE gene

impairs this function (

García-León et al., 2014a

).

SmeVWX

The SmeVWX pump, encoded by a five-gene operon

(smeU1, smeV, smeW, smeU2, and smeX), was identified and

characterized in a multidrug-resistant mutant of S. maltophilia

KJ. Overexpression of the SmeVWX pump resulted in increased

resistance to chloramphenicol, quinolones, and tetracyclines but

increased aminoglycoside susceptibility (

Chen et al., 2011

).

SmeYZ and SmeJK

The smeZ, smeJ, and smeK genes were identified in S.

maltophilia K M5, a selected mutant derivative. SmeZ contributes

to elevated aminoglycoside MICs. SmeJ and SmeK jointly

elevate tetracycline, minocycline, and ciprofloxacin MICs and

confer resistance to levofloxacin (

Gould et al., 2013

). In

addition to drug extrusion, the SmeIJK pump has been

reported to play a physiologic role in the maintenance of

cell membrane integrity (

Huang et al., 2014

). A recent study

further elucidated the physiologic significance of the SmeYZ

pump and demonstrated its correlation with virulence-related

functions, including swimming, flagella formation, oxidative

stress susceptibility, biofilm formation, and protease secretion

(

Lin et al., 2015

).

SmeOP

A pcm-tolCsm operon was recently verified in S. maltophilia

KJ2. The tolCsm gene is involved in the resistance of several

antimicrobial agents, including aminoglycosides, macrolides,

β-lactams, chloramphenicol, nalidixic acid, doxycycline and

TMP/SMX. The deletion of pcm was shown to result in decreased

expression of tolCsm, which compromised the pathogen’s

resistance to amikacin and gentamicin (

Huang et al., 2013b

). A

very recent study characterized a five-gene cluster efflux pump

(tolCSm-pcm-smeRo-smeO-smeP) in S. maltophilia. The study

showed that SmeOP requires TolCSm for efflux pump function

and suggested that TolCSm is the cognate outer membrane

protein (OMP) for the SmeOP pump. The SmeOP-TolCSm

efflux pump was shown to be associated with resistance to

nalidixic acid, doxycycline, amikacin, gentamicin, erythromycin,

and leucomycin (

Lin et al., 2014a

).

ABC Family: SmrA and MacABCsm

SmrA, the first ABC-type efflux pump identified in S. maltophilia,

has been shown to confer resistance to fluoroquinolones and

tetracycline (

Al-Hamad et al., 2009

). The MacABCsm efflux

pump in S. maltophilia was recently shown to confer intrinsic

resistance to antimicrobials (aminoglycosides, macrolides, and

polymyxins) and to play an important role in regulating oxidative

and envelope stress tolerance and biofilm formation (

Lin et al.,

2014b

).

MFS Family: EmrCABsm

Only one MFS-type efflux pump, EmrCABsm, has been

characterized so far. It is involved in the extrusion of

hydrophobic compounds, including the antibiotics nalidixic acid

and erythromycin (

Huang et al., 2013a

).

Fusaric Acid Tripartite Efflux Pump

A novel tripartite fusaric acid efflux pump was found in S.

maltophilia, namely FuaABC, which may constitute a new

subfamily of the tripartite efflux pump. The fuaABC operon was

demonstrated to be induced by fusaric acid and to contribute to

fusaric acid resistance when overexpressed (

Hu et al., 2012

).

Trimethoprim/Sulfamethoxazole (TMP/SMX)

Resistance Mechanisms

The sul1 gene carried by class 1 integrons and the sul2

gene, which is linked to insertion sequence common region

(ISCR) elements, are known to be responsible for resistance to

TMP/SMX in S. maltophilia (

Barbolla et al., 2004; Toleman et al.,

2007; Chung et al., 2015

). The dfrA gene cassettes, which are

located in class 1 integrons and encode for the dihydrofolate

reductase enzyme, have also been reported to confer high-level

resistance to TMP/SMX (

Hu et al., 2011

). Moreover, SmeDEF,

TolCsm, and SmeYZ efflux pumps have recently been reported

to be associated with TMP/SMX resistance (

Huang et al., 2013b;

Lin et al., 2015; Sánchez and Martínez, 2015

).

(12)

Quinolones Resistance Mechanisms

Two mechanisms are associated with resistance of S. maltophilia

to quinolones: efflux pumps and a chromosomally encoded qnr

gene (Smqnr) that protects both gyrase and topoisomerase IV

from quinolones (

Sanchez et al., 2009

). Unlike other bacteria,

clinical isolates of quinolone-resistant S. maltophilia do not

present mutations in topoisomerases (

Valdezate et al., 2005

). To

date, the characterized genetic determinants involving resistance

to quinolones are smeDEF, smeIJK, smeABC, smeVWX, and

Smqnr genes, among which smeDEF and Smqnr are the

best-described. Smqnr belongs to the qnr family. It confers

low-level resistance and contributes to intrinsic resistance to

quinolones in S. maltophilia (

Sánchez et al., 2008; Shimizu et al.,

2008; Sánchez and Martínez, 2010

). García-León et al. further

elucidated the interplay between intrinsic and acquired resistance

to quinolones in S. maltophilia. Their study demonstrated that

the capacity to develop mutation-driven antibiotic resistance

is highly dependent on the intrinsic resistome. Their findings

indicate that the most prevalent cause of acquired quinolone

resistance in S. maltophilia is the overproduction of multidrug

efflux pumps, among which SmeDEF efflux pump plays the

most important role (

García-León et al., 2014b

). In addition,

a more recent report by García-León et al. confirmed that

overexpression of smeVWX in clinical isolates of S. maltophilia

is associated with high-level quinolone resistance (

García-León

et al., 2015

).

