In vitro activity of tigecycline against Bacteroides species

C. Betriu*, E. Culebras, M. Gómez, I. Rodríguez-Avial and J. J. Picazo

Department of Clinical Microbiology, Hospital Clínico San Carlos, 28040 Madrid, Spain


* Corresponding author. Tel: +34-91-3303486; Fax: +34-91-3303478; E-mail: cbetriu{at}efd.net

Received 3 March 2005; returned 4 May 2005; revised 19 May 2005; accepted 20 May 2005


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
Objectives: To ascertain the current susceptibility patterns of members of the Bacteroides fragilis group in our hospital and to assess the in vitro activity of tigecycline against these organisms.

Methods: A total of 400 non-duplicate clinical isolates of the B. fragilis group collected from 2000 to 2002 were studied. Susceptibility testing was performed according to the reference agar dilution method described by the NCCLS. The following antimicrobials were tested: tigecycline, clindamycin, metronidazole, chloramphenicol, cefoxitin, imipenem, amoxicillin–clavulanate and piperacillin–tazobactam.

Results: All strains were susceptible to metronidazole and chloramphenicol. For clindamycin and cefoxitin, the overall susceptibility rates were 59.5% and 83%, respectively. Imipenem and piperacillin–tazobactam were the most active ß-lactam agents tested. Tigecycline inhibited 89.8% of the strains at a concentration of 8 mg/L with an MIC range of ≤0.01 to >16 mg/L. By comparing the MIC50 and MIC90 values of tigecycline among the various species of the group, B. fragilis, Bacteroides thetaiotaomicron and Bacteroides vulgatus were the most susceptible (MIC50/MIC90s of 0.5–1/8 mg/L).

Conclusions: Tigecycline exhibited activity against most isolates of the B. fragilis group tested. These results indicate that tigecycline may be useful in the treatment and prophylaxis of infections involving these organisms.

Keywords: susceptibility , glycylcyclines , Bacteroides fragilis group


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
Among the anaerobic bacteria, members of the Bacteroides fragilis group are the most frequently isolated in clinical infections. Antibiotics currently available with activity against these organisms include clindamycin, metronidazole, cefoxitin, carbapenems and ß-lactam–ß-lactamase inhibitor combinations. However, increasingly frequent resistance to these agents has been reported during recent years, e.g. the emerging resistance to metronidazole in several countries,14 the high prevalence of clindamycin resistance2,5,6 and the isolation of B. fragilis group strains resistant to carbapenems and to ß-lactamase inhibitor combinations.710

The increasing antimicrobial resistance among the B. fragilis group has important implications in the selection of antimicrobial agents for empirical therapy. It has been demonstrated that treatment with inappropriate antibiotics influences the clinical outcome of patients with Bacteroides bacteraemia.11 Therefore, there is a need for periodic susceptibility studies and for the evaluation of new agents to provide data to guide the appropriate empirical antimicrobial therapy. Tigecycline is the 9-t-butylglycylamino derivative of minocycline and has a broad spectrum of activity against aerobic and anaerobic bacteria.1217 The aim of this study was to ascertain the current susceptibility patterns of members of the B. fragilis group in our hospital and to assess the in vitro activity of tigecycline against these organisms.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
A total of 400 non-duplicate clinical isolates of the B. fragilis group collected from 2000 to 2002 at the Hospital Clínico San Carlos were studied. Organisms were identified using the Rapid ID 32A system (bioMérieux, Marcy l'Étoile, France). Distribution of species was as follows: 272 B. fragilis, 40 Bacteroides thetaiotaomicron, 27 Bacteroides uniformis, 16 Bacteroides ovatus, 15 Bacteroides caccae, 14 Bacteroides vulgatus, 10 Bacteroides distasonis, 4 Bacteroides merdae and 2 Bacteroides eggerthii. Sources of the isolates included abdomen (44.3%), skin and soft tissue (38.8%), blood (10.5%), female genital tract (3.2%), bile (1.5%), ascitic fluid (0.5%), pleural fluid (0.5%) and others (0.7%).

Antimicrobial susceptibility tests were performed according to the reference agar dilution method described by the NCCLS18 with brucella agar supplemented with haemin, vitamin K1 and 5% laked sheep blood. Approximately 105 cfu/spot was inoculated using a Steers multipoint replicator. The agar dilution test plates were incubated at 35°C for 48 h in an anaerobic chamber. MICs were defined as the lowest concentration of an antimicrobial agent where a marked reduction occurred in the appearance of growth on the test plate compared with that of growth on the anaerobic control plate. Reference strains B. fragilis ATCC 25285 and B. thetaiotaomicron ATCC 29741 were used as controls.

