Prevalence and risk factors
The reported prevalence of
SM among patients with CF is various, with many differences mainly depending on the country. For the 2021 CFFPR Annual Data Report, including CF patients from North America, the prevalence of the bacteria was 5.6%, declining from the reported prevalence of 12.7% and 13.1% respectively in 2006 and 2016 [
37]. Also the 2021 CCFR reported a decrease in
SM prevalence in the last few years, from 14.2% in 2017 to 13.7% in 2021 [
42,
43]. Interestingly, in contrast with these results, in France an increasing trend in the prevalence of colonization by
SM in CF patients has been reported, from 4.7% in 1999 to 10.5% in 2016 [
32]. The proportion of colonization by
SM in CF patients in France is still decreasing, as the 2021 FCFR reported 9.3% of patients to be colonized [
40]. According to the 2021 ECFSR data, the prevalence of the
SM infections was 6.6% in children and 7.7% in adults, considering both chronic and not chronic or intermittent infections. The highest proportions were observed in Northern Europe, reaching 25.0% in the paediatric population in Iceland [
38]. Differently from the proportion reported by the 2021 ECFPR, the 2021 ACFDR reported a higher prevalence of
SM in children than in adults affected by CF, respectively 7.6% and 6.5% [
41]. In Italy in 2020 the prevalence of
SM reported by the ICFR was 7.6% in the adult population and 8.6% in children. The data reported by the ICFR, in contrast with that of North America, showed an increasing prevalence of
SM, with and increasing from 2.9% in 2018 to 7.6% in 2020 in adults and from 2.6% in 2018 to 8.6% in 2020 in paediatrics [
39].
Figure
2 summarizes the average
SM prevalence in adults and children affected by CF, considering the proportions reported by the Registries included in the review.
While a seasonal variation for some common bacterial pathogens in CF patients has been described, as for
PA, methicillin-susceptible
Staphylococcus aureus,
Achromobacter xylosoxidans and
Haemophilus influenzae, such variation was excluded for
SM [
33].
The differences in prevalence are likely due to variations in local ecology [
32], even if some other factors influencing the acquisition of the infection might play a role. Little is known about factors which could impact on the colonization of
SM, and consequently may influence the prevalence in patients with CF. Firstly, some studies described an association between the severity of lung disease and the acquisition of
SM infection, with a higher risk in patients with a faster decline in FEV1 [
12]. It is debated whether the use of antibiotics could represent a risk factor for the infection. Some studies reported a higher risk of
SM isolation in case of antibiotic therapy [
13,
14], nevertheless, other authors described exposure to antibiotic courses as a protective factor through the preservation of lung function [
12]. Particularly, Denton et al. described an increase in
SM isolation in patients who received anti-
PA antibiotic courses, suggesting that the treatment of common infections in CF patients could raise the risk of colonization by
SM [
15]
. A study by Marchac et al. described an association between the isolation of
Aspergillus fumigatus and subsequent
SM infection, although this finding has not been well supported [
16]. In agreement with Marchac’s study, Paugam et al. observed a higher proportion of
SM colonization in CF patients with
Aspergillus fumigatus [
17]
.
Effect of chronic Stenotrophomonas maltophilia infection on lung function
The effect of chronic colonization of
SM on lung function and clinical status in CF patients is still unclear. Goss et al. analysed data from the CF Foundation National Patient Registry (CFNPR) registers from 1994 to 1999. In this extensive cohort study on 2739 CF patients, there was no association between
SM and a decrease of lung function after controlling for confounders (age, sex, weight, height, pancreatic insufficiency,
PA and
Burkolderia cepacia colonization, use of intravenous antibiotics) [
34]. A subsequent cohort study from 2008 to 2009 compared 82 CF patients with at least one positive culture of
SM to a CF control group with no chronic gram-negative infections. In this study, patients with
SM positive cultures every month for 6 consecutive months or, less often, when combined with an increase in number of specific, precipitating antibodies were defined as chronically infected. They found that patients who had been chronically infected with
SM for at least 2 years, had a significantly larger decline in lung function, demonstrated as change in FEV1% of predicted value per year. However, no change was detected in the rate of FEV1 decline when those patients were compared to themselves in the previous 3 years before they became chronically infected [
18]. A similar retrospective cohort study showed that chronic
SM status (defined as 2 or more positive sputum or bronchoalveolar cultures in the previous 12 months) does not affect FEV1 recovery and
SM antibiotic treatment does not influence the recovery or the gain in FEV1 after a pulmonary exacerbation [
35]. In contrast, the same group found increased rates of mortality and lung transplantation among patients with
SM chronic infection, although this effect was no longer significant in a time-varying model that includes lung function [
19].
