Review For reprint orders, please contact [email protected] 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] . www.expert-reviews.com 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 473 Review Abbott, Slavin, Turnidge, Thursky & Worth 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 474 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] . Expert Rev. Anti Infect. Ther. 9(4), (2011) Stenotrophomonas maltophilia: emerging disease patterns & challenges for treatment 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 www.expert-reviews.com 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 475 476 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 Abbott, Slavin, Turnidge, Thursky & Worth Expert Rev. Anti Infect. Ther. 9(4), (2011) [34,45–47] [34,47] Trimethoprim–sulfamethoxazole resistance Trimethoprim–sulfamethoxazole resistance [32,159] Resistance to fluoroquinolone class Impact upon antimicrobial therapy Ref. Stenotrophomonas maltophilia: emerging disease patterns & challenges for treatment 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] . www.expert-reviews.com 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 Abbott, Slavin, Turnidge, Thursky & Worth 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 Expert Rev. Anti Infect. Ther. 9(4), (2011) Stenotrophomonas maltophilia: emerging disease patterns & challenges for treatment 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. www.expert-reviews.com 479 Review Abbott, Slavin, Turnidge, Thursky & Worth 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, Expert Rev. Anti Infect. Ther. 9(4), (2011) Stenotrophomonas maltophilia: emerging disease patterns & challenges for treatment 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. www.expert-reviews.com 481 Review Abbott, Slavin, Turnidge, Thursky & Worth References 10 Gould VC, Avison MB. SmeDEF-mediated antimicrobial drug resistance in Stenotrophomonas maltophilia clinical isolates having defined phylogenetic relationships. J. Antimicrob. Chemother. 57(6), 1070–1076 (2006). 11 Kaiser S, Biehler K, Jonas D. A Stenotrophomonas maltophilia multilocus sequence typing scheme for inferring population structure. J. 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