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Journal of Clinical Microbiology, November 2002, p. 4349-4352, Vol. 40, No. 11
0095-1137/02/$04.00+0     DOI: 10.1128/JCM.40.11.4349-4352.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

In Vitro Susceptibilities of the Bacteroides fragilis Group Species: Change in Isolation Rates Significantly Affects Overall Susceptibility Data

Kenneth E. Aldridge* and Megan O'Brien

Department of Medicine (Infectious Diseases), Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112

Received 15 April 2002/ Returned for modification 29 May 2002/ Accepted 19 August 2002


   ABSTRACT
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A comparison of antimicrobial susceptibility data of species of the Bacteroides fragilis group for 1989-1990 and 1998-1999 studies showed statistically significant increases or decreases in in vitro activity. Overall significant increases in resistance were noted for ampicillin-sulbactam and clindamycin, while significant decreases in resistance were noted for ertapenem and cefoxitin. Susceptibilities to piperacillin-tazobactam, imipenem, meropenem, and trovafloxacin remained virtually the same for the two studies. Importantly, a change in the rates of isolation of the various species showed the B. fragilis species comprised 58% of the isolates in 1989 to 1990 and 45% of the isolates in 1998 to 1999. This change in rates of isolation of B. fragilis versus non-B. fragilis species had an overall effect on susceptibility data.


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The Bacteroides fragilis group is a predominant component of the normal bacterial flora of the gastrointestinal tract. Moreover, these organisms are frequent isolates from mixed aerobic-anaerobic infections, such as intra-abdominal, diabetic foot, and soft tissue infections and contribute to the severity of the infections due to virulence factors (2). Several reports have indicated that in patients with mixed infections (including bacteremia), the B. fragilis group organisms can serve as a marker for increased morbidity and mortality and that patients treated with inappropriate antibiotics based on in vitro susceptibility data had a poorer clinical outcome than patients receiving appropriate antibiotic therapy (9, 11, 13).

The B. fragilis group is a heterogeneous group of species that vary in their susceptibility to antimicrobial agents, particularly ß-lactams and clindamycin (1, 12). The B. fragilis species unexplainably remains more susceptible to many antimicrobial agents than the other species within the group (1, 7, 17). It is therefore important, especially in the choice of empirical therapy, that sufficient susceptibility data from sufficient numbers of isolates be available for local or regional isolates. The Anaerobe Working Group for the National Committee for Clinical Laboratory Standards (NCCLS) recommends that susceptibility testing of the B. fragilis group be done with a distribution of test isolates to approximate the species distribution normally isolated from infections (7). Several multicenter susceptibility studies have shown that the B. fragilis species comprises 58 to 63% of isolates (1, 5, 6, 17). Such distribution rates have been relatively evident in studies reported during the 1980s and early 1990s. Snydman et al. (15) reported that during 1995 to 1996, 53% of 961 isolates were of the B. fragilis species. However, it was recently reported from an ongoing national susceptibility study that the distribution of isolates has changed (Y. Golan, N. V. Jacobus, L. A. McDermott, S. Supran, D. W. Hecht, E. Goldstein, R. Venezia, L. Harrell, S. Jenkins, J. Rihs, C. Pierson, S. L. Gorbach, S. Finegold, and D. R. Snydman, Abstr. 41st Intersci. Conf. Antimicrob. Agents Chemother., abstr. K1209, p. 412, 2001). They found that the incidence of the B. fragilis species decreased from 63% in 1984 to 1985 to 50% in 1999 to 2000. Here we report a similar comparison of changing isolation rates from 1989 and 1990 to 1998 and 1999 and the effect on antimicrobial susceptibility results.

