Review Iain J Abbott , Monica A Slavin

Transcription

Review
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Stenotrophomonas
maltophilia: emerging
disease patterns and
challenges for treatment
Expert Rev. Anti Infect. Ther. 9(4), 471–488 (2011)
Iain J Abbott†1,
Monica A Slavin1,2,
John D Turnidge3,
Karin A Thursky1,2
and Leon J Worth1
Department of Infectious Diseases,
Peter MacCallum Cancer Centre, East
Melbourne, Victoria, Australia
2
Victorian Infectious Diseases Service,
Royal Melbourne Hospital, Parkville,
Victoria, Australia
3
Division of Laboratory Medicine,
Women’s and Children’s Hospital,
North Adelaide, Australia
†
Author for correspondence:
Tel.: +61 396 561 599
Fax: +61 396 561 185
[email protected]
1
Stenotrophomonas maltophilia is a ubiquitous organism associated with opportunistic infections.
In the immunocompromised host, increasing prevalence and severity of illness is observed,
particularly opportunistic bloodstream infections and pneumonia syndromes. In this article, the
classification and microbiology are outlined, together with clinical presentation, outcomes and
management of infections due to S. maltophilia. Although virulence mechanisms and the genetic
basis of antibiotic resistance have been identified, a role for standardized and uniform reporting
of antibiotic sensitivity is not defined. Infections due to S. maltophilia have traditionally been
treated with trimethoprim–sulfamethoxazole, ticarcillin–clavulanic acid, or fluoroquinolone
agents. The use of combination therapies, newer fluoroquinolone agents and tetracycline
derivatives is discussed. Finally, measures to prevent transmission of S. maltophilia within
healthcare facilities are reported, especially in at-risk patient populations.
Keywords : antibiotic resistance • immunocompromised • opportunistic infection • Stenotrophomonas maltophilia
• trimethoprim–sulfamethoxazole • virulence factors
Classification, microbiology &
identification
The genus Stenotrophomonas is phylogenetically
classified as part of the Gammaproteobacteria
group. Currently, this genus is comprised
of eight species: Stenotrophomonas acidaminiphila, Stenotrophomonas chelatiphaga,
Stenotrophomonas humi, Stenotrophomonas
koreensis, Stenotrophomonas rhizophilia,
Stenotrophomonas terrae, Stenotrophomonas
nitritireducens and Stenotrophomonas maltophilia [1] . S. maltophilia was originally named
as a member of the genus Pseudomonas [2] before
assignment to the Xanthomonas genus [3] and
was recently reclassified as Stenotrophomonas [4] .
The full genomic sequence of two S. maltophilia isolates (K279a, a clinical isolate and
R551–3, an environmental isolate) is now
available [1,5] . Subclassification according to
genomic subtypes has been performed [6–11]
and demonstrates remarkable diversity among
S. maltophilia isolates. One recent study identified a unique strain associated with respiratory
tract specimens from cystic fibrosis (CF) and
intensive care unit (ICU) patients, suggesting
www.expert-reviews.com
10.1586/ERI.11.24
an adaptation to colonization of the airway [11] .
However, a clear relationship with virulence
or other clinical presentations has not been
determined.
Gram-stain, culture and biochemical properties are all used for routine laboratory identification. The features of S. maltophilia are
summarized in B ox 1 and F igur e 1. Although
not widely practiced, molecular diagnostic
techniques may also be used, reducing identification times by 24–48 h. Matrix-assisted
laser desorption ionization-time of flight mass
spectrometry (MALDI-TOF MS) produces
specific mass spectral fingerprints for different
organisms. When compared with multi-locus
sequence analysis (MLSA), which uses partial
genes and 16s rRNA amplified by PCR and
sequenced, MALDI-TOF MS was less expensive and correlated well with MLSA results
[12] . In a comparative study of conventional
identification methods and MALDI-TOF MS,
however, identification failures occurred in
S. maltophilia [13] . Greater clinical experience
with these new diagnostic tests is required
before routine application.
© 2011 Expert Reviews Ltd
ISSN 1478-7210
471
Review
Abbott, Slavin, Turnidge, Thursky & Worth
Box 1. Characteristics of Stenotrophomonas
maltophilia.
Microscopy
• Gram-negative straight, or slightly curved, rod
• Multiple polar flagella
• Motile
Culture
• Blood agar – faint lavender colonies
• Nutrient agar – opaque gray/yellow colonies
• MacConkey agar – nonlactose fermenter
• Koser’s citrate medium – no growth
• Selective culture medium† – colony growth
Biochemical tests
• Oxidase reaction –negative
• Indole – negative
• Acid from – maltose and glucose
• Lysine decarboxylase – positive
• DNase – positive
Selective medium containing vancomycin, imipenem and amphotericin B with a
mannitol/bromothymol blue indicator system [150]. Meropenem may be used in
place of imipenem [151].
†
Febrile neutropenic sepsis and CF pulmonary exacerbations
are two clinical areas where application of these molecular diagnostic techniques could dramatically impact on management.
Given that many first-line empiric antibiotic agents used for the
management of febrile neutropenia do not have activity again
S. maltophilia [14] , the early identification of S. maltophilia from
blood cultures would allow for earlier change of antibiotics to
active agents [15] . In the management of CF pulmonary exacerbations, which can be commonly due to multiple copathogens, the
ability to identify S. maltophilia and detail the bacterial load,
the presence of other copathogens and detect virulence factor
expression, would direct antibiotic treatment [16] .
Virulence factors & antibiotic resistance
Isolation of S. maltophilia in human specimens may represent
colonization rather than infection. Being an opportunistic pathogen, the relationship between host and organism is important,
with immunocompromised hosts and hospitalized patients being
predisposed to infection.
The ability to survive in biofilms and respond to environmental stressors makes S. maltophilia a persistent and adaptable pathogen. Biofilm production is associated with resistance
to environmental factors by promoting intimate attachment
to surfaces, resistance to phagocytic activity and other host
immune factors, shielding from antimicrobial activity and
enhanced spread throughout surfaces via bacterial motility
[17–19] . Biofilm production is caused by the interplay of multiple
contributory virulence factors including the flagella [20–22] , fimbriae, pili and afimbrial adhesin [5,23] and the outer-membrane
lipopolysaccharide layer [1,5,24,25] . These factors have also been
shown to produce significant immunostimulatory affects that
promote inflammation, especially within the lungs [22,24,25] .
