Stenotrophomonas maltophilia: an emerging opportunist human pathogen

Problem Pathogens

Stenotrophomonas maltophilia: an emerging opportunist human pathogen W John Looney, Masashi Narita, Kathrin Mühlemann Lancet Infect Dis 2009; 9: 312–23 Institute for Infectious Diseases, University of Bern, Bern, Switzerland (W J Looney CSci FIBMS, K Mühlemann MD); Ohta Nishinouchi General Hospital, General Internal Medicine Department, Infectious Disease Section, Fukushima, Japan (M Narita MD); and University Hospital, University of Bern (K Mühlemann) Correspondence to: William John Looney, Institute for Infectious Diseases, University of Bern, Friedbühlstrasse 51, CH-3010 Bern, Switzerland john.looney@ifik.unibe.ch

Stenotrophomonas maltophilia has emerged as an important opportunistic pathogen in the debilitated host. S maltophilia is not an inherently virulent pathogen, but its ability to colonise respiratory-tract epithelial cells and surfaces of medical devices makes it a ready coloniser of hospitalised patients. S maltophilia can cause blood-stream infections and pneumonia with considerable morbidity in immunosuppressed patients. Management of infection is hampered by high-level intrinsic resistance to many antibiotic classes and the increasing occurrence of acquired resistance to the first-line drug co-trimoxazole. Prevention of acquisition and infection depends upon the application of modern infection-control practices, with emphasis on the control of antibiotic use and environmental reservoirs.

Introduction Stenotrophomonas maltophilia is a bacterium that can occur in almost any aquatic or humid environment, including the drinking water supply.1,2 Although not highly virulent, S maltophilia can be the cause of serious human infections (figure). Several factors make this bacterium a cause for concern for modern medicine. Its rate of isolation as a cause of serious infection in immunocompromised patients is reported to be

increasing.3–6 But in the clinical setting, differentiation between colonisation or contamination, or both, and true infection with S maltophilia is often difficult. Antibiotic treatment is greatly hampered by extensive drug resistance, uncertainties about the value of in-vitro susceptibility testing, and the lack of controlled clinicaltreatment trials.7–10 A major difficulty in selecting optimal agents arises when the established drug of choice, co-trimoxazole (trimethoprim-sulfamethoxazole), is not an option due to resistance or other contraindications. Progress has been made in identifying risk factors for the acquisition of severe S maltophilia infections, such as bacteraemia, pneumonia, and the risk of mortality.11–13 Control of antibiotic use has been identified as a cornerstone of prevention of S maltophilia infections in hospitals.14–16 Results from molecular-typing studies suggest that certain strains of S maltophilia have characteristics favouring colonisation and infection.17,18 The recently published sequence of the S maltophilia genome19 is a landmark in our understanding of this organism and should greatly improve our ability to understand drug resistance and pathogenicity, and develop new strategies directed at preventing and treating infection. The development of new approaches to the treatment of S maltophilia has received some attention but is still experimental.20–24 In essence, S maltophilia is an emerging human pathogen that increasingly challenges clinicians, microbiologists, and infection-control specialists with difficult situations. We therefore aim in this Review to explore the current status of knowledge about the pathogenicity, epidemiology, and clinical issues relating to this problematic opportunist.

Taxonomy, microbiology, and identification

Figure: S maltophilia isolated in pure culture Culture following enrichment from a biopsy of an open fracture wound (ankle). Enterobacter amnigenus and E cloacae were also isolated from contemporary biopsies.

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Bacterium bookeri, now known as S maltophilia, was first isolated in 1943 and was subsequently classified as a member of the genus Pseudomonas in 1961 and then Xanthomonas in 1983, finally coming to rest in Stenotrophomonas in 1993.25,26 The genus Stenotrophomonas currently consists of four species, www.thelancet.com/infection Vol 9 May 2009

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only one of which, S maltophilia, is known to cause infection in human beings.27 Genetic analysis suggests that S maltophilia has adapted to human colonisation, having lost certain plant pathogenic traits and gained potential human virulence factors.19 The closest sequenced relatives of S maltophilia are the plant pathogenic xanthomonads.19 S maltophilia isolates from environmental and clinical sources represent a number of genomic groups (defined by DNA fingerprinting, DNA hybridisation, and 16S rDNA sequencing).28 Three groups A, B, and C have been recognised so far through 16S rRNA sequencing, with group A strains showing the highest similarity to the S maltophilia-type strain.17,29 Analysis of a collection of clinical isolates from three continents showed that most clinical isolates fall into group A (44%) or B (34%), with high genetic homology within group A and considerable genetic heterogeneity within group B.17 It is possible that group A strains share certain characteristics that favour the development of infection.17 It has also been postulated that isolates from specific genomic groups (defined by gyrB RFLP analysis) might be better adapted to colonising the respiratory tracts of patients with cystic fibrosis.18 S maltophilia can form biofilms on its own or together with other species; once growing in biofilms it is more resistant to phagocytes and antibiotics.30 Although S maltophilia engages in cell-to-cell signalling (quorum sensing) it does not use the usual LuxIR systems of Gram-negative bacteria, but instead uses the diffusible signalling factor (DSF) molecule found in the Xanthomonas and Xylella signalling systems.19,31 Disruption of DSF signalling leads to diminished biofilm development, loss of motility, reduced production of extracellular proteases, and increased susceptibility to certain antibiotics and heavy metals.31 S maltophilia can also modify the biofilm formation and polymyxin tolerance of Pseudomonas aeruginosa via DSF signalling.32 S maltophilia can form small-colony variants, a form adapted for survival in chronic infections, which can be difficult to detect in clinical specimens.33 Culture from normally sterile body sites is straightforward, and bacteraemia and severe sepsis can be detected with standard blood-culture techniques.34 Selective media can improve culture sensitivity for specimens from non-sterile sites, such as respiratory secretion from patients with cystic fibrosis.35 The use of PCR for diagnostic purposes still requires further evaluation.34,36

