Introduction
Stenotrophomonas maltophilia, an aerobic Gram-negative bacillus, represents an increasingly common cause of nosocomial infections, especially in immunocompromised patients. Due to its intrinsic resistance to multiple antibiotics and propensity for biofilm formation, S. maltophilia infections pose a unique therapeutic challenge. Reference Mojica, Rutter and Taracila1–Reference Dales, Ferris, Vandemheen and Aaron4 Pneumonia is the most frequent clinical syndrome observed with S. maltophilia infections and is associated with significant morbidity and mortality, particularly when the initiation of effective antibiotic therapy is delayed. Reference Fujita, Yamadori and Xu5–Reference Falagas, Kastoris, Vouloumanou, Rafailidis, Kapaskelis and Dimopoulos8
Trimethoprim-sulfamethoxazole (TMP-SMX) is considered the drug of choice for S. maltophilia infections, either as monotherapy or in combination with other active agents, due to low rates of in vitro resistance Reference Chang, Lin, Chen and Hsueh9,Reference Vartivarian, Anaissie, Bodey, Sprigg and Rolston10 and decades of clinical experience without explicit evidence of treatment failure. Reference Muder, Harris and Muller11–Reference Wang, Scipione, Dubrovskaya and Papadopoulos14 Many references recommend a weight-based dose of 15–20 mg/kg/day of the TMP component in divided doses, a scheme reminiscent of that which is employed for Pneumocystis jirovicii pneumonia. Reference Brown15,Reference Gibb and Wong16 However, considering the established risk of dose-dependent toxicities including nausea and vomiting, hyperkalemia, and nephrotoxicity, Reference Stevens, Laizure, Williams and Stein17 the optimal TMP-SMX dose from both an efficacy and safety standpoint remains unknown.
Clinical data investigating the efficacy of TMP-SMX in S. maltophilia infections are scarce. Small prospective observational studies and retrospective cohort studies have not provided definitive results on which to base recommendations. These studies boast similar rates of clinical success with TMP-SMX despite wide variability in median daily dose utilized. Moreover, significant heterogeneity in patient immune status and use of combination therapy in the literature limit the ability to draw broad conclusions. Reference Muder, Harris and Muller11–Reference Wang, Scipione, Dubrovskaya and Papadopoulos14 As such, more conservative TMP-SMX dosing regimens of 8–12 and 10–15 mg/kg/day have been suggested by infectious diseases (ID) specialists in recently published guidance documents. Reference Tamma, Aitken, Bonomo, Mathers, van Duin and Clancy18,Reference Tamma, Heil, Justo, Mathes, Satlin and Bonomo19 We designed a single-center, retrospective, cohort study to evaluate the impact of TMP-SMX dosing on outcomes of patients with S. maltophilia pneumonia.
Methods
Study design, site, and patient selection
This was a retrospective cohort study performed at The Ohio State University Wexner Medical Center, a tertiary academic hospital in Columbus, Ohio, USA. Clinical outcomes of patients treated with TMP-SMX at doses of 8–12 mg/kg/day (low-dose, LD) versus >12 mg/kg/day (high-dose, HD) of the TMP component were compared. Those who experienced an adverse drug event requiring the TMP-SMX dose to be reduced from HD to LD were included in the HD group. Actual body weight was used to determine the weight-based dose, except in the case of obesity (i.e., actual body weight >120% of ideal body weight), in which case adjusted body weight with an adjustment factor of 0.4 was used.
Patients aged 18–89 years with a respiratory culture positive for S. maltophilia and who received TMP-SMX at a dose of ≥8 mg/kg/day for ≥96 hours between October 1, 2012, and September 30, 2022, were screened for eligibility. Patients were included if they were diagnosed with pneumonia based on clinical and radiographic findings at the time of initiation of antibiotics. Exclusion criteria included index S. maltophilia isolate non-susceptible to TMP-SMX; creatinine clearance <30 mL/min or receiving hemodialysis or peritoneal dialysis at time of TMP-SMX initiation; and receipt of combination therapy targeting S. maltophilia for >50% of the treatment course. Protected patient populations, including prisoners and pregnant women, were also excluded. This study was approved by The Ohio State University Office of Responsible Research Practices Institutional Review Board (IRB).
Study endpoints
The primary outcome was clinical success at the end of therapy, which was defined as resolution or improvement in the clinical features of infection and no further S. maltophilia-specific treatment required. This outcome was determined retrospectively by an ID physician assessor. Pneumonia was defined as the presence of radiographic changes (ie, new or progressive infiltrate or consolidation suggestive of bacterial pneumonia) and at least one clinical feature of infection, such as temperature ≥100.4 °F or ≤95.0 °F, white blood cell count >10,000 cells/mm Reference di Bonaventura, Spedicato, D’Antonio, Robuffo and Piccolomini3 or <4,500 cells/mm Reference di Bonaventura, Spedicato, D’Antonio, Robuffo and Piccolomini3 , >15% immature neutrophils regardless of leukocyte count, new onset or acute worsening of pulmonary symptoms or signs (i.e., cough, dyspnea, sputum production), or need for increased suctioning or ventilatory support in terms of fraction of inspired oxygen (FiO2) or positive end-expiratory pressure (PEEP). 20
Secondary outcomes (defined in the Supplementary Table 1). included microbiological success, infection-related inpatient mortality, all-cause inpatient mortality, infection recurrence, development of TMP-SMX resistance, treatment-emergent AKI and/or hyperkalemia, and adverse effects necessitating TMP-SMX dose reduction or discontinuation.
