Stenotrophomonas Maltophilia

Mina Said; Ekta Tirthani; Emil Lesho

Stenotrophomonas Maltophilia

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Continuing Education Activity

Stenotrophomonas maltophilia is one of the less known drug-resistant bacteria that can cause challenging infections. This activity reviews the epidemiology of this organism as well as the risk factors of developing these infections. It also illustrates the pathophysiology and virulence factors of this pathogen and its relation with the clinical picture. It describes the modern evaluation and up-to-date treatment for the infections caused by this organism, as well as their estimated prognosis. Further, it highlights the role of the interprofessional team in case management.

Objectives:

Review the risk factors for developing Stenotrophomonas maltophilia infections.
Describe the epidemiology and statistical data of Stenotrophomonas maltophilia infections.
Outline the evaluation of Stenotrophomonas maltophilia infection cases and the challenges encountered.
Summarize the recommended treatment by interprofessional team and prevention modalities for Stenotrophomonas maltophilia infections.

Introduction

Stenotrophomonas maltophilia is a gram-negative bacillus, initially called Bacterium bookeri, when it was first identified in 1943 from a specimen of human pleural fluid.[1] It was later classified as Pseudomonas maltophilia in 1961, then reassigned to the gammaproteobacteria class as Xanthomonas maltophilia in 1983, and eventually classified as a Stenotrophomonas in 199.[2][3][4] The name has Greek roots meaning “The narrow feeder - that loves malt.” The whole-genome sequence of representative isolate K279a genome sequence was published in 2008.[5][6]

S. maltophilia can be considered a “newly emerging pathogen of concern” that is being isolated more frequently.[7][8][9] It is also recognized as one of the underestimated important multi-drug resistant organisms in hospitals by the World Health Organization (WHO).[10][11] It was ranked as the ninth most important one per British microbiologists and one of the challenging pathogens in the infectious disease community and studies.[12][2] It is widely known as an opportunistic organism associated with high morbidity and mortality rates among immunocompromised patients.

Etiology

Stenotrophomonas maltophilia, a non-fermenting gram-negative rod, is the third most common after Pseudomonas aeruginosa and Acinetobacter and similar to Achromobacter xylosoxidans and Burkholderia cepacia.[13][4][9] It is the only species among the seventeen of the Stenotrophomonas genus that infects man.[14]

Risk factors for this infection include chronic respiratory diseases, especially cystic fibrosis, hematologic malignancy, chemotherapy-induced neutropenia, organ transplant patients, human immunodeficiency virus (HIV) infection, hemodialysis patients, and neonates.[9][11][15][16] Also, hospital settings, prolonged intensive care unit stays, mechanical ventilation, tracheostomies, central venous catheters, severe traumatic injuries, significant burns, mucositis or mucosal barrier damaging factors, and the use of broad-spectrum antibiotic courses were shown to increase the risk of infection.[9][17]

These empiric broad-spectrum antimicrobials usually do not cover this particular pathogen, especially carbapenems, although no specific predominance was identified with them over other antimicrobials.[18] The risk from antibiotic exposure varies directly with both the duration and number of antimicrobials used.[8]

Epidemiology

Stenotrophomonas maltophilia prevalent.[2] It is frequently isolated in the environment, particularly from water bodies like rivers, wells, and lakes, also bottled water, sewage, swine/chicken feces, soil, plants, salads, frozen fish, and raw milk.[2][8][17][19] It has also been isolated from animals, especially aquatic species, with some of those animal isolates found to be within the same genogroups as the human strains, suggesting the possibility of strain or gene exchange with the human infection-causing isolates.[9][20] Specific isolates are being utilized for the biosynthesis of organic compounds or their degradation, plant growth promotion against agricultural fungal pathogens, and bioremediation of soil or water.[21][6][22][23][24]

More importantly, it can be found in multiple healthcare settings, such as hospital tap water faucets, sinks, shower outlets, air-cooling systems, ice-making and soda fountain machines, disinfectant solutions, intravenous fluids, catheters, ethylenediaminetetraacetic acid (EDTA) containing blood collection tubes, blood gas analyzers, dialysis machines, intra-aortic balloon pumps, nebulizers, oxygen humidifiers, breathing circuits, scopes, dental equipment, lens care systems, and the hands of healthcare workers.[18][2][17][21][22][25]

Most Stenotrophomonas maltophilia infections are, in fact, nosocomial, and many outbreaks have been reported within the previous years in hospitals and intensive care units.[26][27][26] Studies have proven genomic diversity among nosocomial infection isolates, which strongly suggests multiple independent environmental sources of transmission, though the patient-to-patient transmission has also been reported.[28][29]

Stenotrophomonas maltophilia is estimated to be the most common carbapenem-resistant gram-negative bacterial cause of bloodstream infections in US hospitals, causing about 1% of nosocomial bacteremia cases.[30][31] The incidence of infection cases is estimated to be from 5.7 to 37.7 cases per 10 thousand hospital discharges, which has been progressively higher than previously reported over the last decades since the 1970s.[32][33][34][35][36] This rising infection rate is believed to be primarily due to the increase in the number of immunocompromised patients and the wide use of broad-spectrum antibiotics.

