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 ~  Abstract
 ~ Introduction
 ~  Historical Backg...
 ~ Epidemiology
 ~ Virulence Factors
 ~  Global Problem S...
 ~  Stenotrophomo...
 ~ Indian Scenario
 ~ Laboratory Diagnosis
 ~  Matrix-Assisted ...
 ~  Treatment of ...
 ~  Antimicrobial Re...
 ~ Conclusion
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  Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 35  |  Issue : 4  |  Page : 469-479
 

Stenotrophomonas maltophilia: From trivial to grievous


1 Department of Microbiology, Government Medical College and Hospital, Chandigarh, India
2 Department of Biotechnology, Amar Shaheed Baba Ajit Singh Jujhar Singh Memorial College, Bela, Ropar, Punjab, India
3 Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication1-Feb-2018

Correspondence Address:
Dr. Vikas Gautam
#229, Department of Medical Microbiology, 1st Floor, Research Block-A, Postgraduate Institute of Medical Education and Research, Chandigarh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmm.IJMM_16_430

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 ~ Abstract 

Stenotrophomonas maltophilia, once regarded as an organism of low virulence, has evolved as a significant opportunistic pathogen causing severe human infections in both hospital and community settings, especially amongst highly debilitated patients. Globally, S. maltophilia ranks third amongst the four most common pathogenic non-fermenting Gram-negative bacilli (NFGNBs), others being Pseudomonas aeruginosa, Acinetobacter baumannii and Burkholderia cepacia complex (Bcc). The worth of accurate identification of S. maltophilia comes to the forefront as it needs to be differentiated from other NFGNBs such as Acinetobacter, P. aeruginosa and Bcc due to its inherently contrasting antibiotic susceptibility pattern. Consequently, its correct identification is essential as no single drug is amply effective against all NFGNBs, which hinders initiation of appropriate empirical treatment resulting in increased morbidity and mortality.


Keywords: Multidrug resistance, Stenotrophomonas maltophilia, virulence


How to cite this article:
Singhal L, Kaur P, Gautam V. Stenotrophomonas maltophilia: From trivial to grievous. Indian J Med Microbiol 2017;35:469-79

How to cite this URL:
Singhal L, Kaur P, Gautam V. Stenotrophomonas maltophilia: From trivial to grievous. Indian J Med Microbiol [serial online] 2017 [cited 2018 Dec 10];35:469-79. Available from: http://www.ijmm.org/text.asp?2017/35/4/469/224415



 ~ Introduction Top


Stenotrophomonas maltophilia is a glucose non-fermenting Gram-negative multidrug-resistant organism found extensively distributed in natural and unnatural environments. It has been suggested for bio-remediation of polluted grounds on the basis of its competence to degenerate xenobiotic compounds and metal resistance.[1],[2]

S. maltophilia, once regarded as an organism of low virulence, has evolved as a significant opportunistic pathogen causing severe human infections, especially amongst highly debilitated patients. Globally, S. maltophilia ranks third amongst the four most common pathogenic non-fermenting Gram-negative bacilli (NFGNBs), others being Pseudomonas aeruginosa, Acinetobacter baumannii and Burkholderia cepacia complex (Bcc).[3]

S. maltophilia causes a variety of infections including respiratory tract infections (pneumonia and acute exacerbations of chronic obstructive pulmonary disease), bloodstream infections (BSIs), bone and joint infections, urinary tract infections, endocarditis and meningitis.[4],[5],[6],[7] In cystic fibrosis (CF) patients, S. maltophilia can account perseverant colonisation and chronic infection.[7]

The inert bio-chemical profile, difficulty in interpretation of phenotypic characteristics and poor laboratory know-how exert challenge to a routine laboratory to identify S. maltophilia. Due to this reason, reports on S. maltophilia infection are less from India though its isolation incidence is booming with increased awareness in clinical settings. The correct identification of S. maltophilia has its significance as it needs to be differentiated from other NFGNBs such as A. baumannii, P. aeruginosa and Bcc due to its inherently contrasting antibiotic susceptibility pattern. Consequently, its correct identification is essential as no single drug is amply effective against all NFGNBs, which hinders initiation of appropriate empirical treatment resulting in increased morbidity and mortality.