472
Quorum sensing via diffusible signal molecules can influence
the behavior of S. maltophilia populations within biofilms by
intraspecies signaling [26] . Other virulence factors of importance include a positively charged surface [27] , the production
of melanin-like pigment [28] , the production of extracellular
enzymes [5] and growth of small colony variants [29] . These
factors are discussed in detail in Table 1.
An important role for interspecies interactions in bacterial virulence has been demonstrated in CF patients, where S. maltophilia
may protect antibiotic-sensitive strains of Pseudomonas aeruginosa
by degrading antibiotics [30] . P. aeruginosa can also respond to
the signaling system mediated by diffusible signal molecules that
are produced by S. maltophilia, which then promote alteration
of biofilm architecture to increase tolerance to antibiotics [31] .
S. maltophilia has also been implicated as a potential reservoir
of resistance elements leading to transference to other bacteria
[5,32,33] . Resistance plasmid and transposon carriage has been demonstrated in S. maltophilia, as has transmission of these elements
to Escherichia coli, in vitro [34,35] .
Mechanisms of antibiotic resistance may be intrinsic, inducible
or acquired. Functional genomic analysis of S. maltophilia reveals
considerable capacity for drug and heavy metal resistance [5] .
Resistance patterns are largely due to b-lactamases, multidrugefflux pumps, modifying enzymes, outer membrane changes and
target site modification (Table 2) .
b-lactam resistance is via two chromosomal b-lactamases, L1
and L2, that hydrolyze and inactivate these antibiotics [36–38] .
Their expression may be induced by the presence of b-lactam
antibiotics [39,40] . Clavulanic acid is an effective inhibitor of L2,
but not L1 b-lactamase [41] . Resistance to the aminoglycoside class
of antibiotics is seen in a variety of mechanisms including specific aminoglycoside-modifying enzymes that cause intrinsic resistance to all aminoglycoside antibiotics except gentamicin [42,43] .
Resistance by multidrug-efflux pumps affects multiple antibiotic
classes, including fluoroquinolone, tetracycline and macrolide
antibiotics [5,44] . Resistance to trimethoprim–sulfamethoxazole
has more recently been reported owing to modified target genes
sul1 and sul2 [34,45–47] .
Variations in resistance rates have been reported from region
to region, but resistance to trimethoprim–sulfamethoxazole is
generally accepted to be less than 10% in most settings. Data
collected from the Asia–Pacific region, Canada, Europe, Latin
America and the USA showed that the trimethoprim–sulfamethoxazole resistance rates ranged from 2 to 10% (n = 842)
depending on location [48] . The SENTRY Antimicrobial
Surveillance Program (1997–2003) reported a global resistance
rate of 4.7% [49] . This is to be contrasted with a Taiwanese study
of 103 S. maltophilia isolates from hospitalized patients, which
demonstrated 25% trimethoprim–sulfamethoxazole resistance
[45] . Recent data obtained from the SENTRY Antimicrobial
Surveillance Program (1998–2009; 679 S. maltophilia isolates)
suggest that current trimethoprim–sulfamethoxazole resistance rates in the Asia–Pacific region remain less than 10%
(7.8% resistant when applying Clinical Laboratory Standards
Institute, MIC breakpoint) [Turnidge JD, Pers. Comm.] .
Expert Rev. Anti Infect. Ther. 9(4), (2011)
Stenotrophomonas maltophilia: emerging disease patterns & challenges for treatment
Review
Epidemiology
Environment
With adaptability to hostile and nutrientlimited environments, S. maltophilia occurs
ubiquitously and may be isolated from water,
soil, plants, animals (reptiles and aquatic
animals [50–52]), foods (ready-to-eat salads
[53] , raw and microfiltrated milk [54,55]) and
materials used in clinical laboratories and
medical practice.
In hospital environments, S. maltophilia
may survive in disinfectant solutions containing chlorhexidine–cetrimide or hexamidine [27] and can colonize inanimate
surfaces, including intravenous and urinary catheters. Other healthcare-associated sources of S. maltophilia include
contaminated intravenous fluids, hospital
water and ice supplies, nebulizers, dialysis
machines, ventilator circuits, thermometers, blood gas analyzers, intra-abdominal
balloon pumps and central venous or arterial pressure monitors [56] . Furthermore,
the hands of healthcare workers may be
a potential source of transmission [57] .
Predisposing factors for the acquisition
of S. maltophilia are summarized in Box 2.
Immunocompromised hosts are at highest risk for infection, often with multiple
contributory risk factors.
Incidence
Figure 1. Laboratory appearance of Stenotrophomonas maltophilia.
(A) Gram stain showing evenly stained Gram-negative straight, or slightly curved, rods.
(B) Culture on MacConkey agar demonstrating lack of lactose fermentation. (C) Culture
on blood agar demonstrating faint lavender-colored colonies. (D) Scanning electron
micrograph of a S. maltophilia biofilm grown at 30°C for 24 h in a flow cell.
Reproduced with permission from the American Society for Microbiology [18] .
The incidence of S. maltophilia ranges from
7.1 to 37.7 cases per 10,000 hospital discharges, depending on the degree and severity of immunocompromise and underlying medical conditions in the population studied
[38] . International reports from tertiary healthcare facilities suggest that these numbers have increased over time [58–60] . Reports
of S. maltophilia bacteremia episodes from England, Wales, and
Northern Ireland demonstrated a 93% increase between the years
2000 and 2006, but then a decrease by 31% in the period 2005–
2009 [301] . Overall, this still accounted for a 30% increase over
the 10-year period of observation. At the MD Anderson Cancer
Center (TX, USA), an increased proportion of S. maltophilia
isolates (from 2 to 7% of Gram-negative bacilli isolates between
1986 and 2002) has been reported, representing an incremental increase in S. maltophilia’s ranking from ninth to fifth most
common Gram-negative organism [59] . S. maltophilia is the third
most common nonfermenting Gram-negative bacilli responsible
for healthcare-associated infections, behind P. aeruginosa and
Acinetobacter spp. [49] . Factors potentially contributing to increased
incidence include: an expansion of at-risk populations, the widespread use of intensive chemotherapy, the prolonged use of central
venous catheters (CVCs) and the selection pressure afforded by the
use of broad-spectrum antibiotics [61] .
