Stenotrophomonas maltophilia: The common but unknown story

The growing global challenge posed by drug-resistant infections.

Antimicrobial resistance is nowadays a hot topic in medicine as it is projected to cause 10 million deaths annually worldwide by 2050 (1). It is therefore very surprising how little evidence there is about one of the most common carbapenem-resistant pathogens in the USA (2), Stenotrophomonas maltophilia. This aerobic, Gram-negative bacillus poses unique treatment challenges due to a combination of intrinsic and acquired resistance mechanisms.

As always, this blog tries to answer some questions:

1. Why don’t we have a good idea how to treat Stenotrophomonas maltophilia?

2. Should S. maltophilia always be treated by combination therapy?

3. How to best treat S. maltophilia?

1. Why don’t we have a good idea how to treat Stenotrophomonas maltophilia?

Infectious diseases will most likely never be the frontrunner in evidence-based medicine. However S. maltophilia really is lagging behind. For this, there are several explanations:

• S. maltophilia is resistant to most broad-spectrum antibiotics due to a combination of efflux pumps, enzymes and inducible beta-lactamases (2). Hence, it mostly falls outside the scope of the traditional trials about Gram-negative bacteria. As a consequence, in the case of S. maltophilia, all important clinical data come from retrospective observational studies and thus are prone to all kind of biases (3).

  The interpretation of these clinical data is further complicated by two other facts:

  
  

  1. S. maltophilia is a low-virulent microorganism, which can both colonize and infect the lower respiratory tract. For instance, it frequently forms a biofilm in the airways of patients with cystic fibrosis (4). Furthermore, a recent Canadian study found this microorganism in 10% of the sputa of ambulatory COPD patients, which was considered as a marker of overall morbidity (5).

  2. S. maltophilia is part of a polymicrobial infection in 33 to 70% of cases (4).

     
     

  In conclusion, S. maltophilia is often not the only possible pathogen present and even when it is, it might simply reflect the overall morbidity of the patient. This makes both the interpretation of the available, retrospective data, as well as the encounter in clinical practice even harder (3).

• Antimicrobial susceptibility testing in S. maltophilia poses some important challenges.

  
  

  Firstly, the broth microdilution method for S. maltophilia is derived from P. aeruginosa, not withstanding the fact that there are important growth and susceptibility differences between the two species (3,4). Moreover, the disc diffusion breakpoints were determined using only 10 isolates across 8 laboratories.

  Furthermore, EUCAST only defines breakpoints for trimethoprim-sulfamethoxazole (TMP-SMX) whereas CLSI additionally defines breakpoints for levofloxacin, minocycline, and cefiderocol (7). Nevertheless, even the defined breakpoints of S. maltophilia have not been without controversy:

  • Previously, CLSI also had defined breakpoints for ceftazidime. However, these breakpoints were withdrawn in 2023, due to the lack of reproducibility between replicates of the same isolate and the abscence of support for ceftazidime monotherapy from clinical studies (8).

  • The breakpoint of minocycline was lowered from 4 μg/mL to 1 μg/mL (8). Monte Carlo simulations had shown, after all, that there was only a very small chance of 1-log10 kill at the old breakpoint (2).

  • There is an ongoing debate regarding the current breakpoint for levofloxacin of 2 mg/L as a murine thigh infection model showed only a 26.6% chance of a 1-log10 kill at this breakpoint (2).

In conclusion, highly accurate in vitro susceptibility testing is often not available to the clinician (4).

• S. maltophilia is prone to develop a biofilm on both biotic and abiotic surfaces (2), which also will impact its in vivo susceptibility and thus its treatment.

2. Should S. maltophilia always be treated by combination therapy?

In 2024, IDSA guidelines recommended treating S. maltophilia initially with a combination of two active antibiotics or ceftazidime-avibactam combined with aztreonam (9). Let’s take a closer look at these two options:

1. A combination of two active antibiotics (cefiderocol, levofloxacin, trimethoprim-sulfamethoxazole, and minocycline)

   
   

   The main reason for this recommendation is the uncertainty surrounding S. maltophilia as mentioned above. However, the limited observational data that exist don’t show any benefit of combination therapy:

   One recent meta-analysis of four observational studies found that combination therapy was not superior to monotherapy in treating S. maltophilia infection. Moreover, monotherapy led to a significant reduction in mortality of S. maltophilia pneumonia compared to combination therapy (10).

   
   

   Another recent meta-analysis of four studies (one of which similar to the previous meta-analysis) also demonstrated a trend in favor of monotherapy (3).

   
   

   My view: Considering the fact that monotherapy often generated better results than combination therapy, an important selection bias is most likely present in the clinical data, and therefore no strong conclusions can be drawn. However, S. maltophilia is generally seen as a less pathogenic microorganism (9). This makes the regular use of two antibiotics seem like an overkill. In my opinion, a more nuanced approach is indicated (see below).