 ~ Historical Background and Taxonomy Top


S. maltophilia was first isolated in 1943 by J. L. Edward and named as 'Bacterium bookeri.' In 1958, Hugh and Ryschenkow isolated a strain from an oral carcinoma patient and named it as Pseudomonas maltophilia; they also reclassified 'B. bookeri' as Pseudomonas maltophilia.[8] In 1981, on the evidence of similar G + C content, comparative enzymology, similar ubiquinones and cellular fatty acid composition, P. maltophilia was re-classified as Xanthomonas maltophilia.[9] Finally, in 1993, after a very long period of debate, Palleroni and Bradbury proposed a genus Stenotrophomonas with only one species S. maltophilia.[10]

At present, the genus Stenotrophomonas is heterogeneous both genetically and phenotypically and encompasses 12 recognised species that include Stenotrophomonas acidaminiphila, Stenotrophomonas chelatiphaga, Shinella daejeonensis, Sphingomonas dokdonensis, Stenotrophomonas ginsengisoli, Stenotrophomonas humi, Stenotrophomonas koreensis, S. maltophilia, Stenotrophomonas nitroreducens, Stenotrophomonas pavanii, Stenotrophomonas rhizophila and Stenotrophomonas terrae. Spirostachys africana, which had been recognised as a new species in 1997, was afterwards found to be similar to S. maltophilia.[11],[12] The clinically significant species of this genus is S. maltophilia which is extensively found in the environment as well as in clinical setting.[6] The term S. maltophilia is derived from Greek and Latin words: Stenos, narrow; trophos, one who feeds; monas, a unit, monad; i.e., a unit feeding on few substrates; and malt, malt; philos, friend; i.e., a friend of malt. S. maltophilia can ferment maltose but not glucose.[3]


 ~ Epidemiology Top


S. maltophilia is ubiquitous in nature. It exists in various types of environments and extreme geographical regions such as Antarctica.[13] Due to its ubiquitous nature, many fomites and medical devices in the clinical settings may serve as promising reservoirs of infection. It resides in various ecological niches both inside and outside the hospital settings as catheters, contaminated chlorhexidine-cetrimide disinfectant, ventilator inspiratory/expiratory circuits, endoscopes, faucets, showerheads, hand washing soaps, haemodialysis water and dialysate of renal units, hospital suction tubing, nebulisers, tap water and water fountain drains. It also has an ability to form biofilm on any kind of humid surface. The biofilms have been identified in contact lens stock solution, home use nebulisers of CF patients, micro-filtered water dispensers, plant Rhizosphere, river water and water treatment process.[7]

The well-recognised risk factors for S. maltophilia infections are lengthened hospitalisation requiring invasive procedures, admission in an Intensive Care Unit (ICU), indwelling catheters, mechanical ventilation, recent exposure to antibiotics, corticosteroid or immunosuppressant therapy, CF, severe mucositis, underlying malignancy, human immunodeficiency virus infection and organ transplantation.[7],[14]


 ~ Virulence Factors Top


Despite its rising incidence, the virulence factors of S. maltophilia have been poorly characterised.[6] Some of the virulence factors are extracellular protease, lipases, exopolysaccharides and lipopolysaccharides,[15] siderophores [16] and a phage-encoded zonula occludens-like toxin.[17]

Another crucial virulence factor produced by S. maltophilia is its ability to form biofilms on both biotic and abiotic surfaces.[18],[19] A higher level of biofilm formation was demonstrated in multidrug resistance (MDR) isolates in a study that included 70 S. maltophilia clinical isolates (40 MDR and 30 non-MDR isolates). Biofilm formation was found in correlation (P < 0.01) with resistance to aztreonam, cefepime, ceftazidime, piperacillin-tazobactam, ticarcillin-clavulanic acid and gentamicin but not in correlation with resistance to trimethoprim-sulphamethaxazole (TMP-SMX), ciprofloxacin, levofloxacin and meropenem.[20]