Special patient groups
Hematological malignancy
Patients with hematological malignancies (e.g., leukemia or
lymphoma) are at risk of colonization and opportunistic infection [62] . Chen et al. examined the epidemiology of bloodstream
infections in patients with hematological malignancies between
2002 and 2006 and found S. maltophilia to account for 6% of
all bloodstream isolates in neutropenic patients [63] . Individual
risk is related to the degree and duration of neutropenia, presence
of indwelling devices and loss of integrity of mucosal and skin
surfaces. A range of predisposing factors for S. maltophilia infection may be present in the one patient (Box 1) . Severe mucositis
has been identified as an important risk factor [64] .
Cystic fibrosis
Approximately 10–15% of patients with CF are colonized with
S. maltophilia [65,66] . Recent retrospective studies have showed
reductions in the prevalence of P. aeruginosa and Burkholderia
cepacia complex, but an increase in emerging pathogens including S. maltophilia [67,68] . Colonization with S. maltophilia has,
however, not been associated with reduction in lung function or
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Review
Table 1. Potential virulence factors for Stenotrophomonas maltophilia infection.
Virulence
factor
Virulence gene(s)/structures
Proposed mechanisms
Ref.
Biofilm formation Interplay of multiple contributory factors: Significantly higher biofilm production at 32°C compared to
flagella, pili/fimbriae, quorum sensing
18°C or 37°C; produced as the bacteria spread and intimately
and outer-membrane LPS
attach to surfaces such as medical implants and venous or
urinary catheters; resist host immune factors and shield from
antimicrobial activity
[17–19,152]
Flagella
Composed of a 38–42-kDa flagellin
subunit (SMFliC)
Stimulates innate immunity and provides enhanced motility;
considerable shared sequence identity to the flagellins of Serratia
marcescens, Escherichia coli, Proteus mirablis, Shigella sonnei and
Pseudomonas aeruginosa
[20–22]
Pili/fimbriae/
adhesins
17-kDa fimbriae subunit, Smf-1, seen as Contributes to adherence, autoaggregration, colonization of
peritrichous semi-flexible fimbriae of
biotic and abiotic surfaces, evasion of the host immune response
5–7 nm under electron microscopy. Also and increased drug resistance
identified are TadE-like pili/fimbrial
genes, type IV pili, afimbrial adhesin,
Hep–Hag family adhesins and two
hemagglutinin/hemolysin family proteins
[5,23]
Outer-membrane SpgM, also known as xanA gene, is a
LPS
phosphoglucomutase and is a
homologue of AlgC in P. aeruginosa that
is associated with LPS and alginate
biosynthesis. Mutations in manA, rmlA
and rmlC affect LPS structure.
Considerable level of variation in
O antigens between isolates, defining
31 serotypes
Forms an integral component of the extracellular matrix of
bacterial biofilms; has a role in resistance of bacteria to
antibiotics; involved in colonization and resistance to
complement-mediated cell killing; immunostimulatory effects,
implicated in airway inflammation, via mechanisms including
TNF-a and IL-8 expression, and polymorphonuclear leukocyte
recruitment. Variations in LPS biosynthetic gene clusters,
particularly the O-antigen moiety, may be implicated in evading
the host immune system
[1,5,24,25]
Intercellular and Uses the Xanthomonas and Xylella
intracellular
signaling system mediated by a diffusible
signaling
signal factor, methyl dodecenoic acid
(quorum sensing)
A cell–cell signaling factor to regulate a number of virulence
traits and antimicrobial resistance (e.g., motility, extracellular
proteases, LPS synthesis, microcolony formation, and tolerance
toward antibiotics and heavy metal ions); likely to be responsive
to environmental cues; interspecies signaling occurs in
polymicrobial infections
[26,31]
Extracellular
enzymes
Produces protease and phospholipases. StmPr1 protease is a
phage-encoded zonula occludens-like toxin enabling
S. maltophilia to degrade human serum and tissue proteins
(e.g., the IgG heavy chain, protein components of collagen,
fibronectin and fibrinogen) and contribute to local tissue damage
and hemorrhage
Characterized by small colony size, slow growth (or no growth)
on agar media compared to wild-type isolates and the inability to
generate in vitro susceptibility results (broth MIC, Kirby-Bauer or
E-test) under standard conditions. May be implicated in latent or
recurrent infections
Resistance to antiseptics and disinfectants that bind with high
affinity to the negatively charged cell walls and membranes
of bacteria
Protects cells from environmental insult. Associated with
resistance to ciprofloxacin and ticarcillin–clavulanic acid antibiotics
SCV
StmPr1, an alkaline serine protease;
plcN1, nonhemolytic phospholipase C;
other enzymes from the phospholipase D
family; other strain-specific extracellular
enzymes include DNase, gelatinase,
hemolysin, lipases and proteinase K
Interference with the dihydrofolate
reductase pathway; prolonged exposure
to antibiotics may select for both the SCV
S. maltophilia phenotype and
trimethoprim–sulfamethoxazole resistance
Positively charged
surface
Melanin-like
pigment
Tyrosinase gene (mel)
[5]
[29]
[27]
[28]
LPS: Lipopolysaccharide; SCV: Small colony variant.
short-term survival [69,70] . Information regarding the impact of
S. maltophilia post-lung transplantation is limited, but unlike
other resistant organisms such as Burkholderia cenocepacia, the
presence of S. maltophilia is not a contraindication to transplantation [71] . Polymicrobial infections are common, especially
with P. aeruginosa as a copathogen. More than one strain of
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S. maltophilia has been identified in one third of patients with
repeated episodes of S. maltophilia infection or colonization [72] .
Small-colony variant forms of S. maltophilia have been isolated
from the sputa of CF patients. These are significant because
slower growth and increased antibiotic resistance enable persistence in the airway [29] .
ICU patients
Patients requiring ICU support frequently require intubation
and mechanical ventilation and are at risk for development of
ventilator-associated pneumonia (VAP). Between 1993 and 2004,
4.3% of Gram-negative infections in intensive care patients in the
USA were due to S. maltophilia [73] . In ICU patients with nosocomial pneumonia, S. maltophilia has been identified as the cause of
VAP in 6% of cases [74] . Chronic obstructive airway disease and
duration of antibiotic treatment were independent risk factors for
ICU-acquired S. maltophilia in an observational ICU study [75] .