Aminoglycosides Resistance Mechanisms

The aminoglycoside-resistant mechanisms in S. maltophilia

primarily involve aminoglycoside-modifying enzymes and efflux

pumps. The reported enzymes to date include AAC(6

′

)-Iz (an

aminoglycoside acetyltransferase) (

Li et al., 2003

), APH(3

′

)-IIc

(an aminoglycoside phosphotransferase) (

Okazaki and Avison,

2007

) and a novel AAC(6

′

_{)-Iak, which was recently identified}

in a MDR strain from Nepal (

Tada et al., 2014

). Efflux pumps

including SmeABC, SmeYZ, SmeOP-TolCsm, and MacABCsm

are associated with resistance as described above.

Antimicrobial Treatment Studies

Trimethoprim/sulfamethoxazole

(TMP/SMX)

remains

the

most effective antimicrobial agent against S. maltophilia,

with

an

overall

susceptibility

rate

higher

than

90%

(

Falagas et al., 2008

). A recent study investigated the

efficacy

of

sulfametrole/trimethoprim,

an

alternative

sulphonamide/trimethoprim combination available in several

Europe countries against non-fermenters (40 S. maltophilia

included) and found that the activity of the alternative

combination was similar to that of TMP/SMX (

Livermore

et al., 2014

). Other common options include ceftazidime,

ticarcillin-clavulanate, fluoroquinolones, and tetracyclines such

as tigecycline, minocycline, and doxycyclines. As previously

mentioned, resistance rates to ceftazidime and

ticarcillin-clavulanate are high and rising and are, therefore, unreliable

choices. Fluoroquinolones are now popular alternatives because

of their less prominent side effects compared to TMP/SMX and

their greater potency compared to β-lactams.

Fluoroquinolones

Fluoroquinolones (FQs) are commonly used to treat infections

due to S. maltophilia (

Nicodemo and Paez, 2007

). However, their

overuse worldwide has resulted in higher resistance rates in many

kinds of pathogenic bacteria, including S. maltophilia (

Chang

et al., 2014; Pien et al., 2015

).

To evaluate the effectiveness of FQs in this era of high FQ

resistance, a retrospective study published in 2014 compared the

outcomes of patients with S. maltophilia infections treated with

TMP/SMX and those of patients treated with FQs monotherapy

(

Wang et al., 2014b

). A total of 38 adults received TMP/SMX and

63 adults received FQs (levofloxacin n = 48 and ciprofloxacin

n = 15). The overall microbiological cure rate was 63% (65%

in the TMP/SMX group and 62% in the FQ group), and the

overall clinical success rate was 55% (61% in the TMP/SXT

group and 52% in the FQ group). The antibiotic regimens were

equally effective in both groups. Another retrospective study

compared the effectiveness of TMP/SMX (n = 51) with that

of levofloxacin (n = 35) in treating S. maltophilia bacteremia

and revealed no significant differences in treatment outcome

between the two groups, including 30-day mortality, length

of hospital day, and antibiotic withdrawal (

Cho et al., 2014

).

However, the rate of adverse events was significantly lower in

the levofloxacin group (0%) than in the TMP/SXT group (23.5%,

p = 0.001).

Several new quinolones have been developed and some

of them have recently been approved for clinical application,

including nemonoxacin (

Huang et al., 2015

) and delafloxacin

(

Bassetti et al., 2015

). Oral nemonoxacin, a novel nonfluorinated

quinolone antibiotic, has been shown to have good activity

against Gram-positive bacilli, such as methicillin-resistant

Staphylococcus aureus (

Huang et al., 2015

). However, in vitro

susceptibility assays on 32 clinical isolates of S. maltophilia

revealed high MIC90

(32 mg/L) and MIC50

(8 mg/L) values (

Lai

et al., 2014a

). Regarding delafloxacin, a phase II study published

in 2009 that compared two doses of delafloxacin to tigecycline

in adults with complicated skin and skin structure infections

found that only one patient was infected with S. maltophilia

and was treated successfully with delafloxacin (

O’Riordan et al.,

2015

). More in vivo studies are needed to better understand the

effectiveness of these new quinolones in treating S. maltophilia

infections.

Tetracyclines

Tetracyclines such as tigecycline, minocycline, and doxycycline

are some of the most active antimicrobial agents against S.

maltophilia other than TMP/SMX, even in the cystic fibrosis

population (

Cantón et al., 2003; San Gabriel et al., 2004; Gülmez

et al., 2010; Milne and Gould, 2012; Castanheira et al., 2014

).

The results agree with our aforementioned observation that

these antibiotics consistently exhibited good activity against S.

maltophilia in global surveillance studies (Table 2).

Tigecycline, a derivative of minocycline, has broad-spectrum

antimicrobial activity (

Stein and Babinchak, 2013

) and is an

alternative agent against S. maltophilia infections. A recent

study from Brazil showed that the MIC50

and MIC90

values of

tigecyline for S. maltophilia isolates, including isolates resistant

(13)