Stenotrophomonas (Xanthomonas) maltophilia is inherently resistant to multiple antimicrobial agents. In order to investigate the in vitro potential of combinations of antimicrobial agents, we obtained 230 epidemiologically unrelated clinical isolates from seven hospitals across Canada and from Northwestern Memorial Hospital in Chicago. Ticarcillin-clavulanate combined with ciprofloxacin or trimethoprim-sulfamethoxazole were assayed for synergy against 31 ticarcillin-resistant strains of S. maltophilia by using microtiter checkerboard panels and against 20 strains by using time-kill methodology. The combination of ciprofloxacin with ceftazidime was also evaluated by time-kill studies. Ticarcillin-clavulanate plus trimethoprim-sulfamethoxazole demonstrated synergy by checkerboard panels, with fractional inhibitory concentration indices ranging from 0.033 to 0.49, and by time-kill studies for all 20 strains tested. Synergy between ticarcillin-clavulanate plus ciprofloxacin was found by the checkerboard method for 24 of 31 strains (77%), with fractional inhibitory concentration indices ranging from 0.188 to 0.75. A correlation between synergy by the checkerboard method and the reference time-kill study method was not observed for ticarcillin-clavulanate plus ciprofloxacin, with results for 3 of 10 strains being nonconcordant. Synergy with both ticarcillin-clavulanate plus ciprofloxacin and ceftazidime plus ciprofloxacin by the time-kill method was found to correlate with ciprofloxacin MICs of <32 g/ml and zone diameters of >15 mm on Mueller-Hinton agar. Evaluation of these combinations in vivo may be warranted.Stenotrophomonas (Xanthomonas) maltophilia is an aerobic, gram-negative bacillus which has been isolated from humans, animals, food, pharmaceuticals, and various environmental sources. Because of the low level of pathogenicity and limited invasiveness of S. maltophilia, serious community-acquired infection is infrequent (12, 18). However, significant morbidity and mortality are widely recognized among neutropenic, immunocompromised, and debilitated patients, in whom this organism may become disseminated and result in life-threatening disease (12,18,23,27,37).The antimicrobial resistance of S. maltophilia is attributed to low outer membrane permeability (9,14,15,20,21,39) and the unusual production of multiple chromosomally mediated, broad-spectrum -lactamases, among which are L1 and L2 (1,10,14,15,29,30,32,33). L1 and related -lactamases are group 3 metallopenicillinases and carbapenemases (1,7,15,20,30,33), while L2 and related -lactamases are group 2e cephalosporinases capable of hydrolyzing penicillins and monobactams (1,7,15,20,29,32). All -lactamases are induced synchronously, indicating an apparent overlap of regulatory systems (1,22,30).In vitro susceptibility testing of S. maltophilia is problematic, and results obtained by such tests should be interpreted with caution (1,6,10,13,16,21,38). The National Committee for Clinical Laboratory Standards (NCCLS) (26) currently recommends broth or agar dilu...