Pathophysiology

Although previously thought to have limited virulence, Stenotrophomonas maltophilia has shown to possess different powerful virulence factors that are believed to be present in all environmental isolates without any specific evolutionary branching, similar to Pseudomonas aeruginosa.[18][22][37]

The first noteworthy virulence factor is its ability to form a biofilm, which was demonstrated around 1996.[38] These biofilms consist of a polymeric matrix of polysaccharides, proteins, lipids, nucleic acids, and minimally active bacteria, which can become mature very rapidly, colonizing new surfaces within less than 24 hours.[11][38][39] The process starts with adherence to the surface, followed by irreversible attachment, then final maturation, and is mediated through its motile flagella, fimbriae/pili, adhesins, and the outer membrane lipopolysaccharide positively charged surface, quorum sensing by diffuse single molecules, and extracellular polymeric substances.[8][38] This biofilm allows Stenotrophomonas maltophilia to firmly adhere to both animate surfaces such as the respiratory epithelial tissue and inanimate surfaces such as ventilation tubes and circuits.[2][21][38] This enables it to escape the natural human phagocytosis and complement-mediated immune killing defenses, evade the activity of most antibiotics up to a thousand times more, and further spread throughout the surfaces.[8][3][26][38][39]

Often, the biofilms are polymicrobial and contain other organisms that benefit from the same advantages. The spgM gene was recognized to promote high biofilm production by isolates, along with several other genes.[38][40] Iron acquisition pathways through siderophore, heme-mediated, and Feo system uptake mechanisms play an essential role in regulating multiple virulence factors, including biofilm formation esp. on iron restriction.[41] Stenotrophomonas maltophilia in biofilms was also shown to tolerate a wide range of pH, nutrient scarcity, and exposure to free radicals.[21]

Second, Stenotrophomonas maltophilia is typically intrinsically resistant to multiple and broad-spectrum antibiotic agents.[42][43] It shows resistance to most beta-lactams through two inducible enzymes; the class B zinc-dependent penicillinase (L1) and the class A serine cephalosporinase (L2), rendering it resistant to ceftriaxone, piperacillin-tazobactam, and carbapenems.[4][18] Clavulanic acid has shown activity against the L2 enzyme but not L1.[9] It also confers resistance to aminoglycosides by its aminoglycoside-modifying acetyl-transferase enzyme.[4] Several other antimicrobial resistances are achieved through the efflux pumps (for example, the SmeDEF and SmeABC) that act on quinolones, aminoglycosides, macrolides, and tetracyclines.[4][18][42][44]

Trimethoprim-sulfamethoxazole resistance is mediated through the target site modification genes sul1 and dfrA through class 1 integrons, as well as sul2 gene through insertion sequence common region elements.[8][9] Another mechanism involves the gyrase and topoisomerase targets of quinolones.[4][45] Lastly, its outer-membrane lipopolysaccharide shows temperature-dependent structural variation, which confers more resistance to aminoglycosides and polymyxins in particular.[2] Interestingly, Stenotrophomonas maltophilia can both acquire and transfer antibiotic and heavy metal resistance mechanisms with other pathogens if they co-exist, such as the transfer of the beta-lactamases to previously susceptible Pseudomonas isolates.[2][17][46][47] This process is referred to as “indirect pathogenicity” and is mediated through integrons, transposons, plasmids, genomic islands, and others.[8][48]

Third, Stenotrophomonas maltophilia utilizes different virulence exoenzymes, such as elastase, gelatinase, hyaluronidase, proteases, lipases, DNase, RNase, and mucinase, for tissue invasion and escaping the host immunity.[18] Lipases, in particular, are also believed to damage the lipid-rich lung tissues leading to focal lung necrosis and initiating strong inflammatory responses.[2]

Fourth, in chronic infections, Stenotrophomonas maltophilia is capable of forming small-colony variants, which are slowly growing and sometimes challenging to detect.[49]

