ABSTRACT
A combination therapy (CT) is recommended for S. maltophilia infections; however, supporting clinical data are limited. This study aimed to compare the effectiveness and safety of CT and monotherapy (MT) in the treatment of S. maltophilia bacteremia. A total of 292 adult inpatients with monomicrobial S. maltophilia bacteremia who received in vitro active CT or MT for >48 h were included for comparison. Multivariable logistic regression analysis was performed. The primary outcome was 30-day mortality, and the secondary outcomes included in-hospital mortality, microbiological eradication rate, clinical response, recurrent bacteremia, isolation of non-susceptible S. maltophilia isolates, and adverse drug reaction (ADR) occurrence. Thirty-seven patients received CT, and 255 received MT. Overall, the 30-day mortality was 24.0%, and patients treated with CT had lower 30-day mortality than those with MT (10.8% vs 25.9%; P = 0.045). The multivariable regression analysis revealed that CT was an independent protective factor. In addition, sensitivity analyses excluding patients with bacterial co-infections showed a consistent trend. Other outcomes were similar between the groups: in-hospital mortality (37.8% vs 36.9%, P = 0.909), clinical response (73.0% vs 71.8%, P = 0.879), microbiological eradication rate (94.6% vs 93.0%, P = 1.000), recurrent bacteremia (0% vs 9.4%, P = 0.087), non-susceptible S. maltophilia isolation (24.3% vs 14.9%, P = 0.145), and ADR occurrence (8.1% vs 13.7%, P = 0.441). CT for S. maltophilia bacteremia was associated with improved outcomes and comparable rates of ADRs and resistance emergence; however, randomized trials with larger cohorts are warranted to confirm these findings.
KEYWORDS: Stenotrophomonas maltophilia, bacteremia, combination therapy, monotherapy, mortality, adverse drug reactions
INTRODUCTION
Stenotrophomonas maltophilia is a non-fermenting, aerobic, Gram-negative bacillus commonly found in water-associated environments, both within and outside healthcare settings (1). Despite its relatively low virulence, S. maltophilia has emerged in recent years as an important opportunistic pathogen that can cause severe infections in vulnerable populations in both the community and healthcare environments (2). Among the various clinical presentations of S. maltophilia infection, pneumonia and bacteremia are the most common and are associated with high mortality rates reported to range from 18% to 69% (2, 3). Optimal treatment options for S. maltophilia are limited owing to its multidrug-resistant phenotype driven by both intrinsic and acquired resistance mechanisms, restricted availability of reliable susceptibility testing, and insufficient pharmacokinetic/pharmacodynamic data for accurate clinical breakpoint interpretation (4). Recent pharmacodynamic studies have shown that several antibiotics with in vitro activity against susceptible S. maltophilia isolates exhibit limited antimicrobial efficacy at the current susceptibility breakpoints, whereas combination antibiotic regimens demonstrate enhanced bactericidal activity (5–9). In light of these findings, the Infectious Diseases Society of America (IDSA) and the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) recommended combination therapy (CT) with at least two active agents for the treatment of S. maltophilia infections (10, 11). Nevertheless, the superior in vitro antimicrobial activity of CT has not consistently translated into improved clinical outcomes. Several studies conducted in patients with pneumonia have shown no clinical benefit of CT over MT among overall patient cohorts (12–15). One study focused on deep seated S. maltophilia infections showed levofloxacin-based combination therapies were associated with reduced odds of clinical failure compared to monotherapy (16). In bacteremia, another severe manifestation of S. maltophilia infection, the potential clinical benefits of CT have not been clearly demonstrated (17–21). Moreover, the safety outcomes of CT and MT have not been well studied. Therefore, this study aimed to compare the clinical efficacy and safety of CT and MT for the treatment of S. maltophilia bacteremia.
MATERIALS AND METHODS
Study design and population
This retrospective cohort study was conducted at the Tri-Service General Hospital, a 1,800-bed tertiary care center in northern Taiwan, and was approved by the Institutional Review Board (2-101-05-074). Adult inpatients (>18 years) with a first episode of S. maltophilia monomicrobial bacteremia between January 2004 and June 2025 were identified via the microbiology database. Each identified patient was assigned a unique case number for subsequent analyses.
