Comparative activity of new quinolones against 326 clinical isolates of Stenotrophomonas maltophilia
Karl Weissa,*,
Christiane Restieria,
Emidio De Carolisb,
Michel Laverdièrea and
Hélène Guaya
a Hôpital Maisonneuve-Rosemont, University of Montreal, Montreal, Quebec, Canada H1T 2M4 and
b Pfizer Pharmaceuticals (Canada), Kirkland, Quebec, Canada
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Abstract
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Stenotrophomonas maltophilia is an important emerging pathogen causing a variety of infections in severely ill patients. This microorganism is inherently resistant to many antibiotics, and only a few therapeutic options are available. The principal aim of this study was to assess the in vitro activity of new quinolones against this pathogen. Three hundred and twenty-six single clinical isolates were tested in this study. The MIC90 was 16 mg/L for ciprofloxacin, 8 mg/L for levofloxacin and gatifloxacin, 4 mg/L for trovafloxacin, moxifloxacin and sparfloxacin and 2 mg/L for clinafloxacin. At a 2 mg/L concentration, a Cmax lung:MIC ratio of
10 can be reached for 95%, 84.3%, 83.1% and 81.5% of isolates, respectively, for clinafloxacin, trovafloxacin, moxifloxacin and sparfloxacin (P < 0.001 compared with levofloxacin and ciprofloxacin). In spite of the rare but serious adverse events associated with the new-generation quinolones, these agents may become very useful in the treatment of certain severe or life-threatening infectious conditions due to S. maltophilia, notably lower respiratory tract infections.
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Introduction
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Stenotrophomonas maltophilia is an increasingly important pathogen implicated in numerous nosocomial infections. The clinical manifestations include bacteraemia, respiratory infections, endocarditis and urinary tract and gastrointestinal infections. This microorganism has the propensity to cause serious infections in cancer patients undergoing chemotherapy or in patients hospitalized in critical care units.1
As S. maltophilia is inherently resistant to many antibiotics such as ß-lactams and aminoglycosides, only a few therapeutic choices are available. Trimethoprimsulphamethoxazole is the most active agent against this microorganism and has long been regarded as the agent of choice for the therapy of S. maltophilia infections. However, this drug is only bacteriostatic for most isolates. Furthermore, it is not a very convenient antibiotic to use for severely ill patients who may be diagnosed with polymicrobial infections resulting in complicated antibiotic regimens. Older-generation quinolones such as ciprofloxacin have been known to have some in vitro activity with about 50% of isolates being susceptible to this antibiotic.1,2 The newer quinolones could become a therapeutic option for treating infections caused by this microorganism.
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Materials and methods
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The main objectives of this study were to compare the in vitro activity of different quinolones against clinical isolates of S. maltophilia and to determine the MIC50 and MIC90 of the different quinolones.
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Isolates
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Three hundred and twenty-six single clinical isolates of S. maltophilia were collected from different areas of our institution from March 1995 to February 1999. Of these isolates, 200 (62%) originated from the respiratory tract, 69 (21%) from wound cultures, 17 (5.2%) from blood cultures, 15 (4.2%) from urine samples, 11 (3.3%) from catheters and 14 from others. Strains were frozen at 70°C in a suitable stabilizer (1015% glycerol in tryptic soy broth).
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Antibiotics
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Antibiotic powders were provided by their respective manufacturers. The following antibiotics were tested in the study: ciprofloxacin and moxifloxacin (Bayer Canada Inc., Etobicoke, Ontario, Canada), levofloxacin (The R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey, USA), gatifloxacin (Bristol Myers Squibb, Montreal, Quebec, Canada), sparfloxacin (Rhône Poulenc Rorer, Ville St-Laurent, Quebec, Canada), trovafloxacin (Pfizer Canada, Kirkland, Quebec, Canada), clinafloxacin (Parke-Davis, Scarborough, Ontario, Canada). Trimethoprim sulphamethoxazole and ticarcillinclavulanic acid were purchased from Nucrotechnics (Scarborough, Ontario, Canada).
