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

This study evaluated the susceptibility of 123 Xanthomonas maltophilia strains to ticarcillin, ticarcillinclavulanate, ampicillin, amoxicillin-clavulanate, ampicillin-sulbactam, piperacillin, piperacillin-tazobactam, imipenem, and ciprofloxacin by Kirby-Bauer disk, E test, and Sensititre dehydrated microdilution MIC and conventional agar dilution MIC methodology. Intermediate susceptibility breakpoints for members of the family Enterobacteriaceae were used. When results were analyzed as MICs for 50 and 90%Yo of the strains tested and percentages of strains susceptible at the breakpoint, good correlation between the methods was observed, with ticarcillin-clavulanate clearly the most active P-lactam by all four methods. However, when the various methods were compared with the agar dilution methodology by regression analysis, poor r2 values (0.3 to 0.7)were obtained for compounds with sufficient on-scale values to permit analysis. When the number of strains with log2 ratios of reference agar dilution MICs to test MICs of +3 to -3 were analyzed, correlation was also poor, with many major and very major discrepancies for all methods tested. Results obtained with time-kill studies of nine strains with discrepant ticarcillin-clavulanate MICs appeared to correlate best when compared at 24 h with agar dilution MICs. The concentration of ticarcillin-clavulanate required to reduce the colony count by .2 log10 reduction values for eight of nine strains compared with that for growth controls was <16.0/2.0 ,ug/ml at 6 h and ranged from 16.0/2.0 ,ug/ml to 128.0/2.0 ,ug/ml at 24 h. Parallel kill curves with piperacillin4azobactam yielded .2 log1o reduction values ranging from -16.0/4.0 ,ug/ml to 128.0/4.0 ,ug/ml at 6 h and >128.0/4.0 ,ug/ml at 24 h. The susceptibility method of choice for X. maltophilia has not yet been standardized, but time-kill studies correlated best with agar dilution MICs.Infections with Xanthomonas maltophilia are increasingly encountered, especially in immunocompromised patients (9,(14)(15)(16)25). This organism is inherently resistant to most P-lactam and non-13-lactam agents by virtue of permeability barriers and elaboration of at least two ,B-lactamases; trimethoprim-sulfamethoxazole and, perhaps, moxalactam are currently suggested as the drugs of choice for treating infections with this organism (4, 7, 9-11, 14-16, 25). P-Lactam resistance in X maltophilia is mediated by production of at least two P-lactamases-a zinc-dependent metalloenzyme that breaks down carbapenems and is resistant to P-lactamase inhibitors and a cephalosporinase that is susceptible to 1-lactamase inhibitors (3,23,24). A previous preliminary study by our group, as well as reports by other workers, have documented apparent increased susceptibility of X maltophilia strains to ticarcillin-clavulanate by disk diffusion and MIC methodology compared with susceptibility to ticarcillin, ampicillin, amoxicillin-clavulanate, ampicillin-sulbactam, piperacillin, and piperacillin-tazobactam (8, 19, 21 ampicillin, amoxicillin-clavulanate, amp...

supporting

confidence: 59%

Susceptibilities of 123 strains of Xanthomonas maltophilia to eight beta-lactams (including beta-lactam-beta-lactamase inhibitor combinations) and ciprofloxacin tested by five methods

Pankuch

Jacobs

Rittenhouse

et al. 1994

“…However, due to the selection of resistant mutants by both fluoroquinolones, moxifloxacin should be administered at the maximum tolerated doses and in combination. Given the existence of cross-resistance between fluoroquinolones and trimethoprim, the combination of moxifloxacin plus ticarcillin-clavulanate might represent the most promising regimen, as much as synergy has been demonstrated between ciprofloxacin and ticarcillin-clavulanate (31).…”

Section: Discussionmentioning

confidence: 99%

Activities of Ciprofloxacin and Moxifloxacin against Stenotrophomonas maltophilia and Emergence of Resistant Mutants in an In Vitro Pharmacokinetic-Pharmacodynamic Model