Finally, a cell–cell signalling factor has been determined, which controls the expression of virulence genes and antimicrobial resistance through a two-component regulatory system.[21]


 ~ Global Problem Statement Top


With a worldwide occurrence, the incidence and fatality rate due to S. maltophilia have been reported from various countries. A high mortality rate ranging from 23.0% to 77.0%[22],[23],[24],[25],[26] and 21.0% to 62.0%[27],[28],[29],[30] was found associated with pneumonia and bacteraemia, respectively, caused by S. maltophilia. A study during 1993–2004, based on data recovered from multiple hospitals in US, reported S. maltophilia accounted for 4.3% of total 74,394 GNB isolates causing infections in patients admitted to the ICU.[31] In another US study, an increased incidence rate of S. maltophilia from 6.7% to 12.0% was observed among CF patients.[32] A worldwide study as a part of SENTRY Antimicrobial Surveillance Program during 1997–2008 reported 3.1% incidence rate of S. maltophilia among the hospitalised patients suffering from pneumonia.[33] With respect to age group, S. maltophilia isolation rate among respiratory infections was found to be 3.0% higher in patients of age group 16–25 years than in patients with age >25 years.[34] In paediatric patients, S. maltophilia ranked amongst the top 15 pathogens in Europe, Latin America and North America.[35] A German study carried out in ICUs reported S. maltophilia amongst the top 13 most common pathogens causing nosocomial infections.[36]


 ~ Stenotrophomonas Maltophilia-Associated Infections Top


Recently, S. maltophilia has arisen as a crucial nosocomial pathogen responsible for high mortality rate. The most common infections caused by S. maltophilia include pneumonia, BSI and wound and urinary tract infections.[37],[38],[39],[40] Other less common infections associated with S. maltophilia include meningitis, endocarditis, eye infections, epididymitis, arthritis, sinusitis, mastoiditis, cholangitis, peritonitis and osteochondritis.[22],[24],[37],[41] Very less reports are documented on community-acquired S. maltophilia infections. These occur mostly in patients with pre-existing comorbidities (chronic obstructive pulmonary disease, trauma, malignancy or immunosuppression) and include bacteraemia, respiratory tract infections, ocular infections, otitis, conjunctivitis, wound/soft tissue infections, urinary tract infections and cellulitis.[5]

Respiratory tract infections

In majority of the cases, S. maltophilia isolated from respiratory tract represents colonisation and indicates an immunocompromised state of the patient. S. maltophilia has also evolved as one of the most common bacteria isolated from the airway of CF patients.[42],[43]

S. maltophilia is usually collaterally isolated along with other pathogens of respiratory tracts, which creates problem in proper interpretation of the colonisation.[44] One of the studies conducted in a tertiary care hospital reported 30 cases of nosocomial pneumonia, 27 cases of ventilator-associated pneumonia and 3 cases of pneumonia in non-ventilated patients by S. maltophilia.[40] The symptoms developed by S. maltophilia pneumonia patients are non-specific, which include fever, cough and dyspnoea. Pulmonary infiltrates on examination by radiology appear lobular-shaped and unusual pleural effusions.[24] In one of the retrospective studies carried out to analyse the effect of inhalation of tobramycin for the treatment of P. aeruginosa infections in CF patients, they showed that this treatment was lesser effective in patients who were also colonised with S. maltophilia.[45] Various studies have reported the high mortality rates with S. maltophilia pneumonia ranging from 23% to 77% with maximum rates observed amongst cancer and bacteraemia patients.[22],[23],[24],[25],[26],[46]

S. maltophilia isolates have been implicated in increasing inflammatory response that includes increase in expression of interleukin-8 and tumour necrosis factor (TNF)-α in airway epithelial cells and macrophages, respectively, contributing to airway inflammation. In a study, S. maltophilia isolates from CF patients showed higher level of inflammatory response during murine lung infection model.[47] Moreover, in CF patients with chronic S. aureus cultures, co-infection with S. maltophilia is independent risk factor for worse lung function.[48] Air-borne transmission of S. maltophilia is known to occur by aerosols generated from cough of CF patients.[49]