Patient–patient clonal transmission of S. maltophilia within the
ICU environment has been reported [76] .
Review
hospitalized patients (53 cases), 56% had an underlying hematological disorder and the mortality rate was 51% [87] . Neutropenia
and mixed infection with Enterococcus spp. were independent factors associated with mortality. A 10-year audit of 32 S. maltophilia
bacteremia episodes in pediatric patients showed early and effective targeted antimicrobial therapy and early removal of CVC to be
associated with improved outcomes [101] . Bloodstream infections
can be polymicrobial (i.e., S. maltophilia isolated with copathogens) and this finding may indicate underlying catheter-related
bacteremia [91,98,99,102] . In a retrospective study of hematopoietic
stem cell transplant recipients, 11 of 19 patients (58%) had a polymicrobial infection [103] . The most common copathogens were
Acinetobacter baumannii, P. aeruginosa and Enterococcus faecalis.
Other patient groups
Patients with end-stage renal disease receiving both peritoneal dialysis
and maintenance hemodialysis are another at-risk group for S. maltophilia infections [77,78] . These infections are frequently related to the
presence of indwelling dialysis catheters. High mortality rates have
been reported for S. maltophilia pneumonia in this population [79] .
Stenotrophomonas maltophilia is an important cause of respiratory infections in neonates [80,81] , where it has also been detected
in gastric aspirates. Trimethoprim–sulfamethoxazole-resistant
isolates [82] and interpatient transmission have been reported [83]
in neonatal populations.
Lower respiratory tract infection remains a leading cause of
morbidity and mortality following solid organ transplantation,
where S. maltophilia has been implicated as a causative agent [84] .
Following liver transplantation, S. maltophilia bacteremia accounted
for 14.9% of all bacteremic episodes in a single-center cohort [85] .
Stenotrophomonas maltophilia has also been identified as an
opportunistic infection in patients with significant burns [86] . Over
a 9-year period, 14 episodes of S. maltophilia bacteremia were seen
in 13 of 666 patients admitted to a single burn center [86] .
Pneumonia
Clinical presentation
Management of infections
In at-risk patient populations, S. maltophilia may result in a range
of clinical syndromes (Table 3) . Most commonly, bacteremia (usually in the presence of an indwelling venous catheter) [63,77,87–91]
and pneumonia (especially in the setting of mechanical ventilation
or underlying chronic lung disease) [92–95] are observed. Although
predominantly a pathogen that causes infections in hospitalized and immunocompromised patients, community-acquired
S. maltophilia infections have been reported [61] . The attributable
mortality of S. maltophilia infection has been estimated to be
between 26.7 [96] and 37.5% [97] . In a retrospective hospital cohort,
the rate of septic shock associated with S. maltophilia infection was
30% and was an independent risk factor for 14-day mortality [98] .
Susceptibility testing & clinical breakpoints
Bloodstream infections
Approximately 1% of all nosocomial bacteremias are caused by
S. maltophilia [1] . S. maltophilia bacteremia is frequently associated
with an indwelling device, most commonly a CVC, and prognosis
is improved following the removal of the device [99] . Recurrent
bacteremia has been observed in the setting of failure to remove an
infected CVC and neutropenia [88,100] . In a retrospective review of
The respiratory system is the most common site from which S. maltophilia is cultured. Pneumonia-causing isolates from the SENTRY
Antimicrobial Surveillance Program (1997–1999) were four-times
more prevalent than bloodstream isolates (3.3% of all respiratory
isolates versus 0.8% of all blood isolates) [48] . Severely debilitated
patients may be colonized asymptomatically with S. maltophilia [95]
and this organism may also be identified with other organisms in
respiratory specimens. It may therefore be difficult to distinguish
between colonization and infection with S. maltophilia. Clinical
and radiological findings will aid in the diagnosis of pneumonia or
VAP. The attributable mortality for S. maltophilia pneumonia has
been estimated to be 20–30%, even in non-neutropenic, non-ICU
patients [104] . Pulmonary hemorrhage is a fatal complication of fulminant S. maltophilia pneumonia and may arise in patients with an
underlying hematological malignancy [94] . In a retrospective study
of 406 patients with S. maltophilia pneumonia, S. maltophilia was
a component of polymicrobial infection in 43.6% of patients and
P. aeruginosa was the most common copathogen [93] .
Universal and standardized methods for the susceptibility testing
and reporting for S. maltophilia are not available. There remain
uncertainties surrounding which antibiotic agents should be tested
and what is the best in vitro methodology to be used. MIC and
disc diffusion zones are affected by both temperature and medium.
Many isolates grow optimally at 30°C and some isolates grow poorly
(or not at all) at 37°C. Similarly, some S. maltophilia isolates may
appear falsely susceptible at 37°C to many antibiotic classes [105] .
