CMR-Brooke-S Maltophilia Global Opportunistic Pathogen-2012

Subscription Information for: Clinical Microbiology Reviews
Stenotrophomonas maltophilia: an Emerging Global

Opportunistic Pathogen
Joanna S. Brooke
Department of Biological Sciences, DePaul University, Chicago, Illinois, USA
Downloaded from http://cmr.asm.org/ on February 12, 2015 by University of Pittsburgh HSLS

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
HISTORICAL AND CLINICAL SIGNIFICANCE OF S. MALTOPHILIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
MICROBIOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
Characteristics of S. maltophilia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
HOST INFECTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
Nosocomial and Community-Acquired Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
Risk Factors and Determining Risk of Infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
TREATMENT OF INFECTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
Emergence of Antibiotic Resistance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
New Treatment Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8
SURVIVABILITY AND PERSISTENCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11
Surfaces and Solutions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11
Biocide Tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12
Resistance to Metals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12
MOLECULAR MECHANISMS INVOLVED IN PATHOGENESIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13
Biofilms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13
Antibiotic Resistance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18
Hydrolytic Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20
Lipopolysaccharide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21
Adherence to and Invasion of Host Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22
Diffusible Signal Factor System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23
S. maltophilia and the Cystic Fibrosis Lung Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23
MICROSCOPY OF S. MALTOPHILIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26
COMPARING CLINICAL AND ENVIRONMENTAL S. MALTOPHILIA ISOLATES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27
Genome Sequencing and Molecular Diversity of S. maltophilia Strains . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27
Linking Clinical Isolates to Sources. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .28
Adaptation and Evolution of Clinical Isolates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .29
MOLECULAR ECOLOGY AND STENOTROPHOMONAS INFECTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .30
Gene Transfer in the Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .30
Climate Change. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31
FUTURE CHALLENGES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .32
ACKNOWLEDGMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .32
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .32
INTRODUCTION those with cystic fibrosis (CF) or those with chronic lung diseases.
P. aeruginosa has been reported to survive for months on dry
C linical microbiologists have long recognized the importance
of identifying infectious microbial pathogens as the cause of
disease in humans. The emergence of new multiple-drug-resistant
surfaces (180), and it is able to persist and grow in contaminated
antimicrobial hand soap containing triclosan, making it a signifi-
(MDR) organisms (MDROs) found in nonclinical environments, cant issue of concern for hospital staff (192).
the increasing reports of community-acquired infections, and the Stenotrophomonas maltophilia is an environmental global
spread of these pathogens in the clinical setting have all under- emerging Gram-negative MDRO that is most commonly associ-
scored the need to monitor these organisms. The increase in re- ated with respiratory infections in humans. It can cause various
ported cases of MDRO-associated infections has resulted in efforts serious infections in humans. This current review focuses on the
to examine possible sources of these pathogens, assess the current strategies used or being developed to treat infections associated
antimicrobial strategies used for the treatment of infections, and with S. maltophilia; the cellular and molecular mechanisms im-
elucidate the molecular mechanisms used by these pathogens dur- portant for its survival, persistence, and pathogenesis; and its mul-
ing infection and disease.
Gram-negative bacterial pathogens have received much atten-
tion, as they are often MDROs due to multidrug resistance pumps,
plasmids harboring antibiotic resistance genes, and various gene Address correspondence to Joanna S. Brooke, jbrooke@depaul.edu.
transfer mechanisms involved in the acquisition of antimicrobial Copyright © 2012, American Society for Microbiology. All Rights Reserved.
resistance. Pseudomonas aeruginosa is an example of such an doi:10.1128/CMR.00019-11
MDRO that causes respiratory infections in patients, particularly
2 cmr.asm.org 0893-8512/12/$12.00 Clinical Microbiology Reviews p. 2– 41

S. maltophilia: a Multiple-Drug-Resistant Pathogen
TABLE 1 S. maltophilia-associated infections TABLE 2 Sources of S. maltophilia

Infection Reference(s) Setting Reference(s)
Pneumonia 115, 310 Clinical/medical
Acute exacerbations of chronic obstructive 101, 247 Hospital suction tubing 377
pulmonary disease Electronic ventilator temp sensors, ventilator 283
Bloodstream, bacteremia 14, 162, 167, 182, 187, 231, inspiratory/expiratory circuits
236, 323, 357, 372 Central venous catheter 188, 228
Soft tissue and skin 33, 297, 343, 372 Nebulizers 80
Cellulitis/myositis 94 Endoscopes 179
Osteomyelitis 191 Dental suction system hoses 250

Catheter-related bacteremia/septicemia 97, 188, 310, 372, 376 Dental solid waste 347
Meningitis 243, 284, 375 Hemodialysis water and dialysate of renal units 15
Endophthalmitis/keratitis/scleritis of the 4, 59, 161, 202, 224, 262, Contaminated chlorhexidine-cetrimide 369
eye; dacryocystitis 370 disinfectant
Endocarditis 19, 135, 171, 237, 326 Hand-washing soap 176
Urinary tract infection 342 Irrigating solutions 4
Biliary sepsis 261 Sink drains 39, 80, 81, 173
Faucets/faucet aerators, showerheads 80, 81, 173, 355, 363
Water fountain drains 40
Patients’ medical charts 327
tiantibiotic resistance and provides a comparison of clinical and Cystic fibrosis patient cough-generated aerosols 351
environmental S. maltophilia isolates. Ice machine 85, 272
Tap water 15, 52, 80, 297, 316,
HISTORICAL AND CLINICAL SIGNIFICANCE OF 345
Water treated by filtration, reverse osmosis, UV 15
S. MALTOPHILIA
exposure, or deionization
S. maltophilia was first isolated in 1943 as Bacterium bookeri and Microfiltered water dispensers 292
then named Pseudomonas maltophilia (154); later, rRNA cistron
analysis determined that it was more appropriately named Xan- Nonclinical
thomonas maltophilia (259, 260, 325). In a large study of Xan- Plant rhizosphere 29, 30, 160, 233
thomonas strains, an analysis of 295 phenotypic characteristics Washed salads 273
resulted in 7 strains being identified as X. maltophilia, with 2 of Soda fountain machines 366
Yellowtail fish, snakes, goats, buffalo, West 117, 138, 140, 141,
these 7 being type strains of Pseudomonas betle and Pseudomonas
African dwarf crocodile 163, 265
hibiscicola (341). There is ongoing debate about nomenclature. Deep-sea invertebrates 286
DNA-rRNA hybridization studies and sequencing and mapping Water treatment process and distribution system 142
of PCR-amplified 16S rRNA genes have resulted in the classifica- Returned liquor from wastewater plant 158
tion and naming of X. maltophilia as S. maltophilia (79, 210, 242, Biofilms on fracture surfaces in aquifers 159
259). Sinkholes of the Yucatan Peninsula 75
S. maltophilia is not a highly virulent pathogen, but it has Saline subterranean Lake Martel (Spain) 279
emerged as an important nosocomial pathogen associated with River water 239
crude mortality rates ranging from 14 to 69% in patients with Water fountain drains and sink drains 40, 81
bacteremia (162, 346). For information about the attributable Showerheads 109
Tap water and bottled water 81, 316, 318, 367
mortality of S. maltophilia infections, the reader is referred to a
Microfiltered water dispensers 292
recent review of the literature (106). The variety of infections as- Home-use nebulizers of CF patients 157
sociated with S. maltophilia is shown in Table 1. Infections asso- Contact lens stock solutions 116
ciated with S. maltophilia include (most commonly) respiratory
tract infections (pneumonia [115, 310] and acute exacerbations of
chronic obstructive pulmonary disease [COPD] [101, 247]); bac-
teremia (182, 187, 236); biliary sepsis (261); infections of the 160, 163, 233, 265), invertebrates (286), water treatment and dis-
bones and joints, urinary tract, and soft tissues (33, 191, 297, 343); tribution systems (142), wastewater plants (158), sinkholes (75),
endophthalmitis (4); eye infections (keratitis, scleritis, and lakes (279), rivers (239), biofilms on fracture surfaces in aquifers
dacryocystitis [202, 224, 370]); endocarditis (19, 135, 171, 237, (159), washed salads (273), hemodialysis water and dialysate sam-
326); and meningitis (243, 284). S. maltophilia is a significant ples (15), faucets, tap water, bottled water (81, 316, 345, 363, 367),
pathogen in cancer patients, particularly those with obstructive contaminated chlorhexidine-cetrimide topical antiseptic (369),
lung cancer. This review will not address in detail infections of S. hand-washing soap (176), contact lens solutions (116), ice machines
maltophilia in cancer patients, and the reader is directed to three (272), and sink drains (39). A significant feature of S. maltophilia
recent articles that address the implications of infection by S. is its ability to adhere to plastics and form bacterial films (bio-
maltophilia in cancer patients (285, 293, 344). films). S. maltophilia has been identified on the surfaces of mate-
S. maltophilia is an environmental MDRO. It has been isolated rials used in intravenous (i.v.) cannulae, prosthetic devices, dental
from aqueous-associated sources both inside and outside the hos- unit waterlines, and nebulizers (80, 157, 188, 200, 228, 250).
pital/clinical setting (Table 2). S. maltophilia has been recovered The incidence of S. maltophilia hospital-acquired infections is
from soils and plant roots, animals (29, 30, 31, 117, 138, 140, 141, increasing, particularly in the immunocompromised patient pop-
January 2012 Volume 25 Number 1 cmr.asm.org 3

Brooke
ulation, and cases of community-acquired S. maltophilia have also patients harboring S. maltophilia in their respiratory tract in-
been reported. S. maltophilia infections can occur in both children creased (P ⫽ 0.02) over the study period from 1 to 4% and was
and adults. The transmission of S. maltophilia to susceptible indi- higher (P ⫽ 0.029) in patients aged 16 to 25 years (7%) than in
viduals may occur through direct contact with the source. The patients ⬎25 years old (4%) (232). In the 2004 SENTRY Antimi-
hands of health care personnel have been reported to transmit crobial Surveillance Program, among pediatric patient isolates, S.
nosocomial S. maltophilia infection in an intensive care unit maltophilia was among the top 15 pathogens isolated from North
(ICU) (307). S. maltophilia has been cocultured with P. aeruginosa America and Latin America but not from Europe (110). Surveil-
in respiratory samples obtained from CF patients. Cough- lance of Antimicrobial Use and Antimicrobial Resistance in Ger-
generated aerosols from CF patients have the potential to provide man Intensive Care Units (SARI) monitored S. maltophilia as one

airborne transmission of S. maltophilia (351). of the 13 most important organisms associated with nosocomial
Molecular analyses, including ribotyping, pulsed-field gel electro- infections; multivariate analyses of the data from 2003 to 2004
phoresis (PFGE), random amplified polymorphic DNA (RAPD), indicated that the use of carbapenems (P ⫽ 0.01) and being in an
and enterobacterial repetitive intergenic consensus sequence-PCR ICU with ⬎12 beds (P ⫽ 0.037) were risk factors for S. maltophilia
(ERIC-PCR), have revealed considerable heterogeneity among S. infection (230).
maltophilia isolates (50, 57, 123, 337, 338). S. maltophilia clinical iso-
lates have a higher rate of mutation than environmental isolates, sug- MICROBIOLOGY
gesting that clinical isolates adapt to their local environment, e.g.,
within different areas of the lungs of CF patients (31). It was proposed Characteristics of S. maltophilia
that antibiotic resistance gene acquisition by S. maltophilia strains S. maltophilia is a Gram-negative obligate aerobe that is rod
occurs in the environment, and upon gaining access to the clinical shaped and motile with a few polar flagella. It is able to persist in
setting, the strains retain the gene(s) (30). These observations empha- nutrient-poor aqueous environments (Table 2). The growth char-
size the need to continue the current monitoring of reported cases of acteristics of S. maltophilia are shown in Table 3. Standard micro-
S. maltophilia, the emergence and spread of antibiotic resistance, and biology reference data currently indicate that S. maltophilia is an
the identification of S. maltophilia isolates from sources within and oxidase-negative bacterium. Recent data, however, suggest that
outside the hospital setting. some S. maltophilia isolates are oxidase positive (48).
Hospitals in several different countries perform surveillance Burdge et al. reported the misidentification of S. maltophilia as
on infections due to S. maltophilia (44, 98, 110, 165, 187, 207, 230, Pseudomonas cepacia (42). In that study, 3 (9%) of 32 clinical
232, 278, 357, 372). A U.S. multiple-hospital study of patient in- isolates were incorrectly identified as being P. cepacia isolates as a
fections in the ICU during 1993 to 2004 reported S. maltophilia as result of a delayed reading (3 min instead of within 1 min) of the
being among the 11 most frequently recovered organisms (4.3% oxidase test and not holding the tests for DNase production 72 h
of a total of 74,394 Gram-negative bacillus isolates) (207). A study prior to observation of the results. The misinterpretation of these
of bacteremia in adult patients in a medical center in northern tests has clinical importance, as P. cepacia is a significant pathogen
Taiwan during 1993 to 2003 reported that risk factors associated in CF patients.
with mortality for patients with S. maltophilia bacteremia in- S. maltophilia has been coisolated with other microorganisms
cluded ICU stay (P ⫽ 0.042), central venous catheter (CVC) (e.g., Pseudomonas aeruginosa, Burkholderia species, Staphylococ-
use (P ⫽ 0.003), and mechanical ventilation (P ⫽ 0.008) (357). cus aureus, methicillin-resistant S. aureus, Acinetobacter bauman-
During 1993 to 2003, a study of bacteremic pediatric patients in a nii, Escherichia coli, Klebsiella species, Enterobacter species, Entero-
university hospital in Taiwan indicated that risk factors associated coccus species, Bacteroides species, Corynebacterium species, and
with mortality in patients with S. maltophilia bacteremia included Candida albicans) in samples recovered from patients (14, 134,
malignancy (P ⫽ 0.049), failure to remove the central venous 187, 333, 357). The nonfermenting Gram-negative bacteria P.
catheter (P ⫽ 0.021), and a lack of effective antibiotic treatment aeruginosa, A. baumannii, and S. maltophilia are all pathogens of
(P ⫽ 0.05) (372). A study during 1993 to 2003 of adult patients the human respiratory tract. The reader is directed to recent pub-
with S. maltophilia bacteremia in two hospitals and a medical cen- lications for further information about the relationship of S.
ter in Taiwan identified thrombocytopenia (P ⫽ 0.001) and S. maltophilia to P. aeruginosa and A. baumannii (35, 205, 309). Se-
maltophilia shock (P ⫽ 0.013) as independent risk factors for mor- lective agar media have been designed to improve the isolation of
tality (187). In a U.S. study of CF sputum microbiology from 1995 S. maltophilia from polymicrobial cultures (77, 235).
to 2008, the prevalence of S. maltophilia increased from 6.7% to To improve the isolation of S. maltophilia from CF patient spu-
12.0% (P ⫽ 0.01), and S. maltophilia was recovered more often tum samples, VIA medium, containing vancomycin, imipenem,
from patients with ⬍40% than from those with ⱖ40% predicted and amphotericin B, was developed (77). VIA medium consists of
forced expiratory volume in 1 s (FEV1) (P ⫽ 0.07) (98). The data a mannitol agar base with a bromothymol blue (BTB) indicator, 5
from the CF Foundation Patient Registry from 1995 to 2005 re- mg/liter vancomycin, 32 mg/liter imipenem, and 4 mg/liter am-
vealed a significant increase (P ⱕ 0.001) in the incidence (range ⫽ photericin B. A comparison of S. maltophilia colony counts recov-
3.0 to 13.8%) and prevalence (range ⫽ 7.0 to 16.4% increase) of S. ered from sputum samples on VIA medium with counts on baci-
maltophilia across all age groups of patients studied (age, 0 to ⬎25 tracin (10,000 U/liter) chocolate (BC) medium revealed that VIA
years) (278). Data from the SENTRY Antimicrobial Surveillance medium detected a higher (P ⬍ 0.0001) number of S. maltophilia-
Program during 1997 to 2008 revealed a 3.1% rate of recovery of S. positive samples than BC medium with an imipenem disk on its
maltophilia from hospitalized patients with pneumonia from 2004 surface. VIA medium was particularly useful for the detection of
to 2008, with regional recovery rates of 3.3% for the United States, low colony counts (102 to 106 CFU/ml) (77).
3.2% for Europe, and 2.3% for Latin America (165). In a British Gram-negative selective agar (GNSA) medium was later devel-
study of adult CF patients during 1985 to 2005, the proportion of oped by Moore et al. (235) to detect Gram-negative microflora in
4 cmr.asm.org Clinical Microbiology Reviews

TABLE 3 Growth characteristics of S. maltophiliaa color differences between S. maltophilia and P. aeruginosa reflect
Growth characteristic Reaction their different metabolic abilities). The production of acid from
Straight or curved rods, 0.5 by 1.5 ␮m
maltose but not from glucose by S. maltophilia has been used to
Oxidase ⫹/⫺ distinguish it from P. aeruginosa, as P. aeruginosa produces acid
Catalase ⫹ from glucose and does not use maltose or lactose to a great extent.
Methionine is required for growth ⫹ Colonies of S. maltophilia appear yellow and blue on BTB-
Optimum growth temp of 35°C containing medium containing maltose and glucose, respectively,
No growth at 4°C or 41°C in contrast to P. aeruginosa colonies, which appear blue on BTB
Survival at refrigeration temp ⫹ medium containing maltose and yellowish green on medium con-
Motility ⫹

taining glucose (169). A selective and differential agar medium,
Nitrate reduction, but nitrate is not used as ⫹ SM2i, contains Mueller-Hinton agar supplemented with maltose,
nitrogen source
dl-methionine, vancomycin, imipenem, amphotericin B, and bro-
Indole ⫺
Lysine decarboxylase ⫹
mothymol blue (3). S. maltophilia colonies are smooth, round,
Ornithine decarboxylase ⫺ and green, with an olive green center with a peripheral lighter
Methyl red ⫺ green area or a dark green center with an olive green peripheral
Voges-Proskauer reaction ⫺ area surrounded by a blue-green halo. The colony appearance of S.
Hydrogen sulfide ⫺ maltophilia is easily distinguished from those of other Gram-
Citrate v negative bacteria, such as P. aeruginosa, which appears white or
Phenylamine deaminase ⫺ colored but very often silver, or E. faecium, which appears minute
␤-Galactosidase (ONPG) v and colorless (3). In one study, this medium was successfully used
Carbohydrate utilization to recover S. maltophilia from water samples and cotton swab
Acid production from maltose ⫹
samples of cold water taps (3). Another study using this medium
Acid production from glucose ⫺
Carbon source for growth
resulted in an increased awareness by health care workers of the
Adonitol ⫺ importance of strict adherence to hand hygiene measures, the use
Arabinose ⫺ of point-of-use (POU) water filtration, and regular maintenance
␤-Hydroxybutyrate ⫺ of swan-necked faucets with a regimen of descaling, disinfection,
Cellobiose v and drying (2).
Dulcitol ⫺ S. maltophilia may be associated with polymicrobial infections
Glucose ⫹ or grow slowly in the host, resulting in some difficulty in isolating
Fructose v this bacterium. Various molecular biology techniques have been
Galactose v used to identify different strains of S. maltophilia. PCR amplifica-
Lactose ⫹
tion of the 16S rRNA gene has been used to detect S. maltophilia in
Maltose ⫹
Mannitol ⫺
blood samples of patients undergoing chemotherapy for acute
Mannose v leukemia or myelodysplastic syndrome (238). That study sug-
Rhamnose ⫺ gested that PCR analysis of blood would be useful for cases where
Salicin ⫺ the bacterial species grows poorly in blood culture medium.
Sorbitol ⫺
Trehalose ⫹/⫺ HOST INFECTIONS
Esculin hydrolysis ⫹
Gelatin liquefaction ⫹ Nosocomial and Community-Acquired Infections
Tween 80 hydrolysis ⫹ S. maltophilia is a waterborne organism, and exposure to this bac-
DNase production ⫹
terium can occur both in and outside the clinical setting. In the
Starch hydrolysis ⫺
health care environment, S. maltophilia has been isolated from
Urea hydrolysis ⫺
a ⫹, ⬎85% of strains positive; v, 16 to 84% of strains positive; ⫺, ⱕ15% of strains
several sources, including suction system tubing of dental chair
positive; ONPG, o-nitrophenyl-␤-D-galactopyranoside. Data are from references 48, 79,
units (DCUs) (250), contaminated endoscopes (179), and tap wa-
169, 258, and 367. ter (297), all of which present possible patient exposure sources. S.
maltophilia-contaminated central venous catheters and tap water
faucets have been implicated in cutaneous and soft tissue infec-
CF patient sputa. GNSA medium contains novobiocin (5 mg/li- tions in patients with neutropenia (297).
ter), cycloheximide (100 mg/liter), amphotericin (2 mg/liter), ni- Patients undergoing hemodialysis can be infected by bacterial
sin (48 mg/liter), and crystal violet (2 mg/liter) and detects 6.70 ⫻ pathogens or endotoxins through contaminated dialysis machine
103 CFU of S. maltophilia/ml sputum. Other Gram-negative or- units (356, 362). MDR S. maltophilia isolates have been recovered
ganisms recovered from adult CF patients and able to grow on this from hemodialysate, tap water, and treated water samples (15).
selective medium include P. aeruginosa, Burkholderia cepacia, E. Treatments of the water included softeners and sand filters, re-
coli, and Alcaligenes xylosoxidans (235). This medium is useful for verse osmosis, bacterial filtration, UV exposure, deionization, and
high-throughput specimen screening, as it is compatible with double reverse osmosis. The membrane filter technique was used
semiautonumeration using digital image capture and processing to detect bacteria present in the samples. Several S. maltophilia
with transilluminal white light. isolates demonstrated resistance to newer-generation cephalospo-
Culture media have been developed to differentiate between the rins (37% and 58% of the isolates were resistant to ceftazidime and
bacterial species present in mixed culture samples (e.g., colony cefepime, respectively) (15). These observations indicate the need