Bloodstream infections

S. maltophilia from blood culture should be properly assessed to demarcate between contamination, colonisation and true BSI. The most common source of bacteraemia by S. maltophilia is central venous line.[50] Catheter-related BSIs are usually polymicrobial and prognosis can be improved by removal of infected catheter.[29]S. maltophilia has been found in relation with advanced bacteraemia in patients suffering from haematological malignancies.[51],[52]

Various studies reported the high mortality rate ranging from 22% to 62% with BSI by S. maltophilia.[27],[28],[29],[30],[52] Increased disease severity and high mortality were associated with hospital-acquired S. maltophilia bacteraemia as compared with community-onset bacteraemia by S. maltophilia.[53]


 ~ Indian Scenario Top


Various case studies on S. maltophilia infections in India such as endophthalmitis,[54] tropical pyomyositis,[55] neonatal sepsis,[56] unilateral conjunctival ulcer,[57] non-healing leg ulcer [58] and meningitis [59] have been reported. In one study from a tertiary care hospital in Karnataka, the isolation rate of S. maltophilia was found to be 2.5% (5 isolates) out of 193 NFGNBs collected from various clinical samples.[60] Another study also from Karnataka region reported 1.8% (15 isolates) isolation rate of S. maltophilia out of 830 NFGNBs from respiratory samples.[61] A tertiary care super-speciality hospital from North India has reported a rise in number of cases due to S. maltophilia over the last decade. It is currently the fourth most common NFGNB in septicaemic patients after A. baumannii, P. aeruginosa and Bcc obtained from blood cultures.[62],[63],[64]


 ~ Laboratory Diagnosis Top


The ancient saying that 'the eyes do not see what the mind does not know' holds very true for S. maltophilia. Only with awareness and suspicion can this organism be identified instead of being reported as just NFGNB or more incorrectly as some Pseudomonas spp. by a routine microbiology laboratory where automation facilities for identification do not exist.

S. maltophilia is a Gram-negative, motile, non-lactose-fermenting bacillus. It is an obligate aerobe. The optimal temperature for its growth is 35°C and no growth occurs below 5°C and above 40°C.[4] It produces lavender-green colonies with ammonical odour on blood agar plates, non-pigmented tiny colonies on MacConkey agar plates and tiny cream colonies on Muller-Hinton agar plates after 24 h of incubation at 37°C [Figure 1]a,[Figure 1]b,[Figure 1]c.
Figure 1: (a) Colonies of Stenotrophomonas maltophilia on blood agar plate. (b) Colonies of Stenotrophomonas maltophilia on MacConkey agar plate. (c) Colonies of Stenotrophomonas maltophilia on Mueller-Hinton agar plate

Click here to view


Initially, for the isolation of S. maltophilia, X. maltophilia selective medium (XMSM) was used. After 2 days of incubation, S. maltophilia produces orange colonies with yellow halo. Because of complexity in its preparation, time consumption and high cost, XMSMs are unattractive for S. maltophilia isolation.[65]

S. maltophilia is usually co-isolated with other microorganisms. Thus, for better isolation of clinical and environmental isolates, vancomycin, imipenem and amphotericin B (VIA) medium was developed.[66] It contains vancomycin to inhibit imipenem-resistant Enterococcus faecium, amphotericin B as an antifungal agent, mannitol agar base to distinguish non-fermenting S. maltophilia from fermenting bacteria and bromothymol blue as an indicator dye. S. maltophilia produces greenish colonies with a blue halo. This medium is more selective and less inhibitory to S. maltophilia than XMSM. In few reports, the use of VIA medium has been demonstrated for the isolation of S. maltophilia from bottled water, salads, sputa, hospital and domestic settings; however, these studies failed to provide specificity in isolation of S. maltophilia from environmental samples.[4],[67],[68],[69],[70]

S. maltophilia can be differentiated from other bacterial species present in mixed culture samples on the basis of their selective fermentation of sugars. For example, S. maltophilia can produce acid from maltose but not from glucose; on the other hand, P. aeruginosa utilises glucose but not maltose.

