Effect of antibiotic therapy on the prognosis of ventilator-associated pneumonia caused by Stenotrophomonas maltophilia

Background Ventilator-associated pneumonia (VAP) caused by Stenotrophomonas maltophilia is poorly described in the literature. However, it has been shown to be associated with increased morbidity and mortality. Probabilistic antibiotic therapy against S. maltophilia is often ineffective as this pathogen is resistant to many antibiotics. There is no consensus at present on the best therapeutic strategy to adopt (class of antibiotics, antibiotic combination, dosage, treatment duration). The aim of this study was to evaluate the effect of antibiotic therapy strategy on the prognosis of patients with VAP caused by S. maltophilia. Results This retrospective study evaluated all consecutive patients who developed VAP caused by S. maltophilia between 2010 and 2018 while hospitalized in the intensive care unit (ICU) of a French university hospital in Reunion Island, in the Indian Ocean region. A total of 130 patients with a median Simplified Acute Physiology Score II of 58 [43–73] had VAP caused by S. maltophilia after a median duration of mechanical ventilation of 12 [5–18] days. Ventilator-associated pneumonia was polymicrobial in 44.6% of cases, and ICU mortality was 50.0%. After multivariate Cox regression analysis, the factors associated with increased ICU mortality were older age (hazard ratio (HR): 1.03; 95% CI 1.01–1.04, p = 0.001) and high Sequential Organ Failure Assessment score on the day of VAP onset (HR: 1.08; 95% CI 1.03–1.14, p = 0.002). Appropriate antibiotic therapy, and in particular trimethoprim–sulfamethoxazole, was associated with decreased ICU mortality (HR: 0.42; 95% CI 0.24–0.74, p = 0.003) and decreased hospital mortality (HR: 0.47; 95% CI 0.28–0.79, p = 0.04). Time to start of appropriate antibiotic therapy, combination therapy, and duration of appropriate antibiotic therapy had no effect on ICU mortality (p > 0.5). Conclusion In our study, appropriate antibiotic therapy, and in particular trimethoprim–sulfamethoxazole, was associated with decreased ICU and hospital mortality in patients with VAP caused by S. maltophilia.


Introduction
Ventilator-associated pneumonia (VAP) caused by Stenotrophomonas maltophilia is relatively common, with the latest report of the European Centre for Disease Prevention and Control stating that this microorganism is one of the 10 most frequently isolated germs in respiratory samples [1]. Depending on the study, the incidence S.  11:160 maltophilia in patients with VAP varies between from 0.3 and 2.0% [2,3]. According to some authors, however, S. maltophilia is of limited pathogenicity and should not be considered as an infectious agent in the majority of VAP cases [4][5][6]. Admittedly, the link between colonization by S. maltophilia and respiratory infection is often difficult to establish. On the one hand, severely ill patients can be colonized with S. maltophilia in the respiratory tract without presenting respiratory symptoms [4,5]. On the other hand, half of respiratory samples containing strains of S. maltophilia show significant growth of other microorganisms with known pathogenicity [2,7]. Several studies nonetheless suggest that VAP caused by S. maltophilia is associated with high morbidity and mortality [3,4,7], in particular due to inappropriate probabilistic treatment [7,8]. In some studies, the mortality rate attributable to S. maltophilia colonization or infection was found to vary between 20.0 and 38.0% [8].
There is no consensus at present on the therapeutic strategy to adopt in cases of VAP caused by S. maltophilia (class of antibiotics, antibiotic combination, dosage, treatment duration). Some authors recommend high doses of trimethoprim-sulfamethoxazole based on clinical data, while others favor combination therapy based on in vitro data [9,10]. In view of this, our study aimed to evaluate the effect of antibiotic therapy strategy on the prognosis of patients with VAP caused by S. maltophilia.

Methods
This single-center retrospective study was conducted in the Multi-Purpose Intensive Care Unit (ICU) of Félix Guyon University Hospital in Reunion Island, a French overseas department located in the Indian Ocean.
All patients hospitalized in ICU with a blood or respiratory culture positive for S. maltophilia between 1 January 2010 and 31 December 2018 were evaluated and considered for inclusion. Patients aged over 18 years who developed VAP caused by S. maltophilia during their ICU stay were included in the study (Fig. 1).
In accordance with the French legislation on non-interventional studies [11], this study was registered with the National Institute of Health Data under the number MR 5611200420 and was approved by the Ethics Committee of the French Society of Infectious Disease and Tropical Medicine (CER-MIT 2021-0302). This study complies with the Strengthening the Reporting of Observational studies in Epidemiology recommendations statement [12].
All patients with a Clinical Pulmonary Infection Score (CPIS) > 6 and those with a CPIS ≤ 6 who were treated by a clinician for VAP were evaluated [14].

Pharmacological management
In accordance with our protocol, all patients with VAP caused by S. maltophilia were treated with: trimethoprim-sulfamethoxazole (1200 mg/240 mg)/6 h and/or ciprofloxacin 400 mg/8 h and/or moxifloxacin and/or ticarcillin-clavulanate 4 g/8 h and/or ceftazidime 2 g/6 h.
Dosages were adjusted to renal function if necessary, and the choice of antibiotics was left to the discretion of the clinician.