Although there are conflicting reports, disc diffusion and Etest
methods have been reported to be reliable for testing susceptibility to chloramphenicol, doxycycline, gatifloxacin, trimethoprim–
sulfamethoxazole and ticarcillin–clavulanate [106] . This is in
contrast to testing for polymyxin B and colistin, where a weak
correlation has been found between disc diffusion and agar dilution techniques, likely related to the poor agar diffusion characteristics of colistin [107–110] . A recent study evaluating susceptibility
results obtained by disc diffusion, Etest and reference agar dilution
method, showed disc diffusion and Etest to be unreliable for ticarcillin–clavulanic acid and ciprofloxacin [111] . Given the current
475
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Resistance to ciprofloxacin, norfloxacin
and tetracycline derivatives
SmrA
Multidrug ATP-binding cassette transporter
Resistance to macrolide class
Resistance to aminoglycoside class,
polymyxin B and fluoroquinolone class
mph(C) gene
SpgM gene encodes a bifunctional enzyme with both
phosphoglucomutase and phosphomannomutase
activities. Mutants lacking spgM gene produce less
lipopolysaccharide and tend to have shorter
O-polysaccharide chains
Resistance to aminoglycoside class
Resistance to tetracycline class,
chloramphenicol, erythromycin and
fluoroquinolone class
SmeDEF (expressed in 33% of S. maltophilia isolates);
loss of function mutations in smeT gene may lead or
contribute to SmeDEF overproduction; additional efflux
system reported include: SmeABC, SmeGH, SmeIJK,
SmeMN, SmeOP, SmeVWX and SmeYZ
Eight tripartite, putative resistant–nodulation–
division efflux pumps that actively extrude organic
solvents, disinfectants and antimicrobials from the
cell
Antibiotic inactivation by direct destruction or
Aminoglycoside-modifying enzymes are a family of
modification of the compound by hydrolysis, group chromosomal genes encoding for
transfer and redox mechanisms
O-nucleotidyltransferase, O-phosphotransferases and
N-acetyltransferase enzymes; aminoglycosideinactivating enzymes AAC(6’)-IIc and APH(3’)Iz
May present low virulence potential in
S. maltophilia, but could spread to
other Gram-negatives
CTX-M-15 and CTX-M-1 b-lactamases
A cephalosporinase. Inhibited by
clavulanic acid
L2 Ambler class A serine-b-lactamases
May act as a reservoir for mobile
b-lactamase genes
Hydrolyzes all b-lactam antibiotics
(penicillins, cephalosporins and
carbapenems) excluding
monobactams. Not inhibited by
clavulanic acid. Carbapenem therapy
shown to induce L1-b-lactamases
Impact upon antimicrobial
therapy
L1 Ambler class B Zn2+ -dependent metallo-b-lactamase
(hometetramer 118 kDa)
Responsible gene(s)
TEM-2 penicillinase (located on an active Tn1-like
transposon)
Changes in the Temperature-dependent changes affecting the
outer membrane fluidity, lipopolysaccharide side chain length and
core phosphate content of the outer membrane
Enzymatic
modification
Efflux systems
Two chromosomal inducible b-lactamases:
L1 and L2. Induced when exposed to b-lactams.
Production controlled by b-lactamase regulator
(AmpR)
b-lactamases
Extended-spectrum b-lactamase
Resistance mechanism
Category
Table 2. Stenotrophomonas maltophilia: mechanisms of antibiotic resistance.
[158]
[157]
[42,43]
[156]
[5,44]
[154,155]
[153]
[36–40]
Ref.
Review
[34,45–47]
[34,47]
Trimethoprim–sulfamethoxazole
resistance
Trimethoprim–sulfamethoxazole
resistance
[32,159]
Resistance to fluoroquinolone class
Impact upon antimicrobial
therapy
Ref.
Review
controversy, disc diffusion and Etest appear to be most appropriate
for the susceptibility testing of trimethoprim–sulfamethoxazole
in S. maltophilia isolates [112] .
The European Committee on Antimicrobial Susceptibility Testing
(EUCAST) and the British Society for Antimicrobial Chemotherapy
(BSAC) report clinical breakpoint data only for trimethoprim–sulfamethoxazole (resistant: MIC >4 mg/l; zone diameter: <16 mm for
EUCAST, ≤19 mm for BSAC; disc content: 1.25/23.75 µg) [302,303] .
By contrast, a broader range of sensitivities has been reported by the
Clinical Laboratory Standards Institute, including data for trimethoprim–sulfamethoxazole, ceftazidime, ticarcillin–clavulanic acid,
minocycline, levofloxacin and chloramphenicol. EUCAST report
S. maltophilia to be intrinsically resistant to ceftazidime, regardless
of the result of susceptibility testing [304] . This is supported by the
wild-type MIC distribution of S. maltophilia and ceftazidime ranging from clinically achievable values to those well above that which
can be achieved with maximum doses [113] .
Sul2
Located on large plasmids; resistance genes are
embedded in a transposon-like structure and can
transfer both intra- and inter-generically
(insertional sequence common region)
Integrase-encoding gene allows site-specific
Sul1
insertion of resistance gene cassettes between two
highly conserved adjacent nucleotide sequences;
located on transposons or plasmids that facilitate
transfer of integrons to other strains and bacterial
species (class 1 intergrons)
Smqnr
Protect DNA gyrase and topoisomerases from
inhibition
Target site
modification
Responsible gene(s)
Resistance mechanism
Category
Table 2. Stenotrophomonas maltophilia: mechanisms of antibiotic resistance.
Recommended antibiotic agents
Current treatment recommendations are based upon historical
evidence, case series, case reports and in vitro susceptibility studies. A summary of treatment options is provided in Table 4. The
recommended first-line agent is trimethoprim–sulfamethoxazole.
Alternative agents include ticarcillin–clavulanic acid, newer fluroquinolone agents (e.g., moxifloxacin) and tetracycline derivatives (e.g., tigecycline and minocycline). Other agents with
documented activity against S. maltophilia include colistin and
chloramphenicol. There are concerns regarding the use of ceftazidime, given high resistance rates and the potential for inducible
resistance. S. maltophilia is intrinsically resistant to carbapenems
and demonstrates high levels of resistance to aminoglycosides and
these agents should not be used as therapeutic options.
Trimethoprim–sulfamethoxazole resistance rates are generally
less than 10% [48,49,106,114–116] and high doses are recommended
given its bacteriostatic action [117] . Bone marrow suppression
side effects, among the other side effects of high-dose trimethoprim–sulfamethoxazole, may limit therapy, especially in
patients with underlying hematological malignancies receiving
myelosuppressive chemotherapy.
Ticarcillin–clavulanic acid is the most active b-lactam antibiotic as clavulanic acid is able to inhibit the L2 b-lactamase of
S. maltophilia [41,118] . Increasing resistance, however, has been
reported [49,106,119] . Clavulanic acid can also be used in combination with aztreonam [120] and aztreonam itself has been reported
as an inhibitor of L2 b-lactamase of S. maltophilia [121] .
Another b-lactam, ceftazidime, shows some in vitro activity,
however resistance rates are high [122] . Although clinical success has
been reported, often when used in combination with other active
agents [62] , its use as empirical therapy is not recommended [56] .
Newer fluoroquinolone agents have been proposed as promising
alternative agents. Moxifloxacin demonstrates a post-antibiotic
effect and activity against biofilms [123,124] . Resistance rates remain
low to the newer fluoroquinolone agents when compared with
ciprofloxacin, however, rapid resistance can emerge on therapy,
limiting their use outside of combination therapy [125–127] .