Unlike P. aeruginosa, S. maltophilia lacks easily discernable phenotypic characteristics. It closely relates to Bcc in its pattern of infections. Identification and differentiation of these two lysine decarboxylase-positive NFGNBs are important. To overcome problem of their identification in routine clinical laboratories, we standardised simple five conventional biochemical tests including oxidase, triple sugar iron, lead acetate paper strip for hydrogen sulphide production and aerobic low peptone medium slants containing ammonium salts with glucose, lysine and ornithine decarboxylase and arginine dihydrolase.[71]S. maltophilia can be differentiated from Bcc, as majority of isolates are oxidase negative and positive for H2S production on lead acetate strips [Table 1] though it has been reported by Carmody et al. that some of the S. maltophilia isolates may be oxidase positive.[72]
Table 1: Simplified identification table for lysine-positive non-fermenting Gram-negative bacilli

Click here to view


Molecular approach based on 23S rRNA gene amplification completes identification schemes. Whitby et al. designed primers SM1 and SM4 based on species level signature sequences in 23S rRNA.[73] This polymerase chain reaction (PCR) is highly selective for S. maltophilia and has proved negative for all other organisms. This PCR showed sensitivity and specificity of 100% for clinical and environmental isolates.[73],[74],[75]

Previous studies reported considerable heterogeneity among S. maltophilia isolates using different typing approaches that included enterobacterial repetitive intergenic consensus sequence-PCR (ERIC-PCR), ribotyping, random-amplified polymorphic DNA and pulsed-field gel electrophoresis.[76],[77] These results revealed large amount of genetic diversity among the clinical isolates of S. maltophilia and also indicated that cross-transmission among patients may not be occurring. Multilocus sequencing typing (MLST) has proven to be a reliable mean for inter- and intra-species delineation of Stenotrophomonas spp. and a highly portable standard for strain characterisation. Such analysis is appropriate to identify the nosocomial or community origin of infections, serving to detect outbreaks and allowing a study of the population structure of the pathogen that is important for molecular epidemiology. Kaiser et al. framed up MLST for S. maltophilia on the basis of partial sequences (444–558 bp) of seven housekeeping genes. Nearby 40–55 alleles have been deposited for each of seven targeted genes and 56 sequence types (ST) in online database though this number is quite less when compared to the other databases available for other bacteria (http://pubmlst.org/smaltophilia/).[78] In an MLST-based study by Cho et al. of 33 clinical isolates of S. maltophilia collected over a period of 1 year at a university hospital in Korea, 26 different STs were found where 23 were new STs and 3 were previously discovered STs.[79]


 ~ Matrix-Assisted Laser Desorption Ionisation Time-Of-Flight Mass Spectrometry for the Identification of Stenotrophomonas Maltophilia Top


Until recently, identification of microbes in clinical diagnostic laboratories has mainly been dependent on conventional biochemical (phenotypic) and gene sequencing-based techniques. The introduction of matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS) devices has transformed the routine identification of microorganisms in clinical diagnostic laboratories. Vasileuskaya-Schulz et al. described the use of MALDI-TOF MS BioTyper system in concordance with MLST for the analysis of 21 strains of different species and showed good consistency between the two techniques.[80] Seng et al. misidentified seven S. maltophilia isolates as Pseudomonas hibiscicola, an invalid name for S. maltophilia entered into the BioTyper database.[81] We tested 50 clinical isolates of S. maltophilia that were confirmed by species-specific PCR. The concordance rate of MALDI-TOF MS was 100% for the genus and 50% (25/50) for the correct species identification. An increase in species identification to 70% (35/50) was noted when altered cut-off ≥1.9 was considered. No isolate was however misidentified by MALDI-TOF.[82] MALDI-TOF MS is emerging as an efficient, accurate and cost-effective alternative tool in microbial identification.