Recently, some observational studies suggested that
SM chronic infection may be associated with worse respiratory outcomes and accelerated lung function decline. In a retrospective review of medical records with CF in the USA, Com et al. compared children with low and high initial FEV1, in order to analyse their baseline characteristics. The authors described a significant correlation between low initial FEV1 measurements and positive respiratory culture for
SM (
p<0.05) [
20]. In 2015, Cogen et al. in a multicenter longitudinal observational study, in order to identify a high-risk group in
PA–negative and ≤12 years of age children with CF, described
SM as a risk factor for FEV1 decline [
21]. A subsequent longitudinal retrospective study of 88 patients demonstrated that the acquisition of
SM is associated with an acceleration in lung function decline. More interestingly, the effect persisted after controlling for confounders. In this study, chronic infection was defined as two or more positive cultures within a 12-month time period following acquisition, otherwise infection was classified as intermittent. Interestingly, both the intermittent and chronic subgroups were associated with lung function decline, and the change in rate of decline did not significantly differ between them. Chronic
SM infection was also associated with an almost twofold increase in mean annual hospitalizations (
p=0.007) [
22].
In a recent retrospective study Poore et al. noticed an association between
SM colonization and frequent fungal infection, especially
Aspergillus (70% of fungal positive cultures in this cohort). Furthermore, they found that patients with
SM and frequent fungal isolation had lower average lung function by almost 10% compared to controls [
23].
We found several limitations in these studies, such as small cohorts of patients, type of study design (lack of prospective studies) and different clinical characteristics among patients included. Moreover, the definition of chronic colonization is based on different criteria among the studies, which makes them barely comparable. However, the most recent studies suggest a more active role of SM in influencing the progression of lung disease rather than simply being an indicator of disease severity. This can probably be explained by the fact that
SM was considered a classical but infrequent bacterium in CF patients until the 2000's, but its incidence appears to be increasing in recent decades [
24].
Genotypic and phenotypic heterogeneity of Stenotrophomonas maltophilia
While the genetic adaptations and resulting phenotypic variations in
PA and
Staphylococcus aureus colonization of CF lungs are well-documented, the specific adaptive characteristics of
SM that contribute to its persistence in CF patient only recently gained interest among many authors[
25‐
28]. Genetic studies have revealed significant genotypic diversity within
SM chronically infected CF patients. Multiple strains of
SM can coexist within an individual patient, suggesting ongoing acquisition and colonization events [
26,
28]. Genotyping techniques, such as pulsed-field gel electrophoresis and multilocus sequence typing have provided insights into the clonal relatedness and genetic variation among different isolates. The phenotypic variability is observed in various aspects, including antibiotic resistance patterns, biofilm formation, and virulence factors.
In a study by Vidigal et al. genotypic diversity, mutation frequency, and antibiotic resistance were examined in 90
SM isolates from 19 CF patients with chronic colonization [
25]. The findings revealed that
SM undergoes significant genetic diversity during chronic CF lung infection, although a decreased mutation rate was observed in the later isolates. In a more focused investigation, Pompilio et al. 2016 evaluated 13
SM strains isolated from a single CF patient with chronic infection over a 10-year period [
26]. They examined various traits including growth rate, biofilm formation, motility, mutation frequencies, antibiotic resistance, and pathogenicity. The results demonstrated that
SM adaptation led to increased antibiotic resistance but decreased in vivo pathogenicity and biofilm formation. However, it is important to note this study's limitation of only considering one chronically infected patient. Interestingly, according to Esposito et al. and Alcaraz et al. the wide range of phenotypes exhibited by
SM strains, only marginally correlates with the distribution of mutations across their genomes [
27,
28].