477
Review
Box 2. Predisposing factors for Stenotrophomonas
maltophilia infection.
• Compromised immune system
– Malignancy (hematologic/nonhematologic)
– Cytotoxic chemotherapy, or neutropenia (especially if prolonged)
– Solid organ transplantation
– Chronic lung disease (CF/COPD)
– HIV infection
– Hemodialysis
• Indwelling devices
– Intravascular catheters
– Other: indwelling urinary catheters or recent instrumentation;
endotracheal or tracheostomy tubes; neurosurgical devices;
prosthetic cardiac values and pacemaker wires;
ophthalmological lenses; and peritoneal catheters
• Intensive care unit admission
• Mechanical ventilation (or tracheostomy)
• Exposure to broad-spectrum antibiotics
– Especially carbapenems, extended-spectrum cephalosporins
and fluoroquinolones
– Risk increases with duration and the number of antimicrobials
used
• Prolonged hospital inpatient stay
• Mucositis
CF: Cystic fibrosis; COPD: Chronic obstructive pulmonary disease.
The tetracycline derivative, tigecycline, has been reported to
have susceptibility rates equivalent to trimethoprim–sulfamethoxazole, but clinical experience is limited [114] . Colistin has variable
activity against S. maltophilia and may offer another alternative
agent [106,107,109,110,128] .
Combination therapy
Combination therapy may be indicated in specific clinical settings. In practice, combination therapy is most often employed
in the setting of severe sepsis, neutropenia or polymicrobial infections, or when trimethoprim–sulfamethoxazole cannot be used
or tolerated. Because of the bacteriostatic action of most active
drugs, combination therapy has also been promoted to reduce the
risk of developing antibiotic resistance during treatment [38,129] .
In vitro synergy of antibiotic agents has been widely reported,
yet the extrapolation of these results for clinical application is
not yet supported by clinical trials [130] . Such synergy has been
reported for trimethoprim–sulfamethoxazole and ticarcillin–clavulanic acid (47–100% displaying synergy in >700 strains tested)
as well as ticarcillin–clavulanic acid and ciprofloxacin (13–75%
displaying synergy in >700 strains tested) combinations [131] . In
an in vitro study comparing trimethoprim–sulfamethoxazole
alone or in combination, all combinations were more active than
monotherapy [117] . More recently, in vitro synergistic activity was
detected predominantly with trimethoprim–sulfamethoxazole and
ticarcillin–clavulanic acid, and trimethoprim–sulfamethoxazole
and ceftazidime, however, concerns remain regarding the reliability
of susceptibility testing methods [111] . A study of trimethoprim–sulfamethoxazole-resistant S. maltophilia isolates showed a beneficial
478
role of combination therapy with trimethoprim–sulfamethoxazole
and polymyxin B in vitro, suggesting that significant benefit may
still be gained using antibiotic agents in combination that are inactive alone or only intermediately susceptible [132] . The interaction
of colistin and rifampin and, to a lesser extent, of colistin and trimethoprim–sulfamethoxazole has also been shown to inhibit the
growth in vitro of multidrug-resistant S. maltophilia [133] .
Clinical data supporting combination therapy is very limited and
although there are case reports detailing the use of many different
antibiotics combinations, clinical evidence for one combination over
another is lacking. In a recent review of 40 hematology patients with
S. maltophilia bacteremia, the most frequent combination therapy
used was trimethoprim–sulfamethoxazole or ceftazidime with ciprofloxacin [62] . Other reported combination regimes include: trimethoprim–sulfamethoxazole and amikacin in the treatment of an
infected pacemaker and epicardial electrodes [134] ; trimethoprim–
sulfamethoxazole and ciprofloxacin for bacteremia in a hemodialysis
patient with a long-term CVC [90]; trimethoprim–sulfamethoxazole
and ciprofloxacin for S. maltophilia meningitis in a preterm neonate
after neurosurgery [135]; trimethoprim–sulfamethoxazole and tobramycin for prosthetic mitral value S. maltophilia endocarditis [136] ;
trimethoprim–sulfamethoxazole, ticarcillin–clavulanic acid and
aztreonam in an allogeneic bone marrow transplant recipient, who
developed myositis with S. maltophilia [137] ; and trimethoprim–sulfamethoxazole and ciprofloxacin for distal necrosis of the fingers
caused by a community-acquired S. maltophilia [138] .
The need for combination therapy becomes more apparent
when the use of trimethoprim–sulfamethoxazole is contraindicated, either due to allergic reaction or intolerance. In a systematic review examining therapeutic options for S. maltophilia
infections beyond trimethoprim–sulfamethoxazole, Falagas et al.
found the most common combinations to include ciprofloxacin,
ticarcillin–clavulanic acid and ceftazidime [139] . More recently, a
case report of recurrent S. maltophilia VAP, which failed initial
trimethoprim–sulfamethoxazole therapy, was successfully treated
with intravenous doxycycline and aerosolized colistin [92] .
Prevention
Stenotrophomonas maltophilia may be identified infrequently, as part
of an outbreak, or as an endemic pathogen. In the setting of an outbreak, review of hospital infection control measures, consideration
of environmental reservoirs and improved antimicrobial stewardship
may be required.
Outbreaks of S. maltophilia infection within healthcare facilities
have been reported. For example, contaminated water supply has
been identified as a source of infection [57,83,140] . Transmission of
S. maltophilia among CF patients is uncommon but may occur [72] .
Within the ICU, clonal spread of S. maltophilia between patients
has been reported [76] .
Infection control
The beneficial role of hand hygiene in prevention of transmission
of S. maltophilia has been demonstrated in patients with CF [141]
and patients in ICU environments [76] . Although the potential role
for aerosolized transmission has been identified in patients with
Review
Table 3. Clinical syndromes associated with Stenotrophomonas maltophilia infection.
System
Syndrome
Clinical details
Associated factors
Cardiovascular
Bacteremia
Polymicrobial infections may be seen in
children or in the presence of an
infected CVC
CVC; hematological malignancy;
ICU patients; hemodialysis
Endocarditis
Subannular abscess has been reported
Prosthetic valve
Pacemaker infection
Delayed infection may occur
Ref.