 ~ Treatment of Stenotrophomonas Maltophilia Infections Top


S. maltophilia is intrinsically resistant to aminoglycosides and commonly used carbapenems. The contrasting susceptibility, high intrinsic resistance and the notable capacity to develop resistance to essentially all commonly used antibiotics including the anti-pseudomonal drugs and dilemma over in vitro susceptibility testing poses a great challenge to clinicians in selecting suitable antimicrobial regimen for the treatment of S. maltophilia infections. In literature, there are limited data available on clinical trials of various treatment regimes. The present-day recommendations for the treatment of S. maltophilia infections are based on previous evidence, case reports and case series and in vitro susceptibility studies. Drug susceptibility among S. maltophilia isolates in routine microbiology laboratory should be determined by Kirby-Bauer disk diffusion test against the following recommended antimicrobial agents (TMP-SMX, 1.25/23.75 μg; minocycline, 30 μg; levofloxacin, 5 μg) according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. As per the CLSI guidelines only, minimum inhibitory concentration (MIC) is determined against ticarcillin-clavulanate (sensitive, S ≤16/2: resistant, R ≥128/2), ceftazidime (S ≤8: R ≥32), minocycline (S ≤4: R ≥16), levofloxacin (S ≤2: R ≥8), TMP-SMX (S ≤2/38: R ≥4/76) and chloramphenicol (S ≤8: R ≥32) (CLSI, 2016).[83]


 ~ Antimicrobial Resistance in Stenotrophomonas Maltophilia Top


Various antimicrobial resistance mechanisms reported in S. maltophilia include efflux pumps, low outer membrane permeability, antibiotic-inactivating enzymes and β-lactamases [Table 2]. Horizontal transfer of resistance genes present on plasmids, transposing and integrons may also lead to antibiotic resistance in S. maltophilia.[95]
Table 2: Various antibiotic resistance mechanisms in Stenotrophomonas maltophilia

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In S. maltophilia, resistance to antimicrobials is also contributed by the activity of multidrug efflux pumps, which are basically made up of membrane fusion protein, an energy-dependent transporter and an outer membrane protein. Stenotrophomonas multiple efflux (sme) smeDEF operon was cloned, sequenced and expressed in  Escherichia More Details coli, which indicated that operon smeDEF encodes a multidrug efflux pump, which is responsible for resistance to β-lactams, tetracyclines, erythromycin, quinolones, chloramphenicol and aminoglycosides.[88]

Another operon smeABC was also identified in S. maltophilia, which was encoded by smeA, smeB and smeC genes, respectively. Expression of smeABC efflux pump has been reported as important for the fluoroquinolone (ciprofloxacin and levofloxacin) and meropenem resistance.[89]

Integrons are non-self mobilisable elements, which contain an integrase enzyme for the insertion of antibiotic resistance genes at specific sites. As integrons lack enzymes for transposition, their movement is usually facilitated by plasmids and transposons.[96] Their role has been discussed below.

Trimethoprim-suphamethoxazole

TMP-SMX is a first line drug for the treatment of S. maltophilia infections owing to its good susceptibility and clinical outcomes in the treated patients. TMP-SMX is a mixture of two antimicrobial agents, which function synergistically and inhibit enzymes involved in synthesis of tetrahydrofolate.[97]

On the background of in vitro data, TMP-SMX is bacteriostatic against S. maltophilia.[98] A high dose of TMP-SMX (15 mg/kg) has been suggested to treat S. maltophilia infections, which is similar in amount used to treat Pneumocystis jirovecii pneumonia.[99]In vitro studies proved that TMP-SMX suppresses the liberation of TNF-α from peripheral blood monocytes that have been induced by S. maltophilia, but further clinical investigation on this observation is required.[100] However, this drug has side effects such as intolerance and hypersensitivity, which may limit its use.

Reports are now emerging relating to the resistance to TMP-SMX throughout the world that ranges from 1.1% in Europe, 2.4% in North America, 4.5% in Latin America and 9.2% in Asian-Pacific regions.[101] It has been reported that increased MIC values of TMP-SMX for clinical isolates of S. maltophilia is due to class 1 integrons.[90] Transposition events transfer the class 1 integrons present in transposons to plasmids or chromosomal DNA. The resistance to TMP-SMX has been attributed to two allelic forms of sul genes (sul1 and sul2). These genes have been found in association with class 1 integrons and insertion sequence common region elements. However, there are also reports on the absence of sul1 gene as a part of class 1integron.[64],[102] On the other hand, sul2 gene has been found located on plasmids and as part of chromosomal DNA.[91]