Brooke
for quality control and assurance measures to screen untreated the filters were in place. Patient infections during the use of filters
water, treated water, and dialysate for the presence of S. malto- were due to coagulase-negative Staphylococcus species and E. coli.
philia. Monitoring of these samples should lead to the more effec- That study provided evidence that POU water filtration may ef-
tive disinfection of dialysis machine units. fectively reduce the infection risk for BMT recipients (52). Ultra-
Central venous catheter (CVC)-related X. maltophilia infec- microcells (UMC) of S. maltophilia are able to pass through a
tions have been reported (97). The organism can contaminate the 0.2-␮m filter (316). More research is needed to determine the
infusate and adhere to the catheter, forming biofilms on the cath- clinical significance of this finding and establish if UMC of S.
eter surface. In a study of 149 episodes of septicemia in 131 pa- maltophilia are present in hospital tap water. The use of a 0.1-␮m
tients from 1972 to 1986, X. maltophilia was the bacterium most filter was suggested to provide better performance for the reten-

commonly isolated in monomicrobial (46%) and polymicrobial tion of waterborne bacteria (324).
(75%) septicemias. That study and several others suggested that S. maltophilia is not solely a nosocomial pathogen. There have
the removal of the CVC is essential for the successful treatment of been reports of S. maltophilia associated with community-
S. maltophilia catheter-associated bacteremia, along with antibi- acquired infections. Studies have identified sink drains, faucets,
otic therapy (14, 97, 187, 188, 372).
water, and sponges, etc., as environmental sources of S. malto-
CVC-related S. maltophilia bacteremia and associated relapsing
philia in the homes of colonized and noncolonized CF patients
bacteremia were reported in a study of hematology and oncology
(81); these observations of this opportunistic pathogen are partic-
patients (188). Nosocomial bacteremia, prior antibiotic therapy,
ularly significant for CF or immunocompromised patients.
immunosuppressive therapy, and neutropenia were clinical char-
acteristics associated with CVC-related S. maltophilia bacteremia. Community-acquired S. maltophilia (defined as infections that
By univariate analysis, two risk factors were revealed, long-lasting occurred 48 or 72 h prior to hospitalization) have been reported
neutropenia and failure to remove the CVC upon the initial diag- for child and adult patients and include bacteremia, ocular infec-
nosis of bacteremia. RAPD analysis of five patients revealed that tions, respiratory tract infections, wound/soft tissue infections,
relapses resulted in recurrent bacteremia. urinary tract infections, conjunctivitis, otitis, and cellulitis (105).
S. maltophilia CVC-associated infections have been reported It is common to find that most patients with these S. maltophilia
for hematopoietic stem cell transplantation (HSCT) recipients infections have some form of comorbidity (e.g., COPD, trauma,
(376). These recipients are at a high risk for infection as a result of central venous catheter, prior antibiotic use, malignancy, prior
prolonged neutropenia and breach of the mucocutaneous barrier. hospitalization, HIV infection, or other immune suppression).
Results of a 4-year study of 570 adult patients at the Chaim Sheba S. maltophilia can grow and form biofilms in potable water dis-
Medical Center in Israel indicated that 3.3% of all HSCT patients tribution systems, presenting a possible risk of infection for im-
had S. maltophilia isolated from culture samples. Seventeen pa- munocompromised individuals. A recent study compared the
tients had a CVC during the infection; 15 had bacteremia, and the abilities of two disinfectants to prevent the contamination of mi-
2 other patients had different invasive infections. Polymicrobial crofiltered water dispensers with S. maltophilia. Following the in-
blood and soft tissue infections were demonstrated for 58% of the oculation of water lines with S. maltophilia, the lines were disin-
patients. S. maltophilia was found to be present in addition to fected with 10% peracetic acid (PAA) or with 3% hydrogen
coagulase-negative staphylococci, Corynebacterium species, Pseu- peroxide. Each line received 3 cycles of disinfection contact times
domonas species, Acinetobacter species, and Candida species. After of 10, 30, and 40 min. Disinfection with 10% peracetic acid tem-
the identification of the organism as S. maltophilia, antibiotic porarily reduced the number of bacterial cells up to 2 days post-
therapy was determined by isolate susceptibility; treatment in- treatment. After a 40-min contact time, disinfection with 3% hy-
cluded high-dose (⬎15 mg kg⫺1 of body weight day⫺1) drogen peroxide was more effective than disinfection with 10%
trimethoprim-sulfamethoxazole (TMP-SMX), ofloxacin, or both. peracetic acid and reduced the number of S. maltophilia cells to
Six patients (31.5%) with S. maltophilia bacteremia died. The au- ⬍1 log CFU/100 ml. In that study, S. maltophilia was more toler-
thors of that study emphasized the importance of proper hand ant to disinfection than P. aeruginosa; this is thought to be due in
hygiene and handling of the CVCs and encouraged the immediate
part to a higher level of catalase activity demonstrated by S. malto-
removal of the CVC upon the initial diagnosis of infection (376).
philia (292). It has been reported that hydrogen peroxide is effec-
Bloodstream infections by S. maltophilia have been reported to
tive against biofilm growth in dental chair unit waterlines (249).
occur during extracorporeal membrane oxygenation used for
It is important to identify these environmental sources, as these
⬎48 h in adult patients (323). A university hospital study from
1996 to 2007 reported nosocomial infections in respiratory and observations have suggested preventative measures to control the
cardiac support for patients. Of 334 patients, 16.7% had S. malto- contamination of water supplies with S. maltophilia (e.g., the use
philia isolated from blood cultures. That study provided evidence of filter units and the treatment of water dispensers with peracetic
that the use of extracorporeal membrane oxygenation can pose an acid and hydrogen peroxide) and increased awareness of the lim-
S. maltophilia infection risk. itations of some of these measures.
Point-of-use (POU) water filtration has significantly reduced Polymicrobial infections with S. maltophilia and other organ-
(P ⫽ 0.0431) health care-associated Gram-negative bacterial in- isms such as P. aeruginosa in the CF lung environment have been
fections in bone marrow transplant (BMT) recipients (52). Mi- reported (203, 204). Recent studies investigating these organisms
crobiological screening of 4 unfiltered hospital tap water outlets in for their adherence to and invasion of human bronchial epithelial
the bone marrow transplant unit of a major U.S. teaching hospital cells will be described below (see “S. maltophilia and the Cystic
identified P. aeruginosa in 2 of 4 outlets and S. maltophilia in 1 of Fibrosis Lung Environment”). Future research is needed to deter-
4 outlets. Clinical infection rates decreased (P ⫽ 0.0068) from 1.4 mine the specific interactions of S. maltophilia with other micro-
to 0.18 per 100 patient-days in the 9-month period during which organisms during infection and disease.

Risk Factors and Determining Risk of Infection teria and provide an opportunity for the acquisition of drug resis-
To prevent the transmission of S. maltophilia to susceptible indi- tance by other bacterial pathogens (49).
viduals, it is important to identify risk factors for infection by this The drug resistance mechanisms are acquired by the horizontal
bacterium. Infection risk assessment must consider criteria that transfer of antibiotic resistance through plasmids, transposons,
include infectious dose, host immune status, pathogen status, and integrons, integron-like elements, insertion element common re-
the ability of the pathogen to cause infection. gion (ISCR) elements, and biofilms (17, 18, 27, 146, 198, 328). The
molecular mechanisms of antibiotic resistance in S. maltophilia
Risk factors for S. maltophilia infection include underlying ma-
are described in more detail below (see “Antibiotic Resistance”).
lignancy (44), the presence of indwelling devices (e.g., catheters
The Clinical and Laboratory Standards Institute provides
[44, 228]), chronic respiratory disease, immunocompromised

guidelines for the testing of antimicrobial agents against S. malto-
host (44), prior use of antibiotics (13, 228), and long-term hospi-
philia using dilution and disc diffusion methods (61, 62). S. malto-
talization or ICU stay (187). Risk factors for S. maltophilia
philia isolates exhibit differences in antimicrobial susceptibility to
infection-associated mortality include malignancy, severe septic
aminoglycosides when tested at different temperatures (e.g., 30°C
shock, and organ failure (120).
and 37°C, with resistance typically observed at 37°C) (275). Dif-
Immunocompromised individuals are at a significant risk for
ferences in resistance rates for S. maltophilia have also been re-
infection by S. maltophilia. Orointestinal mucosal damage result-
ported for observations after 24 h and 48 h of incubation (TMP-
ing from anticancer therapies (185), graft-versus-host disease
SMX, ciprofloxacin, ceftazidime, cefepime, piperacillin, and
(185), and diarrhea (13) have been reported to be risk factors for
piperacillin-tazobactam demonstrated significant differences
infection with S. maltophilia. In a Japanese study (14), prognostic
[P ⬍ 0.05]) (134). It is important to recognize that currently, there
factors associated with mortality were neutropenia (P ⫽ 0.008)
is no worldwide standardized guideline for antimicrobial agent
and polymicrobial bacteremia with enterococci (P ⫽ 0.022) (14).
testing. As a consequence, the MIC values assigned to antimicro-
Risk factors for mortality of patients with nosocomial S. malto-
bial agent resistance alter according to the standards used by dif-
philia pneumonia included stay in an ICU (P ⫽ 0.018), malig-
ferent countries (e.g., those approved by the European Committee
nancy (P ⬍ 0.001), renal disease (P ⫽ 0.001), and inadequate
on Antimicrobial Susceptibility Testing and the European Medi-
initial empirical antibiotic therapy (P ⫽ 0.001) (333).
cines Evaluation Agency for European Chemotherapy) (165).
A study of patients and environmental surfaces in two U.S. pediat-
This observation coupled with reports of differences in results
ric chronic-care facilities identified risk factors for colonization by S.
obtained after using different methods to assess the susceptibility
maltophilia and other antibiotic-resistant Gram-negative bacteria. A
testing of S. maltophilia isolates (133, 199, 223, 244, 337, 357, 372)
strong association (P ⱕ 0.01) with colonization by these bacteria was
highlight the need to establish global standard guidelines that will
observed for patients with prosthetic devices (200). That study also
facilitate the monitoring of antimicrobial-resistant organisms.
revealed that pediatric patients living in chronic-care facilities can
A comparison of the antimicrobial resistances of S. maltophilia
serve as sources of antibiotic-resistant Gram-negative bacteria.
isolates recovered from CF and non-CF (NCF) patients revealed
S. maltophilia is emerging as a significant pathogen worldwide,
that CF strains tended to be more resistant than non-CF strains,
and there is a need to continue to monitor its antibiotic resistance,
with significantly higher (P ⬍ 0.05) levels of resistance to pipera-
persistence, and spread within the community and health care
cillin, cefotaxime, cefepime, moxalactam, ciprofloxacin, ofloxa-
settings.
cin, sparfloxacin (4-␮g/ml resistance breakpoint), gatifloxacin (4-
␮g/ml breakpoint), and doxycycline (8-␮g/ml resistance
TREATMENT OF INFECTIONS breakpoint) (45). That study also revealed that isogenic and
closely related CF strains displayed differences in susceptibilities
Emergence of Antibiotic Resistance
to ticarcillin-clavulanate, moxalactam, ciprofloxacin, newer fluo-
S. maltophilia exhibits resistance to a broad array of antibiotics, roquinolones, doxycycline, and TMP-SMX.
including TMP-SMX, ␤-lactam antibiotics, macrolides, cephalo- In 2006, a study of S. maltophilia recovered from sputum sam-
sporins, fluoroquinolones, aminoglycosides, carbapenems, chlor- ples of CF patients in a large German hospital demonstrated that
amphenicol, tetracyclines, and polymyxins. The low membrane only 34.4% of the isolates were susceptible to TMP-SMX, 25%
permeability that contributes to resistance to ␤-lactams including were susceptible to ciprofloxacin, and all of them were resistant to
cefepime, ticarcillin-clavulanate, ceftazidime, and piperacillin- imipenem (340). Superinfections caused by S. maltophilia, P.
tazobactam (5, 68, 229) and the presence of chromosomally en- aeruginosa, and K. pneumoniae following the use of imipenem to
coded multidrug resistance efflux pumps (6, 11, 54, 129, 196, 198, treat patients with severe pneumonia have been reported (112).
269, 383), ␤-lactamases (9, 17, 18, 227, 295, 296, 352, 353), and The treatment of patients with acute exacerbations of severe
antibiotic-modifying enzymes (174, 190, 195) all contribute to the COPD with imipenem has been associated with a high (30.8%)
intrinsic antibiotic resistance of S. maltophilia (298). The intrinsic risk of superinfection, including those caused by S. maltophilia
resistance of S. maltophilia was suggested to have been acquired in and P. aeruginosa (91). The identification of imipenem as a risk
natural nonhuman environments and is not due solely to the use factor for S. maltophilia infection has not been reported for all
of antibiotics in medical/clinical settings (218, 298). Environmen- studies of S. maltophilia infections. In a large study of 759 patients,
tal intrinsically resistant bacteria such as S. maltophilia were sug- Carmeli and Samore (47) found no significant difference in the
gested to use their metabolic machinery to detoxify and break rates of acquisition of S. maltophilia infection for treatment with
down harmful compounds (including antibiotics) (218). The bio- imipenem compared to treatment with ceftazidime.
chemical pathways used by these bacteria may enable the use of The preferred treatment of S. maltophilia infections has been
antibiotics as food sources (218). The contamination of the envi- the use of the bacteriostatic compound TMP-SMX (119, 146).
ronment with antibiotics can enrich for antibiotic-resistant bac- During 2004 to 2009, S. maltophilia clinical isolates recovered

Brooke
TABLE 4 New treatment strategies for S. maltophilia infections

Antimicrobial approach Mechanism(s) Reference(s)
Antimicrobial peptides Membrane disruption and cell lysis 211, 214, 215
Trimethoprim-sulfamethoxazole and tigecycline Synergy of antimicrobials 100
Tigecycline and amikacin Synergy of antimicrobials 100
Aerosolized colistin and doxycycline Bactericidal combination therapy 371
Aerosolized levofloxacin Bactericidal 121, 175
Tigecycline Inhibition of protein synthesis 108
Moxifloxacin Bactericidal 20, 89, 178, 267
Cationic compounds Interaction with negative charges on cell membrane and cell wall 132

resulting in disruption of binding sites
Nanoemulsions Membrane fusion and cell lysis 206
Phage therapy Cell lysis 53, 93
Plant oils Unknown 103
EGCG from green tea Membrane damage, inhibition of DNA gyrase 125, 130
Peptide inhibitor of ␤-lactamase Inhibitor of ␤-lactamase L1 305
Triple-␤-lactamase inhibitor combination 255
from the adult ICU of a tertiary care center in Saudi Arabia dem- noted for antibiotic cycling and noncycling periods in the surgical
onstrated major increases in resistance to gentamicin, while intensive care unit, medical intensive care unit, and other surgical/
⬎90% of the isolates were susceptible to TMP-SMX (8). Recently, medical wards and incidence rates of S. maltophilia isolates, but
TMP-SMX was used in combination with ciprofloxacin to treat S. the study did reveal a significant increase (P ⫽ 0.01728) in the
maltophilia meningitis in a preterm baby (284), but the emergence rates of S. maltophilia infections in hospitals between 1993 (rate of
of resistance to TMP-SMX is forcing physicians to consider alter- 0.45 infections/1,000 patient days) and 2002 (rate of 0.57 infec-
natives (7, 245, 328, 333, 357). Results from the SENTRY Antimi- tions/1,000 patient days) (257). As one would expect, antibiotic
crobial Surveillance Program in 2004 showed a level of resistance cycling was not linked to increased colonization rates of S. malto-
to TMP-SMX of 3.8% for S. maltophilia (110), and results from philia.
the SENTRY Antimicrobial Surveillance Program in 1997 to 1999
showed a level of resistance of up to 10% across Europe (119).
New Treatment Strategies
Ticarcillin-clavulanate has been proposed as an alternate ther-
apy to TMP-SMX, but resistance to ticarcillin-clavulanate has An overview of new treatment strategies for S. maltophilia infec-
been reported. Antibiotic susceptibility testing of 66 S. maltophilia tions is presented in Table 4. A recent review addressed the use of
clinical isolates (from clinical specimens [respiratory tract, blood, new antimicrobial agents in cancer patients to treat infections of
urogenital tract, cutaneous-mucus specimens, and intravascular MDR bacteria, including S. maltophilia (285). There is ongoing
devices] in two university hospitals in Rouen, France, and Tunis, debate about the use of monotherapy versus combination therapy
Tunisia) collected between 1994 and 1997 revealed that the per- to treat infections of S. maltophilia. New treatment strategies have
centage of isolates resistant to ticarcillin-clavulanate steadily in- included the use of select antibiotics in synergy. Using the check-
creased from 19% (1995) to 32% (1996) to 42% (1997) (26). The erboard method, some synergism has been observed between tige-
increase in antibiotic resistance did not appear to correspond to cycline and TMP-SMX, and between tigecycline and amikacin,
antimicrobial use, as the amount of ticarcillin-clavulanate used against S. maltophilia (100, 349). In vitro pharmacodynamic
decreased from 21.7 kg (1995) to 17.1 kg (1996) to 11.5 kg (1997). model results revealed that TMP-SMX in combination with either
ERIC-PCR demonstrated a high level of heterogeneity among the ciprofloxacin, ceftazidime, or tobramycin demonstrated higher
S. maltophilia isolates, suggesting that the emergence of resistance bactericidal efficacy (P ⬍ 0.0001) against S. maltophilia clinical
to ticarcillin-clavulanate was not due to the spread of an epidemic isolates than TMP-SMX alone (379). Synergy testing by Etest re-
strain but may have been a result of the increased usage of parenteral vealed that TMP-SMX plus ceftazidime and TMP-SMX plus
amoxicillin, amoxicillin-clavulanate, ticarcillin, and piperacillin- ticarcillin-clavulanate demonstrated the highest level of synergis-
tazobactam, at rates of 20%, 58%, 116%, and 48%, respectively, tic activity against S. maltophilia isolates (133). The checkerboard
across 1995 to 1997 (26). The levels of resistance to ticarcillin- method detected synergy for TMP-SMX plus ceftazidime in only
clavulanate for S. maltophilia isolates have been reported to be 17.0% 56% of these isolates and did not detect synergy for TMP-SMX
by the SENTRY Antimicrobial Surveillance Program in 2004 (110) plus ticarcillin-clavulanate in the isolates (133). Synergy or partial
and 40.9% and 60.9% in Brazil (244) and Latin American countries synergy was detected by the checkerboard method for combina-
(108), respectively. tions of ceftazidime plus ciprofloxacin and for TMP-SMX plus
Antimicrobial cycling using broad-spectrum agents, including ticarcillin-clavulanate against S. maltophilia isolates (199). The
carbapenems, has been studied to detect a possible link to ineffective treatment of those patients with S. maltophilia bactere-
creased colonization or infection by S. maltophilia. A retrospective mia and allergy or intolerance to TMP-SMX may be achieved by
study (1992 to 2002) by a U.S. university hospital demonstrated use of ciprofloxacin in combination with ticarcillin-clavulanate or
no significant differences between cycling and noncycling periods ceftazidime (107). A combination of doxycycline and aerosolized
with broad-spectrum agents including piperacillin-tazobactam, colistin was successfully used to treat persistent S. maltophilia
cefepime, and ciprofloxacin (257). No significant differences were ventilator-associated pneumonia (S. maltophilia counts of 500,000

CFU/ml recovered from a bronchoalveolar lavage culture) when tericidal concentration demonstrated a rapid killing of one clinical
high-dose TMP-SMX therapy was ineffective (371). S. maltophilia isolate. The practical value of the Esc(1-18) peptide
A recent case report described an S. maltophilia isolate with for use in humans has yet to be determined, as although it has
extensive drug resistance (according to the terminology proposed demonstrated reduced cytolytic activity against human red blood
by Falagas and Karageorgopoulos [104]) (306). The isolate colo- cells and retains its bactericidal effects in the presence of human
nized and formed biofilms on a bladder device in a patient with serum, it needs to be tested further (e.g., in animal models of
myelofibrosis (306). The isolate demonstrated resistance to TMP- sepsis) to provide further data to support its use in the treatment
SMX, tetracycline, tigecycline, ␤-lactams, fluoroquinolones, ami- of human infections (215).
noglycosides, colistin, and erythromycin but was unusual in its The activity of Esc(1-8) in combination with conventional an-

susceptibility only to chloramphenicol and rifampin. These obser- tibiotics used to treat S. maltophilia infections (amikacin, ceftazi-
vations indicate that older antibiotics should still be considered dime, colistin, and levofloxacin) has been assessed in synergy
for the treatment of S. maltophilia infections (306). Rifampin has studies (211). Synergy studies using five clinical S. maltophilia
shown synergy with gentamicin and carbenicillin in a triple- isolates and S. maltophilia ATCC 13637 were performed in the
combination therapy against S. maltophilia (378). TMP-SMX and presence of sodium phosphate buffer and human serum. In so-
carbenicillin and rifampin together have also shown synergy dium phosphate buffer, Esc(1-8) in combination with amikacin
against S. maltophilia (378). Bactericidal activity can be observed or colistin resulted in synergistic activity against five of six S.
when rifampin is used in combination with ofloxacin and ceftazi- maltophilia isolates. Enhanced killing at subbactericidal concen-
dime (331). trations [0.5-␮g/ml concentration of Esc(1-8) and colistin] was
Moxifloxacin shows some promise for the treatment of MDR observed for the combination of Esc(1-8) and colistin against two
S. maltophilia infections (20, 89, 178, 267). An in vitro representative S. maltophilia isolates. However, no synergistic ef-
pharmacokinetic-pharmacodynamic model used to assess the ac- fect against these two isolates was observed for the combination of
tivity of ciprofloxacin and moxifloxacin against S. maltophilia sug- Esc(1-8) and amikacin. No synergy was observed for Esc(1-8)
gested that maximum tolerable doses are needed to overcome re- used in combination with ceftazidime or levofloxacin. In the pres-
sistant bacterial populations (20). The use of these antibiotics at ence of 20% heat-inactivated human serum, against one represen-
concentrations greater than the MIC is needed for the treatment tative S. maltophilia isolate, Esc(1-8) demonstrated enhanced bac-
of systemic S. maltophilia infections. An in vitro assessment of the
tericidal activity (4 ␮g/ml; 1/8 minimal bactericidal concentration
postantibiotic effect (PAE) of moxifloxacin revealed that the ex-
[MBC]) when used in combination with colistin (0.125 ␮g/ml; 1/2
posure of 20 S. maltophilia clinical isolates to high (8⫻ and 10⫻
MBC) or with amikacin (1 ␮g/ml; 1/16 MBC). The observations
MIC) concentrations of moxifloxacin resulted in an increased de-
of an enhanced killing by subbactericidal concentrations of ami-
lay of cell growth posttreatment. A PAE of ca. 4 h was achieved,
kacin following the preincubation of S. maltophilia with Esc(1-8)
and for some isolates of S. maltophilia, the PAE exceeded 24 h
suggest that the peptide may reduce the outer membrane perme-
(178). The activity of subinhibitory concentrations of moxifloxa-
ability barrier of S. maltophilia, resulting in an increase in the
cin against cell viability in biofilms and against preformed biofilms
uptake of amikacin. That study suggested that the use of Esc(1-8)
is addressed in more detail below (see “Antibiotic Resistance”).
In vitro studies of 1,586 isolates of S. maltophilia recovered from may be helpful for facilitating the antimicrobial activity of drugs
global medical centers revealed that isolates were susceptible to (e.g., aminoglycosides) that have difficulty crossing the cell mem-
tigecycline (95.5% at ⱕ2 ␮g/ml) and to TMP-SMX (96.0% at ⱕ2 branes of S. maltophilia (211).
␮g/ml trimethoprim and 38 ␮g/ml sulfamethoxazole) (108). The peptide Cys-Val-His-Ser-Pro-Asn-Arg-Glu-Cys has been
Tigecycline demonstrated activity against 938 S. maltophilia iso- identified as a specific inhibitor of ␤-lactamase L1 of S. maltophilia
lates from North America and Europe (MIC50 ⫽ 1 ␮g/ml and through the screening of a phage display library (305). The peptide
MIC90 ⫽ 2 ␮g/ml; 94.5 to 95.3% susceptible) and against 648 demonstrated a mixed inhibition of L1 (dissociation constant of
isolates from the Asia-Pacific region and Latin America (MIC50 ⫽ complex enzyme inhibitor [Ki competitive] of 16 ⫾ 4 ␮M and
0.5 ␮g/ml and MIC90 ⫽ 2 ␮g/ml; 96.1 to 96.5% susceptible) (108). dissociation constant of complex enzyme-substrate inhibitor
Cationic peptides (e.g., esculin-1b) from amphibians can in- [Ki= uncompetitive] of 9 ⫾ 1 ␮M) and prevented zinc atoms from an
crease the outer membrane permeability of S. maltophilia (211, optimal association with L1, altering the functional activity of L1.
214). The reported rate of resistance to these antimicrobial pep- The peptide is a compound used for the screening and develop-
tides (AMPs) is lower than the rate of resistance demonstrated for ment of small molecules that can inhibit ␤-lactamases such as L1
conventional antibiotics (181). These observations suggest that (305).
there is the potential for future treatments to take advantage of the BAL30376 is a triple-␤-lactamase inhibitor combination com-
combination of cationic peptides with conventional antibiotics. posed of a siderophore monobactam, a specific inhibitor of class C
The N-terminal region [Esc(1-8)] of the esculentin-1b peptide ␤-lactamases, and clavulanic acid, an inhibitor of most class A and
isolated from Rana esculenta skin secretions contains the antimi- some class D ␤-lactamases (255). BAL30376 demonstrated an
crobial properties of the peptide (214). Esc(1-18) was effective MIC90 of 2 ␮g/ml against S. maltophilia (255).
against MDR S. maltophilia clinical isolates at concentrations of The antibacterial activities of new cationic compounds (e.g.,
0.5 ␮M, 8 ␮M, and 16 ␮M needed for a bactericidal effect when hexamidine diisethionate [HX], chlorhexidine digluconate
tested in sodium phosphate buffer (SPB), in 20% heat-inactivated [CHX], and para-guanidinoethylcalix[4]arene [CxI]) have been
human serum, and in 40% heat-inactivated human serum, re- assessed (132). Cationic compounds act by binding to the nega-
spectively (215). Temporins and bombinin peptides showed vari- tively charged surfaces of the bacterial cell wall and membranes.
ability in their bactericidal activities against all three clinical S. The results of that study showed that two strains of MDR S. malto-
maltophilia isolates. All of these tested peptides at 2-fold the bac- philia demonstrated susceptibility to CHX (MIC ⬍ 1 to 32 mg/