Pathogenicity Clinical experience has shown that whole-genome sequencing of S maltophilia does not reveal whether the organism is highly virulent.19 Nevertheless, several factors may promote the ability of this bacterium to colonise the respiratory tract and plastic surfaces (such www.thelancet.com/infection Vol 9 May 2009

as catheters and endotracheal tubes). These factors include a positively charged surface and flagella and fimbrial adhesins; the latter have been associated with biofilm formation.37–40 The outer-membrane lipopolysaccharide of S maltophilia is a virulence factor involved in colonisation and resistance to complementmediated cell killing.41 Stimulation by the lipid A component of lipopolysaccharide of peripheral-blood monocytes and alveolar macrophages to produce tumour necrosis factor α (TNFα) plays a part in the pathogenesis of airway inflammation.40,42 Interstrain variation in the lipid A component might be associated with different levels of virulence.40 S maltophilia also induces interleukin-8 expression and polymorphonuclear leucocyte recruitment.40 S maltophilia produces proteases and lipases that have been shown to be involved in bacterial pathogenesis in other genera, and several other extracellular enzymes including DNase, RNase, and gelatinase.43,44 The S maltophilia protease coded for by the StmPr1 gene is able to breakdown the protein components of collagen, fibronectin, and fibrinogen and thus may contribute to local tissue damage and haemorrhage.45

Epidemiology and risk factors S maltophilia is an environmental organism found in water (including natural waters, water-treatment plants, and chlorinated distribution networks), in soil, and on plants.1,26,28,36 It has also been isolated from human and animal faeces, frozen fish, woodland ticks, and raw milk.46,47 In the hospital environment S maltophilia has been found as a contaminant of numerous medical devices, edetic acid anticoagulant in vacuum-blood collection tubes, chlorhexidine-cetrimide disinfectant, and sterile water.46 Surveys from several continents document an increasing isolation rate for S maltophilia that probably reflects an increasing population of patients at risk as a result of advances in medical technologies and treatment.3–6 For example, in England and Wales the annual number of blood isolates increased between 2000 and 2006 by 93% to 773 cases, and a Taiwanese tertiary-care hospital reported an 83% increase from 5·3 to 9·8 episodes per 10 000 discharges from 1999 to 2004.3,4 But the rate of S maltophilia isolation varies between hospitals and geographic regions.48 A German study in 34 intensive-care units (ICUs) between 2001 and 2004 showed an increasing rate of S maltophilia infections in some units and a decrease in others.49 A Spanish study (late 1990s)50 reported isolation rates between 3·4 and 12·1 per 10 000 admissions, and in a German study (34 ICUs) the rate of infection varied between 0 and 7·6 per 1000 patient-days.14 In cystic fibrosis patients S maltophilia has been isolated with increasing frequency from the respiratory tract, but prevalence rates vary considerably between centres, with a mean of 4–6% and peaks of 10–25%.51,52 313

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Acquisition of S maltophilia infection is, in most instances, nosocomial.53–57 Molecular typing of S maltophilia isolates from hospitalised patients by pulsed-field gel electrophoresis shows a high genetic diversity between most strains, with occasional small clusters.54,55,58 This finding suggests that most patients acquire S maltophilia from an independent source, possibly even before hospital entry, and the bacterium is then selected from the commensal flora during antimicrobial exposure; nosocomial acquisition might be from a common source or might occur via cross-transmission. Risk factors for acquiring S maltophilia infection are associated with a severely compromised health status, medical treatment involving indwelling devices such as intravascular catheters and ventilation tubes, exposure to broad-spectrum antimicrobials, and long hospital stays. Chronic obstructive pulmonary disease and the duration of antibiotic therapy have been found to be independent risks for ICU-acquired S maltophilia.16 Blood-stream infection due to S maltophilia is more likely in the presence of a central-venous catheter during treatment in hospital and at home, and failure to remove the central-venous catheter increases the risk of relapse.11,53,59–61 In addition, in patients with cancer, profound chemotherapy-induced neutropenia (fewer than 100 cells per μL) of long duration, mucositis, and receipt of total parenteral nutrition have been associated with S maltophilia blood-stream infections.15,62,63 Prolonged mechanical ventilation predisposes to S maltophilia pneumonia.64,65 In critically-ill trauma patients a high injury-severity score and pulmonary contusions were independent predictors for multiple episodes of late-onset S maltophilia ventilator-associated pneumonia (VAP); single episodes of VAP were associated with tracheostomy.64 Colonisation and infection with S maltophilia is favoured by exposure to broad-spectrum antimicrobials such as carbapenems, higher-generation cephalosporins such as ceftazidime and cefepime, and quinolones; the risk increases with duration of administration and the number of antimicrobials given.11,14–16,50,51,60,64

