Stenotrophomonas maltophilia and Burkholderia cepacia Complex

Burkholderia cepacia Complex Species

The BCC comprises a number of phenotypically similar but genotypically distinct species. The number of validly determined species has been increasing. There are currently at least 20 different species that are within the BCC. Given the phenotypic similarity of many of these species, multiple phenotypic and genetic approaches have been used for identification and typing purposes including sequencing of 16S ribosomal RNA and recA genes, multilocus sequence typing, average nucleotide identity, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and biochemical tests. Despite the ever-increasing number of BCC spp., a limited number cause most human disease. An analysis of 151 isolates from an Italian CF center revealed that greater than 70% of isolates were due to three species: Burkholderia cenocepacia (38%), Burkholderia stabilis (19%), and Burkholderia mulitvorans (14.2%). A large study from the United Kingdom that looked at >1000 Burkholderia isolates from both patients with CF and patients without CF showed that 56% of patients had B. multivorans and 15% had B. cenocepacia IIIA.

Stenotrophomonas Genotypes

S. maltophilia is found worldwide and has been isolated from numerous environmental sources. Given this, there is a large amount of genetic diversity among strains. One study illustrated the genetic diversity of clinical isolates; 80 typeable strains from 18 geographically distinct hospitals showed no predominant sequence type, and genogroup 6 represented about 40% of isolates. A study in a pediatric hospital in Serbia also demonstrated high genetic diversity among both CF and non-CF isolates.

Lipopolysaccharides, Adhesion, and Invasion

Both BCC species and S. maltophilia produce lipopolysaccharides (LPSs) that are capable of stimulating cytokine-driven inflammatory responses and allow for resistance to complement-mediated bacterial clearance. B. cenocepacia LPSs can activate immune cells through Toll-like receptor 4–mediated signaling. Blood mononuclear cells that have been activated by BCC LPSs release various cytokines including tumor necrosis factor-α, interleukin-6, and interleukin-8. In S. maltophilia , lipid A has been shown to stimulate tumor necrosis factor-α in both blood mononuclear cells and alveolar macrophages leading to airway inflammation. In addition, interleukin-8 stimulates recruitment of polymorphonuclear neutrophils to sites of infection, further driving a robust inflammatory response. Divergent Toll-like receptor/MD2 signaling has been shown to occur due to changes in the inner core of BCC LPSs.

B. cepacia has been shown to be able to bind to various epithelial cell receptors such as cytokeratin 13 (CK13) through an adhesin that is expressed on cable pili that helps to anchor bacteria. Various epidemiologic studies have provided evidence for the importance of cable pili in establishing colonization as well as allowing for patient-to-patient transmissibility in the CF lung milieu. In one study, chronic inflammation enhanced CK13 expression in patients with CF, and in regions that had high CK13 expression this corresponded with an enhanced B. cenocepacia burden. BCC species not only can invade respiratory epithelial cells but also have been demonstrated to be able to survive and multiply within epithelial cells.

Siderophores and Secreted Enzymes

BCC species have a number of mechanisms for scavenging iron. BCC species possess at least four iron-binding siderophores—pyochelin, ornibactin, cepaciachelin, and cepabactin—for iron chelation and uptake. Likewise, S. maltophilia uses catechol-type iron-binding siderophores, and these siderophores can be both positively and negatively regulated.

S. maltophilia produces a variety of extracellular enzymes including alkaline serine proteases (at least one encoded by StmPr1 ), DNAse, RNase, gelatinase, and lipases that degrade tissue fat. Many of these proteases are resistant to inhibitors such as α ₁ -antitrypsin and α ₂ -macroglobulin. These exoenzymes allow for tissue necrosis and hemorrhage. Various BCC species produce proteases, lipases, and nonhemolytic phospholipase C.