Brooke
liter), some susceptibility to HX (MIC ⫽ 32 to 256 mg/liter), and (Cmax)/MIC and area under the curve (AUC)/MIC values ob-
resistance to CxI (MIC ⫽ 256 mg/liter) (132). tained through aerosolized delivery, in contrast to those values
A surfactant-stabilized oil-in-water nanoemulsion (NB-401) obtained for intravenous or oral delivery (121). Observations of
has shown antimicrobial activity against planktonic and biofilm- CF subjects receiving nebulized formulations of MP-376 (levo-
associated cells of S. maltophilia (206). This nanoemulsion con- floxacin inhalation solution; Aeroquin) at a dose of 180 mg fol-
sists of emulsified cetylpyridinium chloride, poloxamer 407, and lowed by 7 days of daily treatment doses of 240 mg demonstrated
ethanol in water with superrefined soybean oil. The interaction of high sputum and low serum levofloxacin concentrations. Patients
the nanoemulsion with the cell was suggested to result in the fu- tolerated the MP-376 formulations well, with no serious adverse
sion of the outer membrane with the nanoemulsion, leading to events reported and no patients excluded during the study due to

cell lysis. The testing of NB-401 against planktonic cells of 15 S. an adverse event (121). Clinical trials using MP-376 are needed to
maltophilia isolates resulted in MIC values of ⱕ15.6, 31.2, and assess the efficacy and tolerance of this antibiotic in CF subjects
ⱕ15.6 to 62.5 ␮g/ml cetylpyridinium chloride at 50% MIC, 90% with S. maltophilia infections.
MIC, and the range of MIC values for NB-401, respectively. The S. As an alternative to the use of antibiotics, essential oils from
maltophilia isolates demonstrated the greatest susceptibility to plants (e.g., orange, bergamot, cinnamon, clove, cypress, eucalyp-
NB-401 compared with 135 other bacterial isolates found in cystic tus, fennel, lavender, lemon, mint, rosemary, sage, and thyme)
fibrosis sputum. Against biofilm cells of S. maltophilia and in the were investigated and found to demonstrate antibacterial activity
presence of 43% CF sputum, NB-401 activity resulted in an in vitro against S. maltophilia (103). Vero cell assays were performed to
minimum bactericidal activity (SMBC) value of 31.2 ␮g/ml. These determine the cytotoxicity of the oils. Clinical isolates of S. malto-
observations revealed that the nanoemulsion partially preserved philia that were resistant to phosphomycin, imipenem, piperacil-
its antimicrobial activity in CF sputum. The antimicrobial action lin, and aztreonam demonstrated susceptibility to the oils at non-
of the nanoemulsion appears to involve the outer membrane li- toxic concentrations ranging from 0.0005 ml/ml to 0.00005 ml/
popolysaccharide (LPS), as the addition of EDTA, a divalent cat- ml. Cinnamon, thyme, and clove demonstrated the highest level
ion chelator that disrupts the stability of lipopolysaccharide on the of antimicrobial activity and inhibited all tested strains of S. malto-
bacterial cell surface, increases the bactericidal activity of NB-401 philia. It has been suggested that despite the observation of the
against Gram-negative bacteria. NB-401 is suggested to be of use MIC of thyme (0.003125 ml/ml) above the noncytotoxic concen-
as an inhaled antimicrobial therapy, as indicated by preliminary tration, thyme has potential use for the treatment of respiratory
data from studies in which multiple daily exposures of NB-401 in tract infections in humans (103). The toxicity of these oils against
mice were well tolerated (2,000 ␮g ml⫺1 dose⫺1). That study sug- respiratory epithelial cells needs to be assessed. At nontoxic con-
gested that a combination inhalational therapy of NB-401 and centrations, these oils may show potential application for inhala-
hypertonic saline may be of benefit to CF patients and avoids the tion therapy to treat respiratory tract infections. Future research is
risk of antibiotic resistance (206). More studies are needed to de- needed to elucidate the precise chemical composition of the oil
termine the pharmacokinetics and efficacy of this nanoemulsion that determines the mechanism of action (bactericidal/bacterio-
treatment in animal models and in clinical trials with CF patients. static activity) of these oils.
Aerosolized antibiotics are of particular significance for use in The use of phage therapy may be an alternative to the use of
CF patients’ lung infections. Tobramycin was the first antibiotic antibiotics to treat S. maltophilia infections. To the best of my
used for inhalational therapy for CF patients (175). The delivery of knowledge, phage therapy is not used in ordinary clinical practice
antipseudomonal aminoglycoside therapy by nebulizer has been for the treatment of S. maltophilia infections. S. maltophilia phages
associated with an increased risk for colonization by S. maltophilia have been isolated from sputum samples, pleural effusions, and
(82). The intermittent delivery of aerosolized tobramycin by a catheter tips (53). One of these phages, phage ␾SMA5, has been
nebulizer (cycles of 300 mg tobramycin or taste-masked placebo further characterized and exhibits ultrastructural features similar
twice daily for 28 days followed by 28 days without treatment) did to those of phages of the family Myoviridae or Bradley’s group A1.
not increase the selection of tobramycin-resistant S. maltophilia This phage was tested against 87 S. maltophilia strains isolated
and resulted in persistent treatment-emergent S. maltophilia in a from hospitals and was found to have a narrow host range. These
very low number of patients (43, 276). A retrospective study of observations suggest that further research is needed to isolate and
tobramycin in two placebo-controlled trials revealed that most S. identify multiple S. maltophilia phages that can be used as a cock-
maltophilia isolates occurred intermittently and were rarely per- tail against heterogenous strains of S. maltophilia. A recent review
sistent isolates (131); this occasional appearance of S. maltophilia suggested that the use of phages to treat biofilms has potential
in CF patients has been reported by several studies (76, 168, 338). (93). Research is needed to determine if phage-coated catheters
As S. maltophilia has been recovered from nebulizers of CF pa- demonstrate significantly reduced numbers of viable cells when
tients (80, 157), a small study tested the biofilm-forming abilities the catheters are exposed to S. maltophilia, if the S. maltophilia
of environmental and clinical S. maltophilia isolates after exposure biofilms can be reduced or removed, and if S. maltophilia develops
to tobramycin at a concentration (16,000 ␮g/ml) found inside the resistance to the phage.
nebulizers (234). All five biofilm-associated S. maltophilia isolates Together, the observations from the studies described above
remained viable after exposure to tobramycin (234). suggest that it is possible that a cocktail of surfactant, antimicro-
Levofloxacin, a broad-spectrum fluoroquinolone, has been re- bial peptides, and phage may provide a suitable alternative to the
ported to demonstrate an MIC range of 0.25 to 8 ␮g/ml against 51 administration of antibiotics.
S. maltophilia clinical isolates from CF patients (175). That study The green tea polyphenol (⫺)-epigallocatechin-3-gallate
suggested the potential for the use of levofloxacin as an aerosolized (EGCG) has demonstrated antimicrobial activity against clinical
antibiotic in CF patient infections. An additional attractive feature isolates of S. maltophilia (125). EGCG is the major polyphenol
of levofloxacin is the higher maximum concentration of the drug component of green tea (Camellia sinensis). The testing of 40 S.

maltophilia clinical isolates with EGCG resulted in a range of MICs sibility of eutrophication, dissolved oxygen depletion, and a de-
(128 mg/liter to ⬎512 mg/liter) (125). Future work is needed to creased value of the water supply. S. maltophilia BK is able to
determine whether EGCG inhibits the adherence of S. maltophilia reduce Fe(III) to Fe(II) using xenobiotics as sole sources of carbon
to epithelial cells and if exposure to EGCG reduces or alters the under anaerobic conditions. The production of Fe(II) resulted in
biofilms of S. maltophilia. the removal of dissolved phosphate and the increased precipita-
tion of phosphate by S. maltophilia. S. maltophilia BK exhibited a
SURVIVABILITY AND PERSISTENCE rate of phosphate removal of 33 mg/g volatile suspended solids/
day (158).
Surfaces and Solutions Tap water can harbor opportunistic pathogens at levels that are

S. maltophilia is associated with wet surfaces and aqueous solu- significant for immunocompromised individuals. Municipal tap
tions. Cells of S. maltophilia have the ability to survive with min- water can contain 107 bacteria/liter (109). The numbers of S.
imal nutrients, e.g., in drinking water, ultrapure water, treated maltophilia cells in water samples vary with environmental condi-
water (after water treatment of filtration, reverse osmosis, UV tions, including how frequently the water source is used and the
exposure, or deionization), and dialysate effluent (15, 184). In temperature of the water (81). Hospital water sources can serve as
response to starvation or stress, S. maltophilia in tap water reduces reservoirs of nosocomial pathogens such as Pseudomonas spp. and
the energy cost of chemotaxis by forming UMC (0.1 to 0.2 ␮m) S. maltophilia. Showerheads equipped with 0.2-␮m filters may
that can pass through a 0.2-␮m filter (316). UMC are formed in select for UMC that pass through the filter and form biofilms on
water (potable water, mineral water, and reverse osmosis water) the showerhead filter surface, where they can act as a source of
by several genera of bacteria, including Stenotrophomonas, Pando- infection. Showerhead biofilms have been reported to enrich op-
raea, Microbacterium, Afipia, Pseudomonas, Vibrio, Sphingomonas, portunistic pathogens such as chlorine-resistant nontuberculous
and Aeromonas (95, 145, 164, 209, 221, 241, 316). It has been mycobacteria (109). Increased exposure to aerosolized bacteria
reported that biofilm and UMC can pass through these filter units, due to increased shower use was hypothesized to correlate with the
demonstrating that filtration has limited efficacy for the removal rising rates of infection by nontuberculous mycobacteria (248).
of these potential pathogens from water (316). Cultivated UMC Several studies have reported that point-of-use filtration reduced
capable of forming biofilms on polyvinyl chloride (PVC) pipe exposure to the waterborne pathogens Legionella species, Myco-
walls have been recovered from chlorinated drinking water sam- bacterium gordonae, and Pseudomonas species in health care facil-
ples and grown on Alpha agar plates containing 0.005% peptone ities (52, 102, 144, 254, 311, 332). At the time of writing, I found no
of soybean meal. These ultramicrobial cells would not be detected studies that investigated a possible correlation between shower-
by using the standard and total heterotrophic plate counts (HPC). head aerosols of S. maltophilia and infection rates.
These observations suggest that UMC can act as a potential source The dispensers of soda fountain machines have been shown to
of infection if they come into favorable environmental conditions, harbor microorganisms that include MDR S. maltophilia (366).
e.g., through the leaching of nutrients from the PVC pipe (220). Of the beverages (sugar sodas, diet sodas, and water) sampled for
Medical devices with PVC are prepared by combining PVC with microorganisms, 48% contained coliform bacteria and ⬎11%
components such as phthalic esters, organic tin compounds, ep- contained E. coli (366). Since the water supply used for the soda
oxidized soy bean oil, esters, and organic phosphate compounds. fountain machines was reported to be in compliance with U.S.
The leaching of these components from PVC may contribute to Environmental Protection Agency (EPA) standards, this impli-
the adherence of nonmucoid P. aeruginosa strains to PVC. The cated the soda fountain machines as the source of the microbial
adherence of these strains was reported to be greater (P ⬍ 0.05 at contamination of the beverages. It was suggested that communi-
5 days and P ⬍ 0.01 at 7 days) than their adherence to polyure- ties of the bacteria form biofilms inside the fountain dispensing
thane and siliconized latex (220). machines. The contamination of soda fountain machines with
Water treatment processes are designed to prevent the water- potentially pathogenic microorganisms, including S. maltophilia,
borne distribution of pathogens to humans. The treatment typi- is of concern for immunocompromised individuals consuming
cally consists of coagulation, flocculation, sedimentation, filtra- these beverages. It is recommended that the dispensing unit and
tion, and chlorination. HPC are often used to assess the fittings of soda machines be regularly inspected for physical wear
bacteriological quality of water but do not support the growth of and the presence of microbial biofilms and be disinfected to re-
all bacteria that can inhabit chlorination distribution systems. Vi- duce microbial contamination.
able but nonculturable (VBNC) bacteria are not detectable by Nebulizers used for the delivery of aerosolized therapy to CF
HPC. Flow cytometry in combination with dyes to measure num- patients in an adult cystic fibrosis unit have been reported to be
bers of active bacteria together with HPC can be used to determine contaminated with S. maltophilia (80). Environmental sampling
the presence of active and culturable bacteria. PCR-denaturing of sites including taps, tap water, sink drains, and ice-making ma-
gradient gel electrophoresis (DGGE), 16S rRNA gene nested PCR, chines on the unit yielded S. maltophilia in sink drains, taps, and
fluorescence in situ hybridization (FISH), and DNA sequencing water samples; however, none of these isolates shared a genotype
methods are useful to assess bacterial diversity. S. maltophilia with isolates recovered from the nebulizers. It was suggested that
has been identified by PCR-DGGE to survive water treatment, the rinsing of reusable nebulizer equipment with tap water may
avoid detection by HPC, and remain active in distribution sys- result in the adherence and contamination of S. maltophilia on the
tem water (142). wet surface of the nebulizer. That study used ERIC-PCR and
The iron-reducing activity of S. maltophilia has been applied to PFGE profiling to compare the genotypes of environmental and
phosphate removal from the returned liquor of a municipal waste- clinical S. maltophilia isolates. That study did not rule out the
water treatment plant (158). The removal of phosphate from the possibility of or provide direct evidence identifying the ward en-
returned liquor of wastewater is important, as it reduces the pos- vironment as the source of contamination but pointed to the need

Brooke
for caregivers of CF patients to ensure that nebulizer equipment size the importance of maintaining good hygiene practices when
washed with tap water be thoroughly dried before its next use (80). handling antiseptics and preservative solutions.
S. maltophilia has also been recovered from the surface of home- The qacE⌬1 gene, encoding tolerance to antiseptics containing
use nebulizers of CF patients (157). Patients who regularly dried quaternary ammonium compounds, has been detected in associ-
their nebulizers after use demonstrated no or minimal contami- ation with ISCR1 elements as a part of complex class 1 integrons.
nation of their nebulizers (157). The qacE⌬1gene has been detected in S. maltophilia clinical iso-
Recent observations in my laboratory indicate that S. malto- lates from China by PCR amplification (354).
philia is highly susceptible to drying. Cell suspensions (10 ␮l) of S.
maltophilia on stainless steel surfaces following 1 h of air drying Resistance to Metals
showed a ⬎3-log reduction in cell viability (my unpublished ob-

Silver acts as an antimicrobial agent by binding sulfur groups of
servations). proteins in bacterial cell walls, ultimately resulting in cell death.
Silver has been used in catheters in attempts to prevent biofilm
Biocide Tolerance formation (60, 118, 122). The use of an Environmental Protection
Hypochlorite cleaners have been recommended to reduce bio- Agency (EPA) (http://www.epa.gov/safewater/mcl.html)-approved
films of heterotrophic plate count bacteria, coliforms, and fecal level (100 ␮g/liter) of silver nitrate as a disinfectant in drinking water
coliforms in drains (289). Recent experiments in my laboratory did not significantly prevent (P ⱕ 0.05) bacterial biofilm formation in
have shown that S. maltophilia clinical isolate X26332 forms bio- modified Robbins devices with polyvinyl chloride and stainless steel
films in PVC microtiter wells containing Luria-Bertani (LB) broth surfaces in comparison to the control treatment (317). The recorded
with ⱕ0.006% bleach after 18 h of incubation at 35°C (22). This silver concentrations (90 to 122 ␮g/liter) in samples entering the de-
study did not take into account the inactivation of the chlorine by vices were reduced to 14 to 20 ␮g/liter after exit from the devices,
the broth medium. These observations underscore the impor- suggesting that the biofilms absorbed silver. Data from my laboratory
tance of using bleach at a concentration that will eliminate the S. are in agreement with those reported by Silvestry-Rodriguez et al.
maltophilia biofilm, to remove the possibility of a regrowth of the (317), revealing no dramatic inhibition of biofilm formation by an S.
biofilm. maltophilia clinical isolate cultured overnight at 37°C in polyvinyl
The effect of sodium hypochlorite disinfection was tested on S. chloride microtiter plate wells in LB broth containing 100 ␮g/liter of
maltophilia present in suction tubing used for sputum suction silver nitrate (156). Under the conditions of that study, the inhibition
(377). Suction tubing samples containing S. maltophilia at 5.5 ⫻ of biofilm formation was achieved at a silver nitrate concentration of
106 to 6.5 ⫻ 108 CFU/tube were exposed to 0.1% (1,000 ppm) ⱖ10,000 ␮g/liter (156).
sodium hypochlorite for 2 h. Following this disinfection treat- In a study of central venous catheters impregnated with mino-
ment, counts of 5.1 ⫻ 105 to 4.8 ⫻ 106 CFU/tube were recovered. cycline and rifampin (M-R), with silver platinum and carbon
Tubing containing counts of 6.4 ⫻ 104 to 1.0 ⫻ 107 CFU/tube was (SPC), or with chlorhexidine and silver sulfadiazine (CHX-SS),
cleaned with an automatic cleaner, effectively reducing counts to compared with noncoated catheters, only the M-R catheters in-
⬍20 CFU/tube (377). These data suggest that in preference to hibited (P ⬍ 0.005) the adherence and biofilm formation of MDR
sodium hypochlorite, automatic cleaners should be recom- S. maltophilia clinical isolates recovered from catheter-related
mended for the disinfection of suction tubing. It should be noted bloodstream infections in cancer patients (274). The M-R cathe-
that one should always follow established guidelines for the repro- ters also showed more prolonged antimicrobial durability against
cessing of endoscopes, where a precleaning step is performed at the S. maltophilia isolates in comparison with the SPC and
the point of use to remove bioburden and visible debris prior to CHX-SS catheters.
manual or automated high-level disinfection (264). The biocidal efficacies of three silver-impregnated contact lens
S. maltophilia has demonstrated tolerance to the biocides tri- storage cases (Microblock, i-clean, and Nano-case) against S.
closan (2,4,4=-trichloro-2=-hydroxydiphenylether) (193, 303) and maltophilia were tested (70). Case wells contained cell counts (103
sodium dodecyl sulfate (SDS) (22). Repeated exposure to tri- to 106 CFU/ml) that were incubated for 6 to 24 h at 25°C. Antimi-
closan, which acts primarily on Gram-positive bacteria, resulted crobial activity was noticeable only after 24 h of incubation. For
in a slight decrease in the susceptibility of domestic drain biofilm the three cases examined, Microblock, i-clean, and Nano-case, the
isolate S. maltophilia M9.13 (193). SDS has been assessed for its antimicrobial activities were different (P ⱕ 0.001), with the Nano-
ability to reduce bacterial biofilms (197). Data from my laboratory case demonstrating the greatest activity, decreasing cell counts by
indicate that S. maltophilia clinical isolate X26332 survives and 0.2 ⫾ 0.3 logs. Only the Microblock case showed silver release over
persists in a 0.02% solution of SDS for 14 days at 30°C; biofilms of 28 days (70).
this isolate have been observed to form in Luria-Bertani broth All of these observations of the persistence of S. maltophilia
containing 0.02% SDS (22; my unpublished observations). following exposure to silver are significant, as this organism dem-
S. maltophilia has been recovered from a contaminated onstrates resistance to metals in clinical and environmental set-
deionized-water-diluted hospital antiseptic solution (Savlon con- tings. The genome of clinical isolate S. maltophilia K279a contains
centrate; 1.5% chlorhexidine and 15% cetrimide) (369) and from gene clusters used for the import, storage, and efflux of metals
contact lens preservative solutions (116). The preservative solu- (67). A comparison of clinical isolate K279a and environmental
tions ReNu (BLJ Co., Ltd., Japan), Complete (Abbott Medical isolate R551-3 of S. maltophilia revealed that some metal resis-
Optics Japan, Inc., Japan), and Opti-Free (Alcon Japan, Ltd., Ja- tance is common to both isolates and that some operons are found
pan), used for contact lens storage, varied in their bactericidal only in K279a (281).
activities against suspensions of S. maltophilia, and no bactericidal Both environmental and clinical strains of S. maltophilia have
activity against S. maltophilia cells adhered to polystyrene was ob- been found to contain genes encoding resistance to metals. Envi-
served for these preservative solutions (116). These results empha- ronmental strain O2, isolated from East Fork Poplar Creek in