immunocompromised patient.72 Concomitant isolation of other respiratory pathogens is common and complicates interpretation.69,72 The usefulness of quantitative cultures of bronchoalveolar lavage fluids or endotracheal aspirates is often limited by recent antimicrobial exposure.73 Nevertheless, there is evidence that S maltophilia can cause pneumonia. In a recent survey conducted in a tertiary-care academic hospital, S maltophilia accounted for 4·5% (30 cases) of nosocomial pneumonia, for 6% (27 cases) of VAP and for 1% (3 cases) of nosocomial pneumonia in nonventilated patients.68 S maltophilia VAP typically manifests with a late onset, occurring more than 5 days after hospitalisation.68 Clinical presentation of S maltophilia pneumonia is non-specific. Most patients have fever, and respiratory symptoms include productive cough and dyspnoea.71 On radiological examination pulmonary infiltrates appear lobular or lobar with unilateral or bilateral distribution and uncommon pleural effusions.71,74 Cavitary lesions are rarely seen. Histology of lung parenchyma shows focal lung necrosis of haemorrhage in neutropenic patients with haematological neoplasia, and fatal pulmonary haemorrhage might occur.71,74–76 In patients with cystic fibrosis the role of S maltophilia in the progression of disease is undetermined.51,52,77 In a retrospective analysis of patients with cystic fibrosis included in controlled trials of inhalative tobramycin treatment for P aeruginosa, patients colonised with S maltophilia responded to a lesser extent to treatment than did those without colonisation. However, in most studies, detection of S maltophilia did not independently affect disease progression or survival.77,78 Reported mortality rates in patients with S maltophilia pneumonia vary between 23% and 77%, with highest rates observed among patients with cancer and concomitant bacteraemia.12,64,69,71,74,76 Independent predictors for fatal outcome are inadequate empiric antibiotic therapy, admission to ICU, and septic shock.12,64,71 Attributable mortality has been estimated at between 20% and 30%.12

Clinical presentation

Blood-stream infection

The most common clinical manifestation of S maltophilia infection is pneumonia, followed by blood-stream infection and, less frequently, wound and urinary tract infection.5,66–68 Rare cases of an expanding array of other clinical entities have been reported, including meningitis (mostly postsurgery), endocarditis (mainly postsurgery in prosthetic valves or intravenous drug users), sinusitis (which may mimic fungal infection), mastoiditis, cholangitis and peritonitis, eye infections, epididymitis, bursitis, arthritis, and osteochondritis.66,69–71

Isolation of S maltophilia from a blood culture should prompt a careful evaluation of the patient to differentiate between contamination, colonisation, and true blood-stream infection. Central-venous lines are the most common source of S maltophilia bacteraemia.11,13,56,57–59,61 Blood-stream infections and catheterrelated blood-stream infections (CR-BSIs) are often (20–40%) polymicrobial.11,13,53,56,58,59,61,62,79 The prognosis for CR-BSIs is good upon prompt removal of the infected catheter.53,57,59,61 In patients with haematological malignancies, S maltophilia has been associated with breakthrough bacteraemia.62 Senol and colleagues80 estimated a 27% attributable mortality for S maltophilia blood-stream infection, which is similar to that for

Respiratory tract infection Isolation of S maltophilia from the respiratory tract represents colonisation in most cases, and suggests an 314

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other nosocomial blood-stream infections. Polymicrobial blood-stream infections have not been associated with higher mortality than monomicrobial bloodstream infections.56,62