Standard laboratory powders were supplied as follows: tigecycline and piperacillin–tazobactam (Wyeth, Philadelphia, PA, USA), clindamycin (Pfizer Inc., Groton, CT, USA), metronidazole (Aventis Pharma, S.A., Madrid, Spain), chloramphenicol (Sigma–Aldrich Química, S.A., Madrid, Spain), cefoxitin and imipenem (Merck Sharp & Dohme de España, S.A., Madrid, Spain) and amoxicillin–clavulanate (GlaxoSmithKline S.A., Madrid, Spain). MICs were determined for both the group as a whole and for the individual species.


    Results and discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
The range of the MICs, the MICs at which 50% and 90% of the isolates were inhibited (MIC50 and MIC90, respectively) and the percentages of organisms that were susceptible, intermediate and resistant to the antimicrobials tested are summarized in Table 1. All strains were susceptible to metronidazole and chloramphenicol. The overall rate of resistance to clindamycin observed among our isolates (35.8%) is higher than that of other studies, with values between 10.5% and 26.1%.9,10,17 The resistance rate for cefoxitin was 6.5%, while recent reports from the USA have noted higher percentages of cefoxitin resistance, ranging from 10% to 12.6%.9,17 According to the majority of published studies,2,9,10,17,19 a variability in resistance patterns has been observed among the different species in the group. B. fragilis and B. caccae isolates were the most susceptible to clindamycin and cefoxitin. B. uniformis and B. vulgatus were the species with the highest resistance to cefoxitin (14.8% and 21.4%, respectively). B. thetaiotaomicron and B. uniformis showed less susceptibility to amoxicillin–clavulanate than the other species. As can be seen in Table 1, resistance to clindamycin also varied among the different species, ranging from 30.8% for B. fragilis to 62.5% for B. ovatus.


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Table 1. In vitro activities of tigecycline and other antimicrobial agents against the Bacteroides fragilis group

 
Imipenem and piperacillin–tazobactam were the most active ß-lactam agents tested, with MIC90s of 2 and 16 mg/L, respectively. We found three strains (two B. fragilis and one B. thetaiotaomicron) that were resistant to imipenem, and two of these were also resistant to piperacillin–tazobactam. Resistance to imipenem among the B. fragilis group has been detected in our hospital since 1989,7 but with a very low incidence. This agrees with reports from several countries.2,810,19

Previous reports12,13,17 showed that tigecycline exhibited activity against most isolates of the B. fragilis group tested. This new antibiotic inhibited 89.8% of the strains at a concentration of 8 mg/L with an MIC range of ≤0.01 to >16 mg/L. A comparison of the MIC50 and MIC90 values of tigecycline among the various species of the group, revealed that B. fragilis, B. thetaiotaomicron and B. vulgatus were the most susceptible (MIC50/MIC90s of 0.5–1/8 mg/L). Higher tigecycline MICs were observed among the other members of the group. The three isolates resistant to imipenem were inhibited by 0.5, 4 and 8 mg/L of tigecycline, respectively. For the entire group, the MIC50 and MIC90 values of tigecycline are similar to those recently described by Jacobus et al.17 These results, together with its activity against most members of the family of Enterobacteriaceae and enterococci,1416 suggest that tigecycline may be useful in the treatment and prophylaxis of mixed intra-abdominal infections involving these organisms.

Tigecycline has also demonstrated in vivo efficacy in several infection models in animals.2022 A Phase 2 clinical trial demonstrated the efficacy and safety of tigecycline in the treatment of complicated intra-abdominal infections in hospitalized patients.23 Phase 3 clinical trials to evaluate the role of tigecycline in such infections are currently being performed.


    Acknowledgements
 
This work was supported by grant FIS PIO 20037 from de Fondo de Investigación Sanitaria, Madrid, Spain. This study was presented at the Forty-fourth Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, USA, 29 October–2 November, 2004).


    References
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 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
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19. Aldridge KE, Ashcraft D, Cambre K et al. Multicenter survey of the changing in vitro antimicrobial susceptibilities of clinical isolates of Bacteroides fragilis group, Prevotella, Fusobacterium, Porphyromonas, and Peptostreptococcus species. Antimicrob Agents Chemother 2001; 45: 1238–43.[Abstract/Free Full Text]

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