Data collection
The following information was collected: Patients with a positive S.maltophilia blood and/or respiratory culture during their ICU stay n = 172

Excluded from analysis
Positive blood culture alone n = 8 Pneumonia occuring less than 48h after tracheal intubation n = 8 No-ventilated patients n = 8

CPIS < 6* and no treatment n = 18
Patients with a documented S.maltophilia considered analysis n = 130 by introducing an interaction between groups (treated patients versus non-treated patients) and time. All tests were performed at a 2-tailed type I error of 5% using SAS 9.4 software (SAS Institute Inc., Cary, NC).  (Table 1).

Sampling methods and microorganism distribution
Respiratory samples were obtained through endotracheal aspiration in 46.2% of cases, protected distal sampling in 34.6% of cases, and bronchoalveolar lavage in 19.2% of cases.
Infection was polymicrobial in 44.6% of cases. The microorganism most frequently associated with S. maltophilia was Pseudomonas aeruginosa (Table 3).

Susceptibility of Stenotrophomonas maltophilia strains and type of antibiotic therapy
Identified strains of S. maltophilia were susceptible to trimethoprim-sulfamethoxazole in 86.2% of cases, to fluoroquinolones in 85.4% of cases, to ticarcillin-clavulanate in 58.5% of cases, and to ceftazidime in 40.0% of cases. Appropriate antibiotic therapy was initiated after a median of 2 [1][2][3] days.
Dual antibiotic therapy was initiated in 53 (40.8%) patients, 43 (81.1%) of whom received trimethoprimsulfamethoxazole and fluoroquinolone. Triple antibiotic therapy was initiated in 35 (26.9%) patients, 32 (91.4%) of whom received ticarcillin-clavulanate, trimethoprim-sulfamethoxazole, and fluoroquinolone (Table 3). A total of 38 patients (29.2%) received no treatment for S. maltophilia. There was no significant difference between treated and untreated patients with respect to the CPIS (p = 0.17), the SOFA score on the day of VAP onset (p = 0.43), the polymicrobial character of the infection (p = 0.12), or the presence of WLST (p = 0.55). Probabilistic antibiotic therapy was effective against the co-infecting microorganism(s) in 86.2% of cases (50/58) and in The Kaplan-Meier method using the log-rank test found a significant difference in ICU survival and hospital survival between treated and non-treated patients (p = 0.009 and p = 0.02, respectively) (Fig. 2). The only antibiotic therapy associated with a significant difference between treated and non-treated patients was trimethoprim-sulfamethoxazole (p = 0.02) (Fig. 3). For the others, there was no difference between treated and non-treated patients: fluoroquinolones (p = 0.54), ticarcillin-clavulanate (p = 0.14), and ceftazidime (p = 0.64).