TABLE 5 Comparison of metal resistances demonstrated by clumps being formed at 6 h, and bacterial adherence reached a
S. maltophilia O2 and Sm777 maximum level at 18 h (84). High-resolution SEM of bacterial cell
Metal resistance tolerated by monolayers adhered to plastic suggest that flagella and other thin
S. maltophilia (mM)a fibrillar structures are involved in bacterial cell adherence to plas-
Metal O2 Sm777
tic (Fig. 2) (84).
S. maltophilia biofilms have been studied using in vitro tissue
Hg(II) 0.25 0.05
culture assays. TEM, high-resolution SEM, and immunogold la-
Cd(II) 0.33 0.50
Cu(II) 5.00 5.00
beling have identified the S. maltophilia fimbriae 1 (SMF-1) pro-
Au(III) 0.25 Not available tein as being important for adherence to cultured HEp-2 mono-

Ag(I) 0.03 0.02 layers (83). Adherence to eukaryotic cells was inhibited in the
Cr(VI) 8.00 Not available presence of anti-SMF-1 antibodies. The antibodies were most ef-
Se(IV) 40.0 50.0 fective at blocking adherence during the early stages (the first half
Pb(II) Not available 5.00 hour) of infection. The adherence and biofilm formation of S.
a Data from references 143 and 256. maltophilia SMDP92 on glass were inhibited by anti-SMF-1 anti-
bodies in a dose-dependent manner, implying that the fimbriae
facilitate interactions between the S. maltophilia cell surface and
Tennessee, grows in toxic acidic wastes containing gold, mercury, the host cell/abiotic surface (Fig. 3) (83).
platinum, lead, cadmium, chromium, silver, copper, and sele- S. maltophilia can form biofilms on lung cells (73, 83, 268).
nium salts (143). S. maltophilia strain Sm777, isolated as a con- Confocal microscopy of biofilms formed by CF isolate S. malto-
taminant of a Pseudomonas culture, tolerates the presence of sil- philia OBGTC9 on CF sputum-derived bronchial epithelial IB3-1
ver, mercury, copper, lead, cadmium, and selenium salts (256). cell monolayers revealed that S. maltophilia formed microcolonies
The metal resistances demonstrated by both S. maltophilia isolates embedded in a matrix (268). SEM of a 24-h-old biofilm formed by
are shown in Table 5. S. maltophilia Sm777 was proposed to use S. maltophilia OBGTC9 on an IB3-1 cell monolayer revealed mi-
different mechanisms to protect itself against metal toxicity. In the crocolonies of S. maltophilia in the presence of an extracellular
presence of selenite and tellurite, S. maltophilia Sm777 accumu- matrix (268). It is of interest that the degrees of adherence of S. malto-
lated cytoplasmic electron-dense Se0 granules and Te0 granules, philia clinical isolates to the bronchial epithelial cell monolayer varied
indicating that active efflux pumps probably are not the sole and did not correspond with the degrees of biofilm formed on the cell
mechanisms used to control heavy metal tolerance in this strain. S. monolayer. Even more interesting is the observation that the biofilm
maltophilia Sm777 demonstrated tolerance to cadmium through formed by S. maltophilia CF isolates on polystyrene did not corre-
the use of cysteine and the production of CdS particles from spond with the biofilm formation of the isolates on the cell mono-
Cd(II) when grown aerobically on solid agar containing 500 ␮M layer. The latter evidence supports the view that biofilm formation on
CdCl2. These observations of metal resistance in environmental abiotic surfaces may not reflect the biofilm formation observed on
isolates suggest that similar to the acquisition of antimicrobial biotic surfaces in animal models or human patients.
drug resistance, the acquisition of metal resistance occurs in the Environmental factors that can influence the biofilms of S.
natural environment. Environmental isolates of S. maltophilia maltophilia include phosphate (38), chloride concentrations (66),
found in the clinical/medical setting may simply be maintaining pH, temperature, aerobic or anaerobic conditions (90), and the
metal resistance genes when challenged with antimicrobials con- presence of copper and silver ions (312). S. maltophilia can form
taining metals. films on moist surfaces that make direct or indirect contact with
The treatment of S. maltophilia planktonic cells and biofilms patients, including hospital water plumbing systems, respiratory
with copper-silver ionization has demonstrated efficacy (312). tubing, dental suction tubing and unit waterlines, catheters, i.v.
These studies are addressed in more detail below (see “Biofilms”). lines, dialysis equipment, clinical sink drains, domestic sink drains
(40), and faucets (52).
The presence of sodium phosphate was reported to alter the
MOLECULAR MECHANISMS INVOLVED IN PATHOGENESIS
biofilms of clinical S. maltophilia isolates (38). In a study of 11
Bioﬁlms clinical isolates, 9 demonstrated altered biofilm formation when
A significant feature of S. maltophilia is its ability to form biofilms cultured in Luria-Bertani (LB) medium supplemented with 0.1 M
on surfaces including Teflon, glass, and plastics and on host tissues sodium phosphate buffer (SPB) (pH 7.0). Five isolates showed
(83, 84, 166, 268). Biofilms have been estimated to be associated increased biofilm formation (P ⬍ 0.008) in the presence of so-
with 65% of hospital-acquired infections (270). Scanning electron dium phosphate, in comparison to their biofilm formation in LB
microscopy (SEM) images in a study by Di Bonaventura et al. (89) medium without SPB supplementation. This increased biofilm
showed that S. maltophilia SM33 cells can adhere to polystyrene formation occurred with no increase in culture growth. Four iso-
surfaces within 2 h of inoculation and can form biofilms by 24 h lates showed decreased biofilm formation (P ⬍ 0.03), probably as
(Fig. 1). a result of a decrease in culture growth (8.5% less than that of the
One of the early steps of biofilm formation is the adherence of same isolates cultured in LB medium without SPB supplementa-
bacterial cells to a surface. Transmission electron microscopy tion) (38). These findings have relevance for applied situations
(TEM) and SEM identified the presence of flagella on 46 clinical where S. maltophilia may be present and form biofilms. Biofilms
isolates of S. maltophilia (84). Studies of the kinetics of adherence and the selection of S. maltophilia isolates will likely lead to an
of S. maltophilia SMDP92 to polystyrene in minimal medium in- increased resistance of the bacterium to water-diluted disinfec-
dicated that from 30 min to 18 h postinoculation, the bacterial tants. This bacterial pathogen has been isolated from water-
cells attached and formed small clumps, with three-dimensional diluted antiseptic solutions (369). Levels of sodium and phos-

Brooke

FIG 1 (A to E) Scanning electron micrographs of S. maltophilia SM33 biofilms formed on polystyrene surfaces at 2, 4, 8, 16, and 24 h, respectively. Magnifica-
tions, ⫻1,000 (A to D) and ⫻2,000 (E). (F) Transmission electron micrograph of a 24-h biofilm produced by S. maltophilia SM33. Arrows indicate glycocalyx
surrounding bacteria. The asterisk indicates the biofilm limit line in contact with the polystyrene surface. Bar, 0.5 ␮m. (Reprinted from reference 89 with
permission.)
phate in hospital water plumbing systems should be monitored, as reasons for this observation, that the increase in chloride could
phosphate has been reported to alter the microbial communities stress the bacteria and result in altered biofilms and that chloride
in the human water supply (172). ions may block exopolysaccharide groups important for cuprosol-
Clinical S. maltophilia isolates have been observed to form more vency activity. No significant correlations were found between the
biofilms at 32°C than at 37°C and 18°C (90). The level of biofilm biofilms of S. maltophilia and water pH or TOC (66). The results
production was higher under aerobic conditions and in a 6% CO2 of that study demonstrated that in comparison to pH and the TOC
atmosphere than the level of biofilm production under anaerobic concentration, the cuprosolvency activity of S. maltophilia is more
conditions. The S. maltophilia isolates produced comparable bio- sensitive to the level of chloride present in its aqueous environ-
films at pH 8.5 and 7.5 but larger amounts of biofilm than those ment. It is of interest that S. maltophilia has been reported to
produced at pH 5.5. survive and persist in chlorinated water distribution systems.
Biofilms in copper plumbing systems may increase the con- Taken together, these observations suggest that S. maltophilia
centration of soluble copper (cuprosolvency) in drinking water should not be considered a major culprit responsible for the cor-
(66). A concentration of 2 mg/liter of copper in water has been rosion of copper plumbing systems.
associated with gastrointestinal distress (266). The effect of the A recent study examined the use of copper-silver ionization in a
chemical composition of water (e.g., total organic carbon model plumbing system to control biofilms and planktonic cells of
[TOC] and pH) on cuprosolvency by bacteria commonly iso- the waterborne pathogens P. aeruginosa, A. baumannii, and S.
lated from biofilms in copper plumbing, including S. malto- maltophilia (312). A 72-h exposure to copper-silver ion concen-
philia, revealed an inverse correlation of cuprosolvency with in- trations of 0.2 mg/liter-0.02 mg/liter to 0.8 mg/liter-0.08 mg/liter
creasing chloride concentrations for pure-culture S. maltophilia resulted in the inactivation of biofilm-associated and planktonic
biofilms formed on copper coupons. That study suggested two S. maltophilia cells (3-log reduction and ⬎6-log reduction for


FIG 2 Scanning electron micrographs of Stenotrophomonas maltophilia adhering to plastic. (A) SMDP92 cells adhere tightly to the plastic surface. (B) Structures
resembling flagella appear to protrude from the cell surface and interconnect bacteria (arrowheads) or connect bacteria to the plastic (arrows). (C) In addition
to the flagellum-like filaments (arrowheads), high-power magnification shows the presence of thin fibrillar structures (arrows) connecting the bacterial cells to
the abiotic surface. Bars, 10 ␮m (A), 1 ␮m (B), and 2 ␮m (C). (Reprinted from reference 84.)
biofilm-associated and planktonic cells, respectively) in 48 h. uid from suction hoses that were poorly connected to the DCU
Higher concentrations of copper-silver ions (0.4 mg/liter-0.04 baseplates, leading to the corrosion of the baseplates. The liquid
mg/liter and 0.8 mg/liter-0.08 mg/liter) caused a reduction be- seepage problem was solved by replacing the suction hose connec-
yond the 72-h exposure to the copper-silver ionization system. S. tors with interlocking connector collars and bushings that re-
maltophilia showed a greater sensitivity to copper-silver ioniza- sulted in tightly fitting suction hoses that could not be loosened
tion than P. aeruginosa and A. baumannii. These data suggest that during use. Additional corrective measures included the replace-
the use of copper-silver ionization for the disinfection of water ment of the connectors with new fittings that replaced the steel
plumbing systems may be effective against S. maltophilia. More baseplates with new aluminum baseplates. These new fittings were
studies are needed to determine if strain-to-strain differences in observed and sampled over the next 36 months, and no bacterial
susceptibility exist for S. maltophilia isolates. Silver ions have been contamination was observed. That study suggested that most
hypothesized to disrupt biofilms by binding to biological mole- DCU suction systems contain bacterial biofilms due to an inade-
cules and disrupting binding sites that are important for electro- quate disinfectant contact time. The presence of high cell densities
static and hydrophobic interactions on these molecules (58). of Pseudomonas spp. and related bacteria in the suction systems
In a study of 41 dental chair units (DCUs) in a hospital, S. despite regular disinfection is of concern. Some studies have re-
maltophilia was isolated from biofilms in 14.6% of the DCU suc- ported the entry of liquid from the low-volume suction line into
tion host orifice baseplates and was recovered from the internal the patient’s mouth during use, leaving open the possibility of the
lumens of the attachment ends of the high-volume suction hose transfer of biofilm-containing microorganisms into the mouth
and connectors in 21.6% of 37 DCUs (250). The bacterial contam- from the suction line (25, 216, 361). The closing of the lips around
ination and corrosion of the baseplates and suction hoses were the saliva ejector tip can cause a backflow of liquids into the
discovered within 6 months of the opening of a new hospital. The mouths of patients. The recovery of viable bacteria from suction
bacterial contamination appeared to be due to the seepage of liq- lines (361), stresses the importance of the disinfection of the suc-

Brooke

FIG 3 High-resolution scanning electron microscopy. (A) Adherence of SMDP92 cells to HEp-2 cells. In addition to the association of bacteria with eukaryotic
cells, many bacteria adhere to the glass substratum. Bar, 10 ␮m. (B) High-magnification image of adhering SMDP92 cells with lateral fimbriae protruding from
the bacteria (arrows). Bar, 1 ␮m. (C) SMDP92 cells adhering to the glass surface (biofilm formation) without epithelial cells. Bar, 10 ␮m. (D) High-resolution
image of biofilm-forming bacteria showing peritrichous fibers attaching to bacteria. Long and thick filaments, probably flagella, are also shown. Bar, 2 ␮m.
(Reprinted from reference 83 with permission of John Wiley & Sons.)
tion lines between patients to reduce the possibility of the trans- line tubing than in those with flushing with each biocide sepa-
mission of potentially pathogenic organisms. rately. The combination of sodium hypochlorite and phenol re-
The American Dental Association (ADA) has set a water quality duced biofilm bacterial counts on plate count agar, for the air and
standard of ⱕ200 CFU/ml for dental chair units. Regular weekly water tubing (from control counts of 6,384 ⫾ 98 CFU/cm2 to
disinfection of dental chair units using Planosil and Planosil Forte, 156 ⫾ 12 CFU/cm2), for the main water pipe tubing (from control
two waterline disinfectants (Planosil contains 1.5% hydrogen per- counts of 7,838 ⫾ 61 CFU/cm2 to 248 ⫾ 79 CFU/cm2), and for
oxide, 0.003% silver, and 0.0015% phosphoric acid; Planosil Forte patient tubing (from control counts of 5,103 ⫾ 78 CFU/cm2 to
contains 2.5% hydrogen peroxide, 0.012% silver, and 0.0025% 736 ⫾ 44 CFU/cm2). This combination of biocides effected an
phosphoric acid), demonstrated the ability to nearly eliminate wa- almost complete removal of biofilm, as demonstrated by epifluo-
ter unit biofilms (249). Biofilm regrowth was present at 7 days rescence microscopy of the tubing samples.
posttreatment. The regular use of these disinfectants maintained Peracetic acid (PAA) has a wide range of applications, including
bacterial counts in the water unit lines at levels below the ADA disinfection of ultrapure water systems, disinfection of industrial
water quality standard (249). These data indicate that the efficient systems, reprocessing of hemodialyzers for reuse, disinfection of
removal and inhibition of bacterial biofilm regrowth can be dialysis machines, and high-level disinfection of endoscopes
achieved by using disinfectants containing multiple active antimi- (179). In a fetal bovine serum-coated polystyrene microtiter plate
crobial agents. test system, a 10-min exposure to a 1% concentration of the PAA-
Eight biocides (1% sodium dodecyl sulfate, 35% hydrogen per- based disinfecting agent Neodisher Septo PAC (W. Weigert,
oxide, 5.25% sodium hypochlorite, 1% phenol, 4% Tween 20, 1% Hamburg, Germany) inhibited the growth of monoculture S.
EDTA, 0.2% chlorhexidine gluconate, and 1% povidone-iodine) maltophilia and dual-culture S. maltophilia and Candida parapsi-
were studied for their effects on biofilm bacteria present in dental losis biofilms. At the minimum bactericidal concentration, Neod-
unit water lines (197). The flushing of the tubing for 48 h with a isher Septo PAC inhibited the growth of the monoculture and
combination of 5.25% sodium hypochlorite and 1% phenol re- dual-culture biofilms, but in the absence of drying, biofilm re-
sulted in lower biofilm bacterial counts present in the unit water growth was observed at 48 h postdisinfection. The drying (2 h at


FIG 4 Scanning electron micrographs of antibiotic activity against S. maltophilia SM33 biofilm. Shown are the effects of rufloxacin at 100 ␮g/ml (A) and 500
␮g/ml (B) against preformed S. maltophilia biofilm. Magnifications, ⫻2,500 (A) and ⫻2,000 (B). (Reprinted from reference 89 with permission.)
50°C) of the microtiter plates resulted in no biofilm regrowth mass (with the exception of levofloxacin) (89). Moxifloxacin was
(179). These observations emphasize the importance of a thor- the most effective fluoroquinolone at preventing the adherence of
ough drying of endoscopes after disinfection and before their S. maltophilia. All of the tested fluoroquinolones, with the excep-
next use. tion of norfloxacin, reduced preformed biofilm biomass. Moxi-
The adherence and subsequent biofilm development of S. floxacin was most effective at reducing preformed biofilm bio-
maltophilia on surfaces are affected by both the physicochemical mass. Treatment with moxifloxacin at 500 ␮g/ml eradicated
properties of the bacterial cell (e.g., the presence of outer mem- biofilm biomass in 50% of the S. maltophilia isolates and reduced
brane proteins and lipopolysaccharide) and the surfaces to which biomass up to 95% for 60% of the isolates. SEM studies have
the cell attaches (e.g., prosthetic devices covered with host extra- revealed no significant changes in the cellular morphologies of S.
cellular matrix polymers or relatively hydrophilic glass and Tef- maltophilia cells after exposure to subinhibitory concentrations
lon, in contrast to hydrophobic polyvinyl chloride). A study of the (sub-MICs) of moxifloxacin that inhibit biofilm formation on
adherence of two relatively hydrophilic S. maltophilia isolates ob- polystyrene (89). An analysis of cell viability in preformed bio-
tained from a model laboratory drinking water system revealed films treated with antibiotics revealed that rufloxacin was the most
that the S. maltophilia isolates showed no or weak adherence to effective antibiotic, significantly reducing (P ⬍ 0.01) bacterial cell
polyvinyl chloride (PVC), weak or moderate adherence to poly- counts to 0.6%, 5.4%, and 17.1% for concentrations of rufloxacin
ethylene (PE), and no adherence to ASI 316 stainless steel (318). It at 500, 100, and 50 ␮g/ml, respectively. The treatment of pre-
is very difficult to construct human implant materials that deter formed 18-h S. maltophilia SM33 biofilms on polystyrene with
bacterial adhesion, as the implant devices become covered with rufloxacin (500 ␮g/ml) results in ultrastructural changes in the
host substances, including proteins and carbohydrates, that can bacterial cells (Fig. 4) (89). The treatment of preformed biofilms
facilitate the attachment of bacteria. of S. maltophilia with ceftazidime was ineffective at removing bio-
Recently, the interaction of antimicrobial drugs with biofilms of films. A high concentration (500 ␮g/ml) of TMP-SMX was
S. maltophilia has been more closely examined. MDR and non- needed to significantly reduce (P ⬍ 0.01) preformed biofilm bio-
MDR S. maltophilia clinical isolates have been compared for their mass.
abilities to form biofilms (198), and the effects of antibiotics at Moxifloxacin at sub-MICs was tested against S. maltophilia
MICs and at concentrations below the MICs on S. maltophilia cell strains SM132 and Sm144, recovered from CF patients not treated
adherence to surfaces and biofilm formation have been studied previously with this antibiotic (267). At sub-MICs, moxifloxacin
(89, 90, 267). In a study of 70 S. maltophilia clinical isolates (40 reduced the adherence of the S. maltophilia strains to polystyrene
MDR and 30 non-MDR isolates), the MDR isolates demonstrated and inhibited biofilm formation. At a concentration of 0.06⫻
a higher level of biofilm formation (average optical density at 540 MIC, the cell surface hydrophobicity of S. maltophilia strain
nm [OD540] of 0.52) than the non-MDR isolates (average OD540 SM144 changed from hydrophobic (observed at 0.03⫻ MIC) to
of 0.15), and biofilm was correlated (P ⱕ 0.01) with resistance to hydrophilic, in contrast to strain SM132, which remained hydro-
ceftazidime, cefepime, ticarcillin-clavulanic acid, piperacillin- philic at 0.03⫻ MIC and 0.06⫻ MIC of moxifloxacin. The hydro-
tazobactam, aztreonam, and gentamicin. Biofilm formation did phobicity of the cell surface is likely an important factor to con-
not correlate with resistance to ciprofloxacin, levofloxacin, TMP- sider in the adherence and biofilm formation of S. maltophilia, but
SMX, or meropenem (198). as this appears to be a strain-dependent phenomenon, individual
Some antibiotics at suboptimal MICs (e.g., moxifloxacin) have strains would need to be evaluated to determine the efficacy of
demonstrated efficacy for reducing the adherence and biofilm for- moxifloxacin activity against biofilm formation by this opportu-
mation of S. maltophilia (89, 267). A study of 20 biofilm- nistic pathogen. SEM micrographs did not reveal any ultrastruc-
producing S. maltophilia clinical isolates revealed that at one-half tural changes of S. maltophilia SM132 cells treated with these sub-
the MIC, all tested fluoroquinolones (ciprofloxacin, grepafloxa- MICs of moxifloxacin. That study suggested that clinically
cin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin, and ru- attainable concentrations (e.g., 0.015 ␮g/ml corresponds to 0.03⫻
floxacin) effectively (P ⬍ 0.01) reduced the biofilm mass of S. MIC for both SM132 and SM144) of moxifloxacin will effectively
maltophilia, and at one-quarter the MIC, they reduced the biofilm inhibit S. maltophilia adherence and biofilm formation (267).