Fluoroquinolones

Clinafloxacin, gatifloxacin, moxifloxacin, levofloxacin and sitafloxacin represent better in vitro activity than previous quinolones.[103] In an in vitro study, the activities of ciprofloxacin and levofloxacin were compared and results revealed more susceptibility of S. maltophilia isolates to levofloxacin (85.5%) than ciprofloxacin (58.9%).[104] In another study, susceptibility rate was reported to be higher than 95% for newer fluoroquinolones.[105]

The genome analysis of S. maltophilia strain K279a revealed the presence of Smqnr genes that encode for proteins, which are homologous to quinolone protection proteins (Qnr) found in Enterobacteriaceae.[106] The genes encode for pentapeptide repeat proteins that provide protection to DNA gyrase and topoisomerases from quinolones.[107] The qnr genes are thought to have originated from chromosome of aquatic or environmental bacteria, which are transferred to plasmids by horizontal transfer of integrons and other mobile genetic elements carrying qnr genes. It has been reported that plasmid-mediated quinolone resistance may be responsible for stabilising and selecting mutations in DNA gyrase and topoisomerase, which provides high-level resistance to quinolones.[108]

It has been reported that in S. maltophilia, Smqnr genes on chromosomes are responsible for much defined activity because when plasmid carrying qnr genes were provided in wild-type and Smqnr mutants, the resistance to quinolones increased in both the cases.[109]

β-lactams

S. maltophilia exhibits high intrinsic resistance rates towards penicillins, cephalosporins and carbapenems. However, the combination of clavulanic acid, a β-lactamase inhibitor, with these antimicrobials may improve their activity against S. maltophilia.[110] Ticarcillin-clavulanic acid has been prescribed as the second drug of choice owing to its in vitro activity for treating S. maltophilia infections in patients on which TMP-SMX failed to work.[4] The addition of ticarcillin to combination of aztreonam with clavulanic acid (2/1 or 1/1) further enhanced the in vitro activity of combination against S. maltophilia.[99],[110],[111] Although favourable treatment in selected cases has been reported, pharmacokinetics of aztreonam and clavulanate are different, which inhibits the clinical use of combination.[112],[113]

In S. maltophilia resistance to β-lactam antibiotics is due to two inducible β-lactamases, L1 and L2, which are chromosomally encoded. The β-lactamase L1, a homotetramer of 118 kDa, belongs to an Ambler class B Zn + dependent metalloenzyme. It hydrolyses all the classes of β-lactams except monobactams. The β-lactamase L2 belongs to an Ambler class A serine active site β-lactamases and is inhibited by clavulanic acid.[84] Cephalosporins of higher class such as ceftazidime, cefoperazone and cefepime exhibit some in vitro activity and ceftazidime has been successfully used as monotherapy in few cases.[5] The inconsistent occurrence of inducible β-lactamases inhibits their activity and is responsible for high resistance rate to this group of antibiotics. Moreover, few studies have reported that the exposure to ceftazidime and cefepime further increases the chances of S. maltophilia infections.[25],[114] The combinations of cephalosporins with β-lactamase inhibitors, such as cefepime-clavulanic acid, ceftazidime-clavulanic and ceftazidime-sulbactam, did not show any in vitro activity.[112],[115]

Tetracycline derivatives

Minocycline, doxycycline and tigecycline have revealed good in vitro activity, but the absence of clinical studies on efficiency of these drugs limits their use in the treatment of S. maltophilia infections.[116] Tigecycline, the broad-spectrum antibiotic, was found effective in TMP-SMX resistant S. maltophilia, and moreover, it can surmount the resistance mechanism of efflux pumps and ribosomal target modifications.[117],[118]