Chronic Infection and Intracellular Survival

BCC species can invade and survive in a number of host cells. Once internalized into respiratory epithelial cells, growth can occur, and microcolonies can be seen ( Fig. 220.1 ). Intracellular survival helps facilitate immune evasion. Although autophagosomes appear to form, BCC species appear to block the full autophagocytic pathway in both epithelial cells and macrophages and use the endoplasmic reticulum for multiplication. A number of mechanisms are thought to play a role in intracellular survival including blocking enzyme production, degradation of enzymes, and melanin pigment–associated superoxide quenching. The BCC type III secretion system assists in delaying the maturation of bacteria-containing phagosomes. The failure of B. cenocepacia to fuse with lysosomes allows for prolonged survival in patients with CF. Although less is known about the intracellular life cycle of S. maltophilia, there are data to support that some strains can survive in human monocyte-derived dendritic cells.

Biofilm and Quorum Sensing

Biofilms normally contain aggregates of bacteria in extrapolymeric substances and can form on numerous foreign objects, on avascular necrotic tissue, and in certain host environments such as the lung affected by CF. Quorum sensing systems and the ability to form biofilm are traits of both BCC species and S. maltophilia . The presence of biofilm allows for the ability to withstand both immune cell activity and antibiotic efficacy. In S. maltophilia, regulation of biofilm occurs through the production of diffusible signaling factor, and diffusible signaling factor mutants show a number of phenotypes including loss of motility, increased susceptibility to antibiotics, and reduced production of proteases. B. cenocepacia has been shown to use N -acyl homoserine lactones and cis -2-dodecenoic acid to regulate biofilm.

Stenotrophomonas maltophilia

The rate of S. maltophilia isolation and infections has increased in multiple regions of the world. There is a broad environmental range where S. maltophilia has been isolated, including from animals. It is not clear whether increased numbers of infections in vulnerable patient populations are due to enhanced lifesaving medical advances or an overall increase in incidence. However, there has also been an increase in the isolation of this pathogen from various medical devices and solutions. One study of gastrointestinal endoscopes found S. maltophilia among a group of potential pathogens isolated after routine cleaning of the instruments. Outbreaks have been described from other equipment sources including from contaminated bronchoscopy suction valves. Nosocomial infections have been described through contamination of treated hospital water supplies.

Health care–associated infections due to S. maltophilia have been described in both cancer and noncancer patient populations. Infections at two different hospitals in patients with cancer illustrate this point. At a comprehensive cancer hospital, S. maltophilia increased among gram-negative bacterial infections during the period 1986–2002, and at the same hospital there was an increase in moderate-to-severe S. maltophilia bacteremias. A cluster of bacteremia cases among stem cell transplant patients at a large German hospital illustrated that environmental contamination leading to documented patient transmission was rare, as most patients had prior colonization. Studies from various regions of the world support the increasing prevalence of infections. For the years 2000–06, there was a 93% increase in the annual number of bloodstream isolates in the United Kingdom, and for 1999–2004, there was an 83% increase in a large tertiary hospital in Taiwan. S. maltophilia has also been increasing in frequency in respiratory specimens from patients with CF, although there is variability of rates based on the specific CF center. In one study, having S. maltophilia correlated with more severe lung disease in patients with CF. It remains unclear what the impact of S. maltophilia colonization is in both the pretransplant setting and the posttransplant setting. There was no difference in lung function decline in CF patients in the 3 years prior to acquiring S. maltophilia and up to 2 years after. Although S. maltophilia is frequently considered a nosocomial pathogen, the high genetic diversity that has been demonstrated suggests that host colonization is likely a frequent source of the infection.

Factors that have been associated with a high risk of infection include critical illness associated with pulmonary disease, prolonged use of broad-spectrum antibiotics, prolonged assisted ventilation, and prior respiratory tract colonization with S. maltophilia. In immunocompromised individuals, such as patients with cancer and transplant recipients, risk factors include prolonged neutropenia, recent or current use of broad-spectrum antibiotics (including carbapenems, third- and fourth-generation cephalosporins, and fluoroquinolones), indwelling medical devices, prolonged hospitalization, hyperalimentation, and the presence of mucositis.

Update: Stenotrophomonas maltophilia treatment