History and Physical

Stenotrophomonas maltophilia infections usually occur as a nosocomial infection, though community-acquired infections have also been reported.[50] One of the challenges with Stenotrophomonas maltophilia is that its clinical manifestations are non-specific and almost cannot be distinguished from other infections. As mentioned above, it is, therefore, essential to identify the most vulnerable population to such infection, most importantly the immunocompromised population.[51] However, one characteristic feature is the late-onset of the related illnesses, which can be about 5 days for hospital-acquired pneumonia and 19 days for bacteremia.[52][50]

It is crucial to differentiate between non-invasive colonization from non-sterile samples and an actual infection that warrants treatment, mainly by the clinical judgment on the symptoms, signs, laboratory, and radiographic evidence of infection.

The most common isolates were reported from respiratory infections, namely pneumonia cases, whether sputum or bronchioalveolar lavage cultures, at 55% of the total infections.[53][38] Many times, as mentioned above, it occurs in patients with cystic fibrosis with almost 15% colonization prevalence, tracheostomy patients, or those on mechanical ventilation.[9] It was also implicated in cases of chronic obstructive pulmonary disease exacerbations.[54] In certain situations, especially with underlying hematologic malignancies, a fatal fulminant hemorrhagic pneumonia syndrome can occur.[55][9] Sinopulmonary infections, particularly in neutropenic patients, can raise suspicion for this infection as well.[18]

The second most common form of Stenotrophomonas maltophilia infections is bacteremia, at 33% of the infections.[38] Sometimes the bacteremia is polymicrobial, especially along with Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterococcus faecalis.[9][56] More than 70% of the reported cases were deemed to be central venous catheter-related infections. Recurrence has also been encountered in cases of retained central venous catheters or delayed targeted antibiotics [57].

There have been less commonly reported cases of other sites of infection, such as skin and soft tissue infections, at 7.8% of the total infections, most notably wound infections, metastatic cellulitis, and ecthyma gangrenosum.[58] Others, in no particular order, include meningitis (mostly post-surgery), ocular infections, especially after surface compromise (keratitis, conjunctivitis, endophthalmitis, dacryocystitis, scleral buckle infections, preseptal cellulitis, orbital necrotizing fasciitis, etc.), gingivitis, periodontitis, epiglottitis, sinusitis, otitis externa, mastoiditis, endocarditis, pacemaker infections, intra-abdominal infections (peritonitis, cholangitis, abscesses, enteritis, etc.), urinary tract infections (especially with catheterization and structural abnormalities), epididymitis, septic arthritis, osteochondritis, and bursitis.[9][18][59][2][8][60][17][61]

Evaluation

Stenotrophomonas maltophilia easily grows on standard culture media, either as a single isolate or mixed with other culture growths like Pseudomonas aeruginosa.[53] Its culture colonies typically are yellow-green in color on nutrient agar, non-hemolytic with a faint lavender color and an ammonia odor on blood agar, and colorless on MacConkey plates since it is non-lactose fermenting.[18][17][21] It also resembles Pseudomonas in having opaque flat surfaces with uneven borders. Selective media were shown to be better in isolating Stenotrophomonas maltophilia from non-sterile samples and usually contain imipenem, vancomycin, amphotericin-B, and mannitol/bromothymol blue as an indicator.[2][62][3]

For in vitro laboratory identification, Stenotrophomonas maltophilia is a strict aerobe that is usually oxidase negative, though it was shown that up to 20% could show positive oxidase activity.[17][63] It is also catalase-positive, DNase-positive, lysine decarboxylase positive, indole negative, HS negative, and urease negative.[4][9] It is known to produce acid from maltose, hence the name maltophilia, but not always from glucose. Many commercial systems are available for identification but are not very accurate.[2] Therefore, it has been misdiagnosed as Burkholderia cepacia-complex, Achromobacter xylosoxidans, Pseudomonas aeruginosa, and Bordetella bronchiseptica an identification challenge.