Feghali

Arpin

et al. 2004

A two-compartment in vitro pharmacokinetic-pharmacodynamic model, with full computer-controlled devices, was used to accurately simulate human plasma pharmacokinetic profiles after multidose oral regimens of ciprofloxacin (750 mg every 12 h) and moxifloxacin (400 mg every 24 h) during 48 h. Pharmacodynamics of these drugs was investigated against three quinolone-susceptible strains of Stenotrophomonas maltophilia (MICs of ciprofloxacin and moxifloxacin of 0.5 to 2 and 0.0625 to 0.5 g/ml, respectively). The first dose of ciprofloxacin and moxifloxacin reduced the bacterial count by 1 and 2 log CFU/ml, respectively, prior to a bacterial regrowth that reached the plateau value of the growth control curve at 13 to 24 h versus 24 to 36 h and persisted despite repeated administration of both drugs. The surviving bacterial cells were quinoloneresistant mutants (2 to 128 times the MIC) that exhibited cross-resistance to unrelated antibiotics. Their antibiotic resistance probably resulted from the overproduction of different multidrug resistance efflux system(s). C max /MIC and area under the concentration-time curve from 0 to 24 h (AUC 0-24 )/MIC values were at least threefold higher for moxifloxacin than for ciprofloxacin. Moreover, integral parameters of ciprofloxacin and moxifloxacin, in particular the area under the killing and regrowth curve from 0 to 48 h (AUBC 0-48 , 342.3 to 401.3 versus 295.2 to 378.7 h ؋ log CFU/ml, respectively) and the area between the control growth curve and the killing and regrowth curve from 0 to 48 h (ABBC 0-48 , 40.4 to 101.1 versus 72.9 to 144.7 h ؋ log CFU/ml, respectively), demonstrated a better antibacterial effect of moxifloxacin than ciprofloxacin on S. maltophilia. However, selection of resistant mutants by both fluoroquinolones, although delayed with moxifloxacin, emphasizes the need to use maximal dosages and combined therapy in the treatment of systemic S. maltophilia infections.

“…The treatment of choice for S. maltophilia infection is trimethoprim-sulfamethoxazole (TMP-SMZ; cotrimoxazole), alone or in combination with ticarcillin-clavulanate (25,32,33). TMP-SMZ is bacteriostatic for most isolates; hence, high doses (12 to 15 mg/kg of body weight/day based on TMP) are usually recommended.…”

mentioning

confidence: 99%

Antifolate Activity of Epigallocatechin Gallate against Stenotrophomonas maltophilia

Navarro-Martínez

Navarro-Perán

Cabezas‐Herrera³

et al. 2005

The catechin epigallocatechin gallate, one of the main constituents of green tea, showed strong antibiotic activity against 18 isolates of Stenotrophomonas maltophilia (MIC range, 4 to 256 g/ml). In elucidating its mechanism of action, we have shown that epigallocatechin gallate is an efficient inhibitor of S. maltophilia dihydrofolate reductase, a strategic enzyme that is considered an attractive target for the development of antibacterial agents. The inhibition of S. maltophilia dihydrofolate reductase by this tea compound was studied and compared with the mechanism of a nonclassical antifolate compound, trimethoprim. Investigation of dihydrofolate reductase was undertaken with both a trimethoprim-susceptible S. maltophilia isolate and an isolate with a high level of resistance. The enzymes were purified using ammonium sulfate precipitation, gel filtration, and methotrexate affinity chromatography. The two isolates showed similar levels of dihydrofolate reductase expression and similar substrate kinetics. However, the dihydrofolate reductase from the trimethoprim-resistant isolate demonstrated decreased susceptibility to inhibition by trimethoprim and epigallocatechin gallate. As with other antifolates, the action of epigallocatechin gallate was synergistic with that of sulfamethoxazole, a drug that blocks folic acid metabolism in bacteria, and the inhibition of bacterial growth was attenuated by including leucovorin in the growth medium. We conclude that the mechanism of action of epigallocatechin gallate on S. maltophilia is related to its antifolate activity.