Brooke
TABLE 6 Molecular mechanisms of antimicrobial resistance in among L1 and L2 ␤-lactamase genes. The L1 and L2 ␤-lactamase
S. maltophilia genes showed levels of sequence changes as high as 20% and 25%,
Mechanism References respectively, with the corresponding amino acid sequence diver-
␤-Lactamases chromosomally and plasmid 9, 17, 18, 227, gences for L1 and L2 ␤-lactamases being as high as 21% and 32%,
encoded and on mobile elements, e.g., 295, 296, respectively. For these clinical isolates, changes in amino acid res-
Tn1-like transposon 352, 353 idues important for the binding of the L1 ␤-lactamase to its sub-
Multidrug efflux pumps, e.g., SmeDEF, 6, 10, 11, 54, strate were reported to alter its activity (17). S. maltophilia clinical
SmeABC, and SmrA, associated with 129, 196, isolates have demonstrated considerable heterogeneity for
resistance to quinolones, tetracycline, 198, 269, ␤-lactamase induction upon exposure to three antibiotics (imi-
chloramphenicol, erythromycin, 383 penem [50 ␮g/ml], cefoxitin [50 ␮g/ml], or ampicillin [1 mg/ml])

aminoglycosides, and ␤-lactams (227). In that same study, the L1 ␤-lactamase genes from clinical
Class 1 integrons and ISCR elements associated 27, 146, 198,
isolate 39/95 and from reference strain S. maltophilia ULA-511
with resistance to 328
trimethoprim-sulfamethoxazole
were cloned and sequenced; a comparison of the deduced amino
Phosphoglucomutase (SpgM) associated with 198, 225 acid sequences revealed a high level of homology (98%) between
resistance to polymyxin B, polymyxin E, the enzymes (227). These observations suggest that ␤-lactamase
nalidixic acid, gentamicin, vancomycin, activity is not just a result of the gene being present in the S.
ceftazidime, ticarcillin-clavulanic acid, and maltophilia isolate but point to another mechanism for the control
piperacillin-tazobactam of ␤-lactamase expression.
Reduction in outer membrane permeability 5, 229 The isolation of S. maltophilia mutants and the generation of
SmQnr determinants associated with 126, 300, 358 isogenic L1 and L2 gene knockout mutants have shown that
resistance to quinolones ␤-lactamase L1 and L2 expressions are differentially regulated (16,
Modification of antibiotics 174, 195
148). The expression of the ␤-lactamases is controlled at the level
Mutations of bacterial topoisomerase and 126, 339
gyrase genes
of transcription by the ampR gene, positioned upstream of L2, as
part of an ampR-L2 module (201, 251). AmpR is needed for the
basal-level expression of L1 but not L2 and is needed for the in-
duced expression of L1 and L2 (201). The binding of AmpR to the
Further studies are needed to test this hypothesis with an animal intergenic sequence positioned between ampR and the L2 gene
model of S. maltophilia infection. induces the expression of lactamase (56). The genetic diversity of
The roles of extracellular DNA and D-amino acids in the biofilm selected L2 proteins and the intergenic sequences are relatively
matrix surrounding S. maltophilia cells need to be studied. If ex- high (up to 32%), in contrast to the highly conserved AmpR pro-
tracellular DNA is a major structural component of the biofilm teins, suggesting that the expression of the chromosomal
matrix, as seen for other bacterial biofilms (365), it could serve as ␤-lactamase gene is mediated by changes in the sequences of the
a target for treatment with DNase I. DNase I has been reported to intergenic region or in the L2 gene (56). AmpR is a transcriptional
disrupt biofilms (65). D-Amino acids have been reported to pre- regulator of ampC expression. AmpC is associated with the recy-
vent biofilm formation (177). Further work is needed to establish cling of bacterial cell wall components. AmpC expression is acti-
whether D-amino acids have the same effects on S. maltophilia vated when AmpR is bound with anhydro-N-acetylmuramyl-
biofilms and if they and DNase I could be considered alternative peptide, and the expression of AmpC is repressed when AmpR is
treatments for patients with S. maltophilia biofilm infections. bound with UDP-N-acetylmuramic acid-pentapeptide (374). Ad-
ditional proteins used in cell wall recycling include AmpG, which
Antibiotic Resistance is involved in the transport of degraded cell wall components into
Several molecular mechanisms of S. maltophilia contribute to its the cytoplasm, and AmpD, which is associated with the cleavage of
multiantibiotic resistance, including plasmids, integrons, and the components into 1,6-anhydromuramic acid and peptide
transposons (27). A summary of these antibiotic resistance mech- (374). Two ampD homologues encoding AmpDI and AmpDII
anisms is shown in Table 6. S. maltophilia has two chromosomally have been identified in S. maltophilia K279a and in R553-1, and
encoded ␤-lactamases, L1 and L2. The ␤-lactamase L1 is a AmpDI is an anhydro-N-acetylmuramyl-l-alanine amidase and is
metallo-␤-lactamase (352), and L2 is a clavulanic acid-sensitive involved in the regulation of both lactamases L1 and L2, while
cephalosporinase (353). Several studies have reported differential AmpDII is not associated with the regulation of expression of the
␤-lactamase activities among S. maltophilia isolates (16, 17, 56, 78, ␤-lactamases (374).
147, 148, 153, 170, 227, 251, 374). The L1 ␤-lactamase uses a Sec In addition to the ampR, ampC, ampN, and ampD genes, an
export system, while the L2 ␤-lactamase uses a Tat export system ampN-ampG operon is needed for the expression of lactamases L1
for periplasmic translocation (194, 271). and L2 in S. maltophilia (153). The disruption of the ampN gene
A study to examine the heterogeneity of ␤-lactamase production exhibits a polar effect on the expression of the downstream ampG
among 17 clinical and 9 environmental S. maltophilia isolates using gene. The partial complementation of S. maltophilia strain
PFGE, the MICs of six ␤-lactam antibiotics, and isoelectric focusing KJN2xylE⍀ containing an ampN polar mutant with ampG from E.
found no correlation between MIC, isoelectric focusing electropho- coli indicates that ampG is needed for the expression of functional
resis (IEF), and genotyping data. The results of that study suggested lactamases. It was suggested that AmpN is a cytosolic protein that
that the mechanism underlying the variation in ␤-lactamase expres- interacts with AmpG to form a permease and interacts with
sion was unclear and needed to be further investigated (78). AmpG-associated ligands to form the inducer for lactamase ex-
Both the L1 and L2 ␤-lactamase genes have been found on pression (153).
200-kb plasmids in S. maltophilia (17). There is allelic variation Charge variants of L2 ␤-lactamases have been identified in S.

maltophilia isolates (147). IEF analysis of the isolates revealed two ABC and smeSR operons. The ␤-lactam resistance of an SmeABC-
major patterns, with most isolates exhibiting pattern I (with one overexpressing strain is due to increased ␤-lactamase activity and
band of pI ⬍7.0 [L1] and one band of pI ⬎7.0 [L2]) and some not efflux. A deletion of smeC in S. maltophilia alters the hydrolysis
exhibiting pattern II (multiple bands representing two acidic of nitrocefin. There was a difference in the hydrolysis rates of
␤-lactamases [pI ⬍7.0] and several ␤-lactamases [pI ⬎7.0]). The nitrocefin by parental MDR S. maltophilia strain K1668 (⌬L1 ⌬L2
different ␤-lactamase charge variants are products of the same L2 MDR) of 14 nmol g⫺1 min⫺1, compared with a hydrolysis rate of
gene, suggesting that S. maltophilia has the ability to maintain the 0.016 nmol g⫺1 min⫺1 by S. maltophilia strain K1785 (⌬smeC ⌬L1
production of ␤-lactamase activity even in environments with a ⌬L2 MDR). The rate of hydrolysis of nitrocefin by wild-type S.
changing pH (147). maltophilia strain ULA-511 (L1⫹ L2⫹) of 47 nmol g⫺1 min⫺1 was
reduced to 0.023 nmol g⫺1 min⫺1 in S. maltophilia strain K1784

The multiantimicrobial resistance of S. maltophilia is in part
due to the activity of multidrug efflux pumps (6, 10, 11, 54, 129, (⌬smeC), suggesting that the presence of SmeC is linked to the
196, 198, 269, 383). These multidrug efflux pump systems consist expression of the L2 ␤-lactamase (196).
of a membrane fusion protein, an energy-dependent transporter, Integrons, common regions (329), and integron-like elements
and an outer membrane protein. The cloning and sequencing of have been reported for S. maltophilia isolates worldwide. Inte-
the Stenotrophomonas multiple-efflux (sme) smeDEF operon from grons are not self-mobilizable elements but contain an integrase-
S. maltophilia and the expression of the operon in E. coli indicated encoding gene that permits the insertion of antibiotic resistance
that smeDEF encodes a multidrug efflux pump (11). The SmeDEF gene cassettes in between highly conserved nucleotide sequences
efflux pump contributes to resistance to ␤-lactams, tetracy- (330). Transposons and plasmids can facilitate the movement of
cline, erythromycin, quinolones, aminoglycosides, and chlor- integrons between bacterial cells (46). Class 1 integrons have been
amphenicol. Experiments that examined the intracellular ac- found within transposons, which can be transferred to plasmids/
cumulation of ethidium bromide and norfloxacin in the absence chromosomal DNA by transposition events. Class 1 integrons can
and in the presence of the proton uncoupler carbonyl cyanide capture gene cassettes by using a specific attachment site (att1),
m-chlorophenylhydrazone (CCCP) revealed that the activity of resulting in composite elements. The 5=-conserved end of the in-
the multidrug efflux pump SmeDEF is linked to the membrane tegron contains the integrase gene (intl1) and a promoter needed
potential. The smeF gene encodes an outer membrane protein that for the expression of the gene cassette integrated into the att1 site
displays immunological cross-reactivity with an antibody gener- (64, 137). The 3=-conserved end of the class 1 integron contains
ated against outer membrane protein 54 (Omp54), a diagnostic the sul1 gene, encoding resistance to sulfonamides, and the
protein for multidrug resistance in S. maltophilia (11). qacE⌬1 gene, encoding tolerance to antiseptics containing quater-
A MexAB-OprM-like multidrug efflux system was identified in nary ammonium compounds (137, 321). Class 1 integrons have
S. maltophilia by Zhang et al. (383). Studies of gene knockout been found in S. maltophilia isolates in North and South America,
mutants of the ␤-lactamase L1 and L2 genes in multidrug- Australia, Asia, and Europe (27, 55, 198, 328). Clonal expansion
resistant strain K1385 of S. maltophilia containing MexAB-OprM plays an important role in drug resistance dissemination.
efflux systems revealed that L1 knockout mutants were unable to The distribution of class 1 and 2 integrons has been examined
hydrolyze imipenem but were able to hydrolyze nitrocefin. The L2 for their associations with the presence of SmeABC and SmeDEF
knockout mutants did not show an altered hydrolytic activity pumps and antibiotic resistance in 93 S. maltophilia clinical iso-
against imipenem but did demonstrate a decreased hydrolytic ac- lates recovered from Kkaohsiung Medical University Hospital in
tivity against nitrocefin. In the knockout mutants of L1 and L2 and Taiwan during January to December 2002 (54). As determined by
the L1 L2 double mutant, the remaining ␤-lactam resistance was PCR, 22% of the isolates harbored class 1 integrons, whereas class
due to the overexpression of the multidrug efflux system respon- 2 integrons were not detected. Resistances to aminoglycosides
sible for the resistance of S. maltophilia to quinolones, chloram- (aacA4) and to trimethoprim (dfrIIa) and the small multidrug
phenicol, and erythromycin (383). resistance gene smr were found in association with the class 1
The smeABC operon of S. maltophilia was identified and cloned integrons. The isolates harboring smr demonstrated a 4-fold in-
by using a PCR-amplified probe for the mexB sequence within the crease in MICs of ciprofloxacin compared to isolates lacking this
mexAB-oprM multidrug efflux operon of P. aeruginosa (196). The gene. Only 1 out of the 93 isolates contained a plasmid carrying a
putative proteins encoded by the SmeA, SmeB, and SmeC genes class 1 integron (this carried an aacA4 gene cassette), suggesting
are an inner membrane fusion lipoprotein, a resistance- that integrons and plasmids together may not be the major mech-
nodulation-cell division (RND) transporter, and an outer mem- anism used for the dissemination of antibiotic resistance among
brane efflux lipoprotein, respectively. The smeABC operon is reg- strains of S. maltophilia. Real-time PCR, used to measure the gene
ulated by a two-component regulatory system encoded by the expression of the sme efflux pumps, demonstrated that the SmeABC
smeS (encodes a sensory kinase) and smeR (encodes a response and SmeDEF efflux pumps contribute to the resistance of S. malto-
regulator) genes. An analysis of smeABC in multidrug-resistant philia isolates to ciprofloxacin and meropenem, respectively (54).
mutants of S. maltophilia revealed that the expression of smeC is Upstream of the smeDEF operon is smeT, a proposed transcrip-
important for drug resistance and that SmeABC does not act as a tional repressor of the smeDEF operon in S. maltophilia (301).
multidrug efflux system in S. maltophilia (196). SmeT was suggested to bind to an operator sequence in the inter-
When introduced into P. aeruginosa, SmeC of S. maltophilia genic sequence of smeT-smeD containing the promoters for smeT
restored antibiotic resistance, indicating that it was able to func- and smeDEF (301). The overexpression of smeDEF in MDR S.
tion as a component of a MexAB-SmeC multidrug efflux system in maltophilia strains that harbor wild-type smeT and SmeT binding
P. aeruginosa (196). The smeC gene has its own weak promoter sites appeared to be influenced by additional mechanisms other
similar to that of the oprM gene of the mexAB-oprM multidrug than SmeT (302). A comparison of the 16S rRNA sequence and
efflux operon of P. aeruginosa. SmeR positively regulates the sme- the ␤-lactamase gene sequence showed them to be linked, result-

Brooke
ing in three distinct rRNA groups of S. maltophilia (17). Sequence S. maltophilia (146). Of 102 S. maltophilia isolates recovered from
data showed that the intergenic sequence of smeT-smeD from 10 hospitals in China, 16 carried dfrA genes, and each dfrA-positive
clinical S. maltophilia isolates representing the three 16S rRNA isolate carried a class 1 integron. The class 1 integrons contained
groups is more conserved in isolates of the same rRNA group than gene cassettes, including dfrA17-aadA5, dfrA12-aadA2, aacA4-
in isolates of different rRNA groups (129). These data suggest that catB8-aadA1, aadB-aadA4, aacA4, aadA5, aadA1, aadB–aac(6=)-
the grouping of S. maltophilia clinical isolates based on genotypic II– blaCARB-8, arr-3–aacA4, and cmlA1. That study revealed that
properties is feasible. the sul2 and dfrA genes were present on a 7.3-kb plasmid. To-
In a recent study of 40 MDR and 30 non-MDR S. maltophilia gether, the sul2, dfrA, and sul1 genes contribute to resistance to
clinical isolates, high-level expression of SmeD and SmeA was TMP-SMX (146).

observed more for the MDR isolates (85% and 60% for SmeD and Liaw et al. (198) reported that of 40 MDR and 30 non-MDR S.
SmeA, respectively) than for the non-MDR isolates (33% and 17% maltophilia isolates, 42 (60%) harbored class 1 integrons with
for SmeD and SmeA, respectively) (198). The high level of expres- drug resistance genes, most commonly against aminoglycosides,
sion of smeA or smeD correlated with resistance to gentamicin, with isolates showing resistance to ciprofloxacin, ceftazidime,
ciprofloxacin, levofloxacin, ceftazidime, cefepime, ticarcillin- cefepime, ticarcillin-clavulanic acid, piperacillin-tazobactam,
clavulanic acid, piperacillin-tazobactam, aztreonam, and mero- TMP-SMX, meropenem, and gentamicin. Of the MDR isolates,
penem (198). 83% carried class 1 integrons, while 30% of the non-MDR isolates
The qnr gene present in S. maltophilia chromosomal DNA carried these integrons. Gene cassettes within the class 1 integrons
(Smqnr) contributes intrinsic resistance to quinolones (300). This included aacA4, aadB, aacC4, aacA6=-1b, smr, smr/aacA4, qac,
resistance appears to be present in limited amounts in wild-type S. cmlA, catB2, and blaIMP-8/aac6-II/aadA5 (198).
maltophilia, as providing the qnr gene on a plasmid in both the A TEM-2 ␤-lactamase on a Tn1-like transposon in the genome
wild type and an ⌬Smqnr mutant results in increased resistance to of S. maltophilia clinical isolate J675Ia was reported (18). The
quinolones in both the wild type and the mutant. A gene dosage transposon was able to be mobilized onto the broad-host-range
effect of SmQnr was observed when the gene was plasmid borne, conjugative plasmid R388 and moved into E. coli UB1832, dem-
in contrast to the relatively low-level expression of chromo- onstrating the ability of S. maltophilia to harbor and exchange
somally carried Smqnr. The expression of the Smqnr gene has been DNA with other bacteria. This observation has clinical signifi-
reported to result in low-level resistance to quinolones in a heter- cance when considering the potential for the spread of antibiotic
ologous host (299, 313). Resistance to quinolones in S. maltophilia resistance in the clinical setting.
can occur as a result of mutations of the bacterial topoisomerase The deletion of the aac(6=)-Iz acetyltransferase gene in wild-
and gyrase genes (126, 339) and may also arise due to the over- type S. maltophilia K1449 resulted in mutant strain K1669, which
expression of the efflux pump SmeDEF (11, 12). The expres- demonstrated increased susceptibility to 2-deoxystreptamine
sion of several new variants of the Smqnr genes in E. coli re- aminoglycoside antibiotics, including netilmicin, sisomicin, to-
sulted in the increased resistance of E. coli to quinolones (126). bramycin, neomycin, and gentamicin (all MICs of ⬍4 mg/liter)
It was proposed that S. maltophilia isolates harboring Smqnr (195). Resistance to these antibiotics was restored (all MICs of ⬎8
genes may act as a reservoir for the transfer of these genes into mg/liter) in complemented S. maltophilia K1669 mutants con-
Enterobacteriaceae (126). Two new Smqnr genes have recently taining the aac(6=)-Iz gene, and E. coli transformants expressing
been identified in S. maltophilia clinical isolates. The cloning and this S. maltophilia gene demonstrated increased (up to 8-fold)
expression of these genes in E. coli increased resistance to quino- MICs of tobramycin, netilmicin, and sisomicin.
lone antibiotics, including ciprofloxacin, ofloxacin, gatifloxacin, The ease of acquisition and spread of these antibiotic resistance
moxifloxacin, gemifloxacin, and enoxacin (358). The qnr genes genes in S. maltophilia emphasizes the need for antibiotic suscep-
were proposed to originate in the chromosomal DNA of environ- tibility testing of isolates from patients. The monitoring of clinical
mental aquatic bacteria, and horizontal transfer to other bacteria isolates may identify sources of transmission of S. maltophilia.
appears possible through the genes’ presence in conjugative plas-
mids (322).
Hydrolytic Enzymes
Class 1 integrons have been reported to be responsible for in-
creased TMP-SMX MIC values for S. maltophilia clinical isolates The S. maltophilia K279a genome encodes extracellular enzymes
(27). The sul genes that contribute to resistance to TMP-SMX including proteases, lipases, esterase, DNase, RNase, and fibroly-
(328) have been reported to be associated with class 1 integrons sin (67). Clinical S. maltophilia isolates have been reported to
(27) and insertion element common region (ISCR) elements. The demonstrate cytotoxicity activity (111). Supernatants of some
sul1 gene has been found as part of the class 1 integron in TMP- clinical S. maltophilia isolates recovered from liver and trachea
SMX-resistant S. maltophilia isolates recovered from Taiwan, exhibited hemolytic and enzymatic activities. The exposure of
Spain, Turkey, Italy, Germany, North America, and South Amer- Vero (African green monkey) and HeLa (human cervix) cells to S.
ica (27, 328). The sul2 gene has been found on plasmid DNA maltophilia culture supernatant filtrates resulted in endocytosis,
(⬃120 kb) and as part of chromosomal DNA in S. maltophilia cell aggregation, and cytotoxicity effects on HEp-2 (human larynx
TMP-SMX-resistant isolates (328). Some sul2 genes have been epidermoid carcinoma) cells. These effects included rounding,
linked to ISCR2, with the element linked to ⌬glmM, a deletion of membrane blebbing, a loss of intercellular junctions, and cell
a phosphoglucosamine mutase gene; this molecular arrangement death after 24 h. The tested protease inhibitors failed to inhibit the
has also been observed for other bacterial species, including Vibrio cytotoxic activity of the S. maltophilia isolates. In addition to the
salmonicida, Shigella flexneri, and E. coli (328). hemolytic and cytotoxic activities, these S. maltophilia isolates
The dfrA gene, encoding the dihydrofolate reductase enzyme, demonstrated additional virulence factors, including protease,
has been reported to contribute to the trimethoprim resistance of lipase, and lecithinase activities, while isolates recovered from

blood did not demonstrate any of these virulence factors or he- dTDP-glucose 4,6-dehydratase, glucose-1-phosphate thymidy-
molytic and cytotoxic activities (111). lyltransferase, dTDP-dehydrorhamnose 3,5-epimerase, and
The rhizosphere is an adverse environment, and the ability of S. dTDP-4-dehydrorhamnose reductase, respectively. The xanA and
maltophilia to express proteolytic activity provides an advantage xanB genes encode phosphomannomutase and phosphomannose
for the survival, growth, and spread of this organism. A rhizo- isomerase/GDP-mannose pyrophophorylase, respectively. Bio-
sphere S. maltophilia isolate harbored serine protease activity film production was assessed for rmlA, rmlC, and xanB trans-
against the free-living nematode Panagrellus redivivus and a plant- poson insertion mutants after growth in polystyrene microtiter
parasitic nematode, Bursaphelenchus xylophilus (152). It is plausi- plate wells containing Trypticase broth at 30°C at 50 rpm for 2
ble, therefore, to suggest that nosocomial isolates of S. maltophilia days. The rmlA, rmlC, and xanB S. maltophilia mutants displayed
a significant decrease (P ⬍ 0.05) in biofilm production on poly-