Another diagnostic challenge involves antibiotic susceptibility testing due to difficulties in setting standard minimal inhibitory concentration (MIC) breakpoints for Stenotrophomonas maltophilia through different methods.[2] However, currently, in the U.S., the Clinical and Laboratory Standards Institute (CSLI) has set MICs for trimethoprim-sulfamethoxazole (2 mg/L), levofloxacin, and minocycline by the disc diffusion method, as well as for levofloxacin, ticarcillin-clavulanate, minocycline, ceftazidime, and chloramphenicol by the broth dilution method. Other agents in studies, even in the same classes of these antimicrobials, do not have established breakpoints yet.[64]

Nucleic-acid amplification testing (NAAT) and species-specific 23S rRNA-directed polymerase chain reaction (PCR) techniques are also well used for identification successfully with almost 100% sensitivity and specificity when available.[65][66] The matrix-assisted laser desorption ionization, time of flight (MALDI-TOF) mass spectrometry has shown good identification as well, in addition to its potential ability to recognize biofilm-producing strains.[67][29] The use of these rapid methods on samples from critically ill patients can facilitate more rapid use of appropriate antibiotics.[9]

Chest x-rays may reveal lobar or lobular infiltrates in pneumonia cases, either unilateral or bilateral, with uncommon pleural effusions or cavitary lesions on rare occasions.[68]

Treatment / Management

Treatment with specific antibiotics is required when evidence for a true Stenotrophomonas maltophilia infection is established or in critically sick patients with a Stenotrophomonas maltophilia growth until further data are available. Treatment recommendations mostly come from in vitro studies, retrospective studies, non-randomized clinical trials, and expert opinions.[64]

The first-line treatment is trimethoprim-sulfamethoxazole, which has been the recommended empiric single agent against Stenotrophomonas maltophilia for many years.[17][69] Given the in vitro data suggesting bacteriostatic activity against Stenotrophomonas maltophilia, trimethoprim-sulfamethoxazole is recommended at high doses at 15 mg/kg or more of the trimethoprim component, as used for severe Pneumocystis jirovecii pneumonia.[9][70] It has shown activity against more than 90% of the tested isolates in most studies to date, though as mentioned above, resistance has now been increasingly reported at up to 22-38% in some 21st-century studies.[71][72][69][73][74]

One recent study from Mexico showed an 80% resistance rate to trimethoprim/sulfamethoxazole in a combination of environmental and clinical isolates from Mexico.[75] Also, since trimethoprim-sulfamethoxazole has risks of hypersensitivity, hyperkalemia, deterioration of kidney functions, and bone marrow suppression, those with either a contraindication, intolerance, or adverse events to it must subsequently be treated with another alternative agent, unless there is a chance and benefit from an oral desensitization trial.[76]

Alternatives treatments are the bacteriocidal fluoroquinolones, with up to 80-90% susceptibility rates, because of their specific biofilm active properties and their high concentration in the lungs.[9][4][77][39][17][69][78] These include levofloxacin, moxifloxacin, and the newer agents clinafloxacin and rufloxacin (which both showed even better activity than the others), also gatifloxacin, travofloxacin, grepafloxacin, and sparfloxacin.[79][80][77] Some new studies observed fluoroquinolones susceptibilities down to 73% [81][82][69]. Overall, several studies demonstrated equal effectiveness to trimethoprim/sulfamethoxazole with better fluoroquinolones adverse effects profile.[83][84]

For second-line treatments, minocycline and tigecycline have been reported to have good effectiveness against many isolates at around 80% to 100% susceptibility rate even for isolates resistant to trimethoprim-sulfamethoxazole.[85][86][87][88] Further, ticarcillin-clavulanic acid has been well studied as one of the effective treatment options for Stenotrophomonas maltophilia infections [17], with a susceptibility rate ranging from below 50% sometimes to above 80%.[64][89] Other options include ceftazidime, though some bodies report it as intrinsically resistant and with increasing resistance. Next, colistin is considered a good option at about a 72% to 77% susceptibility rate.[90] Another uncommonly used but effective agent is chloramphenicol, with a wide range of susceptibility reports.[17][22]

Resistance to many of these antimicrobials and the co-existence of multiple resistances together are being reported at higher rates in the literature, which creates the need for new agents and regimens to be utilized.[69][91] Sulfametrole/trimethoprim is an alternative combination to trimethoprim/sulfamethoxazole that was tested and showed good activity in some studies.[92] Cefiderocol is a new injectable siderophore cephalosporin that has shown promising data against carbapenem-resistant gram-negative bacteria, including Stenotrophomonas maltophilia.[93][94][95]

Eravacycline, omadacycline, and delafloxacin have demonstrated good in-vitro activity as well for their respective infection indications.[69][96][97] On the other hand, several new antimicrobials like ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam, cilastatin/relebactam, plazomicin, and fosfomycin did not show activity against Stenotrophomonas maltophilia in recent reports.[98] Combinations of antimicrobials have been studied with good synergistic promising results, including trimethoprim-sulfamethoxazole/ciprofloxacin, ceftazidime/levofloxacin, ticarcillin-clavulanate/trimethoprim-sulfamethoxazole, ticarcillin-clavulanate/aztreonam, tigecycline/colistin, colistin/rifampicin, ceftazidime/minocycline, levofloxacin/erythromycin, and tigecycline/fosfomycin.[99][100][101][102]