Management of infections In-vitro susceptibility testing In-vitro susceptibility testing of S maltophilia poses numerous technical problems. Both the British Society for Antimicrobial Chemotherapy (BSAC) and the US Clinical Laboratory Standards Institute (CLSI) have published standard methods for the susceptibility testing of S maltophilia to co-trimoxazole.7,8 Both standards use a minimum inhibitory concentration (MIC) of 2 mg/L or lower to indicate susceptibility to co-trimoxazole. The CLSI standard includes broth dilution MIC breakpoints for ticarcillin-clavulanic acid, ceftazidime, minocycline, levofloxacin, and chloramphenicol, and disc-diffusion breakpoints for minocycline, levofloxacin, and co-trimoxazole.8 The CLSI and BSAC disc-diffusion methods differ in inoculum density, length and temperature of incubation, and zone diameters for the disc diffusion breakpoint for co-trimoxazole. To confuse matters, the Expert Rules in Antimicrobial Susceptibility Testing of the European Committee on Antimicrobial Susceptibility Testing consider S maltophilia to be intrinsically resistant to ceftazidime.81 Laboratory testing of moxifloxacin and levofloxacin against 763 isolates showed that in-vitro susceptibility to moxifloxacin can be predicted by testing levofloxacin.82 Extended-spectrum β-lactamase (ESBL) detection using the double-disc diffusion test requires expert interpretation because of the various confounding factors specific to S maltophilia.83 The BSAC specifically advises that there are no data, at present, to support a relation between laboratory susceptibility testing and clinical outcome with S maltophilia infection.9 Certain antibiotic combinations exert a synergistic effect in vitro against S maltophilia.84,85 The three main tests used are the checkerboard, the time-kill, and the multiple-combination bactericidal test.86,87 Different tests may either give the same or differing results when testing the same strain–antibiotic combinations, and this should be borne in mind when interpreting results.88–90 A logistical problem with synergy testing is the delay before results become available. The role of synergy testing in management of individual patients is thus extremely limited.

Antimicrobial resistance Mechanisms of resistance S maltophilia exhibits high-level intrinsic resistance to a variety of structurally unrelated antibiotics, including β-lactams, quinolones, aminoglycosides, tetracycline, disinfectants, and heavy metals.91,92 Sequencing of the S maltophilia K279a genome showed numerous resistance www.thelancet.com/infection Vol 9 May 2009

genes, such as genes encoding for multidrug-efflux pumps, β-lactamases, and aminoglycoside-modifying enzymes.19 Multidrug-efflux pumps and low permeability of the outer membrane are major determinants of the intrinsic antibiotic resistance of S maltophilia.10,41 S maltophilia can also acquire resistance through the uptake of resistance genes located on integrons, transposons, and plasmids. Resistance to co-trimoxazole has been linked to class 1 integrons carrying sul1, and insertion sequence common region (ISCR) elements carrying sul2.93,94 In Taiwan, isolates collected during 2003 showed a class 1 integron carriage rate of 21%.95 The mobilisation of sul genes by means of class 1 integrons and ISCR elements will probably increase with increased use of co-trimoxazole.93,94 Clinical experience has shown that co-trimoxazole resistance may emerge during treatment, although this does not seem to be a frequent event.84,96 Resistance to β-lactams arises from the expression of two inducible β-lactamases: L1 and L2. L1 is an Ambler class B Zn²+-dependent metalloenzyme that hydrolyses all classes of β-lactams except the monobactams.97 L2 is an Ambler class A serine active site β-lactamase (an ESBL) that is inhibited by clavulanic acid.98 These two chromosomal β-lactamases are usually, but not always, induced when cells are exposed to β-lactams.19,99 The production of both β-lactamases is controlled by the same β-lactamase regulator (AmpR); however, L1 production requires more AmpR than does L2 production.100 The L1 and L2 β-lactamases of phylogenetic group A strains are inducible.17 Group B strains have an inducible L1, but express L2 constitutively at low levels.17 Group C isolates express both L1 and L2 constitutively at low levels and are more susceptible than groups A and B to all β-lactams except imipenem.17 Additional β-lactamases have been detected in clinical isolates: a TEM-2 penicillinase located on an active Tn1-like transposon and a CTX-M-1 β-lactamase (belonging to the ESBLs).101,102 Resistance to quinolones is mediated primarily by over expression of efflux pumps (in particular SmeDEF) and possibly low permeability of the outer membrane.103 The role of recently identified quinolone-resistance determinants remains to be clarified.104,105 However, mutations in topoisomerases do not seem to be important.106 Rapid emergence of quinolone resistance in vitro and in vivo has been observed, and this often coincides with increased resistance to other nonquinolone antibiotics.96,103,106,107 Resistance of S maltophilia to aminoglycosides can be due to aminoglycoside-modifying enzymes, efflux pumps, and temperature-dependent resistance due to outermembrane protein changes. Chromosomal genes encode for aminoglycoside acetyltransferase AAC(6Ľ)-Iz and aminoglycoside phosphotransferase APH(3Ľ)-IIc.108–110 These confer reduced susceptibility to amikacin (AA6Ľ), tobramycin (AA6Ľ), netilmicin (AA6Ľ), kanamycin (APH3Ľ), 315

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Percentage Percentage Number of of strains of strains susceptible* resistant* strains tested†

MIC50 μg/mL (range)

MIC90 μg/mL (range)