may have already acquired the genes for these enzymes from the
environment outside the hospital. Extracellular serine proteases in styrene in comparison to the parental isolate. The rmlA and rmlC
nosocomial S. maltophilia isolates have been reported. These pro- mutants produced significantly more (P ⬍ 0.05) biofilm on glass
teases contribute to the pathogen’s ability to degrade connective than that produced by the wild type and the xanB mutant (151). In
tissues (collagen and fibronectin) (368). my laboratory, analyses of an S. maltophilia rmlA transposon in-
The protease (elastase) production of S. maltophilia has been sertion mutant grown for 30 h at 37°C revealed that it formed
reported to exacerbate influenza A virus infection of human, more (P ⬍ 0.05) biofilm on polyvinyl chloride than that formed
equine, and pig host cells (213). Of the 13 samples confirmed to by its parental wild-type strain (334). In contrast to the growth of
contain influenza virus from animals, including pigs, horses, and the parental wild-type isolate, the mutant also demonstrated sen-
humans working in close contact with the animals, 21.11% of sitivity to growth on Luria-Bertani agar containing 0.1% SDS
them were coinfected with S. maltophilia. It was suggested that the (334).
elastase produced by S. maltophilia cleaves and activates the hem- The spgM gene encodes a bifunctional enzyme that has both phos-
agglutinin glycoprotein spike of influenza A virus, enabling the phoglucomutase and phosphomannomutase activities, which are
virus to enter host cells and resulting in cytopathic effects on the important for O-polysaccharide chain assembly (41, 225). A
infected cells. Following the treatment of the samples with sulfa- knockout mutation of the spgM gene results in reduced levels of
diazine, protease production by S. maltophilia and the cytopathic phosphoglucomutase and phosphomannomutase activities.
effects of influenza virus on the host cells decreased (213). Complementation experiments in which the cloned S. maltophilia
The gene encoding the extracellular protease StmPr1 was found spgM gene was provided on a plasmid to the knockout mutant
in only 2 of 11 S. maltophilia clinical isolates (strains OBGTC9 and restored the activities of both enzymes (225).
OBGTC10, recovered from persistent infections in CF patients), S. maltophilia spgM mutant strains display a lower yield of
suggesting that the gene may be found in isolates that have been high-molecular-weight O-antigen than that of their parental
able to cause chronic infections in these patients (88). strains (41, 225, 348). The structure of the core region of LPS is
not altered by the knockout mutation of the spgM gene (225). A
Lipopolysaccharide comparison of the monosaccharide composition of O-antigen
S. maltophilia has lipopolysaccharide (LPS) that contains lipid of spgM chromosomal knockout mutant strain K2049 and that
A, core oligosaccharide, and O-antigen. The lipid A structure of its parental wild-type strain, K1014, revealed that they har-
of S. maltophilia strain NCTC 10257 contains phosphorylated bored similar rhamnose/fucose/glucose ratios, indicating that
glucosamine residues with N-fatty acyl and O-fatty acyl com- the spgM knockout mutant was able to synthesize and assemble
ponents (240). Components of the core oligosaccharide have in- an O-antigen with the same chemical structure as that of the
cluded D-glucose, D-mannose, D-galactose, D-galactosamine, wild-type strain (225).
D-galacturonic acid, 3-deoxyoctulosonic acid, and L-glycero-␣-D- In my laboratory, an analysis of S. maltophilia spgM transposon
mannoheptose (225, 240). O-antigen components have included insertion mutant strain JB12-23 showed that it formed more bio-
rhamnose, fucose, xylose, and glucose (166, 225, 382). film (P ⬍ 0.001) than that formed by its parental wild-type strain,
Charged lipopolysaccharides have been reported to influence X26332, on polyvinyl chloride microtiter wells (41, 348). The
bacterial cell adhesion to surfaces by covering charges present in spgM mutant formed more (P ⬍ 0.05) biofilm than that formed by
deeper cell wall layers (212). The positively charged cell surface of the parental strain on polystyrene microtiter wells and on boro-
S. maltophilia strain 70401 was reported to be important for ad- silicate glass (41, 348). The doubling times of the parental and
herence to glass and Teflon (166). The absence of outer membrane mutant strains in the microtiter plates were 96.8 and 93.5 min,
proteins in this strain was suggested to have resulted in the positive respectively, suggesting that differences in biofilm production
charge of the cell surface, and this combined with a noncharged were not due to increased growth rates. No significant difference
lipopolysaccharide resulted in an increased ability of S. malto- (P ⬎ 0.05) in hydrophobicity between the spgM mutant strain and
philia to adhere to Teflon and glass in comparison to that of a P. the parental strain was observed. It is possible that the sensitivity
aeruginosa isolate with a negatively charged cell surface. of the hydrophobicity assay may not have been able to distinguish
Incomplete LPS can alter the biofilm production of S. malto- between the subtle differences in LPS present on the wild-type and
philia (41, 151). Mutagenesis of S. maltophilia identified two oper- mutant cell surfaces. In contrast to the growth of the wild-type
ons, rmlBACD and xanAB, that are important for the production strain, the spgM mutant was unable to grow on LB agar containing
of LPS (151). SDS-PAGE analysis of purified LPS from S. malto- 0.1% SDS. spgM mutant JB12-23 colonies failed to absorb Congo
philia rmlA, rmlC, and xanB mutants revealed that rmlC and red stain, in contrast to the parental X26332 colonies, which ap-
rmlA are needed for O-antigen biosynthesis and that xanB is peared dark red when grown on Congo red agar. Together, these
needed for the biosynthesis of O-antigen and the core region of observations suggested that the incomplete LPS expressed by the
LPS (151). The rmlB, rmlA, rmlC, and rmlD genes encode mutant unmasked cell surface components otherwise concealed

Brooke

FIG 5 Transmission electron micrographs of epithelial respiratory cells exposed to S. maltophilia CF 1 (A) and NCF 13 (B) for 3 h. Note the presence of
intracellular bacteria in membrane-bound endocytic vacuoles. Magnifications, ⫻30,000 (A) and ⫻35,000 (B). (Panel A courtesy of M.-C. Plotkowski; panel B
reprinted from reference 73 with permission of Wiley-Blackwell.)
by LPS, thereby enabling the cells to more easily adhere to the binding to the cell membranes of these strains revealed that sig-
selected plastic or glass surface (41, 348). nificantly larger amounts (P ⬍ 0.01) of gentamicin were bound at
Deficits of LPS reduced S. maltophilia virulence in a rat lung 37°C than at 30°C (275). That study suggested that when S. malto-
model of infection (225). S. maltophilia spgM chromosomal philia strains are grown at 37°C, increased numbers of aminogly-
knockout mutant strain K2049 was unable to colonize rat lungs, in coside binding sites may be available as a result of the greater
contrast to its parental strain, K1014, which was recovered from number of negatively charged phosphate groups. These experi-
rat lungs at 7 days postinfection. The complementation of the mental results may therefore explain why it is common to see
mutant with the introduction of the spgM gene on plasmid resistance of S. maltophilia clinical isolates to aminoglycosides at
pGAM03 restored the ability to colonize rat lungs, providing evi- 30°C and susceptibility at 37°C. These observations can have clin-
dence that full-length LPS is important for colonization. Rat lung ical significance when taking into consideration antimicrobial
tissues inoculated with spgM mutant strain K2049 showed no his- treatment at various sites of S. maltophilia infection in the host.
topathological changes, in contrast to wild-type strain K1014 or
the complemented mutant. spgM mutant strain K2049 was sus- Adherence to and Invasion of Host Cells
ceptible to complement-mediated cell killing, unlike parental S. maltophilia can adhere to and form biofilms on human bron-
strain K1014 or the complemented mutant (225). These observa- chial epithelial cells and is able to invade them (73, 90, 268).
tions emphasize the importance of LPS as a virulence factor in- Transmission electron microscopy indicates that both cystic fi-
volved in S. maltophilia infection. brosis (CF) and non-cystic fibrosis (NCF) S. maltophilia isolates
Alterations in LPS may change the bacterial cell’s susceptibility adhere to and are able to invade transformed human bronchial
to particular antimicrobial compounds, e.g., cationic peptides and epithelial 16 HBE14o⫺ cells (Fig. 5) (73). No significant differ-
aminoglycosides. S. maltophilia spgM chromosomal knockout ence between the adherences of CF and NCF isolates to host bron-
mutant strains K2048 and K2049 exhibited sensitivity to poly- chial cells was observed.
myxin B, polymyxin E, nalidixic acid, gentamicin, and vancomy- Flagella have been reported to mediate the adherence of S.
cin, in contrast to their parent strains (225). In a recent study of 40 maltophilia isolates to mouse tracheal mucus. Flagella are highly im-
MDR and 30 non-MDR S. maltophilia clinical isolates, the expres- munogenic structures and are conserved among clinical isolates of S.
sion of spgM was weakly correlated (P ⬍ 0.05) with multidrug maltophilia (84, 360). S. maltophilia cells preexposed to antiflagellin
resistance, with high levels of SpgM expression being associated decreased the adhesion of the bacteria to mucus, and the decrease
with only three lactams (ceftazidime, ticarcillin-clavulanic acid, corresponded to the concentration of antiflagellin. The pretreatment
and piperacillin-tazobactam) (198). of the mouse tracheal mucus with pure flagellin resulted in a decrease
Temperature has been reported to alter the chemical composi- in bacterial adhesion. Deflagellated bacteria also demonstrated a re-
tion of LPS, resulting in changes in susceptibility to aminoglyco- duced adherence to mouse tracheal mucus (381).
sides (275). The growth of 33 clinical S. maltophilia isolates and In contrast to their parental wild-type isolates, two flagellum-
five reference strains (NCTC 10257, NCTC 10258, NCTC 10259, deficient S. maltophilia fliI CF mutants demonstrated decreased
NCTC 10498, and NCTC 10499) at 37°C and 30°C revealed that adherence to CF-derived bronchial epithelial IB3-1 cells and were
23 out of the 38 strains demonstrated a ⬎4-fold difference in defective in swimming motility (268). The fliI mutants caused
MICs of gentamicin and other aminoglycosides, showing in- IB3-1 monolayer cell disruption after 6 h, suggesting that the mu-
creased sensitivity at 37°C. Chemical composition analysis of the tants have increased virulence; further research is needed to ex-
LPS of these 23 strains showed that LPS had a significant increase plain this altered virulence. Swimming and twitching motilities of
(P ⬍ 0.001) in the phosphate content at 37°C compared to that of S. maltophilia CF isolates did not correlate with adherence or bio-
LPS when strains were grown at 30°C; there was no significant film formation on bronchial cells (88, 268). In another study, S.
difference in the 3-deoxy-D-manno-octusolonic acid (KDO) con- maltophilia CF isolates and two nonrespiratory S. maltophilia ref-
tents at the two temperatures. Data from fluorescence-activated erence strains (environmental strain LMG959 and blood-isolated
cell sorter (FACS) analysis of fluorescently labeled gentamicin strain K279a) were examined for swimming and twitching motil-

ity and biofilm formation; no correlation was observed for biofilm hemolysis, in contrast to wild-type S. maltophilia (149). Together,
formation and motility (88). these observations suggest that rpfF and crp are important for the
In my laboratory, S. maltophilia fliF transposon insertion mu- virulence of S. maltophilia.
tant strain JB5-39 is flagellum defective and motility defective, as Providing rpfF in trans in wild-type S. maltophilia and in S.
determined by negative-staining TEM and motility agar assays maltophilia ⌬rpfB and ⌬rpfBF mutants resulted in swimming and
(37). Under the culture conditions used, there was no major dif- radial translocation of these strains (150). The ability of the wild
ference in the adherences and amounts of biofilm formed on PVC type and a flagellum-defective S. maltophilia xanB mutant to dem-
surfaces by the fliF mutant and its parental wild-type isolate (37). onstrate radial translocation in the presence of an ⌬rpfB/prpfF
Taken together, studies of flagella and the adherence of S. malto- (plasmid prpfF contains the 975-bp rpfF native promoter and cod-

philia to lung cells and PVC surfaces suggest that flagella may play ing sequences in pBBR1MCS5) S. maltophilia strain suggested that
an important role in the early stages of adherence but do not the ⌬rpfB/prpfF strain secreted molecules that enabled flagellum-
significantly influence biofilm formation. independent translocation. High-performance liquid chromatog-
S. maltophilia isolates have demonstrated a limited ability to invade raphy, electrospray ionization mass spectrometry, and gas
human respiratory cells. Tested S. maltophilia CF clinical isolates have chromatography-mass spectrometry analyses of these extracellu-
been reported to adhere to A549 cells, along intercellular junctions. lar compounds have shown them to be derivatives of cis-⌬2-11-
The adherence of S. maltophilia to A549 cells was not dependent on methyl-dodecenoic acid. Synthetic cis-⌬2-11-methyl-dodecenoic
the ability of the bacterial strain to form biofilm or demonstrate mo- acid or 11-methyl-dodecenoic acid enabled the surface transloca-
tility. The CF S. maltophilia isolates were able to invade these cells with tion of wild-type S. maltophilia carrying pBBR1MCS5 (150).
a reported range of 0.002% to 0.005% (88). The rates of invasion of The DSF activity of S. maltophilia is recognized by P. aeruginosa,
bronchial epithelial 16 HBE14o⫺ cells by isolates CF 1 and NCF 13 of alters susceptibility to polymyxin, and influences biofilms of P.
S. maltophilia were reported to be 0.45% and 0.40%, respectively aeruginosa (Fig. 6) (291). An rpfF mutant of S. maltophilia does
(73). Observations of CF and NCF isolates within membrane-bound not synthesize DSF, and biofilms of the mutant are not as filamen-
endocytic vacuoles suggest that microbial division can occur in the tous as those produced by wild-type S. maltophilia (113, 291). The
intracellular compartment of host epithelial cells. S. maltophilia CF complementation of the S. maltophilia rpfF mutant with the
isolates were limited in their abilities to invade IB3-1 bronchial cells, cloned rpfF gene or the supplementation of the mutant with DSF
with rates of invasion ranging from 0.01 to 4.94% (268). The limited (10 or 50 ␮M) restores the filamentous structure of the biofilm
invasiveness of S. maltophilia has been reported for the transient low- (291). P. aeruginosa formed flat biofilms when grown in monocul-
level presence of the bacteria in the spleens of DBA/2 mice infected ture or in coculture with the S. maltophilia rpfF mutant. In cocul-
with an S. maltophilia CF isolate through the use of an aerosol delivery tures with DSF-producing S. maltophilia and P. aeruginosa, the
system (87). Limited invasion and rapid clearance of the bacterium biofilm of P. aeruginosa changed from a flat to a filamentous bio-
from the lungs were reported for S. maltophilia introduced intrana- film. A filamentous biofilm was also observed in monocultures of
sally into mice (380). The invasion of host cells and subsequent pro- P. aeruginosa supplemented with 10 or 50 ␮M DSF. The PA1396
tection from host immune defense provide one explanation for the protein of P. aeruginosa was identified as a two-component sensor
ability of S. maltophilia to persist in chronic lung infections. of DSF (291). The addition of DSF or the mutation of PA1396
resulted in increased resistance to polymyxins B and E. Mutations
Diffusible Signal Factor System of PA1396 also resulted in the increased expression of a number of
S. maltophilia has a diffusible signal factor (DSF) system that was proteins involved in stress tolerance (291). The recent identifica-
first identified in Xanthomonas campestris pv. campestris (113, tion of cis-2-decenoic acid as a fatty acid that induces the dispersal
149). The DSF activity of S. maltophilia strain WR-C is due to of P. aeruginosa PAO1 biofilms provides further evidence for the
cis-⌬2-11-methyl-dodecenoic acid and seven structural deriva- role of select fatty acids as cell-cell signaling molecules that influ-
tives (150). rpfF, part of the rpf (regulation of pathogenicity fac- ence biofilm architecture (72). Together, these observations have
tors) gene cluster of S. maltophilia K279a, complemented the rpfF clinical significance for the treatment of polymicrobial infections
mutant of X. campestris, resulting in DSF production (113). The of S. maltophilia and P. aeruginosa. The DSF system may be a
rpfF mutant of S. maltophilia K279a demonstrated reduced motil- target for pharmacological therapy.
ity, reduced extracellular protease production, altered LPS, and
reduced tolerance to select antibiotics and heavy metals. In con- S. maltophilia and the Cystic Fibrosis Lung Environment
trast to wild-type S. maltophilia, the rpfF S. maltophilia mutant is The role of S. maltophilia in the pathogenesis of CF lung disease is
unable to form microcolonies in artificial sputum medium. The not clear. It was reported that approximately 11% of CF patients
exogenous addition of DSF (1 ␮M or from S. maltophilia extracts) are colonized by S. maltophilia (69). Determining if S. maltophilia
restored the ability of the rpfF S. maltophilia mutant to form mi- is colonizing or causing infection can be challenging (245). S.
crocolonies and restored motility and extracellular protease pro- maltophilia has been reported to impair lung function in CF pa-
duction. In a nematode model, the rpfF S. maltophilia mutant tients, but several studies have reported no difference in lung
demonstrated reduced killing activity, in contrast to wild-type S. function in S. maltophilia-positive CF patients, and one study
maltophilia (113). The rpfF gene regulates the expression of FecA, demonstrated that the presence of S. maltophilia did not reduce
an outer membrane receptor used for ferric citrate uptake (149). the survival of CF patients (76, 128, 168, 217, 320).
The cyclic AMP receptor protein (CRP) positively regulates rpfF In a retrospective cohort study of the period from 1997 to 2008
transcripts; complementation studies and the presence of two po- using the Toronto (Canada) CF database, CF patients with
tential CRP binding sites upstream of the rpfF promoter suggest chronic S. maltophilia infection had a lower mean percent pre-
that CRP is a transcriptional activator of rpfF. Transposon mu- dicted FEV1 (47.06%) than patients with intermittent S. malto-
tants in crp of S. maltophilia were defective in proteolysis and philia infection (78.6%) or patients never infected with S. malto-

Brooke

FIG 6 The biofilm architecture of P. aeruginosa is influenced by S. maltophilia and DSF. Images are of 4-day-old biofilms in flow cells in FABL medium. (A) P.
aeruginosa PAO1; (B) S. maltophilia K279a; (C) coculture of P. aeruginosa PAO1 and S. maltophilia K279a; (D) coculture of P. aeruginosa PAO1 and S. maltophilia
K279arpfF; (E) P. aeruginosa PAO1 with 50 ␮M exogenous DSF; (F) coculture of P. aeruginosa PAO1 and the complemented S. maltophilia K279arpfF mutant.
P. aeruginosa was tagged with mini-Tn7gfp, and S. maltophilia was visualized with Syto62. Scale bars, 20 ␮m. The confocal scanning laser microscopy images
shown are representative of 12 images from three independent experiments. (Reprinted from reference 291 with permission of John Wiley & Sons.)
philia (73.40%) (P ⬍ 0.0001) (359). Chronic S. maltophilia FEV1 reported in that study agrees with the results obtained by
infection was identified as an independent risk factor for pulmo- Goss et al. (127). In a cohort study, CF patients aged ⱖ6 years in
nary exacerbation requiring hospitalization and antibiotic ther- the CF Foundation National Patient Registry from 1994 to 1999
apy. Using a model adjusted for patient age, pancreatic insuffi- demonstrated a negative correlation of S. maltophilia with FEV1
ciency, P. aeruginosa, body mass index, and percent predicted (P ⱕ 0.0001); however, S. maltophilia did not appear to have an
baseline FEV1, patients with chronic S. maltophilia infection had a effect on lung function decline (127).
significantly higher risk of pulmonary exacerbation (P ⫽ 0.0002) The sputum of CF patients contains glycoproteins and high-
than patients without S. maltophilia infection. The rate of decline molecular-weight DNA at high concentrations, resulting in a
in the percent predicted FEV1 for patients with chronic S. malto- highly viscous physical barrier that surrounds and protects bacte-
philia was ⫺1.02% predicted per year, that for patients with inter- rial inhabitants from the antimicrobial activities of pharmaceuti-
mittent S. maltophilia was ⫺0.94% predicted per year, and that for cal treatments (206). The ability of these macromolecules to bind
patients never infected with S. maltophilia was ⫺1.06% predicted to antimicrobial drugs and interfere with the drugs’ ability to enter
per year. The lack of an association of chronic S. maltophilia in- bacterial cells and the relatively low pH of CF sputum can all
fection with an increased rate of decline in the percent predicted reduce the activity of antimicrobial drugs (206). As mentioned

above, under nutrient limitation conditions, S. maltophilia forms tribute to disease development by providing a favorable growth
UMC (316). It is interesting to speculate whether in artificial environment for P. aeruginosa in the CF lung.
sputum medium, S. maltophilia UMC form and assemble into Panresistant bacteria are a concern for lung transplant CF pa-
biofilms. tients. A recent study reported that CF patients harboring panre-
Molecular biology strategies have been developed to improve sistant bacteria (defined as resistant bacteria demonstrating inter-
the ability to detect S. maltophilia in CF patient sputum samples. mediate resistance to an antibiotic from each class of antibiotics)
PFGE, ERIC-PCR, gyrB restriction fragment length polymor- other than B. cepacia have slightly decreased survival following
phism (RFLP) analysis, and ribotyping have been used to analyze lung transplantation. Compared with CF patients harboring sus-
S. maltophilia isolates recovered from sputum samples (45, 57, 63, ceptible bacteria, the survival rates of CF patients with panresis-