The final evaluable cohort comprised patients with Stenotrophomonas maltophilia bacteremia who received at least 48 h of in vitro active antimicrobial therapy administered either intravenously or orally (trimethoprim/sulfamethoxazole [SXT], levofloxacin, or minocycline). Patients were excluded if they had polymicrobial bacteremia, did not receive in vitro active antimicrobial therapy (SXT, levofloxacin, or minocycline), or died within 48 h after the initiation of in vitro active therapy. Patients were classified as receiving monotherapy (MT; a single in vitro active agent, including trimethoprim/sulfamethoxazole, levofloxacin, or minocycline) or combination therapy (CT; two or more active agents, including trimethoprim/sulfamethoxazole plus levofloxacin, levofloxacin plus minocycline, trimethoprim/sulfamethoxazole plus minocycline, or all three agents). In cases where both MT and CT regimens were administered during the treatment course, patients were classified according to the regimen used for the longer duration, which was defined as the index regimen.
Data collection and definitions
Demographic data, comorbidities, source of infection, clinical status, treatment, and outcomes were extracted from the hospital’s electronic medical records (EMR) system. This system has maintained comprehensive inpatient clinical records since 2004. Data extraction and review were independently conducted by three investigators (W.-P.C., M.-H.T., and J.-C.L.). Hospital-acquired infection was defined as bacteremia ≥48 h after admission. Comorbid conditions documented at the time of admission were recorded, and the overall comorbidity burden was assessed using the Charlson Comorbidity Index (22). The source of bacteremia was identified according to the National Healthcare Safety Network (NHSN) surveillance definitions (23). Cases lacking an identifiable infectious focus were categorized as having an unidentified source of infection. The severity of infection at the onset of bacteremia was assessed using the Acute Physiology and Chronic Health Evaluation II (APACHE II) score. Acute kidney injury was defined as stage 2 and 3 based on KDIGO (Kidney Disease: Improving Global Outcomes) classification (24). Septic shock was defined according to previously established criteria (25). Concurrent infections caused by other bacteria or fungi within 48 h of the onset of S. maltophilia bacteremia were documented as co-infections. Patients with bacterial infections at distinct anatomical sites were recorded according to the NHSN surveillance definitions as corroborated by the growth of pathogens in the corresponding appropriate culture specimens (23). Only proven invasive fungal co-infections were documented based on the European Organization for Research and Treatment of Cancer/Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) consensus definitions since this category can apply to any patient regardless of whether the patient is immunocompromised (26). Two senior infectious disease specialists (F.-Y.C. and J.-C.L.) reviewed each case to differentiate between infection and colonization and identified proven invasive fungal infections from them according to EORTC/MSGERC criteria. Immediate effective antibiotic use for S. maltophilia was deemed appropriate if at least one active agent against S. maltophilia was administered within 48 h of bacteremia onset. Appropriate antibiotic dosing for S. maltophilia bacteremia followed the Sanford Guide to Antimicrobial Therapy for S. maltophilia infections (27). For combination therapy, appropriate dosing was defined as the administration of all antibiotics targeting S. maltophilia within the recommended dosage ranges. Infection source control was defined as the removal of a pre-existing central venous catheter or drainage of a localized abscess presumed to be the infection source, performed after the onset of bacteremia.
The primary study outcome was all-cause 30-day mortality. Secondary outcomes were in-hospital mortality, length of hospital stay (LOS) after bacteremia among survivors, clinical response, microbiological eradication, recurrent S. maltophilia bacteremia, non-susceptible S. maltophilia isolation, and antibiotic-related adverse reactions (ADRs). Clinical response was assessed at the end of therapy (EOT) by two senior infectious disease specialists (F.-Y.C. and J.-C.L.) and was defined as the improvement of all signs and symptoms of infection, together with the normalization or improvement of relevant inflammatory biomarkers (C-reactive protein [CRP] or procalcitonin [PCT] levels). Microbiological eradication was defined as the absence of S. maltophilia in the follow-up cultures before and after EOT. Patients without follow-up blood culture results were excluded from the analysis. Recurrent bacteremia was defined as a positive blood culture for S. maltophilia within 30 days after EOT in patients with prior eradication. The emergence of non-susceptible S. maltophilia was defined as the isolation of S. maltophilia that demonstrated non-susceptibility to previously administered antibiotics from any clinical specimen during treatment or within 30 days after EOT. The patients were also evaluated for ADRs related to the drug administered by two investigators (W.-P.C. and J.-C.L.) using the Naranjo Adverse Drug Reaction Probability Scale, as described in our previous study (28).
