By Jake Scott, MD
Synopsis: Stenotrophomonas maltophilia is an opportunistic gram-negative bacillus with intrinsic resistance to a variety of antibiotics. Since clinical trial data are lacking, the optimal antimicrobial regimen is unknown. These factors make S. maltophilia increasingly challenging for the treating clinician. A recent study by Sader and colleagues analyzed the antimicrobial susceptibility of 1,400 S. maltophilia isolates collected from U.S. medical centers between 2019 and 2023. Aztreonam-avibactam, which inhibited 99.6% of isolates at ≤ 8 mcg/mL, was found to have the highest levels of in vitro activity. Trimethoprim-sulfamethoxazole, which has historically been a preferred agent, had slightly lower activity (96.9% susceptible), followed by minocycline (89.2%) and levofloxacin (78.9%). The results from this in vitro study suggest that aztreonam-avibactam may be a highly effective option for treating S. maltophilia infections, especially in multidrug-resistant cases.
Source: Sader HS, Castanheira M, Arends SJR, Doyle TB. Antimicrobial susceptibility of Stenotrophomonas maltophilia from United States medical centers (2019-2023). Antimicrob Agents Chemother. 2025; Mar 6:e0012425. doi:10.1128/aac.00124-25. [Online ahead of print].
A study by Sader and colleagues published in Antimicrobial Agents and Chemotherapy provides new insights into the antimicrobial susceptibility patterns of Stenotrophomonas maltophilia isolates collected from U.S. medical centers between 2019 and 2023.1 The investigators analyzed 1,400 clinical isolates of S. maltophilia from 62 medical centers in the United States as part of the International Network for Optimal Resistance Monitoring (INFORM) surveillance program. The isolates were collected from various infection sites, with the majority obtained from pneumonia cases (n = 1,020; 72.9%), followed by skin and soft tissue infections (SSTIs; n = 124; 8.9%), bloodstream infections (BSIs; n = 117; 8.4%), urinary tract infections (UTIs; n = 48; 3.4%), and intra-abdominal infections (n = 30; 2.1%). Only isolates considered to be clinically significant as the likely cause of infection were included in the study, although it is notably challenging to discern whether S. maltophilia represents a colonizing organism or a true pathogen. Susceptibility testing was performed using Clinical and Laboratory Standards Institute (CLSI) broth microdilution methods. Aztreonam-avibactam testing was conducted with avibactam at fixed 4 mcg/mL and a pharmacodynamic/pharmacokinetic-susceptible breakpoint of ≤ 8 mcg/mL used for comparison. Comparator agents included trimethoprim/sulfamethoxazole (TMP-SMX), minocycline, levofloxacin, and tigecycline.
Aztreonam-avibactam was found to be the most active agent, inhibiting 99.6% of isolates at ≤ 8 mcg/mL (minimum inhibitory concentration at which 50% and 90% of isolates were inhibited [MIC50/90], 2/4 mcg/mL, respectively), with potent activity demonstrated against isolates from all infection types. Aztreonam-avibactam inhibited 99.7% of pneumonia isolates, 99.2% of SSTI isolates, and 100% of BSI and UTI isolates at ≤ 8 mcg/mL. It also retained activity against isolates resistant to other agents, including TMP-SMX (100% inhibited, MIC50/90; 4/8 mcg/mL), minocycline (99.3% inhibited, MIC50/90; 2/4 mcg/mL), levofloxacin (99.3% inhibited, MIC50/90; 2/4 mcg/mL), and tigecycline (99.5% inhibited, MIC50/90; 2/4 mcg/mL). Only five isolates had aztreonam-avibactam MIC > 8 mcg/mL: four at 16 mcg/mL and one at > 16 mcg/mL.
The most active comparators were TMP-SMX (MIC50/90, ≤ 0.12/0.5 mcg/mL; 96.9% susceptible) and minocycline (MIC50/90, 0.5/2 mcg/mL; 89.2% susceptible). TMP-SMX susceptibility was lower among isolates not susceptible to minocycline (85.8%), levofloxacin (88.8%), or tigecycline (90.7%) compared to the overall collection (96.9%). Minocycline was active against only 51.2% of TMP-SMX-nonsusceptible isolates, 55.6% of levofloxacin-nonsusceptible isolates, and 31.1% of those with tigecycline MICs > 2 mcg/mL. Fluoroquinolones showed modest activity against S. maltophilia. Levofloxacin (MIC50/90, 1/8 mcg/mL) inhibited 78.9% of isolates at the CLSI-susceptible breakpoint (≤ 2 mcg/mL), while ciprofloxacin (MIC50/90, 2/> 4 mcg/mL) inhibited only 3.7% at ≤ 0.5 mcg/mL. Moxifloxacin was the most active fluoroquinolone (MIC50/90, 0.5/4 mcg/mL), inhibiting 79.7% at ≤ 1 mcg/mL and 43.0% at ≤ 0.25 mcg/mL (European Committee on Antimicrobial Susceptibility Testing [EUCAST] breakpoint for Enterobacterales). Tigecycline activity varied by breakpoint: 87.0% of isolates were inhibited at ≤ 2 mcg/mL (Food and Drug Administration [FDA] Enterobacterales breakpoint), but only 37.7% at ≤ 0.5 mcg/mL (EUCAST E. coli and C. koseri breakpoint). Colistin (MIC50/90, 8/> 8 mcg/mL; 34.9% inhibited at ≤ 2 mcg/mL) and ceftazidime (MIC50/90, > 32/> 32 mcg/mL; 22.2% inhibited at ≤ 8 mcg/mL) had limited activity.