During 1989 to 1990 and 1998 to 1999, respectively, 1,240 and 401 nonduplicate clinical isolates of species of the B. fragilis group were collected from intra-abdominal, wound, blood, tissue, and abscess specimens. Isolates were identified with selective media, biochemical profiles, and gas-liquid chromatography (8, 16). Each antimicrobial agent listed in Table 2 was provided by the manufacturer. Susceptibility testing in both studies was performed by a broth microdilution method as recommended by the NCCLS (10) with Anaerobe MIC broth (Difco) to prepare twofold dilutions of each agent within a dilution range of 0.03 to 256 µg/ml. Ampicillin was combined with sulbactam in a 2:1 ratio, while twofold dilutions of piperacillin were combined with tazobactam at a constant concentration of 4 µg/ml. The inoculum for each isolate was prepared by suspending growth from a 24- to 48-h sheep blood agar plate to a suspension equal to a no. 1 McFarland standard. The suspension was further diluted to give a final inoculum size of 105 CFU per well (106 CFU/ml). All susceptibility plates were incubated at 35°C anaerobically for 48 h and read. The MIC was defined as the lowest concentration of each antimicrobial agent that inhibited the visible growth of the test isolate. With each susceptibility run, quality control was performed with B. fragilis ATCC 25285 and Bacteroides thetaiotaomicron ATCC 2974.


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  		TABLE 2. Comparison of effects of the change in isolation rates of B. fragilis versus non-B. fragilis speciesa during 1989 to 1990 and 1998 to 1999

 
Individual MICs for each antimicrobial were collated to establish MIC ranges, MICs at which 50 and 90% of the isolates tested are inhibited(MIC50s and MIC90s, respectively), and the percentage of isolates categorized as susceptible (S), intermediate (I), and resistant (R) based on NCCLS recommendations (10). Breakpoints for ertapenem were <=4 as S, 8 as I, and >=16 as R (provisional breakpoints from the NCCLS summary minutes, Meeting of the Subcommittee on Antimicrobial Susceptibility Testing, Reston, Va., 7 to 9 June 1998, p. 15-16).

Table 1 compares the temporal distributions of the test isolates. In the 1989-1990 study, the B. fragilis species accounted for 57.6% of the isolates, whereas in 1998 to 1999, B. fragilis species isolation rates decreased by 12.6 to 45% of the isolates (P < 0.0001). Concomitantly, the isolation rates of the non-B. fragilis species rose from 42.4% to 55% (P < 0.0001), with a notable increase in the percentage of B. uniformis and B. caccae isolates. These percent changes are similar to those recently reported by Golan et al. (41st ICAAC). They found a decrease of 13% (P < 0.0001) in B. fragilis species isolates in an ongoing antimicrobial resistance survey between 1984 to 1985 and 1999 to 2000.


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  		TABLE 1. Distribution of test isolates for susceptibility studies during 1989 to 1990 and 1998 to 1999

 
The changes in antimicrobial susceptibility parameters of the B. fragilis group varied by type of antimicrobial agent and percentage of B. fragilis isolates within the test pool for the two studies (Table 2). Table 3 compares the statistical significance of these differences for the susceptibility rates. For piperacillin-tazobactam, a single B. ovatus isolate had an intermediate MIC in the 1989-1990 study, with all other isolates susceptible, while 100% of the isolates were susceptible during 1998 to 1999. In contrast, susceptibility to ampicillin-sulbactam decreased overall from 96.9% in 1989 and 1990 to 89% in 1998 and 1999. This decrease in ampicillin-sulbactam susceptibility was seen among both B. fragilis and non-B. fragilis species, but a greater contribution was made by a greater percentage of non-B. fragilis species. Overall, susceptibility to the carbapenems remained the same for imipenem and meropenem from 1989 and 1990 to 1998 and 1999. Among the members of the B. fragilis group, resistance to imipenem is primarily among the B. fragilis species (1, 3, 4, 13, 15), whereas resistance to meropenem is found among other species as well (3). Our data presented here support these findings. Ertapenem, a newly approved carbapenem, however, showed a significant increase in susceptibility between 1989 to 1990 and 1998 to 1999. In 1989 to 1990, the highest rates of resistance to ertapenem were noted among non-B. fragilis species; however, in 1998 to 1999, even though the percentage of non-B. fragilis isolates tested increased, the resistance rate decreased appreciably, was lower than that among the B. fragilis species, and was similar to those of imipenem and meropenem. Interestingly, cefoxitin susceptibility increased in the latter study for both the B. fragilis and non-B. fragilis species. Clindamycin resistance increased from 1989 and 1990 to 1998 and 1999 and was higher among the non-B. fragilis species in both studies. Similarly, overall resistance to trovafloxacin decreased slightly in the later study, including a decrease in non-B. fragilis species resistance rates compared to those in the 1989-1990 data.


