Antimicrobial susceptibility studies
Synergy of colistin with rifampin and trimethoprim/sulfamethoxazole on multidrug-resistant Stenotrophomonas maltophilia

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Abstract

Stenotrophomonas maltophilia is characterized by intrinsic resistance to a variety of antimicrobials. Therapeutic options are often limited particularly after the emergence of isolates resistant to trimethoprim/sulfamethoxazole. The application of colistin for infections caused by multidrug-resistant Gram-negative pathogens is limited due to its toxicity. In order to evaluate the activity of the interaction of colistin with rifampin or trimethoprim/sulfamethoxazole on S. maltophilia, 24 different isolates resistant to trimethoprim/sulfamethoxazole were in vitro exposed over-time to the combination of 1× and 4×MIC of colistin with 2ÎŒg/ml of rifampin or 2/38ÎŒg/ml of trimethoprim/sulfamethoxazole. The applied concentrations for rifampin and trimethoprim/sulfamethoxazole reflect their mean serum levels. Synergy of colistin and rifampin was documented after the first two hours of bacterial growth for approximately 60% of isolates and it occurred with both applied concentrations of colistin. The interaction of colistin and rifampin prevented regrowth observed when single colistin was applied. Synergy of colistin and trimethoprim/sulfamethoxazole was mainly found when colistin was applied at a concentration of 4×MIC involving 41.7% of isolates after 24 h of growth. In the presence of trimethoprim/sulfamethoxazole bacterial regrowth, observed when single colistin was applied, was prevented. It is concluded that growth of multidrug-resistant S. maltophilia is significantly inhibited by the interaction of colistin and rifampin and to a lesser extent of colistin and trimethoprim/sulfamethoxazole. These results merit further study in both the animal model and the clinical setting.

Introduction

Multidrug-resistance of Gram-negative nosocomial isolates has become a problem in everyday clinical practice particularly in the ICU (Hanberger et al., 2001). Stenotrophomonas maltophilia is a pathogen affecting immunocompromized and delibitated patients (Denton & Kerr, 1998). That species is intrinsically resistant to most ÎČ-lactams, quinolones and aminoglycosides; trimethoprim/sulfamethoxazole is considered the treatment of choice for infections by these isolates (Berg et al., 1999). Isolates resistant to trimethoprim/sulfamethoxazole rarely emerge (Gales et al., 2001a) but whenever they occur the available therapeutic alternatives are limited.

Colistin is an old antimicrobial belonging to polymyxins that has been proposed as an adequate therapeutic alternative for infections by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii (Levin et al., 1999). Its application is however limited due to its high toxicity and poor pharmacokinetics. Polymyxins have been shown to possess a considerable in vitro activity on S. maltophilia Gales et al 2001b, Giacometti et al 2000. Based on the in vitro synergy of colistin and rifampin on multidrug-resistant Acinetobacter baumannii (Giamarellos-Bourboulis et al., 2001), the present study aimed to the interaction of colistin with rifampin or trimethoprim/sulfamethoxazole against nosocomial isolates of S. maltophilia resistant to trimethoprim/sulfamethoxazole.

Section snippets

Selection of isolates

A total of 24 S. maltophilia clinical isolates were applied. All were derived from seven different hospitals of the territory of Athens and isolated from different patients with nosocomial infections. The biologic source of isolation was as follows: sputum 11; urine 9; pus 2; blood 2. Identification was performed by the API20E system (bioMĂ©rieux, Marcy L’ Etoile, France). Inclusion criterion was high resistance to amplicillin/sulbactam (MIC > 64/4ÎŒg/ml), to trimethoprim/sulfamethoxazole (MIC >

Results

MIC50 and MIC90 of colistin were 4 and 16ÎŒg/ml respectively. Seventeen isolates (70.8%) were inhibited at the susceptibility breakpoint of 4ÎŒg/ml Gales et al 2001b, Giamarellos-Bourboulis et al 2001, whereas the remaining seven isolates were inhibited at MICs equal to 8 or 16ÎŒg/ml. Changes of viable cell counts by the interaction of colistin and rifampin on S. maltophilia are shown in Table 1. Synergy of 1× MIC of colistin with rifampin was found in 16 (66.7%), 14 (58.3%), 14 (58.3%) and 13

Discussion

S. maltophilia is characterized by intrinsic resistance to a wide variety of antimicrobial agents and trimethoprim/sulfamethoxazole is the most active antimicrobial on that species Betriu et al 2001, Valdezate et al 2001. Since isolates resistant to trimethoprim/sulfamethoxazole seem to emerge over the last years in the ICUs Hanberger et al 2001, Tsiodras et al 2000, the present study investigated the activity of the interactions of colistin with rifampin or trimethoprim/sulfamethoxazole on 24

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