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  REVIEW Antimicrobial therapy for  Stenotrophomonasmaltophilia  infections A. C. Nicodemo  &  J. I. Garcia Paez Published online: 3 March 2007 # Springer-Verlag 2007 Abstract  Stenotrophomonas maltophilia  has emerged asan important nosocomial pathogen capable of causingrespiratory, bloodstream, and urinary infections. The treat-ment of nosocomial infections by  S. maltophilia  is difficult,as this pathogen shows high levels of intrinsic or acquiredresistance to different antimicrobial agents, drasticallyreducing the antibiotic options available for treatment.Intrinsic resistance may be due to reduced outer membrane permeability or to the multidrug efflux pumps. However,specific mechanisms of resistance such as aminoglycoside-modifying enzymes or the heterogeneous production of metallo- β -lactamase have contributed to the multidrug-resistant phenotype displayed by this pathogen. Moreover,the lack of standardized susceptibility tests and their interpre-tative criteria hinder the choice of an adequate antibiotictreatment. Recommendations for the treatment of infections by  S. maltophilia  are based on in vitro studies, certainnonrandomized clinical trials, and anecdotal experience.Trimethoprim-sulfamethoxazole remains the drug of choice,although in vitro studies indicate that ticarcillin-clavulanicacid, minocycline, some of the new fluoroquinolones, andtigecycline may be useful agents. This review describes themain resistance mechanisms, the in vitro susceptibility profile, and treatment options for   S. maltophilia  infections. Introduction Stenotrophomonas maltophilia  is a nonfermentative gram-negative bacillus, previously known as  Pseudomonasmaltophilia  and later as  Xanthomonas maltophilia  [1  –  4].This bacterium is found in various environments such aswater, soil, plants, food, and hospital settings, among others[5, 6]. The pathogenic factors and virulence associated with S. maltophilia  include the production of proteases andelastases and the ability to adhere to synthetic materials.  S.maltophilia  adheres avidly to medical implants and catheters,forming a biofilm that renders natural protection against host immune defenses and different antimicrobial agents [7  –  10].The incidence of   S. maltophilia  isolates provided bydifferent hospitals ranges from 7.1 to 37.7 cases per 10,000discharges [6, 11, 12]. Nosocomial  S. maltophilia  pneumo-nia is associated with high mortality, particularly whenassociated with bacteremia or obstruction. In uncontrolledclinical trials, mortality rates associated with  S. maltophilia  bacteremia range from 21 to 69% [13, 14]. Senol et al. [13] reported an attributable mortality rate of 26.7% in  S.maltophilia  bacteremia. The risk factors for infection by S. maltophilia  include prolonged hospitalization requiringinvasive procedures, previous exposure to broad-spectrumantibiotics, mechanical ventilation, and severe mucositis[12, 15  –  22].  Stenotrophomonas maltophilia  is associatedwith a broad spectrum of clinical syndromes, including pneumonia, bloodstream infection, skin infections andsurgical-site-related infections, urinary tract infections,endocarditis, meningitis, intra-abdominal infections, andendophthalmitis [6, 23  –  35].Patients with cystic fibrosis, a hereditary metabolicdisorder of the exocrine glands that mainly affects the pancreas, respiratory system, and sweat glands, are com-monly colonized by  S. maltophilia . Eur J Clin Microbiol Infect Dis (2007) 26:229  –  237DOI 10.1007/s10096-007-0279-3A. C. Nicodemo ( * ) : J. I. G. PaezDepartment of Infectious Diseases,University of São Paulo Medical School,São Paulo, SP, Brazile-mail: A. C. NicodemoRua Barata Ribeiro 414, Conjunto 104,CEP 01308-000 São Paulo, SP, Brazil  Sometimes it is difficult to distinguish between coloniza-tion and infection.The differential diagnosis shouldbe basedon the association of factors such as physical examination,radiograph results, other clinical or image findings, andlaboratory test results, including