Microbiological testing
During the study period from 2004 to 2015, pathogen identification was performed using a VITEK 2 automated system (bioMérieux, Marcy l’Etoile, France). Since 2016, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), specifically the VITEK MS system (bioMérieux, Marcy l’Etoile, France), has been adopted for microbial identification. Antimicrobial susceptibility testing of the cultured pathogens was conducted using a VITEK 2 system. For S. maltophilia, susceptibility testing included levofloxacin, SXT, and minocycline susceptibility testing (the disk diffusion method), which began in 2022. All susceptibility interpretations were performed according to the 2024 Clinical and Laboratory Standards Institute guidelines. Carbapenem-resistant organisms were defined as those resistant to at least one carbapenem.
Statistical analyses
Continuous variables were reported as median (interquartile range) and categorical variables as counts (%). Normality was assessed using the Kolmogorov-Smirnov test. Between-group comparisons were performed using the Student’s t-test or Mann-Whitney U test for continuous variables and Chi-square or Fisher’s exact test for categorical variables. Logistic regression identified factors associated with 30-day mortality; variables with P ≤ 0.1 in univariable analysis and deemed clinically relevant were, thus, included in a multivariable logistic regression analysis (3, 29). Because comparison of antimicrobial therapy regimens was the primary aim of the current study, variables related to antimicrobial therapy—including combination therapy, appropriate dosage, and timing of administration—were included in the multivariable regression model regardless of statistical significance. Results were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Kaplan–Meier survival curves were compared using the log-rank test. We conducted several additional sensitivity analyses. First, patients in the MT group who concurrently received tigecycline, colistin, or quinolones other than levofloxacin were excluded to minimize potential confounding effects of these antimicrobial agents in the MT group. Second, patients with co-infections by other bacteria were excluded, as the presence of additional pathogens could influence outcome analyses. The remaining subgroups after exclusion were reanalyzed to evaluate the impact of CT on 30-day mortality. Statistical analysis was performed using SPSS v27.0 (SPSS Inc., Chicago, IL, USA); P <0.05 was considered statistically significant.
RESULTS
Study population
During the study period, 755 adult inpatients with a first episode of S. maltophilia bacteremia were initially identified, of whom 292 met the inclusion criteria. Among the corresponding 292 S. maltophilia isolates, non-susceptibility to SXT was observed in 0% (0/22), 1.4% (1/71), 6.8% (8/117), and 12.1% (10/82) of isolates during 2004–2009, 2010–2014, 2015–2019, and 2020–2025, respectively. Non-susceptibility to levofloxacin was 4.5% (1/22), 5.6% (4/71), 4.2% (5/117), and 10.9% (9/82) across the same periods. An increasing trend in resistance to both agents was observed over time (Fig. S1). The patients were categorized into two groups: 37 patients who received CT and 255 who received MT (Fig. 1). Baseline characteristics were comparable between the groups in terms of demographics, comorbidities, bacteremia sources, and clinical status at onset (Table 1). A total of 136 co-infection episodes caused by bacteria other than S. maltophilia were identified in 117 patients (Table S1), with the causative pathogens listed in Table S2. Forty patients had co-infections with carbapenem-resistant organisms, with no significant differences between the groups; details are shown in Table S3. Patients in the CT group were more likely to receive immediate effective antimicrobial therapy than those in the MT group (40.5% vs 16.5%, P <0.001). The most common regimen in the CT group was SXT plus levofloxacin (26/37, 70.2%), whereas levofloxacin MT predominated in the MT group. Details of regimen changes in both groups were summarized in Table 1. Only 123 patients (42.1%) received the appropriate antibiotic dose for S. maltophilia, with appropriate dosing more frequent in the MT group (45.1% vs 21.6%, P = 0.007). Treatment duration was longer in the CT group than in the MT group (20 vs 14 days, P <0.001). Concurrently administered antibiotics for coinfections (excluding those targeting S. maltophilia) are summarized in Table S4, with no significant differences between the groups.
Fig 1.
Flowchart of patients’ inclusion criteria for Stenotrophomonas maltophilia bacteremia treated with combination vs monotherapy.
TABLE 1.
