Stenotrophomonas maltophilia is difficult to treat due to the production of multiple intrinsic and acquired mechanisms of resistance. Trimethoprim-sulfamethoxazole (TMP-SMZ) and the fluoroquinolones have traditionally been considered the drugs of choice but are plagued by increasing resistance and adverse drug effects. The objective of this study was to evaluate the in vitro activities of 12 clinically relevant antimicrobials against clinical S. maltophilia isolates nonsusceptible to levofloxacin and/or TMP-SMZ. A diverse panel of 41 clinical S. maltophilia isolates collected through the SENTRY Antimicrobial Surveillance Program from 2008 to 2018 was evaluated against ceftazidime, ceftazidime-avibactam, chloramphenicol, delafloxacin, levofloxacin, moxifloxacin, eravacycline, minocycline, omadacycline, polymyxin B, and tigecycline. MICs were determined in triplicate via reference broth microdilution and interpreted according to CLSI guidelines where available. MIC distributions and susceptibilities were also compared across infection type, acquisition setting, and geographic origin. Susceptibilities to levofloxacin and TMP-SMZ were 29.3% and 36.6%, respectively. Minocycline displayed the highest susceptibility rate overall (92.7%) and the lowest MIC90 value (4 mg/liter) of any of the 12 agents tested. Only 3 isolates were resistant to levofloxacin, TMP-SMZ, and minocycline. Polymyxin B and tigecycline were the second most active agents. No significant differences were observed in MIC distributions across the 3 strata evaluated. These data demonstrate that few antimicrobials, old or new, maintain reliable activity against resistant S. maltophilia. The role of minocycline in the treatment of infections due to S. maltophilia warrants further clinical investigation given its potent in vitro activity and favorable adverse effect profile.

The intrinsic L1 metallo- and L2 serine-β-lactamases in Stenotrophomonas maltophilia make it naturally multidrug resistant and difficult to treat. There is a need to identify novel treatment strategies for this pathogen, especially against isolates resistant to first line agents. Aztreonam in combination with avibactam has demonstrated potential, although data on other aztreonam-β-lactamase inhibitor (BLI) combinations are lacking. Additionally, molecular mechanisms for reduced susceptibility to these combinations have not been explored. The objectives of this study were to evaluate and compare the in vitro activity and understand the mechanisms of resistance to aztreonam in combination with avibactam, clavulanate, relebactam, and vaborbactam against S. maltophilia. A panel of 47 clinical S. maltophilia strains non-susceptible to levofloxacin and/or trimethoprim-sulfamethoxazole were tested against each aztreonam-BLI combination via broth microdilution and 6 isolates were then evaluated in time-kill analyses. Three isolates with varying aztreonam-BLI MICs were subjected to whole-genome sequencing and quantitative reverse transcriptase polymerase chain reaction. Avibactam restored aztreonam susceptibility in 98% of aztreonam-resistant isolates, compared to 61%, 71%, and 15% with clavulanate, relebactam, and vaborbactam, respectively. The addition of avibactam to aztreonam resulted in a ≥2 log10 CFU/mL decrease at 24 hours vs. aztreonam alone against 5/6 isolates compared to 1/6 with clavulanate, 4/6 with relebactam, and 2/6 with vaborbactam. Molecular analyses revealed that decreased susceptibility to aztreonam-avibactam was associated with increased expression of genes encoding for L1, L2, and the efflux pump smeABC. Aztreonam-avibactam is the most promising BLI-combination against multidrug resistant S. maltophilia. Decreased susceptibility may be due to the combination of overexpressed β-lactamases and efflux pumps. Further studies evaluating this combination against S. maltophilia are warranted.

The ex vivo bactericidal activity and pharmacodynamics of fosfomycin in urine were evaluated in 18 healthy subjects. Subjects received 3 g every other day (QOD) for 3 doses and then every day (QD) for 7 doses or vice versa. Serial urine samples were collected before and up to 24 h after dosing on days 1 and 5. Eight bacterial strains with various genotypic and phenotypic susceptibilities to fosfomycin were used for all experiments (5 Escherichia coli, 2 Klebsiella pneumoniae, and 1 Proteus mirabilis). MICs were performed via agar dilution. Urinary bactericidal titers (UBTs) were performed via modified Schlichter test using participant’s drug-free urine as the diluent. Urinary time-kill analyses were performed on pooled 24-h urine aliquots from days 1 and 5. All experiments were performed in triplicate with and without the addition of 25 mg/liter of glucose-6-phosphate (G6P). Mean 24-h urine concentrations of fosfomycin ranged from 324.7 to 434.6 mg/liter regardless of study day or dosing regimen. The urinary antibacterial activity of fosfomycin was also similar across study days and dosing regimens. UBT values did not correlate with MICs determined in the presence of G6P. Fosfomycin was reliably bactericidal in urine only against the 5 E. coli strains, regardless of genotype or MIC value. Together, these data do not support the use of oral fosfomycin tromethamine for pathogens other than E. coli or at a dosing frequency higher than QOD. Fosfomycin MICs determined in the presence of G6P may not accurately reflect the in vivo activity given the lack of G6P in human urine. (This study has been registered at ClinicalTrials.gov under identifier NCT02570074.)

Stenotrophomonas maltophilia most often infects the lungs, where the physiologic environment is naturally slightly acidic (pH ~6.6), compared to most parts of the body (such as the bloodstream), which have neutral pH values (~7.4). Pneumonia due to S. maltophilia is often treated with the antibiotic levofloxacin, despite the activity of levofloxacin being known to be impaired at acidic pH.