the microbiological assays.The treatment of infection caused by  S. maltophilia  iscontroversial and difficult due to genotypic and phenotypicvariability amongst members of   S. maltophilia  species;intrinsic resistance mechanisms expressed by  S. maltophilia against most antimicrobial agents; the ability of   S. maltophilia to develop resistance during treatment; poorly standardizedsusceptibility tests and their interpretative criteria; and thedifficulty of transferring in vitro findings to clinical practice,given the lack of randomized clinical trials comparing theefficacy of antimicrobial agents [6, 36, 37]. Resistance mechanisms Resistance due to production of beta-lactamasesBeta-lactam resistance is due to the expression of twoinducible  β -lactamases, L1 and L2, although not all clinical S. maltophilia  isolates express  β -lactamases, even after induction with a  β -lactam agent. L1 metallo- β -lactamase isa homotetramer of 118 kDa. It is a Zn 2+ -dependent metal-loenzyme that hydrolyzes virtually all classes of   β -lactamagents, including penicillins, cephalosporins, and carbape-nems, but not monobactams. Furthermore, the L1 enzymeis not inhibited by clavulanic acid. L2 serine- β -lactamase isa cephalosporinase that hydrolyzes aztreonam and iscompletely inhibited by clavulanic acid and partiallyinhibited by other   β -lactamase inhibitors [38  –  41]. Theexpression of such  β -lactamases is determined by chromo-somal genes, which are highly polymorphic within thespecies [42].In 2000, Avison et al. [43] demonstrated a constitutivelyexpressed  β -lactamase gene from a clinical isolate of   S.maltophilia . Its DNA sequence is almost identical to that of  bla TEM2 , and the expressed enzyme is a Bush type 2a penicillinase with an amino acid sequence identical to that of TEM-2. This gene was present within a transposon in thegenome of this strain. These findings suggest that this pathogen can act as a reservoir for mobile  β -lactamase genes.Resistance due to efflux systemsMultidrug resistance efflux pumps have been identified as animportant resistance mechanism in  S. maltophilia . The efflux pump is composed of a membrane fusion protein, an energy-dependent transporter, and outer membrane proteins (OMPs).Alonso and Martinez [44] described the cloning and thecharacterization of a multidrug efflux pump from  S.maltophilia  for the first time and named the new systemSmeDEF. In 2001, the same authors [45] showed SmeDEFexpression in 33% of the  S. maltophilia  strains studied anda resultant increase in the MICs of tetracyclines, choram- phenicol, erythromycin, norfloxacin, and ofloxacin.Gould and Avison [46] examined a collection of 30 phylogenetically grouped clinical  S. maltophilia  isolatesfrom Europe and North, South, and Central America andcompared their resistance profiles to SmeDEF expressionlevels. Of 20 spontaneous  S. maltophilia  drug-resistant mutants tested, four overexpressed SmeDEF, but only twocarried mutations within the  smeT   gene, which is therepressor of the  S. maltophilia  multidrug SmeDEF efflux pump. Therefore, mutation in  smeT   might be responsiblefor SmeDEF overproduction in multidrug-resistant strainsof   S. maltophilia  [47, 48]. In the above-mentioned study of 30 clinical isolates, 6significantly overexpressed SmeDEF. However,  smeT   is not the only gene product that affects SmeDEF expression, andno general SmeDEF-mediated phenotype can be defined.Li et al. [49] later described the SmeABC system,identifying the SmeC as an outer membrane multidrugefflux protein of   S. maltophilia . However, resistance isdependent only upon the SmeC OMP component of thismultidrug efflux system. The fact that SmeC but not SmeAB contributes to antimicrobial resistance and can beexpressed independently of these genes suggests that SmeCalso functions as part of an additional as-yet-unidentifiedefflux system. Chang et al. [50] have shown that strainsexpressing the SmeABC and SmeDEF efflux systems areresistant to ciprofloxacin and meropenem, respectively.Aminoglycoside