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.