   
   

2. ceftazidime-avibactam combined with aztreonam

   
   

   Theoretically, combining ceftazidime-avibactam with aztreonam is logical as together they block all of S. maltophilia’s inducible beta-lactamases (2). This is supported by a higher susceptibility in clinical strains compared to for instance trimetroprim-sulfamethoxazole (9). Clinical data are however lacking (3). Moreover, ceftazidime-avibactam combined with aztreonam also is used to treat many Carbapenemase producing Enterobacterales. Therefore, in my opinion, this combination shouldn’t be a frontline option in S. maltophilia.

3. How to best treat S. maltophilia?

As S. maltophilia is not your typical pathogen, a more nuanced strategy for treatment is indicated. The following steps might guide such strategy.

Step 1: Is there an infection or a mere colonization with S. maltophilia?

S. maltophilia is known to colonize the airways in chronic respiratory disease. If patient is asymptomatic or if other, more virulent bacteria are cultured, this microorganism is most likely a bystander and no specific antibiotic therapy should be initiated. By contrast, positive blood cultures with S. maltophilia should always be treated. Due to its ability to form a biofilm, part of the treatment should consist in removing foreign material such as central lines.

Step 2: Are there signs of a severe infection by S. maltophilia?

As mentioned earlier, IDSA recommends empirical combination therapy for S. maltophilia until clinical improvement is observed (9). This differs from previous guidelines, which allowed monotherapy for mild infections (10). While this goes against the current common practice of treating S. maltophilia without any clinical data supporting combination therapy, it also might lead to overuse of antibiotics for a low-virulent microorganism. Furthermore, it also creates a dilemma for clinicians regarding which antibiotic to discontinue once the patient improves.

My view: Monotherapy should be safe unless there are multiple risk factors of severe infection such as positive blood cultures, immunosuppression, or a vasopressor requirement.

Step 3: Which antibiotic is the preferred treatment option for S. maltophilia?

IDSA favors four frontline agents in the following order: cefiderocol, minocycline, trimethoprim-sulfamethoxazole (TMP-SMX) and levofloxacin (9).

However, there are good arguments against the empirical use of cefiderocol:

• Like ceftazidime-avibactam combined with aztreonam, cefiderocol should be kept in reserve to treat multi-drug resistant gram-negative bacteria.

• Pharmacokinetic data of cefiderocol raise concern about its effectiveness in treating respiratory infections. After all, the penetration of cefiderocol into lung tissues is only 25 to 50% of the plasma concentration. Moreover, acidosis impairs its activity (which is present in the alveoli in case of a respiratory infections) (7).

• Clinical data for cefiderocol use in S. maltophilia are so far limited to small case series without any comparator drug. These data haven’t demonstrated any sign of a superior efficacy of cefiderocol in treating S. maltophilia (7).

Furthermore, there are also valid arguments to prefer minocycline or levofloxacin over TMP-SMX, an opinion recently shared by Dr. Sakoulas on NEJM Journal Watch (11).

• Why clinician should favor minocycline in S. maltophilia:

  • The main two reasons why IDSA put minocycline in second place are high susceptibility rates and excellent pharmacokinetic/pharmacodynamic (PK/PD) data in mouse models (9). However, since the revision of minocycline susceptibility breakpoints in 2023 (8), the susceptibility rate might be a concern in certain parts of the world. An Indian study, for instance, found that S. maltophilia was only susceptible to minocycline in 35% of cases (13) while a U.S. case series reported 93.8% susceptibility rate (14).

  • Clinical data for minocycline are limited. Two retrospective studies comparing minocycline with TMP-SMX found no significant difference in clinical cure rates (2, 12). However, one of them observed a much higher all-cause in-hospital mortality in the TMP-SMX group (12), potentially due to minocycline’s anti-inflammatory properties (11). This observation is probably the biggest argument in favor of the clinical use minocycline so far.

  
  

• Why clinician should favor levofloxacin in S. maltophilia:

  • IDSA doesn’t prefer levofloxacin due to the high baseline resistance, the potential for resistance to emerge during therapy and poor PK/PD data (9).

  • However, two meta-analyses (with all their limitations) point to a survival benefit of levofloxacin in comparison to TMP-SMX, both in lower respiratory tract infections as in blood stream infections (3). It is important to note though the major influence of one large, retrospective study in 154 US hospitals (15).

My view: In essence, there are three frontline agents to treat S. maltophilia. While TMP-SMX is definitively a valid option, levofloxacin and minocycline have a small advantage.

Step 4: So how should I treat S. maltophilia?

Empirical treatment with one of the frontline agents should be based on the local epidemiology and the previous antibiotic therapy of the patient. Especially if fluoroquinolones have been used previously, S. maltophilia has most likely become resistant to levofloxacin (3).