Discussion
We performed a search of the literature in English and French using the terms pneumonia, S. maltophilia, intensive care unit, and outcome. We found three articles on VAP caused by S. maltophilia, two of which were conducted in adult populations. The first was the multicenter study by Guerci [2,16]. Both studies examined the impact of therapeutic modalities (antibiotic combination,  Other 1 treatment duration, etc.) on the prognosis of patients, but neither of them evaluated the association between prognosis and lack of appropriate treatment.
As in other studies of VAP caused by S. maltophilia [4,16], the risk factors associated with increased ICU mortality were older age and high SOFA score on the day of VAP onset.
An original finding of our study was that appropriate antibiotic therapy, and in particular trimethoprim-sulfamethoxazole, is associated with decreased ICU mortality (HR: 0.42; 95% CI 0.24-0.74, p = 0.003) and hospital mortality (HR: 0.47; 95% CI 0.28-0.79, p = 0.04). However, time to start of appropriate antibiotic therapy and duration of appropriate antibiotic therapy had no effect on mortality.
Most studies of ICU patients with pneumonia caused by S. maltophilia found no association between mortality and antibiotic therapy strategy [2,16]. The only exceptions are the study by Tseng et al. [17] and Hanes et al. [7], in which mortality was associated with delayed initiation of appropriate antibiotic therapy. We found no such association in our study, even though appropriate antibiotic therapy was initiated 2 days after VAP onset. The discrepancy between our results and those of Hanes et al. may be partly explained by the fact that the latter found a higher rate of co-infection in their cohort, and in particular a higher rate of co-infection with P. aeruginosa (92.3% of patients with a co-infection and 34.6% with a co-infection with P. aeruginosa versus 44.6% with a co-infection and 18.5% with a co-infection with P. aeruginosa in our study) [7]. Likewise, in the study by Tseng et al., the association between mortality and delayed initiation of appropriate antibiotic therapy was especially strong in cases of co-infection [17]. In line with these findings, Yin et al. observed that co-infection with P. aeruginosa, which is common in cases of S. maltophilia pneumonia, is a poor prognostic factor [18]. In our study, however, the rate of co-infection was the same in survivors and non-survivors (p = 0.29).
Studies examining VAPs caused by non-fermenting Gram-negative bacilli (GNB) found no effect of treatment duration on mortality, MV duration, or length of stay in ICU. However, in the randomized prospective study by Chastre et al., prolonged antibiotic therapy (15 days) was associated with fewer relapses than short antibiotic therapy (8 days) in the subgroup of patients infected with non-fermenting GNB (41.0% of relapses in patients who received 8 days of treatment versus 25.0% in patients who received 15 days of treatment) [19]. Similarly, in a systematic review of prolonged treatment for hospitalacquired pneumonia, Pugh et al. observed fewer relapses in patients infected with non-fermenting GNB who had received prolonged treatment (OR: 2.18; 95% CI 1.1-4.2) [20]. It should be noted, however, that the most frequently implicated non-fermenting GNB in the evaluated studies was P. aeruginosa [19,20]. A randomized study is currently underway that evaluates the effect of treatment duration on the prognosis of patients with VAP caused by P. aeruginosa [21].
In our study, patients were treated mainly with combination therapy, with no difference in effect on mortality between dual and triple therapy. The difference in effect on mortality between combination therapy and monotherapy could not be evaluated, as only 4 of our patients received monotherapy. Our study suggests that trimethoprim-sulfamethoxazole has a protective effect in patients with VAP caused by S. maltophilia. This finding is in line with other studies of patients with S. maltophilia pneumonia, in which trimethoprim-sulfamethoxazole was not associated with excess mortality or the emergence of resistance, even when used as monotherapy [2,[22][23][24]. One in vitro study did find that combination therapy broadens the spectrum of antibiotics and constitutes as such a more effective probabilistic treatment for patients with sepsis, particularly in cases of non-fermenting GNB   infection [25]. However, clinical studies found no superiority of combination therapy over monotherapy in cases of sepsis, whether in terms of clinical cure or mortality, and this even in cases of non-fermenting GNB infection [26,27]. The incidence of VAP caused by S. maltophilia was relatively high (1.4%) in our ICU compared to what has been reported in the literature. Ibn Saied et al. and Guerci et al. reported an incidence of 0.5% and 0.3%, respectively-keeping in mind that the latter study examined all cases of hospital-acquired S. maltophilia pneumonia [2,16]. The study by Nseir et al. found an incidence of 2.0%, but it included cases of colonization with S. maltophilia in addition to infection cases [3]. The discrepancy between these and our results may be explained by the fact that our study was conducted in a tropical environment, which has been shown to favor the development of the parent microorganism Acinetobacter baumannii [28]. Another potential explanation is that our patients were diagnosed using the highly sensitive sampling technique of endotracheal aspiration.
In our study, ICU mortality was 50.0% and hospital mortality was 56.2%. These findings are in line with the study by Saugel et al., in which ICU mortality was 50.0% [4]. While Guerci et al. found a hospital mortality of 50.0%, their study included all cases of hospital-acquired pneumonia caused by S. maltophilia and not just those of VAP [2]. The study by Ibn Saied et al., in which the median SOFA score on the day of VAP onset was the same as in our study, found an ICU mortality of 40.0% despite the fact that 68.0% of patients received no treatment [16]. It may be that Ibn Saied et al. included cases of colonization with S. maltophilia in addition to cases of infection in their sample, which could explain this lower ICU mortality [16]. The study by Saugel et al., in which ICU mortality was 29.0% in colonized patients, would tend to support this hypothesis [4].
Our study has some limitations. The single center and retrospective nature of the study may have led to biases. In addition, the relatively small size of our sample limits the statistical power of the results. The size of our sample stems from our decision to exclude patients with a CPIS ≤ 6 who were not treated by a clinician for VAP, as we assumed these to be cases of colonization with S. maltophilia or ventilator-associated tracheobronchitis [4,29]. It should be noted, however, that the retrospective studies by Guerci et al. and Ibn Saied et al. included a comparable number of patients: 228 (80.0% of whom had VAP) and 102, respectively [2,16].
Another limitation of our study is that we did not collect data on relapse or emergence of resistance. Lastly, we used mostly endotracheal aspiration with quantitative cultures, which may have led us to overestimate the incidence of S. maltophilia in our population due to heightened sensitivity. Current guidelines for the management of VAP allow the use of endotracheal aspirates (in addition to invasive respiratory specimens), but with semi-quantitative as opposed to quantitative cultures. In France, however, endotracheal aspiration with quantitative cultures is the most commonly used technique for the diagnosis of VAP [30]. Thus, in the study by Guerci et al., which represents the largest sample of patients with VAP caused by S. maltophilia to date, 30.0% of cases were diagnosed using this technique [2].

Conclusion
This is the third retrospective study of VAP caused by S. maltophilia to use a large sample of patients and the first to focus primarily on the effect of antibiotic therapy on the prognosis of infected patients.
In our study, appropriate antibiotic therapy, and in particular trimethoprim-sulfamethoxazole, was associated with decreased ICU and hospital mortality in patients with VAP caused by S. maltophilia.