resistanceCurrent literature suggests that multiple mechanisms may beinvolved in aminoglycoside resistance, such as aminoglyco-side-modifying enzymes, temperature-dependent resistancedue to outer membrane changes, the efflux-mediatedmechanism, and target modification.The enzymatic modification of the aminoglycosides is dueto a family of enzymes that includes O-nucleotidyltransferases,O-phosphotransferases, and N-acetyltransferase. In 1999,Lambert et al. [51] identified the chromosomal  aac(6  ′   )-Iz  gene of   S. maltophilia  and established that   aac(6  ′   )-Iz   enzyme- producing strains show higher resistance to gentamicin. Li et al. [52] have demonstrated that   aac(6  ′   )-Iz   acetyltransferaseenzyme-expressing strains exhibit reduced susceptibility, particularly to tobramycin. Recently, Okazaki and Avison[53] have demonstrated the  aph(3 ′   )-IIa  determinant of   S.maltophilia , which encodes resistance to the aminoglycosidesclass, except for gentamicin.Changes in the lipopolysaccharide (LPS) structure have been correlated with changes in resistance to a variety of  230 Eur J Clin Microbiol Infect Dis (2007) 26:229  –  237  antimicrobial agents [54].  S. maltophilia  exhibits a temper-ature-dependent variation in susceptibility to several anti- biotics, including aminoglycosides and polymyxin B [55].Temperature-dependent changes in outer membrane fluidity[56], LPS side-chain length [57], and, possibly, core  phosphate content [58] seem to explain the temperature-dependent variation in aminoglycoside susceptibility, im- plicating LPS as determinant in the aminoglycosideresistance in this organism. The ability of   S. maltophilia to alter the size of O-polysaccharide and the phosphatecontent of LPS at different temperatures, increasingresistance to aminoglycosides at 30°C compared to 37°C,has been shown. McKay et al. [59] cloned a  spgM   genefrom  S. maltophilia  that was shown to encode a bifunc-tional enzyme with both phosphoglucomutase and phos- phomanomutase activities. Mutants lacking  spgM   producedless LPS than the  spgM  +  parent strain and tended to haveshorter O-polysaccharide chains. However,  spgM   mutantsdisplayed a modest increase in susceptibility to severalantimicrobial agents and were completely avirulent in ananimal infection model. The latter may be related to theresultant serum susceptibility of   spgM   mutants, which,unlike the wild-type parent strain, were rapidly killed byhuman serum. This data highlights the contribution made by LPS to the antimicrobial resistance of   S. maltophilia .Proteins of the small multidrug resistance (SMR) familyhave been characterized in some gram-negative bacteria inwhich resistance is attributed specifically to aminoglycosides.Chang et al. [50] detected the  smr   gene in six  S. maltophilia strains analyzed, although the role of the  smr   gene in drugresistance by  S. maltophilia  requires further study.The resistance to aminoglycosides can also be due totarget modification (16S rRNA methylation or ribosomalmutations), which has been documented in some gram-negative pathogens and  Mycobacterium  spp. [60].Trimethoprim-sulfamethoxazole resistance Stenotrophomonas maltophilia  resistance mechanisms totrimethoprim-sulfamethoxazole (SXT) have not been stud-ied thoroughly. Barbolla et al. [61] mentioned the presenceof the  sul I   gene (plasmid-mediated resistance) in threeclones for which the MICs of SXT were increased.According to the authors, these findings not only support the increased spread of class one integrons compared toother mechanisms, but also reveal the potential limitationsof using SXT therapy in severe infections.Biofilm formationAlthough the biofilm formation is not precisely a  “ resis-tance mechanism, ”  it can increase the resistance toantimicrobial agents, which typically fail to eradicate biofilms.  