78, 222, 246, 287, 338, 364). Multiplex PCR has been used to tant bacteria other than B. cepacia are excellent (136).
identify S. maltophilia, P. aeruginosa, and B. cepacia complex iso- S. maltophilia and P. aeruginosa have been coisolated from the
lates in respiratory samples from CF patients (71). Primers de- human lung environment. It may be that in the CF lung environ-
signed to amplify a 149-bp fragment of the chitinase A gene of S. ment, P. aeruginosa infection is followed by S. maltophilia infec-
maltophilia were included in a multiplex procedure with universal tion. The cell adherence and invasion of S. maltophilia in the pres-
primers to detect 16S rRNA genes and primers specific for P. ence of P. aeruginosa have been studied. The incubation of
aeruginosa and 16S rRNA genes of the B. cepacia complex. The transformed host human bronchial epithelial 16 HBE14o⫺ cells
method successfully detected 50 pg of S. maltophilia DNA, 5 pg of with P. aeruginosa strains 1412, 1440, and PAK prior to incubation
P. aeruginosa DNA, and 250 pg of B. cepacia genomovar I DNA. with S. maltophilia isolate CF 1 did not alter the adhesion of S.
This multiplex protocol demonstrated high negative predictive maltophilia to the host cells, suggesting that the two bacteria are
values (⬎90%) for the identification of the three pathogens, in not competing for the same host cell receptors (73). These data are
contrast to the relatively low positive predictive values. It was pro- in contrast to data from a study reported by Pompilio et al. (268),
posed that the genomic heterogeneity observed among S. malto- in which the preexposure of human bronchial CF-derived epithe-
philia strains may provide a reason for the low sensitivity of the lial IB3-1 cell monolayers to P. aeruginosa increased the adhesion
method for the detection of S. maltophilia (71). of S. maltophilia to lung cells.
Cough-generated aerosols from CF patients have been reported When P. aeruginosa was incubated simultaneously with S.
maltophilia, the adherence of P. aeruginosa to human bronchial
to contain respiratory particles of ⱕ3.3 ␮m from which viable S.
epithelial 16 HBE14o⫺ cells was not significantly altered, whereas
maltophilia, P. aeruginosa, Burkholderia cenocepacia, and Achro-
the adherence of S. maltophilia to the host cells was reduced to
mobacter xylosoxidans could be cultured (351). A cough aerosol
approximately 50% (73). A heat-labile substance of P. aeruginosa
sampling system was used to capture aerosolized droplets gener-
appears to inhibit the adherence of S. maltophilia to the respira-
ated from CF patients. S. maltophilia was cultured from 4 patients,
tory cells (73). It is of interest that the preincubation of the epi-
2 of the patients did not produce sputum, and the other patients
thelial cell monolayers with S. maltophilia decreased the adher-
were sputum culture negative for S. maltophilia. These observa-
ence of P. aeruginosa to bronchial epithelial IB3-1 cells (268).
tions indicate that these aerosols can be a potential source of trans-
Future work is needed to determine if the differences in the adhe-
mission of S. maltophilia. Future work is needed to determine the sion of S. maltophilia to the host cells reflected differences in the P.
concentration and size of respiratory particles needed to cause S. aeruginosa and S. maltophilia strains used in the two studies.
maltophilia infection in susceptible individuals. Cell adherence and biofilm studies and the discovery of the
The accumulation of mucous in the CF lung provides a favor- diffusible signal factor of S. maltophilia suggest a relationship be-
able growth environment for P. aeruginosa and S. maltophilia. tween these two bacterial species in the human lung environment.
Iron is restricted in the human lung by lactoferrin, which seques- Both organisms have the ability to form biofilms on lung cells in
ters iron and reduces its accessibility by microbial pathogens. vitro (291). P. aeruginosa may provide a more hospitable environ-
High concentrations (100 ␮M) of ferric chloride inhibit the bio- ment for the adherence, invasion, and persistence of S. maltophilia
film development of P. aeruginosa PAO1, suggesting that the aero- in the CF lung.
solized delivery of ferric chloride may provide an effective nonan- An animal model of acute respiratory infection has been used to
tibiotic treatment for CF patients (373). Recent work in my study lung infection of DBA/2 mice with a CF S. maltophilia isolate
laboratory indicated that this high concentration of ferric chloride (87). An aerosol delivery system was used to inoculate female and
did not prevent biofilm production by S. maltophilia clinical iso- male mice with 8 ml of 1.0 ⫻ 1010 to 3.0 ⫻ 1010 CFU/ml S. malto-
late X26332 (219). Future studies are needed to examine the si- philia CF isolate OBGTC9. Almost all (⬎99%) of the bacteria were
multaneous incubation of S. maltophilia with P. aeruginosa and killed within the first week postinoculation. The invasiveness of S.
test the hypothesis that during the course of infection and disease, maltophilia was assessed by using an analysis of spleen homoge-
S. maltophilia protects P. aeruginosa against the inhibitory effects nates, with the day 1 data showing the highest percentage of S.
of this relatively high concentration of iron. Lactoferrin has dem- maltophilia-positive spleens and no bacteria being recovered from
onstrated efficacy at inhibiting biofilm formation by P. aeruginosa spleens on day 14. A major inflammatory response against the
(319). It is interesting to speculate about the influence of lactofer- bacterial pathogen was observed in the mice. Cytokine and
rin on biofilm production by S. maltophilia. chemokine levels were elevated in infected mice. On day 1, the
In vitro cell viability and antibiotic susceptibility assays indi- following cytokines were observed at higher levels than in control
cated that ␤-lactamases produced by S. maltophilia clinical iso- uninfected mice: interleukin-1␤ (IL-1␤), IL-6, IL-12, gamma in-
lates increase the growth of P. aeruginosa exposed to imipenem (4 terferon (IFN-␥), and tumor necrosis factor alpha (TNF-␣). On
or 16 ␮g/ml) or 32 ␮g/ml of ceftazidime (169). These data are day 3, only the IFN-␥ level was higher in infected than in control
important, as they suggest that S. maltophilia may indirectly con- mice. The higher levels of TNF-␣, IL-1␤, and IL-6 in infected mice

Brooke
than in control mice are in agreement with observations of lung 10 ml twice a day) or rhDNase (2.5 mg/day), improved forced
secretions from CF patients versus healthy individuals (36). On expiratory volume was observed for hypertonic saline (mean ⫽
day 1, the following chemokines were expressed at higher levels in 7.7%; standard deviation [SD] ⫽ 14%) and for rhDNase (mean ⫽
infected than in control mice: keratinocyte-derived cytokine 9.3%; SD ⫽ 11.7%), with no significant difference observed be-
(GRO␣/KC), monocyte chemotactic protein 1 (MCP-1/JE), mac- tween the hypertonic saline and rhDNase treatments (23). In this
rophage chemoattractant protein 5 (MCP-5), macrophage in- small study, patients reported a higher acceptance of the rhDNase
flammatory protein 1␣ (MIP-1␣), MIP-2, and thymus- and than the hypertonic saline, possibly due to the shorter time re-
activation-regulated chemokine (TARC). After day 3, no chemo- quired for its inhalation (23).
kines were observed at higher levels in infected mice than in con- Several studies have investigated the use of combination antibi-

trol mice. These data indicate an immune response defined by a otics to treat CF patients infected with MDR Gram-negative bac-
Th1-type response with the recruitment of polymorphonuclear teria (1, 294, 304). The macrolides azithromycin and clarithromy-
leukocytes (PMNs) and monocytes. Severe weight loss in the in- cin paired with ceftazidime, quinolones, chloramphenicol,
fected mice occurred immediately after the increased expression tetracycline, or tobramycin have demonstrated modest synergistic
of TNF-␣, supporting the role of this cytokine in inducing the and additive effects against S. maltophilia isolates from CF patients
excessive inflammatory response and CF-like systemic effects. Ad- (294). Antibiotic susceptibility testing was performed on S. malto-
ditional research is needed to determine if this inflammatory re- philia isolates recovered from 673 CF patients during 1996 to
sponse is induced by S. maltophilia strains in general or if it is 2001 (304). The study isolates reflected approximately 7 to 23%
bacterial strain specific. One recent study (380) of respiratory tract of CF patients in the United States who were colonized with S.
infection in BALB/c mice inoculated with 1 ⫻ 109 CFU of clinical maltophilia annually. Synergistic or additive effects were demon-
S. maltophilia isolate Sm2 reported similar results of early (4 h strated for TMP-SMX and ticarcillin-clavulanate, ciprofloxacin
postinfection) increased levels of IL-1␤ and TNF-␣ compared and ticarcillin-clavulanate, ciprofloxacin and piperacillin-
with control mice and IL-10 levels in lung homogenates at a max- tazobactam, TMP-SMX and piperacillin-tazobactam, and doxy-
imum of 2 days postinfection. By day 5, levels of IL-1␤, TNF-␣, cycline and ticarcillin-clavulanate (304). A clinical trial of CF pa-
and IL-10 were normal compared to those observed for the con- tients with chronic Gram-negative bacterial infections reported
trol mice. These data provide evidence to support the hypothesis no better outcomes for patients with an exacerbation of pulmo-
that this induced inflammatory response is common across differ- nary disease who had received two blinded intravenous antibiotics
ent strains of S. maltophilia. chosen based on sputum culture testing or results of multiple-
Sodium chloride concentrations are relatively high in the CF combination bactericidal antibiotic testing (MCBT) in compari-
lung environment. Hypertonic saline has been proposed by sev- son with antibiotic therapy chosen based on standard conven-
eral studies to have therapeutic potential in CF patients (23, 92, 96, tional culture testing (1). The suggested explanations for these
99, 280). The inhalation of hypertonic saline improves mucocili- results included the possibility that in vitro bacterial antibiotic
ary clearance, with dose dependency reported for treatments of susceptibility may not correlate with the clinical response to anti-
0.9%, 3.0%, 7.0%, and 12% NaCl (280). It was suggested that biotic therapy; that the antibiotic resistance of bacterial strains can
hypertonic saline increases the hydration of airway surfaces, re- change over time, leading to ineffective treatment outcomes; and
sulting in improved forced expiratory volume and increased mu- that biofilms may inhibit the clinical response to antimicrobial
cus clearance (280). Increased airway inflammation assessed therapy (1). Those studies together underscore the need to con-
through the monitoring of sputum cytokines such as IL-8 has not tinue to monitor the emergence and presence of MDROs in CF
been observed for hypertonic saline, and no increase in the sever- patients, with the intent of developing more effective antimicro-
ity of bacterial infection has been observed for CF patients treated bial therapies for these patients.
with hypertonic saline (96). Bronchodilator use prior to treatment A recent study of S. maltophilia K279a demonstrated that the
with hypertonic saline reduces airway constriction (96). expression of GroEL, a member of the group I chaperonins, is
In my laboratory, the growth and motility of an S. maltophilia influenced by changes in temperature (74). Immunoblot analyses
clinical isolate exposed to 4% sodium chloride were inhibited, demonstrated that sera from CF patients chronically infected with
while culture growth was still observed with 2% sodium chloride S. maltophilia reacted with recombinant GroEL, whereas no reac-
(219). These observations suggest that hypertonic saline should be tivity was observed with sera obtained from patients infected spo-
considered for the treatment of S. maltophilia infections in CF
radically or not infected with S. maltophilia. No cross-reactivity
patients. Hypertonic saline (7%) was reported to abolish the
was observed between GroEL of P. aeruginosa and GroEL of S.
growth and motility of P. aeruginosa (139). These observations
maltophilia. The results of this study suggest that GroEL may serve
suggest that at this concentration, sodium chloride may reduce P.
as a useful indicator of S. maltophilia in CF patients chronically
aeruginosa colonization of CF patient lungs. Future studies are
infected with this organism.
needed to test the hypothesis that salt inhibits the biofilm forma-
tion of binary cultures of S. maltophilia and P. aeruginosa. If
shown to be effective at inhibiting the development of biofilms in MICROSCOPY OF S. MALTOPHILIA
vitro, the aerosolized delivery of salt solutions to the lungs of CF Electron microscopy has been used to examine the ultrastructure
patients may help delay biofilm development in the lung. of S. maltophilia cells. Transmission electron microscopy (TEM)
Regular treatment with recombinant human DNase (rhDNase) and SEM have identified flagellum-like filaments (approximately
has been shown to reduce sputum viscoelasticity and respiratory 40 to 50 nm in width) and thin fibrillar structures (5 to 7 nm in
tract infections and improve lung function in CF patients (114, width) resembling fimbriae of S. maltophilia SMDP92 as being
277). In a randomized crossover pilot study of 14 CF patients important for adherence to plastic and glass surfaces and HEp-2
treated with either inhaled hypertonic saline (5.85% NaCl given as cells (Fig. 2 and 3) (83, 84). TEM studies have revealed that S.

maltophilia is able to adhere to and invade respiratory host cells S. maltophilia strains has been accomplished. One strain is a clin-
(Fig. 5) (73). ical isolate (S. maltophilia K279A) from a cystic fibrosis patient
There are some major limitations of using electron microscopy who was undergoing chemotherapy in 1998 (67), and the other
to examine the interaction of S. maltophilia clinical isolates with strain is an environmental isolate (S. maltophilia R551-3) from the
host cells. The specimens are killed during specimen preparation, poplar Populus trichocarpa (EMBL/GenBank/DDBJ database ac-
and the bacterial cell contact with host cells may potentially be cession no. NC_011071). The genome sequence of clinical isolate
altered or distorted. The dehydration of the specimen during SEM K279a harbors genes that are not found in the genome of environ-
preparation causes a distortion of biofilm matrices. In contrast to mental isolate R551-3. The genome sequence of S. maltophilia
electron microscopy, confocal microscopy offers the opportunity K279A contains 4,851,126 bp and a G⫹C content of 66.7% (67). S.

to examine living S. maltophilia cells within hydrated biofilms. maltophilia K279A harbors 9 antimicrobial RND transporters and
Confocal microscopy has revealed that biofilm formation by P. several genes important for drug resistance mechanisms. The ge-
aeruginosa is altered by the diffusion signal factor expressed by S. nome sequence of isolate R551-3 contains 4,573,969 bp (accession
maltophilia (Fig. 6) (291). The data reported in that study suggest no. NC_011071). Both S. maltophilia genomes (from K279A and
that cell-cell signaling between these two pathogens may offer new R551-3) contain genes for the mismatch repair (MMR) system,
target sites for pharmaceutical intervention and the inhibition of the guanine oxidation system, the nucleotide excision system, the
polymicrobial biofilm formation in patients with compromised recombination repair system, and the SOS system (335). The
lung function. More research is needed to identify and develop MMR genes of both isolates shared high sequence identity, rang-
target inhibitors suitable for testing in animal model systems. ing from 90 to 95%. A closer examination of the MMR genes
Confocal microscopy and flow chamber studies with P. aerugi- mutS, mutL, and uvrD in these isolates and their corresponding
nosa containing green fluorescent protein and rhlA-gfp reporter amino acid sequences revealed polymorphisms in MutS, MutL,
fusions have shown that iron limitation induces rhamnolipid syn- and UvrD. Defects of the MutS protein were suggested to result in
thesis, promotes twitching motility, and alters biofilm structure, the emergence of hypermutable strains from patients (335).
resulting in the formation of thin flat biofilms (124). Rhamnolip- The availability of the genome sequence of S. maltophilia K279a
ids may be important for maintaining water channels in biofilms has enabled efforts to develop a methodology for effectively and
(124). Further studies are needed to establish if the biofilms of S. rapidly typing S. maltophilia isolates (287). PCR has been used to
maltophilia are similarly altered by iron limitation. amplify multilocus variable-number repeats from the genomes of
Recently, fluorescence recovery after photobleaching analysis S. maltophilia isolates. Palindromic elements called SMAG (S.
and confocal laser scanning microscopy have been used to mea- maltophilia GTAG) elements that contain the sequence GTAG at
sure the diffusion of fluorescent dextran inside the biofilm of S. one terminus have been observed for the genome of S. maltophilia
maltophilia (350). A mean diffusion coefficient value of 10 ⫾ 5 K279A (282, 287). These repetitive extragenic palindromic se-
␮m2/s was obtained for fluorescent dextran in the S. maltophilia quences that flank S. maltophilia genes were suggested to control
biofilm. This nondestructive method has the advantage of using gene expression by their folding within the mRNA and either sta-
confocal laser scanning microscopy to analyze the diffusion of bilizing or facilitating the degradation of gene transcripts. The
molecules in situ within the spatial architecture of the biofilms. chromosome of K279A carries 1,650 SMAG sequences assigned to
This technique has potential use for the study of the movement of five major subfamilies based on their consensus sequences. The
antimicrobial agents and their antimicrobial effects on S. malto- stem sequences were complementary in most of the SMAGs
philia biofilms. within the subfamilies, suggesting that the secondary folding of
There is a need for further studies using confocal microscopy the repeat sequences can occur at the DNA and RNA levels of
to look at the adherence and development of biofilms of S. malto- organization. Gene transcription analyses of S. maltophilia ge-
philia on clinically relevant surfaces (e.g., plastic, respiratory tub- nomes from strains K279A, STM2, 545, and 1029 have provided
ing, blood transfusion equipment surfaces, and plumbing sur- evidence to support the hypothesis that SMAG repeats influence
faces) that can come into contact with susceptible individuals. mRNA stability (281). A comparison of the SMAG sequences in
Future studies using confocal microscopy are needed to look at the K279A with the genomes of environmental isolates S. maltophilia
development of S. maltophilia biofilms under different environ- R551-3 and SKA14 revealed them to contain SMAG sequences of
mental conditions (e.g., disinfection treatments). The Live/Dead all 5 subfamilies but with different sizes of these subfamilies. The
BacLight kit (Invitrogen) has been used in combination with flow subfamily SMAG-3 is dominant in strain K279A, and it was pro-
cytometry to assess bacterial viability (32), and the Film Tracer posed that molecular analysis of this subfamily may be helpful for
Dead/Live biofilm viability kit (Invitrogen) has been used with epidemiological and genotyping studies (282). Future research is
confocal microscopy to determine the effects of biocides on the needed for an in-depth analysis of the quantity and identification
biofilm formation of other bacterial pathogens. of genes whose expressions may be controlled by SMAG se-
quences.
COMPARING CLINICAL AND ENVIRONMENTAL Sequencing data for S. maltophilia isolates K279a and R551-3
S. MALTOPHILIA ISOLATES demonstrated the highly variable content of genomic islands
(281). In K279a, 41 genomic islands (constituting 12.1% of the
Genome Sequencing and Molecular Diversity of genome and 597 open reading frames [ORFs]) have been identi-
S. maltophilia Strains fied, with the majority being ⬎15 kb in size, while R551-3 harbors
Recent studies have explored the differences between environ- 36 islands (constituting 6.6% of the genome and 249 open reading
mental and clinical isolates of S. maltophilia to try to determine frames), and just four islands are ⬎15 kb. The presence or absence
what mechanisms are responsible for the bacterium’s pathogenic- of genomic islands is a major source of the heterogeneity observed
ity in humans. It is important that the genome sequencing of two between the two isolates. Genomic island gene products identified

Brooke
to have a role in interactions with the environment have included SMF-1 fimbriae only in the clinically derived strains, providing
metal resistance genes, type I and IV secretion systems, LPS genes, support for the hypothesis that these structures are important for
and filamentous hemagglutinin genes (281). The two S. malto- the colonization of CF patients (83). All strains exhibited only
philia isolates do not share common genomic islands but do con- swimming motility, and no swarming motility was detected. All
tain genes with the same function. No correlation between the tested strains demonstrated the expected PCR product corre-
presence of specific genomic island gene products and the patho- sponding to the StmPr2 gene, encoding an extracellular protease
genic life-style of S. maltophilia K279a has been discovered. (67). Of the 52 tested strains, 38 exhibited a 1,621-bp PCR prod-
Strain-specific ORFs also contribute to the genomic heterogeneity uct, and 11 exhibited an 868-bp PCR product, corresponding to
between the two isolates, constituting ⬃17.5% and 10.1% of the the StmPr1 gene, encoding an alkaline serine protease (368). The

potential gene products for K279a and R551-3, respectively. PCR putative esterase encoded by the Smlt3773 locus was detected by
and slot blot analyses have demonstrated that strains of S. malto- PCR in 49 isolates, but esterase activity was absent from 11 iso-
philia can harbor genomic islands at locations that differ from lates; sequencing and BLAST analysis revealed premature stop
those of isolate KI279a. codons resulting in a significant number of spontaneous nonfunc-
A study of the codon usage by S. maltophilia isolate R553-1 tional variants. The major protease StmPr1 appeared to contrib-
revealed that highly expressed genes are asymmetrically distrib- ute more than the minor protease StmPr2 and the esterase to the
uted and found mostly on the lagging strand of the genome, in virulence of S. maltophilia, as indicated by 50% lethal dose (LD50)
contrast to low-level-expressed genes, which are evenly distrib- values observed for the killing of wax moth larvae; however, it was
uted between the lagging and leading strands (24). Nine of 14 suggested that protease activity is not solely responsible for viru-
genes encoding antibiotic resistance are expressed at low levels, lence, as two environmental protease-positive strains exhibited
and four of these genes were reported to have been acquired poor killing activity. Further studies using mammalian models of
through horizontal transfer. That study proposed that these ac- infection or CF-derived cell assays of strains with defined muta-
quired genes are needed for the pathogenic mode of living of the S. tions in these virulence factor-encoding genes will be helpful to
maltophilia isolate (24). It was also hypothesized that the predom- elucidate the individual contributions of these genes to the viru-
inance of highly expressed genes on the lagging strand of the ge- lence of S. maltophilia.
nome provides an advantage for the relatively slow growth of S. A relatively new method, melting-curve analysis of RAPD-
maltophilia. Further studies are needed to determine if this asym- generated DNA fragments (McRAPD), has shown promise for the
metric distribution of highly expressed genes is common across analysis of small numbers of S. maltophilia isolates at a time (86).
clinical and environmental isolates of S. maltophilia. The method demonstrated a sensitivity comparable to that of
The genetic heterogeneity of S. maltophilia has been identified RAPD analysis followed by agarose gel electrophoresis in its ability
through the use of several molecular biology methods (71, 246, to discriminate between S. maltophilia isolates and group them
308, 339). The use of restriction fragment length polymorphism into genotypes. The McRAPD method is advantageous over tra-
(RFLP) analysis of the gyrase B gene (gyrB) after HaeIII digestion ditional methods used to differentiate DNA sequences, as it does
demonstrated considerable diversity among S. maltophilia isolates not require electrophoresis. The McRAPD method is, however,
(63). Cluster analysis of the gyrB RFLP patterns of 183 Stenotroph- currently restricted, as it is not able to analyze large numbers of
omonas isolates (including S. maltophilia, S. africana, S. nitritire- isolates due to differences observed in DNA fingerprints obtained
ducens, S. acidaminiphila, and S. rhizophila) placed the majority between thermal cycling runs. Further optimization studies may
(36 out of 40) of the S. maltophilia isolates from CF patients into improve the sensitivity and comparability between runs.
two clusters, clusters B and C. Future research is needed to deter-
mine if these two clusters contain S. maltophilia isolates with traits
Linking Clinical Isolates to Sources
advantageous for the establishment and persistence of infection in
CF patients. Several molecular biology methods have been used to compare
PFGE and ERIC-PCR have both been used to type S. maltophilia and link clinical isolates to environmental sources. RAPD-PCR
isolates. Although PFGE is generally accepted as the more reliable used to examine the epidemiology of S. maltophilia isolates from
method of typing, ERIC-PCR has the advantages of ease and lower CF patients demonstrated that patients can harbor one or more
cost than PFGE. Both methods have demonstrated heterogeneity persistent isolates and/or become colonized with new isolates
among S. maltophilia strains. (183). The identification of sources of S. maltophilia isolates can
PFGE and RFLP analysis of the gyrB gene and sequencing of the suggest preventative measures to be designed and implemented to
hypervariable regions of the 16S rRNA gene were used in a 2011 decrease the possibility of infections. PFGE and random primer
study to compare S. maltophilia strains recovered from CF pa- PCR fingerprinting have been used to determine if outbreaks of a
tients and environmental sources (246). In addition, selected vir- particular strain of S. maltophilia have occurred in a hospital
ulence factors were tested for their presence in S. maltophilia (308). In a 1-year study, PFGE with SpeI enzyme digestion of
strains and compared for their expressions using cell assays and chromosomal DNA from 96 S. maltophilia clinical isolates ob-
virulence testing in larvae of the greater wax moth, Galleria mel- tained from patients in a tertiary care university hospital and ran-
lonella. A high degree of genetic diversity was observed among the dom primer PCR fingerprinting were used to identify possible
52 tested strains (41 from CF patients and the remainder from clonality among the isolates. No outbreak was confirmed in that
environmental samples), with 47 different pulsotypes and a simi- study. The particular enzyme chosen for the digestion of chromo-
larity of 78 to 100%. Nine different gyrB RFLP profiles and 6 dif- somal DNA in the PFGE method is important, as it can determine
ferent 16S rRNA groups were observed, with 7 strains exhibiting the level of sensitivity of differentiation between S. maltophilia
highly divergent 16S rRNA signature sequences, making it impos- isolates. The SpeI enzyme has been successfully used to identify
sible to assign them to a group. PCR detected the presence of different S. maltophilia isolates (189). Several studies have used

the XbaI enzyme with PFGE analysis to distinguish between S. study of a regional CF center, no correlation was observed be-
maltophilia isolates (222, 227). tween clinical isolates of S. maltophilia and isolates recovered
ERIC-PCR and PFGE have been used to compare clinical S. from hospital tap water (222). PFGE with XbaI pattern analyses
maltophilia isolates from CF patients with isolates from environ- of the 110 clinical and 24 water isolates resulted in 59 and 14
mental samples (hospital ward, outpatient clinic, and patient different phenotypes, respectively. Of the 22 rooms of the CF
homes) (81). During September 1993 to December 1995, 41 out of center, 6 rooms were positive for S. maltophilia. Each room was
163 patients demonstrated colonization by S. maltophilia, an in- colonized by S. maltophilia isolates of a unique PFGE pheno-
cidence of 25%. Sampling of environmental sites resulted in the type, and most rooms were persistently colonized with S.
recovery of 82 S. maltophilia isolates from 67 positive sites. ERIC- maltophilia. It was suggested that the high frequency of S.