Amikacin55,79,112–115

>32 to 512

>32 to >512

0 to 31

61 to 100

Aztreonam79,112,113,115

>16 to 256

>16 to >1024

0 to 10

85 to 100

2347

Cefepime48,79,112–115

16 to 64

>16 to ≥128

0 to 30

45 to 100

2508

Cefotaxime112,115

60 to ≥64

≥64 to 512

62 to 64

249

8 to 128

>16 to 256

5 to 53

34 to 86

2649 2184

Ceftazidime43,48,55,79,112–116

10

2535

>32 to 256

>32 to >256

1 to 2

92 to 96

Chloramphenicol55,112,115,117

4 to 32

16 to 64

1 to 80

35 to 39

395

Ciprofloxacin43,48,55,79,84,112–116,118, 119

0·25 to >8

2 to 32

0 to 82

13 to 96

3865

Co-trimoxazole43,48,55,79,84,85,112–118

≤0·25 to >64‡

Ceftriaxone113,114

≤0·25 to >64

0 to 100§

4 to 100

3872

Doxycycline55,84,85,115,117

1 to 2

2 to 8

80 to 100

1 to 11

968

Gatifloxacin48,79,113,115,117,118

0·1 to 4

0·12 to 16

23 to 97

0 to 46

2642

Gentamicin112–115

>8 to 64

>8 to >256

14 to 31

58 to 81

2433

Imipenem48,55,84,112,113,115,116

>8 to 512

>8 to >1024

0 to 2

97 to 100

3261 2631

Levofloxacin79,113–115,118 Meropenem112–115 Minocycline79,82,115,116

0·2 to 2

2 to 8

55 to 86

3 to 11

>8 to >64

>8 to 256

0 to 4

88 to 100

2433

0·2 to 1

1 to 4

91 to 100

0 to 5

1014 1405

0·06 to 0·5

Moxifloxacin82,114,115,118,119

16 to ≥16

Norfloxacin112,115,119

0·5 to 0·5

Ofloxacin115,119

0·5 to 4

85

6

≥16 to 64

20

56

358

4 to 4

89

5

208

1 to 2

4 to 8

72 to 77

Tetracycline112,113,115

>8 to 32

>8 to 64

8 to 9

Ticarcillin55,112,115

16 to 512 2 to 128

Polymixin B117,120

Ticarcillin-clavulanate43,48,55,79,84,85,112,

28

1322

70 to 86

2325

64 to >1024 29 to 69

32 to 74

329

32 to >1024 27 to 95

14 to 50

3764

113,115–118

Tigecycline114,121 Tobramycin55,112,113,115

1 to 1

2 to 4

≥16 to 64

≥16 to 512

90 2 to 25

3 68 to 78

239 2405

Extrapolation of in-vitro testing results for clinical use is not yet supported by clinical trials (see text). *As reported by the authors. †Refers to MIC testing columns; not all authors classified their strains regarding susceptibility. ‡Values greater than 2 μg/mL only recorded from cystic fibrosis patients and patients in Taiwan. §71·4% of strains were classed as 95% sensitive or greater, 6·9% of strains were classed as between 75% and 94% sensitive. The remaining 21·6% of strains were classed as 74% sensitive or less; they were isolated from either patients with cystic fibrosis or patients in Taiwan.

Table 1: In vitro susceptibility of S maltophilia to selected antibiotics

neomycin (AA6Ľ, APH3Ľ), paromomycin (APH3Ľ) and butirosin (APH3Ľ).109,110 The temperature-dependent variation in susceptibility to aminoglycosides and polymyxin B has been linked to outer-membrane lipopolysaccharide characteristics.41 S maltophilia can alter the size of the O-polysaccharide and the phosphate content of lipopolysaccharide at different temperatures, and shows greater resistance to aminoglycosides and polymyxin B at 30°C than at 37°C.41 S maltophilia also possesses numerous heavy-metal resistance mechanisms, and can tolerate silver-lined catheters.19,97,111

Prevalence of resistance Reported resistance rates of S maltophilia are generally high for several antimicrobials because of intrinsic resistance, as discussed above (table 1). However, increasing resistance trends to antimicrobials such as 316

co-trimoxazole and ticarcillin-clavulanate, which are recommended for empirical treatment are worrisome (table 1). The worldwide level of resistance to cotrimoxazole between 1997 and 2003 was 4·7%.113 Levels greater than 5% have previously been reported from the Asia-Pacific region (8% of strains resistant) and Europe (10%).67 Resistance levels from Turkey (15%), Taiwan (25%), and Spain (27%) stand out.56,95,115,122 Resistance levels in strains from patients with cystic fibrosis (76–84%), cancer (7–25%), and those in ICU (15%) might also rise above 5%.12,84,85,114,116 The worldwide level of ticarcillin-clavulanate resistance between 1997–2003 was 16·1%.113 Higher rates of resistance have been reported in isolates from the Asia–Pacific region (29%), Taiwan (36%), and Spain (47%), and from patients with cystic fibrosis (50%).67,79,84,115 Worldwide resistance to ciprofloxacin (1997–2003) was 40%, though higher rates have been seen in Taiwan (96%), and in ICU patients (58%) and patients with cystic fibrosis (85%), as well as in hospitals experiencing increasing consumption of quinolones (69%).79,84,112–114 Between 1997 and 2003, worldwide resistance to gatifloxacin was 14%, and 6·5% to levofloxacin.113 Resistance rates to minocycline are reported to be no higher than 5%.79,82,115