Clinical characteristic comparisons among patients with S. maltophilia bacteremia who received CT vs MTe
| Characteristics | Total (n = 292) | CT (n = 37) | MT (n = 255) | P value |
|---|---|---|---|---|
| Demographics, n (%) | ||||
| Age, yearsa | 71.5 (59–80.75) | 71 (61–79.5) | 72 (58–81) | 0.618 |
| Male sex | 194 (66.4) | 20 (54.1) | 174 (68.3) | 0.088 |
| Body weight (kg)a | 59.75 (51–70) | 60 (51.5–70) | 59 (50–70) | 0.840 |
| Hospital acquired | 286 (97.9) | 37 (100) | 249 (97.6) | 1.000 |
| Hospital LOS before bacteremia (day)a | 23 (13–38.75) | 25 (15–45.5) | 23 (13–38) | 0.357 |
| ICU admission at bacteremia onset | 211 (72.3) | 26 (70.3) | 185 (72.5) | 0.844 |
| Comorbidities, n (%) | ||||
| Heart failure | 68 (23.3) | 9 (24.3) | 59 (23.1) | 0.873 |
| Old cerebrovascular accident | 47 (16.1) | 6 (16.2) | 41 (16.1) | 0.983 |
| Chronic obstructive pulmonary disease | 23 (7.9) | 2 (5.4) | 21 (8.2) | 0.750 |
| Diabetes mellitus | 103 (35.3) | 15 (40.5) | 88 (34.5) | 0.473 |
| Liver cirrhosis | 22 (7.5) | 2 (5.4) | 20 (7.8) | 1.000 |
| Chronic kidney diseaseb | 63 (21.6) | 11 (29.7) | 52 (20.4) | 0.197 |
| Malignancy | 94 (32.2) | 13 (35.1) | 81 (31.8) | 0.682 |
| Autoimmune disease | 12 (4.1) | 1 (2.7) | 11 (4.3) | 1.000 |
| Charlson Comorbidity Indexa | 3 (2–5) | 3 (0.5–4.5) | 3 (2–5) | 0.671 |
| Source sites of bacteremia, n (%) | 0.839 | |||
| Respiratory tract | 143 (49.0) | 19 (51.4) | 124 (48.6) | |
| Central line associated | 85 (29.1) | 12 (32.4) | 73 (28.8) | |
| Unidentified | 54 (18.5) | 5 (13.5) | 49 (19.2) | |
| Othersc | 10 (3.4) | 1 (2.7) | 9 (3.5) | |
| Clinical conditions at bacteremia onset, n (%) | ||||
| APACHE II scorea | 19 (14–24) | 19 (13–25.5) | 19 (14–24) | 0.971 |
| Septic shock | 62 (21.2) | 7 (18.9) | 55 (21.5) | 0.713 |
| Thrombocytopeniad | 76 (26.0) | 12 (32.4) | 64 (25.1) | 0.342 |
| Acute kidney injury | 57 (19.5) | 6 (16.2) | 51 (20.0) | 0.587 |
| Concurrent invasive fungal infection | 1 (0.3) | 0 (0) | 1 (0.4) | 0.703 |
| Coinfections by other bacterial species | 117 (40.1) | 15 (40.5) | 102 (40.0) | 0.950 |
| Coinfections by other carbapenem-resistant organisms | 69 (23.6) | 9 (24.3) | 60 (23.5) | 0.915 |
| Antibiotic treatment | ||||
| Immediate effective antibiotic targeting S. maltophilia | 57 (19.5) | 15 (40.5) | 42 (16.5) | <0.001 |
| Different antibiotic regimens targeting for S. maltophilia | ||||
| SXT + levofloxacin | 26 | –f | ||
| SXT + minocycline | 3 | – | ||
| Levofloxacin + minocycline | 4 | – | ||
| SXT + levofloxacin + minocycline | 1 | – | ||
| Levofloxacin + minocycline followed by SXT + minocycline | 2 | – | ||
| SXT + minocycline followed by minocycline + levofloxacin | 1 | – | ||
| Levofloxacin only | – | 129 | ||
| SXT only | – | 97 | ||
| Minocycline only | – | 8 | ||
| Levofloxacin followed by minocycline | – | 3 | ||
| SXT followed by levofloxacin | – | 10 | ||
| Levofloxacin followed by SXT | – | 8 | ||
| Appropriate antibiotic treatment dosage for S. maltophilia | 123 (42.1) | 8 (21.6) | 115 (45.1) | 0.007 |
| Treatment duration, day | 14 (9–18.75) | 20 (14–20.5) | 14 (8–17) | <0.001 |
| Source control measures | 58 (19.9) | 8 (21.6) | 50 (19.6) | 0.774 |
Data are presented as median (interquartile range).
Blood creatinine levels above 3 mg/dL.
One is from wound culture, three from intra-abdominal sites, and six from the urinary tract.
Platelet count of less than 150,000/µL.
CT, combination therapy; MT, monotherapy; LOS, length of stay; ICU, intensive care unit; APACHE, Acute Physiology and Chronic Health Evaluation; SXT, trimethoprim/sulfamethoxazole.
–, not applicable.