Statistical analysis
Given the retrospective nature of this study, sample size was driven by eligible patients rather than statistical power. Descriptive statistics, including median with interquartile ranges (IQR) or calculated proportion as a percentage (%), were used to compare the LD and HD groups for the primary univariate analysis. Quantitative variables were analyzed using the student’s t-test, and qualitative variables were analyzed using Pearson’s chi-squared test or Fisher’s exact test, as appropriate. A multivariable logistic regression model was used to estimate the adjusted odds ratios for the relationship between primary outcome of clinical success and low- versus high-dose of TMP-SMX while adjusting for proven confounders. Variables that were moderately associated (P < 0.2) with both the exposure (TMP-SMX dose) and outcome (clinical success) at the univariate level were considered in the model as potential confounders. A forward selection method was utilized adding only one variable at a time, with variables that affected the relationship between the exposure and outcome by 15% or greater considered proven confounders and included in the final model. All statistical tests were performed at a significance level of P < 0.05 using SAS statistical software (SAS Institute version 9.3, Cary, NC).
Results
Study population
Of 461 patients with a respiratory culture positive for S. maltophilia, 95 were included: 20 in the LD group and 75 in the HD group (Figure 1).
Figure 1. Cohort creation. CrCl, creatinine clearance; TMP-SMX, trimethoprim-sulfamethoxazole.
Demographic and baseline characteristics of each group are shown in Table 1. Amongst the total sample, the median age was 61 years, 60 (63%) were male and 25 (26%) were immunocompromised. On the day of index respiratory culture, 71 (75%) were in an ICU, 63 (66%) were mechanically ventilated, and the median SOFA score was 5 (IQR 3-9). The index respiratory culture was polymicrobial (excluding yeast) in 49 (52%) patients and 50 (53%) were managed by an ID consultant. Notably, more patients in the LD group received continuous renal replacement therapy (CRRT) while on TMP-SMX and their baseline serum creatinine at the time of treatment initiation was higher than that of the HD group.
Table 1. Baseline characteristics
Values presented as median [IQR] or n (%). BAL, bronchoalveolar lavage; BMI, body mass index; CrCl, creatinine clearance; CRRT, continuous renal replacement therapy; ESBL, extended spectrum β-lactamase; HD, high-dose; ICU, intensive care unit; LD, low-dose; SCr, serum creatinine; TMP-SMX, trimethoprim-sulfamethoxazole.
a Prednisone dose ≥20 mg/day (or equivalent).
b Includes cyclosporine, azathioprine, and ocrelizumab.
c Includes Aspergillus spp.
d Includes Achromobacter spp., Streptococcus spp., Enterococcus spp., and Corynebacterium spp.
The median TMP-SMX daily dose received was 10.20 (IQR: 9.6–11.3) mg/kg in the LD group and 14.8 (IQR: 13.7–15.3) mg/kg in the HD group. No difference in median duration of TMP-SMX therapy was observed between groups: 8 (IQR: 6.5–14) days in the LD group versus 10 (IQR: 7–14) days in the HD group. There was also no difference between the LD and HD groups in terms of the number of patients who received combination therapy targeting S. maltophilia for part of the treatment course (20% vs 13%, P = 0.48), and all such patients received minocycline in combination with TMP-SMX.
Outcomes
No difference in clinical success at end of therapy was observed between the LD and HD groups (55% vs 63%, P = 0.53). Only SOFA score was identified as a proven confounding variable in univariate analysis. Of note, variables that are components of the SOFA score, including mechanical ventilation and those describing baseline renal function (CrCl, SCr, and CRRT), were not considered for the model due to co-linearity. On multivariable regression analysis, there remained no significant difference in clinical success rate after controlling for this variable (aOR 1.63, 95% CI 0.49–5.50). In patients with a repeat respiratory culture collected within 30 days of the end of therapy (n = 33), there was no difference in microbiological success between the LD and HD groups. There was also no difference in development of resistance between groups amongst the evaluable population who survived for at least 30 days after the end of therapy (n = 63). No differences in other secondary outcomes were noted between groups (Table 2).
Table 2. Secondary outcomes
AE, adverse event; HD, high-dose; LD, low-dose; TMP-SMX, trimethoprim-sulfamethoxazole.