Selection of antimicrobial agents Selection of an appropriate antimicrobial regimen for the treatment of S maltophilia infection is a challenge given the high-level intrinsic resistance and increasing resistance prevalence of this opportunistic pathogen and the uncertainties related to in-vitro susceptibility testing. There is a lack of controlled trials evaluating treatment regimens in the clinical setting. Current treatment recommendations are therefore based on historical evidence and anecdotes, case series and case reports, and in-vitro susceptibility studies. It is probably wise to select a treatment regimen to which the clinical isolate is susceptible in in-vitro tests, despite uncertainties about the clinical relevance of such results. In-vitro models suggest that combination therapy should be more effective than monotherapy especially for difficult-to-treat infections, but clinical evidence is still lacking or anecdotal.

Single agents Co-trimoxazole alone, or in combination with other agents, is still considered the treatment of choice for suspected or culture-proven S maltophilia infection, based on high in-vitro susceptibility rates. In-vitro data suggest that co-trimoxazole is bacteriostatic against S maltophilia.123 It has therefore been recommended to treat severe infections with a high dose of co-trimoxazole similar to that used for treatment of Pneumocystis jirovecii pneumonia (trimethoprim component 15 mg/kg per day or more).116 Co-trimoxazole in therapeutic concentrations inhibits the release of TNFα from peripheral-blood monocytes that have been stimulated www.thelancet.com/infection Vol 9 May 2009

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by S maltophilia in vitro, but the clinical relevance of this observation still needs investigation.42 Hypersensitivity or intolerance may limit the use of co-trimoxazole. Hypersensitivity is mainly attributed to the nitroso metabolite of sulfomethoxazole.124 Rapid oral desensitisation has been used successfully to overcome drug intolerance in patients with S maltophilia infection.125,126 In general, the β-lactams show little activity against S maltophilia because of its high intrinsic resistance against most penicillins and cephalosporins and all carbapenems. In some instances the combination with a β-lactamase inhibitor, such as clavulanic acid, may increase the activity of these antimicrobials against S maltophilia.127 On the basis of in-vitro susceptibility data, ticarcillin-clavulanic acid has been recommended as a second therapeutic option for patients in whom co-trimoxazole cannot be used.25 There have been doubts about its clinical efficacy, since ticarcillinclavulanic acid may be bacteriostatic rather than bacteriocidal against S maltophilia.96 The combination of aztreonam with clavulanic acid (2/1 or 1/1) shows good in-vitro activity and activity is enhanced by the addition of ticarcillin.116,127,128 The pharmacokinetics of aztreonam and clavulanic acid are, however, quite different, which restricts the clinical use of this combination, although successful treatment has been reported in selected cases.129,130 Higher-class cephalosporins such as ceftazidime, cefoperazone, and cefepime show some in-vitro activity and there are case reports of successful use of ceftazidime as monotherapy.131 But reported resistance rates to cephalosporins are high and their activity is low, a finding that is associated with the diversity of S maltophilia isolates and the variable occurrence of inducible lactamases. In addition, exposure to ceftazidime and cefepime is an established risk factor for the acquisition of S maltophilia infection.50,64 Cephalosporins combined with βlactamase inhibitors, such as ceftazidime-clavulanic acid, ceftazidime-sulbactam, cefoperazone-sulbactam, and cefepime-clavulanic acid, do not seem to be active in vitro.128,132 Cephalosporins have been used in combination therapy as discussed below.10 The new fluoroquinolones (clinafloxacin, gatifloxacin, moxifloxacin, and trovafloxacin) show better in-vitro activity than ciprofloxacin and levofloxacin against S maltophilia.6,10,118,119 Quinolones exert concentrationdependant killing and the new quinolones can achieve lung concentrations five-times that achieved in serum.118 It is not clear whether any of the new fluoroquinolones are superior to the others. Rapid emergence of resistance against quinolones has been observed in vitro and in vivo, and it might therefore be prudent to use them in combination with another active substance.96,103 The tetracycline derivatives minocycline, doxycycline, and tigecycline have shown good in-vitro activity against clinical isolates of S maltophilia, but there is little www.thelancet.com/infection Vol 9 May 2009