Primary outcomes
Patients receiving CT had lower 30-day mortality than those receiving MT (10.8% vs 25.9%, P = 0.045), consistent with Kaplan–Meier analysis (P = 0.035; Fig. 2). Mortality by infection source is shown in Fig. 3 including respiratory tract (33.9% vs 15.8%), central line associated (20.5% vs 8.3%), unidentified (12.2% vs 0%), and other types of infections (33.3% vs 0%) for MT vs CT, respectively. After excluding patients in the MT group who had received concomitant potentially in vitro active agents without available susceptibility data (MT group, n = 204; CT group, n = 37), CT again demonstrated a numerically lower 30-day mortality although the difference was no longer statistically significant (10.8% vs 25.5%, P = 0.052). After excluding patients with co-infections caused by other bacteria (MT group, n = 153; CT group, n = 22), reanalysis showed lower 30-day mortality in the CT group compared with the MT group; however, the difference did not reach statistical significance (13.6% vs 28.8%, P = 0.135). Because Acinetobacter spp. was the most common co-pathogen in our cohort, an additional analysis excluding patients with concomitant Acinetobacter spp. infection was performed to minimize potential confounding (MT group, n = 208; CT group, n = 30). Consistently, the CT group remained associated with lower 30-day mortality although statistical significance was not achieved (13.3% vs 26.9%, P = 0.109). Univariable analysis identified respiratory tract infections (OR 2.278, 95% CI, 1.306–3.972; P = 0.004), unidentified origin (OR 0.331, 95% CI, 0.135–0.810; P = 0.015), APACHE II score (OR 1.127, 95% CI, 1.077–1.179; P <0.001), and thrombocytopenia (OR 3.872, 95% CI, 2.170–6.910; P < 0.001) as significant factors for 30-day mortality. CT (OR 0.347, 95% CI 0.118–1.017; P = 0.054) and source control measures (OR 0.444, 95% CI 0.199–0.989; P = 0.057) demonstrated a trend for improved survival, yet neither were statistically significant. In the multivariable analysis, CT was a protective factor against mortality (aOR 0.229, 95% CI, 0.070–0.750; P = 0.015). In contrast, a higher APACHE II score (aOR 1.101, 95% CI, 1.048–1.156; P <0.001) and thrombocytopenia (aOR 2.708, 95% CI, 1.438–5.102; P = 0.002) were independently associated with increased mortality (Table 2). Sensitivity analyses using multivariable logistic regression analyses yielded consistent findings across models (Tables S5 to S7), with CT remaining associated with lower mortality after adjustment.
Fig 2.
Kaplan–Meier plot in patients with Stenotrophomonas maltophilia bacteremia receiving combination therapy and monotherapy.
Fig 3.
Thirty-day mortality in patients with Stenotrophomonas maltophilia bacteremia of different infection source sites between combination therapy and monotherapy.
TABLE 2.
Variables associated with 30-day mortalitya
| Variable | Survivors (n = 222) |
Nonsurvivors (n = 70) |
Univariable | Multivariable | ||
|---|---|---|---|---|---|---|
| Unadjusted OR (95% CI) |
P value | Adjusted OR (95% CI) |
P value | |||
| Demographics and comorbidities | ||||||
| Age | 73.5 (59–80) | 73.5 (58–83.25) | 1.010 (0.993–1.027) | 0.264 | ||
| Male sex | 147 (66.2) | 47 (67.1) | 1.043 (0.589–1.846) | 0.886 | ||
| Charlson Comorbidity Index | 3 (2–5) | 3 (2–5) | 1.004 (0.897–1.124) | 0.946 | ||
| Hospital acquired | 218 (98.2) | 68 (97.1) | 0.624 (0.112–3.481) | 0.591 | ||
| Source sites of bacteremia | ||||||
| Respiratory tract | 98 (44.1) | 45 (64.3) | 2.278 (1.306–3.972) | 0.004 | 1.146 (0.481–2.734) | 0.758 |
| Central line associated | 69 (31.1) | 16 (22.9) | 0.657 (0.351–1.229) | 0.189 | ||
| Unidentified origin | 49 (22.1) | 6 (8.6) | 0.331 (0.135–0.810) | 0.015 | 0.562 (0.167–1.899) | 0.354 |
| Clinical conditions at bacteremia onset | ||||||
| APACHE II score | 17.5 (13–22.5) | 23 (19.75–27) | 1.127 (1.077–1.179) | <0.001 | 1.101 (1.048–1.156) | <0.001 |
| Thrombocytopenia | 41 (18.7) | 33 (47.1) | 3.872 (2.170–6.910) | <0.001 | 2.708 (1.438–5.102) | 0.002 |
| Co-infection by other bacteria | 94 (42.3) | 23 (32.9) | 0.666 (0.379–1.173) | 0.159 | ||
| Co-infections by other carbapenem- resistant organisms |
52 (23.4) | 17 (24.3) | 1.049 (0/559–1.966) | 0.882 | ||
| Antibiotic treatment | ||||||
| Immediate effective antibiotic targeting for S. maltophilia |
41 (18.5) | 16 (22.9) | 1.308 (0.681–2.513) | 0.420 | 1.229 (0.581–2.598) | 0.590 |
| Combination therapy for S. maltophilia | 33 (14.9) | 4 (5.7) | 0.347 (0.118–1.017) | 0.054 | 0.229 (0.070–0.750) | 0.015 |
| Appropriate antibiotic treatment dosage for S. maltophilia |
94 (42.3) | 29 (41.4) | 0.963 (0.558–1.661) | 0.893 | 0.874 (0.473–1.615) | 0.667 |
| Source control measures | 50 (22.5) | 8 (11.4) | 0.444 (0.199–0.989) | 0.057 | 0.548 (0.175–1.721) | 0.303 |
APACHE II, Acute Physiology and Chronic Health Evaluation; CI, confidence interval; OR, odds ratio.