Stenotrophomonas maltophilia  has the ability toadhere to abiotic surfaces. The positive charge of the cellsurfaceofthebacteriumseemstobeanimportantelementthat favors its adhesion to negatively charged surfaces [8]. The biofilm formation on prosthetic materials such as centralvenous catheters, urinary tract catheters, and heart valves,amongst others, is a biological property of this bacterium.Biofilms are structured communities of bacterial cellsenclosed in a self-produced expolysaccharide matrix andadherent to an inert surface. Di Bonaventura et al. [10], in anin vitro study, characterized the kinetics of   S. maltophilia  biofilm formation: bacteria attach rapidly to polystyrene after 2 h of incubation, and then the biofilm formation increasesover time, reaching maximum intensity at 24 h of culture.The production of extracellular slime or glycocalyx is acrucial factor in bacterial adherence and in bacterial protectionagainst host defense mechanisms and antimicrobial agents,which commonly fail to eradicate the biofilms and consequent-ly, the infection [62]. This highlights the need to remove these prosthetic devices in order to eradicate the infection. Susceptibility tests There are several uncertainties surrounding the in vitrosusceptibility testing of   S. maltophilia , which range from theselection of the antimicrobial agents to be tested, to the best invitro methodology to be used, to the accuracy of the in vitromethods used, to the correlation between the different methods available [37].The recommendations establishedbydifferentprofessionalsocieties for susceptibility testing of   S. maltophilia  vary withregard to the selection of antimicrobial agents to be tested,the disk content, the zone diameter interpretative criteria, andthe equivalent MIC breakpoints. The Clinical and LaboratoryStandards Institute (CLSI) recommends the disk diffusiontechnique in order to establish the susceptibility of   S.maltophilia , but only to SXT, minocycline, and levofloxacin.Other agents may be approved for therapy, but according tothe CLSI, their performance has not been sufficiently studiedto establish disk diffusion breakpoints. The MIC interpreta-tive breakpoints are available only for ticarcillin-clavulanicacid, ceftazidime, minocycline, levofloxacin, SXT, andchloramphenicol [63]. Therefore, further studies are neces-sary in order to enhance the in vitro susceptibility testing of  S. maltophilia  to different antimicrobial agents. Treatment Trimethoprim-sulfamethoxazoleTrimethoprim-sulfamethoxazole should be considered theempirical choice for clinically suspected  S. maltophilia Eur J Clin Microbiol Infect Dis (2007) 26:229  –  237 231  infections and as the treatment of choice for culture-proveninfections by this agent. Susceptibility to this combinationis above 80%, according to the results of studies usingseveral in vitro methods [12, 14, 37, 64  –  77]. Sader andJones [78], studying 2,076 strains as part of the worldwideSentry Antimicrobial Surveillance Program, reported aresistance rate of 4.7%. Nevertheless, resistance to thiscombination is increasing in certain centers.Ticarcillin-clavulanic acid and aztreonam-clavulanic acidIn general, the  β -lactam antibiotics show low activityagainst   S. maltophilia , owing to the previously mentionedresistance mechanisms. Rates of resistance of   S. maltophilia to  β -lactam agents such as ampicillin, amoxicillin, piper-acillin, and aztreonam are invariably high [12, 18, 70  –  84].Beta-lactamase inhibitors such as clavulanic acid cansometimes increase the susceptibility of   S. maltophilia  tosuch agents [82].The ticarcillin-clavulanic acid combination has beenrecommended as a second therapeutic option, mainly in thetreatment of patients who experience adverse effects withSXT therapy [6]. Several studies have demonstrated suscep-tibility above 70% to this in vitro drug combination [66  –  68,70, 81, 83]. However, Sader and Jones [78], studying 2,076 strains as part of the worldwide Sentry AntimicrobialSurveillance Program, reported a resistance rate of 54.7%. Nicodemo et al. [37] reported an in vitro resistance rate of 41%, similar to the rates shown in other studies [79, 85]. Garrison et al. [86], using the pharmacodynamic model toevaluate the ticarcillin-clavulanic