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  		TABLE 3. Comparison of antimicrobial susceptibilities of the B. fragilis group, B. fragilis species, and other speciesa or 1989 to 1990 and 1998 to 1999

 
Table 4 compares the susceptibility rates of the antimicrobials among the B. fragilis group species with >10 isolates in each study. For piperacillin-tazobactam, only a single strain of B. ovatus with an intermediate MIC was noted in 1989 to 1990, all other strains in both studies being susceptible. Imipenem resistance was noted only in B. fragilis isolates compared to the other species. For ertapenem and meropenem, resistance was detected among B. fragilis isolates in both studies, but varied among the non-B. fragilis species in each study, with the exception that B. uniformis isolates for which MICs were >4 µg/ml were isolated in both studies. For ampicillin-sulbactam and clindamycin, all B. fragilis group species showed a decrease in susceptibility from 1989 and 1990 to 1998 and 1999.


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  		TABLE 4. Comparison of the susceptibility rates of the B. fragilis group species tested during 1989 to 1990 and 1998 to 1999

 
A limitation of our analysis was that during the 1989-1990 study, there was a modification of the antimicrobial test panel, and not all isolates were tested against all antimicrobials. The percentage of B. fragilis species isolates tested against piperacillin-tazobactam, imipenem, ertapenem, meropenem, and trovafloxacin varied slightly from the overall average, but not enough to influence the overall susceptibility data.

Anaerobic bacteriology by nature is time-consuming compared with aerobe bacteriology, even for the most-rapidly-growing anaerobes, such as species in the B. fragilis group. This often delays identification and susceptibility data for use in individual patients. Therefore, the empirical choice of antimicrobial therapy by clinicians for mixed aerobic-anaerobic infections is important. Multicenter susceptibility studies are effective tools to monitor changing antimicrobial susceptibilities on a local, regional, or national basis. Today antimicrobial resistance among the species in the B. fragilis group spans all classes of approved antimicrobials, including recent reports of metronidazole resistance responsible for clinical failures (14; R. Chaudry, P. Mathur, B. Dhawan, and L. Kumar, Letter, Emerg. Infect. Dis. 7:485-486, 2001). This study has shown the following. (i) The distribution of species of the B. fragilis group has changed from 10 years previously in favor of greater numbers of non-B. fragilis isolates. (ii) The decrease in B. fragilis isolates, usually the most susceptible species, resulted in increasing resistance rates for some antimicrobials (clindamycin and ampicillin-sulbactam) and decreasing resistance rates for other agents (carbapenems). (iii) Complete species identification and antimicrobial susceptibilities are important because they most accurately delineate any change in antimicrobial resistance. Thus, future surveys like this one will be important in monitoring new and significant changes in antimicrobial susceptibilities among anaerobes.


   FOOTNOTES
 
* Corresponding author. Mailing address: Department of Medicine, LSU Health Sciences Center, 1542 Tulane Ave., New Orleans, LA 70112. Phone: (504) 568-5031. Fax: (504) 568-2127. E-mail: kaldri{at}lsuhsc.edu. Back


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Journal of Clinical Microbiology, November 2002, p. 4349-4352, Vol. 40, No. 11
0095-1137/02/$04.00+0     DOI: 10.1128/JCM.40.11.4349-4352.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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