[63,77,87–91]
[160–166]
[134]
Respiratory tract Pneumonia
New or progressive pulmonary infiltrate
on chest imaging
Ear, nose and
throat
Rhinosinusitis
May present as chronic refractory
rhinosinusitis
Gingivitis
Acute necrotizing ulcerative gingivitis
ALL
[169]
Epiglottitis
Necrotizing epiglottitis
Neutropenia; CMV disease
[170]
CLL
[171]
Otitis externa
Skin, soft tissue
and bone
Cellulitis
Chronic lung disease (CF and
COPD); intubation and mechanical
ventilation (VAP)
[92–95]
[167,168]
[172]
Hematogenous spread (in 58%), primary
cellulitis (in 23%) and ecthyma
gangrenosum (in 17%)
[137,138,173–175]
Deep soft tissue/myositis Acute upper airway obstruction caused
by infection of mucocutaneous and soft
tissues of the neck; distal necrosis of the
fingers reported
Neurological
Intra-abdominal
[176–179]
Septic arthritis and
bursitis
Detected by 16S rRNA gene analysis
from synovial fluid
HIV/AIDS
Osteomyelitis
Vertebral osetomyelitis and
spondylodiscitis
Post-discectomy; chronic hepatitis
B infection; post-renal
transplantation
[180,181]
Neurosurgical procedures
[182,183]
Meningitis
Brain abscess
Secondarily infected spontaneous lobar
cerebral hemorrhage
Enteritis
Chronic diarrhea; malabsorption; failure
to thrive
Cholangitis
[184]
Cerebral amyloid angiopathy
[185]
[186]
Hepatobiliary malignancy; biliary
tract obstruction; biliary tract
instrumentation
HIV; nephrostomy
[187–190]
Peritonitis
Peritoneal dialysis
[78,191]
Renal
Urinary tract infection
Obstructive uropathy; surgery of
urinary tract; neutropenia; urinary
tract structural abnormalities;
neonates
Opthalmic
Conjunctivitis/orbital
cellulitis/keratitis
Component of polymicrobial infection
Endophthalmitis
Acute endophthalmitis; endogenous
endopthalmitis; infected scleral buckle
Intra-abdominal
collection
Infected necrotic pancreatic collection;
liver abscess; superinfection of
perinephric abscess
[192–194]
[61,195,196]
Cataract and retinal reattachment
surgery; contaminated rinsing
solution; penetrating eye injuries
[197–200]
ALL: Acute lymphocytic leukemia; CF: Cystic fibrosis; CLL: Chronic lymphocytic leukemia; CMV: Cytomegalovirus; COPD: Chronic obstructive pulmonary disease;
CVC: Central venous catheter; ICU: Intensive care unit; VAP: Ventilator-associated pneumonia.
479
Review
Table 4. Treatment options for Stenotrophomonas maltophilia infection.
Antibiotic agent or
class
In vitro
Details
susceptibility (%)
Ref.
Trimethoprim–
sulfamethoxazole
>90†
Bacteriostatic, therefore high doses are recommended (trimethoprim
component ≥15 mg/kg per day). Therapy may be limited by side effects
(including cutaneous reactions, hepatotoxicity, myelosuppression, renal and
electrolyte disorders). Resistance may emerge during treatment
Ticarcillin–clavulanic
acid
45.3 to >70
Bacteriostatic. Aztreonam–clavulanic acid (2:1 or 1:1) also demonstrates
in vitro activity. Emergence of resistance reported. Other combinations such
as ticarcillin–sulbactam, piperacillin–tazobactam and ampicillin–sulbactam do
not have good activity
[34,114–116]
[48,49,
106,116,119,
120,201]
Newer fluoroquinolones 85–95
(e.g., clinafloxacin,
gatifloxacin,
moxifloxacin, sitafloxacin
and trovafloxacin)
Bacteriocidal. Newer agents show superior in vitro activity compared to earlier [123–127,202]
fluoroquinolones, such as ciprofloxacin. Moxifloxacin shown to produce a
post-antibiotic effect with daily dosing and decreased adhesion and biofilm
formation. Rapid emergence of resistance may emerge during treatment,
especially if used as monotherapy
Tetracycline derivatives
(minocycline and
tigecycline)
80–100
Limited clinical experience. Tigecycline may overcome the usual tetracycline
resistance mechanisms and has been found to be active against
trimethoprim–sulfamethoxazole-resistant isolates
[114,201–
204]
Colistin/polymyxin B
72.4–79
Variable activity found. Etest susceptibility testing preferred over disc
diffusion. Compared with agar dilution, however, broth microdilution, Etest
and disc diffusion can all give high rates of false susceptibility. Synergistic
activity reported when used in combination
[106,107,109,
110,128,133]
Fourth-generation
cephalosporins (e.g.,
ceftazidime)
0–53
Some in vitro activity, however, resistance rates are high. Combination
with b-lactamase inhibitors does not demonstrate activity in vitro.
EUCAST reports S. maltophilia to be intrinsically resistant to ceftazidime even
if in vitro sensitivity testing suggests the isolate to be sensitive.
Clinical success has been reported when ceftazidime is used in
combination therapy
[62,116,122]
Chloramphenicol
11.5–81.4
Some in vitro activity. Clinical experience is extremely limited and concern
regarding potential myelotoxicity may limit use
[106]
Stenotrophomonas maltophilia demonstrates intrinsic resistance to penicillin G, cefazolin, cefoxitin, cefamandole, cefuroxime, glycopeptides, fusidic acid, macrolides,
lincosamides, streptogramins, rifampicin, daptomycin and linezolid, a feature common to other nonfermentative Gram-negative bacteria [304].
†
Excluding reports from cystic fibrosis or patients from Taiwan, where higher resistance rates have been reported.
EUCAST: European Committee on Antimicrobial Susceptibility Testing.
CF [142] , respiratory isolation precautions are not routinely recommended for healthcare workers caring for patients with pneumonia due to S. maltophilia. Water filtration has been used to reduce
contamination of nebulizer equipment in this population [143] .
Environmental reservoirs
If an increased number of infections are observed within a healthcare facility, environmental sampling may be indicated to identify
a common source. Taps, nebulizers, sinks, portable water and contaminated hand moisturizer solutions have all been identified as
sites for S. maltophilia colonization in ward environments [144,145] .