acid combination, haveshown that   S. maltophilia  strains exhibit partial growthsuppression followed by regrowth, suggesting the need for controlled studies to establish the true efficacy of thiscombination in the treatment of   S. maltophilia  infections.The aztreonam-clavulanic acid combination (2:1 and 1:1)has good in vitro activity, although difficulties with theinterpretation of the diffusion tests in the component ratiosand differences in the pharmacokinetics of these drugsrestrict their use in the treatment of   S. maltophilia  infections[72, 82, 84, 85, 87]. Other combinations such as ticarcillin- sulbactam, piperacillin-tazobactam, and ampicillin-sulbactamdo not show good activity against this bacterium [12, 19, 75, 80, 82, 83, 85]. Cephalosporins and carbapenemsCephalosporins in general show low activity against   S.maltophilia , while cefoperazone, ceftazidime, and cefepimeexert some in vitro activity. However, resistance rates areundesirably high, as reported in various trials [12, 64, 66, 67, 73, 75, 80, 84, 85, 88  –  90]. The risk of resistanceinduction due to  β -lactamase production and low  β -lactamactivity, particularly of the cephalosporins, limits their empirical use in the treatment of   S. maltophilia  infections[12]. Combinations of cephalosporins with  β -lactamaseinhibitors, such as ceftazidime-clavulanic acid, cefopera-zone-sulbactam, and cefepime-clavulanic acid, are oftenmentioned anecdotally, but demonstration of in vitroeffectiveness is scarce [81, 84, 85].  Stenotrophomonasmaltophilia  is intrinsically resistant to carbapenems. Howeet al. [91] have shown that both imipenem and meropenemare L1  β -lactamase inducers and, thus, are not effectiveagainst in vitro  S. maltophilia. Fluoroquinolones New fluoroquinolones such as clinafloxacin, levofloxacin,gatifloxacin, moxifloxacin, and sitafloxacin show superior invitro activity compared to earlier quinolones [37, 66, 68, 70, 73, 85, 88, 90,  92  –  95]. The MIC90 of ciprofloxacin hasincreased over the last few years, which can be explained byciprofloxacin ’ s poor C max  MIC90 ratio [85]. Several studieshave shown the low in vitro activity of this agent against   S.maltophilia  strains [19, 64, 71  –  75, 79, 83, 85, 88  –  90, 92  –  94]. Gesu et al. [92], in an in vitro study comparing the activities of levofloxacin and ciprofloxacin against clinical bacterial isolates, evaluated 124  S. maltophilia  strains andverified susceptibility rates of 85.5 and 58.9%, respectively,to levofloxacin and ciprofloxacin. Valdezate et al. [96]showed that more than 95% of the  S. maltophilia  strainstested were susceptible to the new fluoroquinolones. Clina-floxacin seems to be the most active fluoroquinolone, asshown by Pankuch et al. [97] and confirmed in further studies that showed clinafloxacin to be two- to fourfoldsuperior to levofloxacin, moxifloxacin, trovafloxacin, andsparfloxacin [70, 93]. Weiss et al. [93], in a comparison of  seven fluoroquinolones, showed that clinafloxacin was themost active, inhibiting 95% of the 326 strains analyzed,followed by trovafloxacin (84.3%), moxifloxacin (83.1%),and sparfloxacin (81.5%).Gales et al. [68], as part of the worldwide SentryAntimicrobial Surveillance Program, demonstrated resis-tance rates for gatifloxacin of around 2% in Europe and15% in Canada. Sader and Jones [78] showed lowresistance rates for gatifloxacin (14.1%) and levofloxacin(6.5%). Cohn and Waites [98], using a time-kill assay,showed that gatifloxacin had a bactericidal effect against   S.maltophilia  isolates, suggesting that gatifloxacin might beused to treat strains that show in vitro susceptibility.Biedenbach et al. [94] suggested that gatifloxacin may beused as a monotherapy or together with a second drug inthe treatment of refractory infections due to  S. maltophilia strains.Giamarellos-Bourboulis et al. [95] demonstrated the invitro bactericidal effect of moxifloxacin against genetically 232 Eur J Clin Microbiol Infect Dis (2007) 26:229  –  237
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