Second antibiotic

Percentage of strains showing synergy

Number of strains tested

Ciprofloxacin139

Amikacin

14

Ciprofloxacin90,139,140

Cefoperazone

44 to 58

Ciprofloxacin90

Cefpirome

35

20

Ciprofloxacin90,139

Ceftazidime

33 to 50

29

Ciprofloxacin140

Ceftriaxone

25

20

Ciprofloxacin84

Doxycycline

8

673

Ciprofloxacin90,139

Gentamicin

14 to 20

27

Co-trimoxazole141

Carbenicillin

86

14

7 49

Co-trimoxazole84

Doxycycline

13

673

Co-trimoxazole84,89

Ticarcillinclavulanate

47 to 100

704

Gatifloxacin88

Cefepime

60

Gatifloxacin88

Gentamicin

10

10

Levofloxacin90,140

Cefoperazone

15 to 54

40

Levofloxacin90

Cefpirome

35

20

Levofloxacin90

Ceftazidime

50

20

Levofloxacin140

Ceftriaxone

5

20

Levofloxacin90

Gentamicin

11

10

20

Ticarcillin-clavulanate84,89 Ciprofloxacin

44 to 77

704

Ticarcillin-clavulanate84

16

673

Doxycycline

The clinical relevance of in-vitro synergy testing is not yet established (see text).

Table 2: Synergy of selected antibiotics against S maltophilia— checkerboard testing

clinical experience with treating S maltophilia infections with these compounds.82 The new broad-spectrum glycylcycline tigecycline, can overcome the usual tetracycline resistance mediated by efflux and ribosomaltarget modification, and tigecycline has been found to be active against co-trimoxazole-resistant S maltophilia in vitro.121,133 Tigecycline might be considered as an alternative therapeutic option, particularly as a component of combination therapy, although clinical experience is lacking.10 The aminoglycosides show poor activity against S maltophilia because of high intrinsic resistance and they therefore play virtually no part in monotherapy. Polymyxins have recently gained a role in the treatment of infections caused by non-fermentative, multiresistant Gram-negative bacilli.134 S maltophilia is reported to be susceptible to both colistin and polymyxin B, with susceptibility rates slightly in excess of 70%.10,120 However, susceptibility testing of these drugs is problematic and the clinical value of the in-vitro data is not known with certainty.10,120,134 Three cases of S maltophilia meningitis were successfully treated with chloramphenicol combination therapy (with sulphonamide in two cases, and with gentamicin in one case) in the 1970s.70 Chloramphenicol might be considered, following laboratory confirmation of a lack of resistance, for salvage therapy. The myelotoxicity of this drug must, however, be borne in mind. 317

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Second antibiotic

Number Percentage of strains showing of strains tested synergy

Cefepime142

Amikacin

75

8

Cefepime142

Isepamicin

88

8

Ceftazidime142

Amikacin

88

8

Ceftazidime142

Isepamicin

75

8

Ciprofloxacin142

Amikacin

38

8

Ciprofloxacin142

Cefepime

13

Ciprofloxacin89,142

Ceftazidime

25 to 75

Ciprofloxacin142

Isepamicin

63

8

Colistin143

Rifampin

54

24

Co-trimoxazole142

Amikacin

38

8

Co-trimoxazole143

Colistin

17

24

Co-trimoxazole142

Isepamicin

38

8

Co-trimoxazole89

Ticarcillinclavulanate

100

20

8 28

Garenoxacin144

Amikacin

63

8

Garenoxacin144

Cefepime

50

8

Garenoxacin144

Ceftazidime

38

8

Ticarcillin-clavulanate142

Amikacin

50

8

Ticarcillin-clavulanate142

Cefepime

38

Ticarcillin-clavulanate89,142 Ciprofloxacin

13 to 75

8 28

Ticarcillin-clavulanate144

Garenoxacin

13

8

Ticarcillin-clavulanate142

Isepamicin

63

8

The clinical relevance of in-vitro synergy testing is not yet established (see text).

Table 3: Synergy of selected antibiotics against S maltophilia—killing curve testing

Antimicrobial combinations Despite the lack of clinical trials, treatment of S maltophilia with a combination of two or three antimicrobials has become current practice where co-trimoxazole therapy is contraindicated. The motivation for combination treatment comes from the high-level intrinsic resistance of this microorganism, increasing occurrence of acquired resistance, and the bacteriostatic activity of the first-line drug co-trimoxazole and possibly also the second-line antimicrobial ticarcillin-clavulanic acid. The strategy of combination treatment is supported by in-vitro synergy testing, which shows enhanced activity of drug combinations when compared with the single drugs even in situations where the isolate is resistant to one or both of the tested drugs.123 But it must be emphasised that the extrapolation of such in-vitro results to clinical practice is anecdotal at best and awaits proof from clinical trials. Despite such limitations combination treatment has been recommended for severe invasive infection (such as bacteraemia, endocarditis, and osteomyelitis), for infections in immunocompromised patients, and for empirical treatment in areas with high local resistance prevalence against co-trimoxazole.5,10,125,135–137 Examples of successful combination therapy include S maltophilia early prosthetic-aortic-valve endocarditis and osteomyelitis.125,135 318