Targeted environmental cleaning may be necessary in a commonsource outbreak. Recently, hydrogen peroxide and peracetic acid
have been reported to have activity against S. maltophilia [146] .
Antibiotic stewardship
Given the association of S. maltophilia acquisition with the use of
broad-spectrum antibiotic agents, measures to minimize the indiscriminate use of broad-spectrum antimicrobial therapy should be
encouraged [147,148] . Data analyzed across 39 German ICUs found
480
a significant positive correlation between total antibiotic use, carbapenem, ceftazidime, glycopeptide and fluoroquinolone administration and the isolation of S. maltophilia [149] . It is plausible that
improved antibiotic stewardship could impact upon the incidence
of S. maltophilia isolates and reduce the development of induced
resistance to some antibiotic classes (e.g., fluoroquinolone agents).
Expert commentary
Being an opportunistic pathogen, it is necessary that careful clinical evaluation be performed in all patients in whom S. maltophilia
is isolated. The finding of S. maltophilia in blood or other sterile
sites is generally considered significant. However, nonsterile site
isolates may represent colonization or infection and evaluation of
underlying immunocompromise and clinical findings is necessary.
Patients with hematological malignancy represent an important at-risk population. In this group, the presence of indwelling
devices, administration of broad-spectrum antibiotic therapy and
loss of integrity of gut mucosa means that patients often have
multiple risk factors for acquisition of S. maltophilia. Molecular
or rapid diagnostic techniques would be of considerable benefit,
allowing earlier commencement of targeted therapy, with potential
to improve clinical outcomes.
Patients with chronic lung disease, particularly CF, represent
another at-risk population, with challenges regarding diagnosis.
In this group, long-term colonization of the airways by S. maltophilia is common. As a contributing pathogen in lower respiratory
tract infection, it is important that all clinical parameters are carefully evaluated: the presence of fever, change in respiratory function and radiological findings. Clinical challenges include the fact
that copathogens may be recovered from respiratory specimens in
patients with CF and the pathogenicity of individual isolates may
be difficult to ascertain. This same challenge may be faced in prolonged, mechanically ventilated patients.
First-line therapy for S. maltophilia infections is generally
with trimethoprim–sulfamethoxazole, although the beneficial
role for combination therapy requires further evaluation. Newer
antibiotic agents (e.g., tigecycline and moxifloxacin) also require
additional clinical evaluation. Future research endeavors validating antibiotic susceptibility reporting will directly assist in
the defining of roles for newer agents and combination therapies.
Review
malignancy, solid organ transplantation, chronic lung disease, endstage renal failure and neonatal populations. It will be necessary for
the further development of rapid and molecular diagnostic testing
and for this to be adopted within routine clinical practice.
The relationship between genotypic and phenotypic characteristics of S. maltophilia is not well established, meaning that
future research agendas must focus upon clinical outcomes.
There is an ongoing need for clinically relevant interpretation of
antibiotic susceptibility testing. Translational research, including
functional genomic analyses of S. maltophilia, may reveal alternative targets for new antimicrobial agents or novel mechanisms of
action (e.g., inhibition of quorum sensing or cell–cell signaling).
Given the ubiquitous nature of this organism, it is not likely
that eradication of healthcare facility-associated infections will
be achieved. Nonetheless, control may be achieved by environmental decontamination and optimizing hand hygiene practices.
Collaborative multicenter investigation of longitudinal data is
required to demonstrate the beneficial impact of antibiotic stewardship programs in reducing the incidence of S. maltophilia infections
and modifying antibiotic susceptibility profiles of S. maltophilia
isolates in healthcare facilities.
Five-year view
Over the last decade, increased prevalence of S. maltophilia infections has been reported in immunocompromised and hospitalized
patient populations. During this period, a greater understanding
of pathogenicity, including the genetic basis for disease, has been
gained. Molecular diagnostic methods have also been introduced.
Approaches to management, however, have remained largely
unchanged, with trimethoprim–sulfamethoxazole generally used
as first-line therapy for S. maltophilia infections.
Within the next 5 years, it is likely that disease burden related
to S. maltophilia infections will become increasingly significant if
enlarged immunocompromised patient populations are managed by
current healthcare services – for example, patients with hematological
Acknowledgements
Denis Spelman and Cameron Jeremiah (Department of Microbiology, The
Alfred Hospital, Melbourne, Australia) are acknowledged for the provision
of Gram-stain and culture images in Figure 1.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Key issues
• Stenotrophomonas maltophilia has emerged as an opportunistic pathogen of increasing relevance to immunocompromised and
hospitalized patient populations. Examples of at-risk populations include patients in intensive care environments and patients with
hematologic disorders or cystic fibrosis.
• Biofilm production by S. maltophilia is an important virulence mechanism contributing to enhanced surface spread and adhesion,
resistance to phagocytosis and shielding from antimicrobial activity. A focus upon biofilm disruption is required for newer therapies,
especially for infections associated with indwelling medical devices.
• Molecular diagnostic techniques for S. maltophilia have the potential to improve clinical outcomes. However, further validation and
investigation of clinical correlates (viable bacterial load, antibiotic susceptibility profiles, virulence factor expression and clinical
outcomes) is required before routine application.
• Intrinsic, inducible and acquired mechanisms of resistance are well described for S. maltophilia. However, standardization is required for
reporting susceptibility of clinical isolates.
• The recommended first-line therapy for S. maltophilia infection is trimethoprim–sulfamethoxazole, supported by a high rate of in vitro
susceptibility (>90%) to this agent.
• Alternative therapies include ticarcillin–clavulanic acid and newer fluoroquinolone agents, which may be used as components of
combination regimens. Tigecycline and colistin have also been used in therapy for trimethoprim–sulfamethoxazole-resistant isolates,
although a more defined therapeutic role for these agents is yet to be established. Controversy remains regarding the use of
ceftazidime – the European Committee on Antimicrobial Susceptibility Testing reports S. maltophilia to be intrinsically resistant to
ceftazidime even if in vitro testing suggests susceptibility.
• In clinical practice, combination antibiotic therapy is generally reserved for severe sepsis and patients with neutropenia, or when
trimethoprim–sulfamethoxazole is contraindicated. However, compelling clinical evidence for combination therapies is lacking.
481
Review
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Review Iain J Abbott , Monica A Slavin

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