Secondary outcomes
No significant differences were observed between the CT and MT groups in terms of secondary outcomes, including in-hospital mortality, clinical response, microbiological eradication, and emergence of non-susceptible S. maltophilia isolates (Table 3). Among the 282 patients with follow-up cultures, the rates of non-susceptible S. maltophilia occurrence to levofloxacin, SXT, and minocycline were similar between the groups (Table 3). Resistance patterns are detailed in Table S8, with the most common being concurrent non-susceptibility to levofloxacin and SXT (n = 21), followed by levofloxacin only (n = 12), and SXT-only (n = 11) resistance. Further clinical information for those patients was shown in Tables S9 and S10. ADRs occurred in 38 patients (13.0%) and did not differ significantly between groups (18.9% vs 12.2%, P = 0.293; Table 4). Hyperkalemia (n = 25) was the most common complication. Most events were moderate (n = 30) or mild (n = 8) according to the Hartwig Severity Assessment Scale. Seven patients (2.3%) discontinued antibiotics because of adverse events.
TABLE 3.
Clinical and microbiologic outcomes in patients with S. maltophilia bacteremia treated with CT vs MTd
| Variables, n (%) | Total (n = 292) | CT (n = 37) | MT (n = 255) | P value |
|---|---|---|---|---|
| 30-day mortality | 70 (24.0) | 4 (10.8) | 66 (25.9) | 0.045 |
| In-hospital mortality | 108 (37.0) | 14 (37.8) | 94 (36.9) | 0.909 |
| Clinical response after EOT | 210 (71.9) | 27 (73.0) | 183 (71.8) | 0.879 |
| Microbiological eradication (n = 265)a | 247 (93.2) | 35 (94.6) | 212 (93.0) | 1.000 |
| Recurrence bacteremia (n = 247)b | 20 (8.1) | 0 (0) | 20 (9.4) | 0.087 |
| Non-susceptible S. maltophilia isolation (n = 282)c | 47 (16.0) | 9 (24.3) | 36 (14.9) | 0.136 |
265 patients with follow-up blood cultures available are included in the analysis.
247 patients with documented microbiologic eradication from blood are included for bacteremia recurrence analysis.
282 patients with follow-up cultured S. maltophilia are included for analysis.
CT: combination therapy; MT: monotherapy; LOS: length of stay; EOT: end of therapy.
TABLE 4.
Safety data among patients with S. maltophilia bacteremia who received CT vs MTc
| Factors, n (%) | Total (n = 292) | CT (n = 37) | MT (n = 255) | P value |
|---|---|---|---|---|
| Any adverse reaction | 38 (13.0) | 7 (18.9) | 31 (12.2) | 0.293 |
| Skin rash | 3 | 0 | 3 | |
| Hyperkalemiaa | 24 | 2 | 22 | |
| Agranulocytosisb | 2 | 0 | 2 | |
| Diarrhea | 3 | 3 | 0 | |
| Hepatitis | 5 | 1 | 4 | |
| Hyperkalemia + Diarrhea + Hepatitis | 1 | 1 | 0 | |
| Discontinued antibiotic use due to adverse drug reactions | 7 (2.4) | 0 (0) | 7 (2.7) | 1.000 |
Serum potassium level >5.5 mmol/L.
Absolute neutrophil count <1,500/μL.
CT, combination therapy; MT, monotherapy.