Once in vitro susceptibility data are available, knowing the exact breakpoints for the frontline antibiotics is crucial. After all, these breakpoints are still slightly dubious: recently minocycline’s were lowered and even TMP-SMX’s and levofloxacin’s breakpoints are still a subject of debate (7). Generally, the lower the minimum inhibitory concentration, the more chances of success. In case the MIC is close to the susceptibility breakpoint for all frontline antibiotics, one could consider a combination therapy.

Dosing of the frontline-antibiotics (9, 14):

1. Minocycline 200 mg, twice daily

2. Levofloxacin 750 mg, once daily

3. TMP-SMX 10 to 15 mg/ kg daily dose

In case S. maltophilia is resistant to all first-line antibiotics, treatment should be initiated with ceftazidime-avibactam combined with aztreonam or, as a last resort, with cefiderocol.

References:

1. O’Neill J, Chair. Tackling Drug-Resistant Infections Globally: Final Report and Recommendations. London, UK: Review on Antimicrobial Resistance; 2016; p. 1-84. 

2. Mojica MF, Bonomo RA, van Duin D. Treatment approaches for severe Stenotrophomonas maltophilia infections. Curr Opin Infect Dis. 2023 Dec 1;36(6):572-584. 

3. Maraolo AE, Licciardi F, Gentile I, et al. Stenotrophomonas maltophilia Infections: A Systematic Review and Meta-Analysis of Comparative Efficacy of Available Treatments, with Critical Assessment of Novel Therapeutic Options. Antibiotics (Basel). 2023 May 15;12(5):910. 

4. Mojica MF, Humphries R, Lipuma JJ, et al. Clinical challenges treating Stenotrophomonas maltophilia infections: an update. JAC Antimicrob Resist. 2022 May 5;4(3):dlac040. 

5. Soumagne T, Levesque F, Milot J, et al. Significance of Stenotrophomonas maltophilia When Detected in Sputum of Ambulatory Patients with COPD. Int J Chron Obstruct Pulmon Dis. 2021 Oct 20;16:2895-2900. 

6. Hugh R, Ryschenkow E. An Alcaligenes-like Pseudomonas species (abstract). Bacteriol Proc 1960; 60:78. 

7. Mokrani D, Luyt CE. Effective strategies for managing trimethoprim-sulfamethoxazole and levofloxacin-resistant Stenotrophomonas maltophilia infections: bridging the gap between scientific evidence and clinical practice. Curr Opin Infect Dis. 2024 Dec 1;37(6):554-564. 

8. Bixby ML, Zheng D. What’s New in 2023 From the CLSI Subcommittee on Antimicrobial Susceptibility Testing. Contagion. 2023 Oct;8(5). Available online: https://www.contagionlive.com/view/what-s-new-in-2023-from-the-clsi-subcommittee-on-antimicrobial-susceptibility-testing (accessed on 21 March 2025). 

9. Tamma PD, Heil EL, Justo JA, et al. Infectious Diseases Society of America 2024 Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections. Clin Infect Dis. 2024 Aug 7:ciae403. 

10. Prawang A, Chanjamlong N, Rungwara W, et al. Combination Therapy versus Monotherapy in the Treatment of Stenotrophomonas maltophilia Infections: A Systematic Review and Meta-Analysis. Antibiotics (Basel). 2022 Dec 9;11(12):1788. 

11. Sakoulos G. Trimethoprim-Sulfamethoxazole or Minocycline for Stenotrophomonas maltophilia Pneumonia? NEJM Journal Watch. Available online: https://www.jwatch.org/na58417/2025/02/25/trimethoprim-sulfamethoxazole-or-minocycline (accessed on 21 March 2025). 

12. Graves ET, Wardlow L, Ogake S, et al. Comparison of trimethoprim-sulfamethoxazole versus minocycline monotherapy for treatment of Stenotrophomonas maltophilia pneumonia. J Antimicrob Chemother. 2025 Apr 2;80(4):988-995. 

13. Bakthavatchalam YD, Manoharan Y, Shankar A, et al. Understanding the rationale and clinical impact of the revised CLSI 2024 minocycline susceptibility breakpoints against Stenotrophomonas maltophilia. Eur J Clin Microbiol Infect Dis. 2024 Dec;43(12):2453-2457. 

14. Crowley PD, Mira P, Saleh OMA. Minocycline susceptibility in Stenotrophomonas maltophilia: a closer look at institutional data amid CLSI breakpoint revisions. Eur J Clin Microbiol Infect Dis. 2025 Feb;44(2):459-460. 

15. Sarzynski SH, Warner S, Sun J, et al. Trimethoprim-Sulfamethoxazole Versus Levofloxacin for Stenotrophomonas maltophilia Infections: A Retrospective Comparative Effectiveness Study of Electronic Health Records from 154 US Hospitals. Open Forum Infect Dis. 2022 Jan 17;9(2):ofab644.