Discussion
We found no difference in clinical success between LD and HD TMP-SMX for the treatment of S. maltophilia pneumonia, even after controlling for the proven confounder of SOFA score. To our knowledge, this is the largest study to date comparing LD and HD TMP-SMX for the treatment of such infections. Infection-related and all-cause inpatient mortality, microbiological outcomes, infection recurrence, and AEs of interest were also similar between groups.
No prospective, randomized trials have compared clinical outcomes in patients treated with different doses of TMP-SMX for S. maltophilia pneumonia. To date, only one study has investigated outcomes based on TMP-SMX dose amongst those with such infections. Reference Hall, Ortwine, Wei, Mang, Prokesch and Pichlinski21 Patients in this study were stratified into two groups based on dose received after adjusting for renal function: <15 mg/kg/day and ≥15 mg/kg/day. The median doses between groups compared in the previous study were predictably higher than those in our study (12 vs. 16 mg/kg/day and 10.2 vs. 14.8 mg/kg/day, respectively). While this methodological difference makes it difficult to compare findings from this study to ours, the previous study notably also failed to show a difference in clinical success between groups (41% vs. 59%, P = 0.24).
In several small, retrospective studies comparing TMP-SMX to other active therapies such as minocycline and fluoroquinolones, no differences were observed in clinical success based on therapy received. Patients included in these studies varied in terms of site of infection and immunocompromised status, and those treated with TMP-SMX received doses consistent with our definition for LD (7.8–10.3 mg/kg/day). Reference Hand, Davis, Kim and Duhon12–Reference Wang, Scipione, Dubrovskaya and Papadopoulos14 In these studies, clinical success was observed in 59–82% of patients treated with TMP-SMX, which slightly exceeds our finding of 55% clinical success in the LD group. This difference may be explained by increased severity of illness in our LD group, as evidenced by the high SOFA score, or due to our strict definition of pneumonia which excluded patients treated for what was likely colonization.
The apparent lack of an obvious relationship between TMP-SMX dose and clinical outcomes as demonstrated in these prior studies, combined with established risks of dose-dependent toxicities associated with TMP-SMX, may form the logical basis for minimizing TMP-SMX dose to avert adverse effects. Our study did not show a difference between the LD and HD groups in terms of AEs of interest, AKI and hyperkalemia, nor in the proportion of patients that discontinued TMP-SMX treatment due to an AE. It should be noted, however, that we did not assess other factors that may influence development of these AEs, including concomitant receipt of medications known to be nephrotoxic or associated with elevations in serum potassium level.
Differences in baseline renal function between groups were present in our study; the median CrCl was 58.5 mL/min in the LD group, compared to 103 mL/min in the HD group. Our institutional antimicrobial guidelines, in keeping with the FDA product labeling, recommend renal dose adjustment of TMP-SMX at CrCl <30 mL/min due to decreased excretion of each component and their metabolites at this level of renal dysfunction. Reference Nahata22 While TMP elimination has been shown to be strongly correlated with renal function, its impact on SMX elimination is less clear. Inactive metabolites of SMX appear to be more prone to accumulation in renal dysfunction than active unchanged SMX, though the metabolism of SMX has itself been shown to increase as renal function decreases. Reference Baethke, Golde and Gahl23 As such, the dose-exposure relationship for the combination of TMP and SMX at varying levels of renal dysfunction may be unpredictable and subject to wide interpatient variability. Reference Paap and Nahata24,Reference Rieder25 Routine therapeutic drug monitoring of serum TMP and SMX concentrations is not performed at our institution, making it difficult to discern what impact the differences in renal function between groups had on true exposure to each component.
Our study has several important limitations. Given its retrospective nature, it was difficult to account for all variables that may have influenced the TMP-SMX dose chosen. We attempted to control for confounding variables by performing a multivariable logistic regression, though it is possible that we did not account for all variables. Our sample size was also small and included more patients in the HD group than the LD group. Although the sample size is likely reflective of our intentionally stringent definition of pneumonia, it could have impacted our ability to detect differences in outcomes between groups. In addition, a majority of patients had polymicrobial index respiratory cultures, which limited our ability to assess the effect of S. maltophilia isolation on clinical outcomes versus other pathogens. Repeat cultures necessary to assess microbiological outcomes and infection recurrence were not always available, and those that may have been collected at outside facilities were not captured. Furthermore, patients with evidence of persistent or recurrent infection may have been more likely to have repeat cultures collected, causing confounding results for infection recurrence and microbiological success by selection bias.
This study found no differences in clinical success, infection-related and all-cause mortality, or renal AEs between LD and HD TMP-SMX, suggesting against the need for higher doses. However, further studies, especially those with larger and more balanced patient populations, are warranted to investigate the true impact of TMP-SMX dose on the outcomes of patients with S. maltophilia pneumonia.
Supplementary material
The supplementary material for this article can be found at https://doi.org/10.1017/ash.2025.64
Financial support
The project described in this article was supported by Award Number UL1TR002733 from the National Center for Advancing Translational Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.
Competing interests
All authors report no conflicts of interest relevant to this article.
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