Synergistic interactions of ciprofloxacin and extended-spectrum beta-lactams or aminoglycosides against multiply drug-resistant Pseudomonas maltophilia

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...

Section: Discussionmentioning

confidence: 99%

In vitro activities of antimicrobial combinations against Stenotrophomonas (Xanthomonas) maltophilia

Poulos

Matsumura

Willey

et al. 1995

“…Of commonly used antimicrobial agents, only trimethoprim-sulfamethoxazole has been found to be consistently active in vitro against this organism (10,17). Available quinolones such as ciprofloxacin and ofloxacin are marginally active, with MICs for susceptible isolates clustering around the breakpoint (1,4,9,(12)(13)(14). Clinafloxacin (CI-960, PD 127391) and PD 131628 (the active component of the prodrug CI-990) are two new fluoroquinolones with improved activity against gram-positive cocci, gramnegative nonfermenters, and anaerobes (5,6,8,9,12,16).…”

mentioning

confidence: 99%

Susceptibilities of 123 Xanthomonas maltophilia strains to clinafloxacin, PD 131628, PD 138312, PD 140248, ciprofloxacin, and ofloxacin

Pankuch

Jacobs

Appelbaum

1994

The susceptibilities of 123 clinically isolated strains of Xanthomonas maltophilia to six fluoroquinolones (clinafloxacin, PD 131628, PD 138312, PD 140248, ciprofloxacin, and ofloxacin) were examined by microdilution MIC methodology. Clinafloxacin and PD 131628 were the most active compounds tested (MICs for 50% of the strains tested [MIC50s] of 0.5 and 1.0 ,ug/ml and MIC90s of 2.0 and 4.0 ,ug/ml, respectively). PD 138312, PD 140248, ciprofloxacin, and ofloxacin were less active, with MIC50s ranging from 4.0 to 8.0 ,ug/ml and MIC90s of 16.0 ,ug/ml for all four compounds. Only clinafloxacin and PD 131628 were active against ciprofloxacinresistant strains, with MIC50s of 0.5 and 1.0 ,ug/ml and MIC90s of 2.0 and 4.0 ,ug/ml, respectively.Infections caused by Xanthomonas maltophilia are increasingly encountered, especially in patients with compromised host defense mechanisms (10,11,17). The problem is further complicated by the inherently resistant nature of this species, which is due to a combination of permeability defects and ,B-lactamase production (3,10,11,13,17). Of commonly used antimicrobial agents, only trimethoprim-sulfamethoxazole has been found to be consistently active in vitro against this organism (10,17). Available quinolones such as ciprofloxacin and ofloxacin are marginally active, with MICs for susceptible isolates clustering around the breakpoint (1,4,9,(12)(13)(14). Clinafloxacin (CI-960, PD 127391) and PD 131628 (the active component of the prodrug CI-990) are two new fluoroquinolones with improved activity against gram-positive cocci, gramnegative nonfermenters, and anaerobes (5,6,8,9,12,16). This study compared the activities of clinafloxacin, PD 131628, two other experimental broad-spectrum fluoroquinolones (PD 138312 and PD 140248) (2, 7), ciprofloxacin, and ofloxacin against 123 clinical isolates of X maltophilia.Most clinical isolates (85%) were from different patients at Hershey Medical Center and University Hospitals of Cleveland and were collected over a 3-year period. The remainder were obtained from sources listed in the Acknowledgments and were isolated over a 6-year period. All strains were reidentified and MIC studies performed at Hershey Medical Center. Strains were identified by standard methods (10) Suscep-tibility breakpoints for ciprofloxacin (2.0 ,ug/ml) and ofloxacin (4.0 ,ug/ml) were those recommended by the National Committee for Clinical Laboratory Standards for members of the family Enterobacteriaceae (15). Breakpoints for the other four compounds were all 2.0 pug/ml, on the basis of preliminary data for members of the family Enterobacteriaceae (2). It should be noted, however, that no definitive quinolone susceptibility breakpoints are available for X maltophilia.The results of MIC testing are presented in Tables 1 and 2. Clinafloxacin and PD 131628 were the most active agents against all X. maltophilia strains, with 94 and 80% of the strains susceptible to the respective compounds at the preliminary breakpoints. MIC ranges of 0.06 to 8.0 and 0.125 to 16.0 iig/ml, MI...

“…Its natural resistance restricts the choice of antibiotics for use in the treatment of infected patients (1,2,11,16), and quinolones have been considered as a possible option for therapy (17). The agar diffusion method has revealed a particular phenotype of quinolone susceptibility for this species (12).…”

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confidence: 99%

Susceptibility of Xanthomonas maltophilia to six quinolones and study of outer membrane proteins in resistant mutants selected in vitro

Lecsö-Bornet

Pierre

Sarkis-Karam

et al. 1992

The in vitro susceptibilities of 75 clinical isolates of Xanthomonas maltophilia to nalidixic acid, five fluoroquinolones, latamoxef, and doxycycline were determined. Spontaneous mutants were selected, at a frequency of about 10'-to 10-from four strains by culturing the strains in the presence of each quinolone.Selection in the presence of nalidixic acid provided mutants that were either resistant only to that compound or that exhibited cross-resistance to all the fluoroquinolones tested. Cross-resistance was always observed for mutants selected on any of the five fluoroquinolones. It was always associated with chloramphenicol resistance and, frequently, with doxycycline resistance. The electrophoretic alterations of the outer membrane proteins of the mutants suggest that different mechanisms may be involved in quinolone resistance in X. maltophilia.Xanthomonas maltophilia has recently been isolated with increasing frequency and is mainly responsible for nosocomial infections in compromised hosts (17). Its natural resistance restricts the choice of antibiotics for use in the treatment of infected patients (1, 2, 11, 16), and quinolones have been considered as a possible option for therapy (17). The agar diffusion method has revealed a particular phenotype of quinolone susceptibility for this species (12). In the current study, we determined the MICs of nalidixic acid, pefloxacin, ciprofloxacin, ofloxacin, temafloxacin, sparfloxacin, latamoxef, and doxycycline for 75 clinical isolates ofX. maltophilia. Since the emergence of mutants resistant to quinolones and unrelated drugs has been described in several species of gram-negative bacilli (5-7, 14, 18, 20), especially Pseudomonas aeruginosa (8,15), from 4 of the 75 strains of X. maltophilia, we selected mutants that were resistant to six quinolones. The resistance patterns of the mutants were studied, and the electrophoretic profiles of the outer membrane proteins (OMPs) were analyzed for each type of mutant.MICs were determined by a twofold serial agar dilution method on Mueller-Hinton agar by using a replicating spot device, with an inoculum of about 104 CFU per spot.Spontaneous mutants were selected from four susceptible strains by spreading approximately 2 x 108 CFU onto plates of Mueller-Hinton agar containing each of the six quinolones at concentrations of 4, 8, and 16 times the respective MICs for the strains. After 48 h at 37°C, the frequencies of mutation were evaluated and the MICs of the six quinolones, doxycycline, latamoxef, and chloramphenicol were determined. The mutants were classified according to their patterns of resistance to these nine antibiotics. From each type of mutant, OMP fractions were prepared as described previously (6) and were submitted to sodium dodecyl sulfatepolyacrylamide gel electrophoresis for separation (13.5% acrylamide, 0.36% bisacrylamide).