Since some isolates showed resistance to all known tested antimicrobials, new treatment approaches and modalities are currently being studied, such as aerosolized antimicrobials (colistin and levofloxacin), bacteriophage therapy, efflux pump inhibitors, quorum sensing interference (quorum quenching), antimicrobial peptides like the cathelicidin-derived ones, silver or selenium nanoparticles, cationic compounds, plant oils, green tea epigallocatechin-3-gallate, and using Bdellovivrio exovorus as a bacterial predator.[103][104][105]

The typical duration of antimicrobial courses for Stenotrophomonas maltophilia pneumonia is usually 7 days, which can be extended to 10 to 14 days in immunosuppressed patients. Bacteremia cases, on the other hand, are generally treated for 14 days total.

Source control is essential in certain cases for successful treatment, such as central venous catheter removal, infected metal hardware retrieval, wounds debridement, conjunctival autografting, and collections drainage.[50][59]

Differential Diagnosis

Other Stenotrophomonas species typically do not cause infections in humans.
Other gram-negative non-fermenters like Pseudomonas aeruginosa, Acinetobacter baumannii, Achromobacter xylosoxidans, and Burkholderia cepacia-complex, can be misidentified as, co-exist with, or be responsible for similar infections to Stenotrophomonas maltophilia.
Other more common organisms should be considered first with each infection according to the clinical picture.

Prognosis

There have been controversial data about the high mortality associations with Stenotrophomonas maltophilia. The crude mortality rate is estimated to be around 14% to 69% of cases.[106][107] According to a systematic review, the attributable mortality rate of all Stenotrophomonas maltophilia infections was up to 37.5%.[108] The reported attributable mortality rate in pneumonia cases was at least 20%, while in bacteremia cases was 27%, which was within the same range as other causes of nosocomial bacteremia.[109][18]

It was also shown that colonization with Stenotrophomonas maltophilia in patients undergoing allogeneic hematopoietic stem cell transplants was associated with significantly higher non-relapse mortality, mainly secondary to severe infections.[110]

Complications

Stenotrophomonas maltophilia outbreaks can occur in hospitals and critical care units.[27] Biofilm formation leads to the persistence of the bacteria in hospital settings and on equipment.[38]

Infections with Stenotrophomonas maltophilia have been associated with worsening lung functions in cystic fibrosis patients.[6][111] Severe fulminant lung infections can occur in cases of hematologic malignancies.[55]

Bacteremia cases can be complicated by disseminated intravascular coagulopathy (DIC) and purpura fulminans in severe cases.[18] Recurrence of bacteremia infections occurs when related central venous catheters are not removed or in cases of inappropriate antibiotics.[57]

The aforementioned complications, morbidities, and mortalities, and economic burden highlight the importance of infection prevention.

Deterrence and Patient Education

Stenotrophomonas maltophilia is an intrinsically multidrug-resistant bacteria that usually infects patients with weak immunity. It is often uneasy about treating, given the limited options of antibiotics that can work against it. Always seek your physician’s help to answer any questions about this infection since information about it is not readily available to the public. Patients should mention to their provider if they have allergies to the antibiotic co-trimoxazole since it is usually involved in the treatment.

Enhancing Healthcare Team Outcomes

All interprofessional healthcare team members need to have good communication regarding the treatment plan for Stenotrophomonas maltophilia. This includes the clinicians (including mid-level practitioners), residents, infectious diseases consultants, nurses, pharmacists, and the infection prevention team. By coordinating treatment efforts and sharing information about the case, patient outcomes will be improved with fewer adverse events. [Level 5]

Antibiotic stewardship programs are also critical in preventing and treating Stenotrophomonas maltophilia infections by limiting the unnecessary use of broad-spectrum empiric antimicrobials to the minimum.

Strict infection prevention measures are also to be implemented and stressed to all team members, including hand hygiene, central venous line insertion precautions, appropriate disposal of potentially contaminated solutions, and proper handling and disinfection of medical equipment.[9][8][17] Using disinfectants like 3% hydrogen peroxide and 10% peracetic acid has shown to be effective.[112]

Environmental sampling, especially in outbreak situations, is important to identify potential sources. Maintenance of the water supplies, water filtration, and copper-silver ionization for plumbing systems disinfection is recommended to limit the transmission.[9][8][17] Utilizing new adhesion-resistant materials in medical supplies when made available can also show a positive effect.[2]

Details

References

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