DISCUSSION
This study compared the clinical, microbiological, and safety outcomes of patients receiving CT vs MT for monomicrobial S. maltophilia bacteremia. The results showed that patients receiving CT had a lower risk of 30-day mortality than those receiving MT, both in the crude and adjusted analyses. The rates of bacteremia recurrence, S. maltophilia resistance development, and ADR were comparable between the CT and MT groups.
Several studies comparing the clinical outcomes of CT and MT for S. maltophilia pneumonia or bacteremia have reported conflicting results (12–21). Regarding S. maltophilia pneumonia, four relevant studies were identified (12–15). Two studies found no significant difference in 30-day mortality (12, 13), whereas Shah et al. reported higher mortality with CT (14). Another study by Chen et al. demonstrated significantly lower odds of 30-day mortality associated with CT in two subgroups: immunocompromised patients and those with APACHE II scores ≥15 (15). The diagnosis of S. maltophilia pneumonia in these studies was based on clinical symptoms, imaging findings, laboratory data, and respiratory cultures. However, due to the low virulence of S. maltophilia, distinguishing between colonization and true infection is difficult, complicating the evaluation of treatment efficacy (30, 31). Moreover, S. maltophilia was co-isolated with other respiratory pathogens in 34.3%–54% of cases in these studies, most commonly Pseudomonas aeruginosa. In polymicrobial pneumonia, co-pathogens may also affect the outcomes (32, 33). A recent study of deep-seated S. maltophilia infections found that levofloxacin-based combination therapy was associated with reduced odds of clinical failure in adjusted analyses, suggesting a potential benefit of combination therapy. However, other coinfections commonly observed in S. maltophilia infections were not adjusted for and may have introduced bias (16). Three studies involving patients with S. maltophilia bacteremia were noted (17, 19, 21). One study involving patients with cancer found no association between CT and improved outcomes (21). The study by Muder et al. reported a benefit of CT in immunocompromised patients, whereas the study by Osawa et al. showed opposite results (17, 19). Given the limited number of bacteremia cases, adjustment for certain mortality-related confounders was not feasible, and polymicrobial bacteremia was not consistently excluded, which may have biased the findings. Finally, none of the reported studies on patients with pneumonia or bacteremia evaluated the appropriateness of the dosing regimens used.
To address the limitations of previous studies, the current study included only patients with monomicrobial S. maltophilia bacteremia, which clearly defines true invasive infection and excludes the potential influence of co-pathogens in the blood. Moreover, several confounding factors related to mortality were adjusted for, including antibiotic treatment and coinfections other than bacteremia. Treatment duration, which showed a significant difference between the CT and MT groups in the current study (Table 1), was not included in the multivariable analysis due to the risk of survival bias. In the adjusted multivariable regression models and across several additional sensitivity analyses, CT demonstrated a consistent trend toward improved 30-day mortality (Table 2; Table S5 to S7). Subgroup analysis also showed that the beneficial effects were similar across different infection site sources (Fig. 3). CT can provide broader spectrum coverage than MT, thereby increasing the rate of appropriate immediate antibiotic use, as observed in the current study, which is a factor crucial for improved outcomes in patients with S. maltophilia bacteremia (34). In addition, the enhanced efficacy of CT in in vitro studies may play a role (8, 9). Nevertheless, not all antibiotic combinations have demonstrated similar effects in previous studies, and even the same combination has shown varying antimicrobial activity against different S. maltophilia isolates (8, 9). In the current study, levofloxacin with SXT was the most commonly used combination regimen; however, synergistic antimicrobial activity was observed in only approximately 24% of tested isolates in an in vitro study (21).
We also compared the occurrence of adverse drug reactions (ADRs) and the risk of developing resistance between the CT and MT groups. The overall ADR rate was 13.0%, which is consistent with previous studies (35). All reported ADRs were classified as mild-to-moderate according to the Hartwig Severity Assessment Scale. Only seven patients (2.4%) discontinued antibiotic treatment because of adverse events. SXT-related hyperkalemia was the most frequently reported ADR and the leading cause of treatment discontinuation. Consistent with our findings, a recent study by Chen et al. reported that SXT-related hyperkalemia was a major adverse drug reaction during the treatment of S. maltophilia bacteremia, particularly at higher doses. Notably, that study observed no significant difference in 30-day mortality between patients receiving high- vs low-dose SXT therapy (28). Further studies are warranted to define the optimal SXT dosing strategy for the treatment of S. maltophilia infections; however, clinicians should remain vigilant for this potentially life-threatening ADR. Hepatitis associated with levofloxacin was infrequent and mild in severity; therefore, none of the patients discontinued levofloxacin because of hepatitis. Owing to the favorable safety profile and tolerability of levofloxacin, the combination regimen of levofloxacin and SXT, which was the main CT regimen in this study, did not increase the risk of ADRs or treatment discontinuation.
