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Antimicrobial Agents and Chemotherapy, July 2009, p. 3115-3117, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.00893-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

In Vitro Activity of Doripenem against Burkholderia pseudomallei{triangledown}

Visanu Thamlikitkul* and Suwanna Trakulsomboon

Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand

Received 7 July 2008/ Returned for modification 2 September 2008/ Accepted 19 November 2008


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ABSTRACT
 
The MIC50 and MIC90 values of doripenem, determined by Etest, for 110 isolates of Burkholderia pseudomallei were 0.5 and 0.75 µg/ml, respectively. There were significant correlations between MICs determined by Etest and MICs determined by agar dilution, MICs determined by Etest and inhibition zone size, and MICs determined by agar dilution and inhibition zone size.


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INTRODUCTION
 
Burkholderia pseudomallei, a gram-negative bacterium, causes a disease called melioidosis in humans and animals (13). B. pseudomallei is usually resistant to many antibiotics. Antibiotics currently recommended as therapy for melioidosis are ceftazidime, imipenem, meropenem, amoxicillin-clavulanate, cefoperazone-sulbactam, trimethoprim-sulfamethoxazole, doxycycline, and chloramphenicol (13). The development of resistance by B. pseudomallei to the aforementioned antibiotics was recognized (3, 4, 10, 11, 14); hence, a search for new agents effective against B. pseudomallei is needed.

Doripenem is a new parental 1-β-methyl carbapenem. Doripenem has demonstrated activity against a wide range of gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa (7, 8). Against P. aeruginosa, doripenem exhibits rapid bactericidal activity, with two- to fourfold-lower MICs than those of meropenem. However, the activity of doripenem against B. pseudomallei has not been reported. The present study was undertaken to explore the activity of doripenem against B. pseudomallei.

One hundred ten clinical isolates of B. pseudomallei from different patients were selected from our collection. All isolates of B. pseudomallei were identified by API 20NE (bioMerieux, France). These isolates are susceptible to imipenem and meropenem, according to the inhibition zone diameter criteria for P. aeruginosa (≥16 mm). In vitro susceptibilities of all isolates were determined by Etest. Thirty isolates were randomly selected for determination of the MICs for doripenem by using the agar dilution and Kirby-Bauer disk diffusion methods. Paper disks containing doripenem (10 µg per disk; Becton Dickinson), Etest strips (AB Biodisk, Sweden), and doripenem powder (Johnson & Johnson Pharmaceutical Research & Development) were used. The methodology used for susceptibility testing was direct colony suspension, according to guidelines suggested by the CLSI (2). Quality control was performed by testing the susceptibility of P. aeruginosa ATCC 27853 and Escherichia coli ATCC 25922.

The MICs of doripenem for the quality control organisms, namely P. aeruginosa ATCC 27853 and E. coli ATCC 25922, were 0.125 and 0.012 µg/ml, respectively. Both values were within the reference limits. A distribution of the MICs for doripenem determined by Etest for 110 strains of B. pseudomallei is shown in Table 1. Etest results showed doripenem MICs ranging from 0.19 to 2 µg/ml, and the MIC50 and the MIC90 values were 0.5 and 0.75 µg/ml, respectively. The MIC50 and MIC90 values of doripenem, determined by agar dilution for 30 strains of B. pseudomallei, were 1 and 1.5 µg/ml, respectively. The inhibition zone diameters of doripenem determined for 30 strains of B. pseudomallei ranged from 24 to 36 mm. There was a significant correlation between the MICs determined by Etest and the MICs determined by agar dilution (r of 0.9; P of <0.001), the MICs determined by Etest and the inhibition zone diameters (r of –0.7; P of <0.001), and the MICs determined by agar dilution and the inhibition zone diameters (r of –0.7; P of <0.001), as shown in Fig. 1.


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  		TABLE 1. Distribution of the MICs for doripenem determined by Etest for 110 isolates of B. pseudomallei


Figure 1
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  		FIG. 1. Correlations between the MICs determined by Etest and agar dilution and the inhibition zone diameters. (A) Correlation between the MICs determined by Etest and the MICs determined by agar dilution. (B) Correlation between the MICs determined by Etest and the inhibition zone diameters. (C) Correlation between the MICs determined by agar dilution and the inhibition zone diameters.

The MIC breakpoint recommended by the CLSI for imipenem-susceptible B. pseudomallei, imipenem-susceptible P. aeruginosa, and meropenem-susceptible P. aeruginosa is ≤4 µg/ml. The MIC breakpoint recommended by the FDA for imipenem-susceptible P. aeruginosa and meropenem-susceptible P. aeruginosa is also ≤4 µg/ml. The MIC breakpoint recommended by the CLSI for meropenem-susceptible Burkholderia cepacia is ≤4 µg/ml. However, the breakpoints for the MIC and inhibition zone diameter of doripenem for B. pseudomallei are not available. The U.S. FDA-approved breakpoints of doripenem for P. aeruginosa were a MIC of ≤2 µg/ml and an inhibition zone diameter of ≥24 mm. If the aforementioned breakpoints were used to determine susceptibility of B. pseudomallei to doripenem, all isolates of B. pseudomallei are considered susceptible to doripenem, according to inhibition zone diameter and MICs determined by Etest; more than 90% of B. pseudomallei isolates are considered susceptible to doripenem, according to MICs determined by agar dilution. The susceptibility profiles of B. pseudomallei to imipenem and meropenem were reported (5, 6, 10, 11). The MIC50 and MIC90 values for imipenem against B. pseudomallei were 1 and 1 µg/ml by agar dilution, respectively, and 0.5 and 1 µg/ml by Etest, respectively. The MIC50 and MIC90 values for meropenem against B. pseudomallei were 3 and 4 µg/ml by broth microdilution, respectively, and 1 and 2 µg/ml by Etest, respectively. Therefore, the susceptibility profiles of B. pseudomallei to doripenem are comparable to those of B. pseudomallei to imipenem and meropenem.

The inhibition zone diameters of doripenem for B. pseudomallei were significantly correlated with the MICs determined by Etest or agar dilution. Therefore, Kirby-Bauer disk diffusion could be used to determine in the vitro activity of doripenem against B. pseudomallei. However, the MICs of doripenem determined by agar dilution for B. pseudomallei observed in our study were twofold higher than those determined by Etest. Nevertheless, the MIC90 of doripenem determined by agar dilution was ≤2 µg/ml.

Ceftazidime is the conventional agent used as therapy for acute severe melioidosis (12). Imipenem and meropenem were also found to be effective and safe when used as therapy for acute severe melioidosis (1, 9), and they are considered to be alternative therapeutic agents (15). Since the in vitro activity of doripenem against B. pseudomallei is comparable to the activity of imipenem and meropenem against B. pseudomallei, doripenem should be an effective therapy for melioidosis. However, a clinical trial is required to fully establish the efficacy and safety of doripenem used as therapy for melioidosis.


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ACKNOWLEDGMENTS
 
Johnson & Johnson Pharmaceutical Research & Development provided the doripenem susceptibility disks, Etest strips, and powder for this study.


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FOOTNOTES
 
* Corresponding author. Mailing address: Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand. Phone and fax: 662-412-5994. E-mail: sivth{at}mahidol.ac.th Back

{triangledown} Published ahead of print on 13 April 2009. Back


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Antimicrobial Agents and Chemotherapy, July 2009, p. 3115-3117, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.00893-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.




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