These studies collectively emphasize the remarkable adaptability of
SM during chronic infection in CF patients. This heterogeneity likely arises from the microorganism's need to adapt to a highly challenging CF lung environment, while facing diverse selection pressures based on the host's unique conditions. The mechanisms that drive the development of high genomic heterogeneity, resulting in a wide range of phenotypes, is still unclear and further studies are needed in order to better understand it [
27]. Although the discussion of this topic is beyond the scope of our review, which is focused on clinical aspects of
SM in CF, it will be important to clarify the mechanisms of development of genotypic and phenotypic heterogeneity, giving the possible impact on diagnosis, treatment, and infection control strategies.
Treatment of Strenotrophomonas maltophilia acute and chronic infections
At present there are no clear guidelines regarding the management of SM in people with CF, as literature is poor and it is still uncertain if both the treatment of acute exacerbation and the long-term suppressive therapy are effective.
A Cochrane Intervention Review by Amin et al. was conducted to assess the effectiveness of antibiotic treatment in people with CF, primarily in the setting of acute pulmonary exacerbations and then in chronic colonization of
SM. However, there was no evidence since no randomized control trial met the inclusion criteria for the review [
10].
The objective of administering antibiotics during a CF pulmonary exacerbation is twofold: to decrease the bacterial presence in the airways, potentially eliminating the bacteria altogether, and to reduce inflammation, consequently enhancing lung function and extending the period before another exacerbation occurs [
44].
A retrospective cohort study showed that antibiotic therapy targeting
SM during pulmonary exacerbations in patients with chronic
SM infection did not affect the degree of FEV1 recovery or the time to subsequent exacerbation [
35]. It is worth noting, however, that the majority of patients received treatment with a single antimicrobial drug targeting SM, resulting in successful elimination of
SM from the airways in only a quarter of chronic SM pulmonary exacerbations. It is widely known that
SM exhibits intrinsic resistance to a wide range of antimicrobial agents, and it is often recommended to employ a combination of antibiotics to effectively treat
SM infections. Even the authors suggested that the antimicrobial monotherapy may not be sufficient.
SM is a multidrug-resistant opportunistic bacteria and can rapidly develop antimicrobial resistance mutations [
45]. Trimethoprim-sulfamethoxazole has been historically considered the first line of treatment for
SM infections due to high susceptibility rates and large clinical experience [
45‐
47]. According to Esposito et al. the most effective antibiotics against
SM were minocycline, doxycycline and trimethoprim-sulfamethoxazole, showing comparable susceptibility rates [
27]. Whereas San Gabriel et al. demonstrated that in vitro,
SM appears to be most susceptible to trimethoprim-sulfamethoxazole, ticarcillin-clavulanate and doxycycline [
29].
Thus, treatment of SM infections in CF patients poses a big challenge and until further evidence of the role of antimicrobial regimes is available, clinicians need to decide on clinical judgement on a case-by-case basis.
The Infectious Diseases Society of America (IDSA) provided guidance for
SM infections management in CF and non-CF patients, consisting of "suggested approaches" based on clinical experience, expert opinion, and a review of the available literature [
48]. In case of moderate to severe infections, and also considering the multiple mechanism of antibiotic resistance, they recommended a combination therapy. They suggested 3 approaches: (1) the use of combination therapy, with trimethoprim-sulfamethoxazole and minocycline as the preferred combination; (2) the initiation of trimethoprim-sulfamethoxazole monotherapy with the addition of a second agent (minocycline [preferred], tigecycline, levofloxacin, or cefiderocol) if there is a delay in clinical improvement with trimethoprim-sulfamethoxazole alone; (3) the combination of ceftazidime avibactam and aztreonam, when intolerance or inactivity of other agents are anticipated. For mild infections and polymicrobial infections where the role of SM is unclear, they suggested monotherapy with trimethoprim-sulfamethoxazole, levofloxacin, minocycline, tigecycline or cefiderocol. Table
4 reports the suggested dosages for antimicrobial therapy.
The multicenter randomized controlled clinical trial STOP2 evaluated the antimicrobial therapy duration during acute exacerbations in CF adults, regardless of the bacterial species involved. The outcome was similar for the 10 day, the 14 day and the 21 day regimens [
31].
No suppressive therapy for CF patient with
SM chronic infection is available, despite aerosolized levofloxacin as a potential future strategy [
30].