If combination therapy is considered, it seems wise to base the choice of drugs on in-vitro susceptibility testing. Whether additional synergy testing should be done remains unclear. A recent controlled trial in cystic fibrosis patients showed no substantial advantage in selecting combination treatment based on in-vitro synergy testing compared with conventional susceptibility testing.138 The extent to which this finding can be generalised may be limited, along with other considerations, by the choice of the study population and the small number of cases with S maltophilia infection included. A multitude of different drug combinations have been reported from case studies or have been evaluated by in-vitro synergy testing (table 2, table 3).131,135 It seems reasonable to include co-trimoxazole in a combined regimen if in-vitro susceptibility has been shown. Possible combinations are with ticarcillin-clavulanic acid or a quinolone, such as moxifloxacin.82,89,114,123 Combination with ceftazidime or an aminoglycoside has also shown in-vitro synergy, but, because of limited activity of the latter drugs, we believe that this should not be a first choice.123 In-vitro synergy has also been shown between co-trimoxazole and ticarcillin-clavulanic acid against strains of co-trimoxazole-resistant S maltophilia.10

Experimental agents The increasing lack of antimicrobials with activity against S maltophilia is of concern, and there is an urgent need for new drugs. New approaches have included bacteriophages, inhibitors of L1 β-lactamase, antimicrobial peptides, efflux-pump inhibitors, and constituents of green tea.20–24,145–148 But none of these are close to clinical application.

Prevention Prevention of S maltophilia transmission and nosocomial infections relies on the same cornerstones of modern infection control as formulated for other multiresistant-nosocomial pathogens and nosocomial infections in general, with special emphasis on CR-BSI and VAP. Control programmes should include surveillance of S maltophilia isolation and infection and surveillance of antibiotic consumption, antibiotic stewardship programmes, barrier precautions during care of patients, and measures against CR-BSI and VAP. Since S maltophilia is a ubiquitous environmental microorganism, appropriate handing of medical products and equipment and maintenance of the environment and hospital water supply play a greater part in prevention of S maltophilia transmission than does, for example, prevention of the spread of meticillinresistant Staphylococcus aureus, for which human beings are the relevant reservoir. Clustering of S maltophilia cases should prompt epidemiological investigations, including molecular typing of isolates.149 Transmission from a common source, such as the www.thelancet.com/infection Vol 9 May 2009

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Search strategy and selection criteria A literature review was compiled from the extensive files of the authors. Additional data for this review were identified from PubMed using the key words of “Pseudomonas maltophilia”, “Xanthomonas maltophilia”, and “Stenotrophomonas maltophilia” for the period 1997–2008. The search was limited to publications in English. Articles dealing with antimicrobial therapy and clinical presentation were targeted.

environment (humid reservoirs) or contaminated medical products and equipment, should be considered and sought out.2,150

Conclusions S maltophilia has emerged as an important opportunistic pathogen affecting primarily the hospitalised and debilitated host. S maltophilia does not appear to be inherently virulent, and it is an uncommon cause of invasive infections. Nevertheless, the ability of S maltophilia to colonise airway epithelia and plastic surfaces of indwelling medical devices has led to its emergence as a major nosocomial pathogen especially in the ICU setting. Distinguishing between colonisation and infection can be problematic if the bacterium is isolated from non-sterile sites such as sputum and wounds. S maltophilia may cause blood-stream infection and pneumonia with considerable morbidity and mortality in immunosuppressed patients. Management of infection is hampered by high-level intrinsic resistance to many antibiotic classes, and, more recently, the increasing occurrence of acquired resistance to the first-line drug co-trimoxazole. Prevention of S maltophilia acquisition and infection relies on the cornerstones of modern infection control with, in the case of S maltophilia, somewhat higher emphasis on control of antimicrobial consumption and consideration of environmental reservoirs. Conflicts of interest We declare that we have no conflicts of interest. References 1 Hoefel D, Monis PT, Grooby WL, Andrews S, Saint CP. Profiling bacterial survival through a water treatment process and subsequent distribution system. J Appl Microbiol 2005; 99: 175–86. 2 Cervia JS, Ortolano GA, Canonica FP. Hospital tap water as a source of Stenotrophomonas maltophilia infection. Clin Infect Dis 2008; 46: 1485–86. 3 Communicable Disease Surveillance Centre. Antimicrobial resistance in 2000: England and Wales. London: Public Health Laboratory Service, 2000. http://www.hpa.org.uk/web/ HPAwebFile/HPAweb_C/1194947317696 (accessed March 20, 2009). 4 Tan CK, Liaw SJ, Yu CJ, Teng LJ, Hsueh PR. Extensively drugresistant Stenotrophomonas maltophilia in a tertiary care hospital in Taiwan: microbiologic characteristics, clinical features, and outcomes. Diag Microbiol Infect Dis 2008; 60: 205–10 5 Safdar A, Rolston KV. Stenotrophomonas maltophilia: changing spectrum of a serious bacterial pathogen in patients with cancer. Clin Infect Dis 2007; 45: 1602–09.

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