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Susceptibility testing
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The isolates were tested against the following antibiotics at the following concentrations: ciprofloxacin, levofloxacin, gatifloxacin, sparfloxacin, moxifloxacin, trovafloxacin and clinafloxacin,
0.06>32 mg/L; ticarcillinclavulanic acid, 1/2512/2 mg/L; and trimethoprimsulphamethoxazole,
0.25/4.7516/304 mg/L. MICs were determined by a serial two-fold agar dilution method on MuellerHinton agar using NCCLS recommendations.3 A MacFarland 0.5 suspension was prepared from an overnight culture of S. maltophilia on sheep's blood agar. Appropriate dilutions were then performed in order to obtain a final inoculum on the agar of approximately 104 cfu per spot. Plates were incubated at 35°C for 20 h in ambient air. The lowest concentration of antibiotics showing no growth was read as the MIC. Quality control was assessed by testing Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853. In the analysis of susceptibility, 2 mg/L was chosen as the susceptible/resistant breakpoint in accordance with NCCLS recommendations for ciprofloxacin, as there are no recommendations for other quinolones except for levofloxacin (urine only).
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Results and discussion
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The new-generation quinolones such as trovafloxacin, clinafloxacin and moxifloxacin have significantly better activity in vitro against S. maltophilia than levofloxacin or ciprofloxacin (Table
). Other authors in smaller studies have shown the improved activity of these molecules against S. maltophilia,47 but this is the first study comparing simultaneously a large number of newer quinolones. In this study, we compared older agents as well as newer quinolones against clinically relevant isolates of S. maltophilia using NCCLS currently recommended methods.
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Table. In vitro activity of nine antibiotics against 326 clinical isolates of S. maltophilia, and pharmacokinetic derivatives
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The quinolones exert concentration-dependent killing. These new-generation quinolones can reach a lung concentration at least five times their serum concentration,8 and several models suggest that for quinolones a Cmax:MIC ratio of >10 is predictive of microbiological eradication and prevention of resistance, so these antibiotics may represent an interesting option in the treatment of respiratory tract infections. Interestingly, >60% of the S. maltophilia isolates were recovered from respiratory secretions.
At a concentration of 2 mg/L, 95%, 84.3%, 83.1% and 81.5% of S. maltophilia isolates were inhibited by clinafloxacin, trovafloxacin, moxifloxacin and sparfloxacin, respectively. With the antibiotic concentration in alveolar macrophages achieving concentrations in the 3080 mg/L range, depending on the quinolone,8 the ratio of the maximum alveolar macrophage concentration to the MIC90 will be >10 for several new agents (Table
). It can be as high as 19.8 for trovafloxacin (Table
).
Only five isolates (1.5%) were resistant to trimethoprimsulphamethoxazole which is still considered the most active compound against S. maltophilia. Trovafloxacin, moxifloxacin and clinafloxacin were active against two of these resistant isolates. Thus, in cases of resistance to trimethoprimsulphamethoxazole, newer quinolones could become an alternative.
Increasing resistance of S. maltophilia to quinolones has been described, with the MIC90 to ciprofloxacin increasing from 16 to 64 mg/L over a decade.2 This may be explained by the poor Cmax:MIC90 ratio for this agent. Quinolone resistance in S. maltophilia may be related to an alteration of the outer membrane proteins.9 One way in which the problem of emerging resistance could potentially be avoided would be to use combination therapy. Interestingly, the combination of trovafloxacin associated with a third-generation cephalosporin (either ceftazidime or cefoperazone) was found to have a synergic activity in >50% of cases.7 Muder et al. recently investigated 91 cases of bacteraemia due to S. maltophilia and suggested that combination therapy may be superior to monotherapy.10
The new-generation quinolones have a much enhanced in vitro activity against clinical strains of S. maltophilia, and clinical studies evaluating these drugs in vivo should be initiated. As the use of trovafloxacin has been restricted for severe or life-threatening conditions in North America, this antibiotic may find a use in treating infections due to S. maltophilia in such patients.
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Notes
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* Corresponding author. Tel: +1-514-252-3817; Fax: +1-514-252-3898; E-mail: weisscan{at}aol.com 
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References
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Muder, R. R., Harris, A. P., Muller, S., Edmond, M., Chow, J. W., Papadakis, K. et al. (1996). Bacteremia due to Stenotrophomonas (Xanthomonas) maltophilia: a prospective multicenter study of 91 episodes. Clinical Infectious Diseases 22, 50812.[ISI][Medline]
Received 8 September 1999;
returned 27 October 1999; revised 11 November 1999;
accepted 22 November 1999