S. maltophilia isolates with concurrent non-susceptibility to SXT and levofloxacin were the most frequently observed resistant phenotypes among follow-up cultures after antibiotic use. This resistance mechanism may be attributed to the overexpression of SmeVWX or SmeDEF, which can lead to concomitant SXT and levofloxacin resistance when either agent is used, as previously demonstrated (36). Several in vitro studies have shown that acquired resistance to S. maltophilia may occur after the use of individual agents (36, 37). Therefore, CT for S. maltophilia infection is suggested not only for its potentially enhanced antimicrobial efficacy but also for the possible prevention of resistance emergence. Our study evaluated the effect of CT on preventing resistance development; however, the results did not demonstrate a protective effect against the emergence of resistant strains. Because only 37 patients received CT in the current study, further research involving a larger cohort of CT cases is needed to validate these findings.
This study has some important limitations. First, its retrospective design is inherently susceptible to selection and recall biases. Although major confounders influencing the outcomes were adjusted using multivariable models, unmeasured residual confounders that could affect the analysis remain a concern (29–34). Second, the relatively small sample size of the CT group (n = 37) may have reduced statistical power and affected the interpretation of the results. The limited sample size also precluded subgroup analyses based on different combination regimens or specific host populations. Third, suboptimal antibiotic dosing for the treatment of S. maltophilia infection (only 123 patients [42.1%] in both treatment groups received optimal doses) may have influenced treatment efficacy although this association was not identified in the logistic regression analysis. Fourth, ADRs were assessed through a medical chart review. Given that 211 cases (72.3%) involved ICU admission, multiple comorbidities, and concurrent medical treatments in addition to receiving antibiotics for S. maltophilia infection, it was often difficult to attribute adverse reactions solely to antibiotic therapy. This may have introduced bias in the estimates. Fifth, the high rate of bacterial coinfections in this cohort, including 23.6% caused by carbapenem-resistant organisms, limited our ability to isolate the specific effect of CT vs MT on outcomes of S. maltophilia infection. Sixth, the exclusion of S. maltophilia treatment with other potentially active agents, such as colistin, may limit the generalizability of our findings to centers where these additional agents are commonly used. Finally, the single-center design of this study limits the generalizability of our results to other institutions or geographic regions.
Conclusion
In this observational study, CT for S. maltophilia bacteremia was associated with more favorable outcomes and comparable rates of adverse drug reactions and resistance emergence. Our clinical data support the current recommendations advocating CT for the treatment of S. maltophilia infections. However, given the limitations of this study, further evidence from randomized studies with larger sample sizes is required to confirm these findings.
ACKNOWLEDGMENTS
This work was supported by grants from the Tri-Service General Hospital Penghu Branch (TSGH-PH-E112006) and the Tri-Service General Hospital National Defense Medical University (TSGH_E_115281, TSGH_D_113143, TSGH-E-112255, and TSGH_D_113181).
C.-H.W. contributed to the study design; M.-H.T., W.-P.C., J.-C.L., and Y.-S.Y. contributed to manuscript writing; L.K.S., F.-Y.C., W.-P.C., C.-M.Y., H.-S.S., and J.-C.L. contributed to data collection, analysis, and interpretation; C.-H.W. and J.-C.L. reviewed and approved the final version of the manuscript. All the authors have read and approved the final manuscript.
Contributor Information
Ching-Hsun Wang, Email: sasak0308@gmail.com.
Sarah Doernberg, University of California San Francisco, San Francisco, California, USA.
ETHICS APPROVAL
This study was approved by the Institutional Review Board and Ethics Committee of the Tri-Service General Hospital of the National Defense Medical Center [Approval No no.2-101-05-074]. The requirement for informed consent from each patient was waived because the study design was retrospective, and anonymized patient and hospital data were used.
SUPPLEMENTAL MATERIAL
The following material is available online at https://doi.org/10.1128/aac.01297-25.
Non-susceptibility trend of Stenotrophomonas maltophilia isolates to SXT and levofloxacin over the study period.
Fig. S1 legend.
Tables S1 to S10.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Non-susceptibility trend of Stenotrophomonas maltophilia isolates to SXT and levofloxacin over the study period.
Fig. S1 legend.
Tables S1 to S10.