Commentary
Stenotrophomonas maltophilia is a multidrug-resistant gram-negative bacillus that is ubiquitous in water environments and can cause life-threatening opportunistic infections in vulnerable individuals, particularly those with underlying lung disease, hematologic malignancies, and injection drug use.2,3 It often is detected in patients with prolonged hospitalizations, exposure to broad-spectrum antibiotics, and mechanical ventilation. S. maltophilia remains a significant therapeutic challenge due to its intrinsic resistance mechanisms. It produces an L1 metallo- β-lactamase, which hydrolyzes penicillins, cephalosporins, and carbapenems, but not aztreonam.4 S. maltophilia also produces an L2 metallo-β-lactamase, which hydrolyzes extended-spectrum cephalosporins and aztreonam.4 Therefore, most conventional β-lactam antibiotics are rendered ineffective. However, aztreonam-avibactam, which recently was approved by the FDA for complicated intra-abdominal infections, uniquely retains activity through the inhibition of L2 by avibactam, preserving aztreonam’s efficacy against this pathogen. The 2024 Infectious Diseases Society of America guidance on the treatment of antimicrobial-resistant gram-negative infections recommends the combination of ceftazidime-avibactam and aztreonam as one of the preferred options for the treatment of S. maltophilia.3 This combination mimics aztreonam-avibactam, which had not been FDA approved when the guidance was published.
Although TMP-SMX has been used historically as a first-line agent against S. maltophilia, based on clinical experience and its reliable in vitro activity, higher doses needed for severe infection are associated with risks of myelosuppression and hyperkalemia, particularly in vulnerable populations. Furthermore, growing resistance underscores the necessity of alternative options. Fluoroquinolones, such as levofloxacin, are less reliable due to resistance concerns and are associated with potential adverse effects. In the study by Sader and colleagues, levofloxacin exhibited limited activity, highlighting the need to reevaluate its role in the treatment of S. maltophilia. While minocycline generally is well tolerated, resistance can emerge with monotherapy, and clinical failures have been reported. For these reasons, the 2024 IDSA guidance has recommended using TMP-SMX, levofloxacin, or minocycline in combination with another agent.3 Ceftazidime is not recommended for the treatment of S. maltophilia infections because of intrinsic resistance, and CLSI breakpoints are no longer available.3
As Sader and colleagues point out, one limitation of their evaluation is the absence of cefiderocol as a comparator. Cefiderocol is a newer agent and may be promising, especially as resistance to traditional agents increases. Cefiderocol is a siderophore cephalosporin that hijacks bacterial iron transport to bypass permeability barriers, inhibits PBP3 to disrupt cell wall synthesis, and remains stable against serine and metallo-β-lactamases.5 A study by Nakamura and colleagues demonstrated cefiderocol’s potent in vitro activity (MIC50/90, 0.063/0.25 mcg/mL) and in vivo efficacy, including against TMP-SMX-resistant strains.6 The IDSA 2024 guidance supports cefiderocol as a treatment option, in combination with minocycline, TMP-SMX, or levofloxacin, although clinical data remain limited.3
Sader and colleagues’ findings reinforce the need for an up-to-date, data-driven approach to S. maltophilia infections. As new agents emerge, antimicrobial stewardship will be critical in preserving their efficacy while minimizing resistance development. Since in vitro efficacy alone is not sufficient to dictate clinical use, continued research into real-world clinical outcomes is essential to refining treatment guidelines and optimizing patient outcomes.
Jake Scott, MD, is Clinical Associate Professor, Infectious Diseases and Geographic Medicine, Stanford University School of Medicine; Antimicrobial Stewardship Program Medical Director, Stanford Health Care Tri-Valley.
References
1. Sader HS, Castanheira M, Arends SJR, Doyle TB. Antimicrobial susceptibility of Stenotrophomonas maltophilia from United States medical centers (2019-2023). Antimicrob Agents Chemother. 2025; Mar 6:e0012425.
2. Mojica MF, Humphries R, Lipuma JJ, et al. Clinical challenges treating Stenotrophomonas maltophilia infections: An update. JAC Antimicrob Resist. 2022;4(3):dlac040.
3. 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.
4. Brooke JS. Stenotrophomonas maltophilia: An emerging global opportunistic pathogen. Clin Microbiol Rev. 2012;25(1):2-41.
5. Zhanel GG, Golden AR, Zelenitsky S, et al. Cefiderocol: A siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant gram-negative bacilli. Drugs. 2019;79(3):271-289.
6. Nakamura R, Oota M, Matsumoto S, et al. In vitro activity and in vivo efficacy of cefiderocol against Stenotrophomonas maltophilia. Antimicrob Agents Chemother. 2021;65(4):e01436-20.
Stenotrophomonas maltophilia is an opportunistic gram-negative bacillus with intrinsic resistance to a variety of antibiotics. Since clinical trial data are lacking, the optimal antimicrobial regimen is unknown. These factors make S. maltophilia increasingly challenging for the treating clinician. A recent study by Sader and colleagues analyzed the antimicrobial susceptibility of 1,400 S. maltophilia isolates collected from U.S. medical centers between 2019 and 2023. Aztreonam-avibactam, which inhibited 99.6% of isolates at ≤ 8 mcg/mL, was found to have the highest levels of in vitro activity. Trimethoprim-sulfamethoxazole, which has historically been a preferred agent, had slightly lower activity (96.9% susceptible), followed by minocycline (89.2%) and levofloxacin (78.9%). The results from this in vitro study suggest that aztreonam-avibactam may be a highly effective option for treating S. maltophilia infections, especially in multidrug-resistant cases.
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