Aminoglycosides

The presence of high intrinsic rate of resistance to aminoglycosides limits their use in the treatment of S. maltophilia infections. In S. maltophilia, resistance to aminoglycosides is attributed to temperature-dependent resistance due to outer protein changes, aminoglycoside-modifying enzymes and efflux pumps. Genes located on chromosomes encode for aminoglycoside acetyltransferase aac (6L')-Iz and aminoglycoside phosphotransferase aph (3L')-IIc and are responsible for lowering down susceptibility to amikacin, kanamycin, neomycin, netilmicin, paromomycin and tobramycin.[119],[120],[121]S. maltophilia at different temperatures undergoes changes in the size of the O-polysaccharide and phosphate content of lipopolysaccharides due to which it shows variable amount of resistance to aminoglycosides, more at 30°C than at 37°C.[122] These experimental results explain the susceptibility of S. maltophilia clinical isolates to aminoglycosides at 37°C and resistance at 30°C.

Polymyxins

In the past few years, there has been an increase in the use of polymyxins in the treatment of infections caused by NFGNB.[123] In case of S. maltophilia, high susceptibility rate against colistin and polymyxin B has been reported; however, there is uncertainty about the in vitro clinical data, which creates problem in susceptibility testing of these antibiotics. The resistance to polymyxin B has been found in association with lipopolysaccharide present in outer membrane.[124]

Antimicrobial combinations

The high level of intrinsic resistance, increasing incidence of acquired resistance and the bacteriostatic activity of TMP-SMX are the stimulants for combination therapy for treating S. maltophilia infections. In case, where TMP-SMX fails to treat S. maltophilia infections, combination of two or more antimicrobials might prove boon, but there is lack of clinical data about combination therapy. The design of combination therapy depends upon the enhanced activity of combination of drugs when compared to single drugs even in case where one or both of antimicrobials are resistant to bacteria.[98] The recommendations for such combinations of antimicrobials for treatment depends upon clinical trials; however, instead of these limitations, the use of combination therapy has been recommended in patients suffering from bacteraemia, endocarditis and osteomyelitis with high rate of resistance to TMP-SMX.[124],[125],[126],[127],[128] And, examples in which combination therapy proved successful include S. maltophilia early prosthetic-aortic-valve endocarditis and osteomyelitis.[126],[128] It has been suggested that inclusion of TMP-SMX in a combination therapy is a better choice and combinations of TMP-SMX with ticarcillin-clavulanic acid, moxifloxacin, ceftazidime and tobramycin have shown synergy.[98],[116],[129],[130] Chloramphenicol in combination with sulphonamide and gentamicin has proved successful in treating meningitis caused by S. maltophilia.[41]

Indian Scenario

In India, 13.4% resistance to TMP-SMX was observed from Karnataka.[61] The analysis of antimicrobial susceptibility of 125 clinical isolates of S. maltophilia isolated over 5 years (2007–2012) from North India showed that minocycline and levofloxacin exhibited the highest susceptibility rate followed by TMP-SMX (83%).[63] A more recent study from the same region, conducted on 106 S. maltophilia isolates, demonstrated similar susceptibility rate for minocycline and levofloxacin; however, a decreased susceptibility rate was found for mainstay antibiotic TMP-SMX (77.4%). Twenty-four isolates (out of 106) were found resistant to TMP-SMX and these resistant isolates sustained relatively higher percentage of TMP-SMX resistance gene sul2 than sul1 gene. Moreover, sul1 gene was not found in association with class 1 integrase gene in majority of TMP-SMX-resistant isolates.[64] This decrease in susceptibility may be due to increased antibiotic usage in clinical settings and resulting into TMP-SMX-resistant S. maltophilia strains, which further warrants its judicious use in future.


 ~ Conclusion Top


S. maltophilia has risen from being a trivial environmental organism used in bioremediation to being a grievous opportunistic pathogen during the last two decades. It is not only resistant to multiple antibiotics but can also degrade and use antibiotics as food, which is of great concern especially in nosocomial infections. It further reinforces the need to look into this aspect of the bacterium. The present scenario requires that clinical microbiology laboratories should correctly identify S. maltophilia. To understand better about this bacterium, there is a great need to gather epidemiological data of clinical S. maltophilia isolates in India. Moreover, hospitals should also perform surveillance on S. maltophilia-associated infections.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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2004 - Indian Journal of Medical Microbiology
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