PCR analysis revealed only 1 patient with multiple strains of S. maltophilia isolation from tap water presents the possibility of
maltophilia. The 45 clinical isolates were characterized by 10 dif- its transmission to CF patients, but the lack of evidence in that
ferent biotypes, 13 different antibiograms, and 41 different geno- study did not suggest that the prevention of water contamina-
types by ERIC-PCR. Unique ERIC-PCR types were found in 32 tion is a necessary infection control measure (222).
patients, four pairs of patients had the same ERIC-PCR type, and Electronic ventilator temperature sensors have been identi-
one patient was revealed to have 5 different strains. Twenty-one S. fied as a potential source of respiratory tract colonization with
maltophilia isolates were recovered from the CF ward environ- S. maltophilia (283). In an epidemiological investigation of a
ment, and DNA analysis revealed 12 different ERIC-PCR types. surgical ICU, environmental cultures from case patient room
Three environmental isolates (one from a sink drain, one from a surfaces, including ventilator equipment and taps of sinks;
faucet, and one from a water sample) shared an ERIC-PCR type hand-washing sinks in the staff lounge and nurses station; and
identical to that of a pair of clinical isolates. Six S. maltophilia a quaternary ammonium compound detergent-disinfectant
isolates (three from sink drains, one from a faucet, one from a solution were tested for the presence of S. maltophilia and com-
water sample, and one from a toothbrush) had the same ERIC- pared to S. maltophilia isolates from 5 mechanically ventilated
PCR type and were identical to the ERIC-PCR type of 2 clinical patients. Environmental cultures of S. maltophilia were recov-
isolates. No home environmental S. maltophilia isolates shared the ered from a tracheal tube, traps, ventilator inspiratory and ex-
same ERIC-PCR types as those of the clinical isolates from pa- piratory circuits, patient room surfaces after cleaning, and
tients. PFGE after digestion with XbaI could distinguish all of the temperature sensors. No S. maltophilia cultures were recovered
clinical isolates that shared the same or similar ERIC-PCR types. from water of patient room sinks or hand-washing sinks or
No patient-to-patient transmission was detected. A few patients from the detergent-disinfectant solution. Three patients
may have acquired S. maltophilia from the hospital setting, but the shared the same RAPD profile with an environmental culture
repeated sampling of sites revealed the isolation of genetically dif- recovered from an in-use temperature sensor. These results led
ferent strains, suggesting that genetic drift may have occurred over to a more effective disinfection regimen for the temperature
time in S. maltophilia. The results of that study made it very chal- sensors, with high-level disinfection by immersion in glutaral-
lenging to identify environmental sources of clinical isolates ac- dehyde. The implementation of this new disinfection proce-
quired over time (81). That study highlights the importance of dure resulted in a significantly lower incidence of new cases of
environmental sampling immediately following the diagnosis of S. maltophilia sputum positivity in ICU patients (283).
nosocomial S. maltophilia infection. The sampling of moist envi- S. maltophilia was recently isolated from patients’ charts in a
ronments that come into direct or indirect contact with patients surgical intensive care unit (327). That study reported the recov-
may lead to the identification of the source of the S. maltophilia ery of pathogenic or potentially pathogenic bacteria on 90.0% of
infection. the charts in the surgical ICU and 72.2% of the charts in the sur-
Nosocomial infections of S. maltophilia have been difficult to gical ward. Two S. maltophilia isolates were recovered from the 81
trace to environmental sources within the hospital. A recent re- contaminated charts in the surgical ICU. The S. maltophilia iso-
port investigated the association between the prevalence of non- lates from the patients’ charts demonstrated the same antibi-
fermentative Gram-negative bacillus (NFGNB) species in hospital ograms as those of the S. maltophilia isolates obtained from the
tap faucets and the colonization or infection of patients in inten- patients. It was suggested that charts are fomites in nosocomial
sive care units with these bacteria (355). Seven intensive care units, infections, acting as sources of transmission of the bacterium to
including a neurosurgical ICU, a surgical ICU, a cardiac surgical other patients, and the importance of hand washing in reducing
ICU, a pediatric ICU, two medical ICUs, and a respiratory care the possibility of transmission is underscored (327). Further re-
unit, were sampled for the presence of NFGNB. PFGE and elec- search is needed to determine the survivability of S. maltophilia on
trokaryotyping analyses revealed no similarity between the S. the relatively dry surface of patient charts and assess the risk of
maltophilia, P. aeruginosa, B. cepacia, and A. xylosoxidans isolates infection posed by the microbial contamination of charts.
from faucets and the corresponding species of clinical isolates
(355). That study also reported a strong positive correlation be- Adaptation and Evolution of Clinical Isolates
tween the presence of NFGNB in the hospital tap water and the A reservoir of strains of S. maltophilia has been proposed to exist
prevalence of waterborne NFGNB in ICU patients (355). The in the environment, and this has implications for the possibility of
findings of that study suggest that alternatives to the use of hospi- horizontal drug resistance transfer and subsequent spread within
tal tap water should be considered, including disinfection of the the clinical environment (233). Analyses of clinical and environ-
water supply, point-of-use water filtration, and the use of sterile mental isolates of S. maltophilia have revealed genomic heteroge-
water. neity among isolates (31).
The finding of S. maltophilia in hospital water does not al- A study by Turrientes et al. (335) compared the mutation fre-
ways correlate with patient infection with this organism. In a quencies of S. maltophilia clinical isolates (48 from 13 CF patients

Brooke
and 66 from 53 non-CF patients with different infections) with four isolates displayed antagonistic activities against the fol-
those of 60 isolates recovered from nonclinical environments (rhi- lowing fungi: Aspergillus candidus, Aspergillus flavus, Beauveria
zospheres of different plants, seawater, and sewage). The tested bassiana, Epicoccum nigrum, and Fusarium oxysporum. Three
hypothesis was that upon entry into the host, the S. maltophilia out of four isolates displayed antagonistic activities against C.
isolate adapts to the host environment and that in chronic infec- albicans. Two out of four isolates exhibited antagonistic activ-
tions, strong pressures exerted by the host local environment and ities against the Gram-positive bacteria Enterococcus faecium,
immune defense systems will increase the recovery of a variety of S. aureus, and B. subtilis. These observations demonstrate the
mutants derived from a single isolate, providing evidence for a potential of S. maltophilia environmental isolates as sources of
high mutation frequency. In that study, higher mutation frequen- antimicrobial metabolites.

cies were found for clinical isolates than for environmental iso- In a phylogenetic study of microorganisms, two-primer RAPD
lates. Highly variable mutations were present in isolates recovered analyses and sequencing of 16S rRNA genes were used to identify
from the same patient. The recovery of a number of isolates from S. maltophilia isolates from superficial water of the saline subter-
a single CF patient over a 6-year period demonstrated the persis- ranean Lake Martel in Spain (279). That study offered tourism as
tence of hypermutable strains. These strains were proposed to be an explanation for the recovery of S. maltophilia from human
the result of a mutation of the mutS gene of the mismatch repair infections.
system. The data from that study suggested that the cost of hyper- MDR S. maltophilia strains have been isolated from domestic
mutation does not hinder chronic infection of the lung by these and wild animals (117, 138, 140, 141, 163) (Table 2). All 15 S.
hypermutable strains (335). These results are in agreement with maltophilia isolates recovered from Omani goats with lymphade-
those reported for P. aeruginosa isolates obtained from the lungs nitis demonstrated resistance to cephalosporins (ceftazidime [30
of CF patients (252). ␮g], cefotaxime [30 ␮g], cephalothin [30 ␮g]), ␤-lactams (peni-
Antimicrobial-producing and antimicrobial-resistant S. malto- cillin G, ampicillin [10 ␮g], amoxicillin-clavulanic acid [30 ␮g]),
philia isolates have been recovered from a number of aqueous- or ticarcillin but were sensitive to aminoglycosides (kanamycin
associated habitats in nature and in animals. It is interesting to [30 ␮g], gentamicin [10 ␮g], and amikacin [30 ␮g]), erythromy-
speculate on the clinical significance of these isolates, as they have cin (15 ␮g), tetracycline (30 ␮g), chloramphenicol (30 ␮g), enro-
potential as sources of antimicrobial agents and/or as opportunis- floxacin (5 ␮g), and TMP-SMX (25 ␮g) (163). That study sug-
tic pathogens if they come into direct contact with susceptible gested the potential for S. maltophilia-colonized goats living in
humans. close proximity to humans to serve as a reservoir of S. maltophilia
A comparison of the antifungal activities and 16S rRNA se- infection of humans.
quences of 25 clinical and 25 environmental isolates of S. malto- Mouth swabs of 16 out of 22 species of captive snakes revealed
philia was reported (233). Of the clinical isolates, just one demon- the presence of S. maltophilia (140). PFGE profiling revealed the
strated antifungal activity against tested plant-pathogenic fungi heterogeneity of S. maltophilia isolates, as 8 snake species had
(Rhizoctonia solani, Verticillium dahliae, and Sclerotinia sclerotio- more than one strain of S. maltophilia. In total, 47 isolates of S.
rum), and 32% of the clinical isolates demonstrated activity maltophilia were recovered from 34 (29.6%) individual snakes.
against C. albicans. Of the environmental isolates, 62% demon- Antibiograms demonstrated that the most effective antibiotics
strated activity against the plant-pathogenic fungi, and just 21% against these isolates were TMP-SMX, levofloxacin, ofloxacin,
were active against C. albicans. The data indicate that the S. malto- colistin, and gentamicin. It was suggested that the presence of S.
philia antimicrobial activity against plant-pathogenic fungi and C. maltophilia originated in the water dishes of the vivariums (288).
albicans is not exclusive to either set of clinical and environmental In another study, 45 S. maltophilia isolates recovered from captive
isolates. 16S rRNA gene sequencing of the isolates suggested that snakes were tested for antibiotic susceptibility (141). After 24 h
the majority of the clinical and environmental isolates could be and 48 h of incubation at 37°C, the percentages of isolates dem-
differentiated (233). A limitation of that study was its inability to onstrating resistance were 44.4% and 71.1% against ceftazidime,
answer the question of whether clinical isolates have evolved from 28.9% and 51.1% against chloramphenicol, 0% and 8.9% against
environmental S. maltophilia isolates. levofloxacin, and 2.2% and 2.2% against TMP-SMX, respectively
An environmental, moderately halotolerant (growth in Trypti- (141). The results of the increased effectiveness of the antibiotics
case soy agar [TSA] medium with 75 g/liter sodium chloride) iso- at 37°C compared to 30°C are in agreement with results from an
late of Stenotrophomonas from sinkholes of the Yucatan peninsula earlier study (140). These studies raise the issue of risk assessment
demonstrated limited antimicrobial activity (75). S. maltophilia for multidrug-resistant S. maltophilia infection of snake handlers.
isolate 1X25 produced a bacteriocin-like substance and exhibited All 6 S. maltophilia isolates recovered from yellowtail fish from
inhibitory activity against Bacillus subtilis (ATCC 6633) but no a marine fish farm exhibited resistance to ampicillin, panipenem,
activity against the five additional target organisms, including C. cefotaxime, and ceftazidime (117). In veterinary medicine, S.
albicans (ATCC 10231), S. aureus (ATCC 6536), Pseudomonas sy- maltophilia is not commonly considered to be a significant patho-
ringae pv. pisi (ATCC 11043), X. campestris pv. carotae (ATCC gen. This assessment of S. maltophilia may need to be revised, as
10547), and Erwinia carotovora subsp. carotovorum (ATCC 138). future research is needed to establish whether animals harboring
S. maltophilia isolates with antimicrobial activities have been S. maltophilia are potential sources of infection for humans.
recovered from deep-sea invertebrates (286). Four strains of S.
MOLECULAR ECOLOGY AND STENOTROPHOMONAS
maltophilia, KMM349, KMM339, KMM3045, and KMM365,
INFECTION
were isolated from sponge, sea urchin, and ophiura specimens
from the Philippine Sea, the Fiji Sea, and the Bering Sea. All four Gene Transfer in the Environment
isolates are MDROs, with resistance to kanamycin (30 ␮g/disc), S. maltophilia can acquire genes from other bacterial species. S.
tetracycline (30 ␮g/disc), and erythromycin (15 ␮g/disc). All maltophilia has been reported to acquire genes involved in antibi-

otic and heavy metal resistance from Gram-positive bacteria (12). ria in river water samples supplemented with a CAR-dimethyl
S. maltophilia can transfer antibiotic resistance to other bacteria sulfoxide (DMSO) solution. Natural pressures such as the pres-
(21). S. maltophilia has been isolated from the rhizosphere of ence of CAR appear to have resulted in a higher number of
plants; the rhizosphere was suggested to be a source of antibiotic transconjugants in growth medium supplemented with CAR than
resistance (30). In the rhizosphere, horizontal gene transfer has the number of transconjugants identified in growth medium
been reported for S. maltophilia (29). without CAR. That study suggested that the bacteria harboring the
The acquisition of DNA from other bacterial species has serious plasmid have an advantage for growth on CAR.
implications for gene transfer within microbial communities in Lightning has also been implicated in DNA transfer between
environments such as wastewater and biofilms in plumbing, bacterial cells (51). Two Pseudomonas sp. strains, N3 and Ee2.2,

where S. maltophilia has been found in association with other isolated from soil demonstrated the ability to be transformed in a
MDROs that are members of the genera Citrobacter, Sphingomo- laboratory-scale lightning experiment. Strains N3 and Ee2.2 dem-
nas, Serratia, and Klebsiella. S. maltophilia has been reported to onstrated an electrotransformation frequency for the uptake of
transfer antimicrobial resistance genes to bacteria, including P. pBHC, an 8.1-kb plasmid, of 10⫺4 in the absence of sucrose at
aeruginosa, members of the Enterobacteriaceae, and Proteus mira- 22°C, in comparison with control strains E. coli DH10B (fre-
bilis (34, 155). Sphingomonas paucimobilis is a persistent nosoco- quency of 10⫺4) and Pseudomonas fluorescens C7R12 (frequency
mial infectious bacterium that is emerging as an opportunistic of ⬍10⫺8). The electrotransformation frequencies increased for
pathogen and is able to form biofilms in water-associated environ- both N3 and Ee2.2 in the presence of 0.5 M sucrose in comparison
ments (39, 263, 290). The reported recovery of S. paucimobilis and to E. coli DH10B (frequency range of 10⫺6 to 10⫺7), and P. fluo-
S. maltophilia from the same biofilm (39) suggests that gene trans- rescens C7R12 required 10 mM MgCl2 to achieve electrotransfor-
fer is possible between these organisms. A recent report of dental mation (frequency of 10⫺7). In two lightning-induced transfor-
solid waste harboring S. maltophilia (347) raises new questions mation experiments at 20°C, strains N3 and Ee2.2 achieved their
about the viability and persistence of this opportunistic pathogen highest transformation frequencies, 10⫺4 and 10⫺5, respectively,
and whether DNA transfer from this organism can increase the in comparison to the transformation frequency of ⬍10⫺9 dis-
potential pathogenicity and virulence of other microorganisms. played by both control strains E. coli DH10B and P. fluorescens
PCR amplification has been used to detect the presence of L1 C7R12. The electroporation efficiencies for the uptake of pBHC in
metallo-␤-lactamase (L1) and L2 serine ␤-lactamase (L2) in six the presence of 0.5 M sucrose by strains N3 and Ee2.2 ranged from
strains of S. maltophilia isolated from yellowtail (Seriola quinque- 104 to 105 CFU/␮g of plasmid DNA (51). These data suggest that
radiata) in a fish farm (117). 16S rRNA gene sequencing revealed antibiotic resistance gene acquisition by S. maltophilia strains can
two clusters, clusters A and B, of the strains. Differences in DNA occur through lightning-induced transformation in the environ-
sequences of the ␤-lactamase genes within these clusters suggested ment, and subsequently, when these strains gain entry into the
that horizontal gene transfer of the ␤-lactamase genes had oc- clinical setting, they can retain the antibiotic resistance phenotype
curred. The possibility of the horizontal transfer of L1 and L2 (31, 51).
␤-lactamases is supported by their reported presence on 200-kb The acquisition of genes from environmental bacteria by S.
plasmids (17). maltophilia emphasizes the importance of monitoring the antibi-
The conjugation of plasmids has contributed to the spread of otic resistance of S. maltophilia clinical isolates. Such monitoring
antibiotic resistance among different bacterial species. The conju- can provide insight into the environmental source of antibiotic
gal transfer of plasmid-bearing genes coding for multiple-drug resistance genes, show how these genes are being spread among
resistance has been reported for E. coli isolates (336). Out of clinical isolates, and suggest prevention strategies to reduce the
105 clinical isolates of E. coli, 67 (64%) isolates carried plas- level of antibiotic resistance.
mids, and 51 (76.1%) were able to transfer their plasmids into
recipient cells. A high frequency of the isolates carrying plas- Climate Change
mids was resistant to antibiotics, including ampicillin, imi- There is a potential impact of climate change on the spread of
penem, and TMP-SMX (336). infection associated with S. maltophilia through the transmission
The conjugative transfer of plasmid DNA into S. maltophilia- of waterborne infectious agents and the importance of sanitation
like bacteria in river water has been reported (28). IncP-1 for providing safe drinking water supplies (186, 253, 315). It was
plasmid pJP4 carrying genes for the degradation of 2,4- predicted that global temperatures will rise 1.8°C to 5.8°C by the
dichlorophenoxyacetic acid (2,4-D) was successfully transferred end of this century, resulting in changes to the hydrologic cycle
from the Pseudomonas putida SM1443 donor into members of the and rainfall and drought patterns (315). These temperature
genus Stenotrophomonas that are present in mixed liquor from a changes will likely shift the geographical distribution of water-
wastewater treatment plant (28). The data from that study suggest borne diseases. Alterations in rainfall patterns and water chemical
that as pJP4 is self-transmissible and is a broad-host-range plas- composition from pollution can alter the population diversity of
mid, it may be useful in genetic engineering for complementation microbes present, and it is expected that these changes will enable
experiments in which wild-type genes are introduced into S. the emergence of new opportunistic pathogens. It is expected that
maltophilia mutants to restore the wild-type phenotype. some geographical areas will experience more droughts, and this
Stenotrophomonas maltophilia IAM12423 (EMBL/GenBank/ may lead to poor sanitation as the population is forced to work
DDBJ database accession no. AB294553) has been reported to with limited water supplies.
acquire plasmid pCAR1, a conjugative IncP-7 plasmid involved in S. maltophilia is a common water inhabitant. An increase in
the degradation of carbazole (CAR) from the donor P. putida the global temperature is likely to result in an increased growth
SM1443 (314). A fluorescent protein reporter gene cloned into rate of cells and higher cell concentrations that can come into
plasmid pCAR1 was used to track the plasmid’s transfer to bacte- contact with susceptible individuals and possibly pose an in-

Brooke
creased risk of infection. Increases in cell concentrations of S. possibility of organism transfer from tap water to patients. The
maltophilia in aqueous environments may lead to increases in avoidance of the use of hospital tap water for bathing and cleaning
the uptake of foreign DNA and the further acquisition of genes of wounds is a necessary measure of care for particularly vulnera-
important for drug resistance and pathogenicity. This specula- ble populations such as neonatal patients. The discarding of resid-
tion must also consider the likelihood that the growth of other ual antibiotic solutions, residual and possibly contaminated hand
microorganisms is keeping S. maltophilia in check by their soap solutions, and patient body fluids into the hospital plumbing
competition for space and nutrients. system should be avoided. An increased vigilance for the observa-
S. maltophilia colonization or infection of plants and animals in tion and replacement of worn parts of susceptible surfaces, such as
close proximity/contact with humans may pose a risk of infection old deteriorating plumbing systems, can help reduce the risk of

to human handlers. The concern for the impact of climate change infection. Steps taken such as these are actions that can help lower
on the distribution of infectious disease must therefore extend to the number of fatalities associated with S. maltophilia infections.
workers in agriculture and aquaculture (186).
More information is needed about the survival and biofilm for- ACKNOWLEDGMENTS
mation of S. maltophilia and its ability to transfer genetic material I have received research grant support from the National Institutes of
to and receive genetic material from other emerging pathogens. As Health (National Institute of Allergy and Infectious Diseases) and grant
noted above in this review, S. maltophilia has acquired genes from support from the College of Liberal Arts & Sciences and the University
Gram-positive bacteria. It will be interesting to see if this oppor- Research Council at DePaul University.
tunistic pathogen develops adequate strategies to acquire genes
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Joanna S. Brooke is a tenured Associate Profes-

sor in the Department of Biology at DePaul
University. She received her B.Sc. Honors (Co-
op) in microbiology from the University of
Guelph, Canada (1989), and an M.Sc. (1992)
and a Ph.D. (1996) in microbiology and immu-
nology from the University of Western Ontario,
Canada. Following postdoctoral research at the
University of Texas Southwestern Medical Cen-
ter, she joined the faculty at DePaul University

in 2001. Her area of research focuses on the mo-
lecular mechanisms underlying the biofilms of S. maltophilia. She also has a
research track that investigates the presence of potentially pathogenic bacte-
ria on surfaces. Dr. Brooke teaches courses including medical bacteriology,
microbiology, and biotechnology. (Photo by Flip Chalfant.)

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Stenotrophomonas maltophilia: an Emerging Global

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TABLE 1 S. maltophilia-associated infections TABLE 2 Sources of S. maltophilia

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