Abstract
The antimicrobial activities of trovafloxacin, moxifloxacin, sanfetrinem, quinupristin-dalfopristin, and 14 other antimicrobial agents against 218 Bacteroides fragilis group strains were determined. A group of 10 imipenem-resistant strains were also tested. Imipenem, meropenem, and sanfetrinem had the lowest MICs of all of the β-lactams. Quinupristin-dalfopristin inhibited all of the strains at 2 μg/ml. Overall, the MICs of trovafloxacin and moxifloxacin for 90% of the strains tested were 1 and 2 μg/ml, respectively.
Increasing resistance of Bacteroides fragilis group bacteria to drugs commonly used in the treatment of anaerobic infections, such as several β-lactam agents or clindamycin, has been reported in the last 2 decades (5, 7, 10, 18, 19). Effective alternative antimicrobials with antianaerobic activity have become necessary. The older quinolones have a wide antibacterial spectrum and potential bactericidal activity against aerobic bacteria but have poor activity against anaerobes. Several newer quinolones, such as trovafloxacin and moxifloxacin, possess a broad antimicrobial spectrum which covers gram-positive and gram-negative bacteria. They are also effective against anaerobes. Sanfetrinem is the first member of a new class of tricyclic β-lactam compounds, the trinems (previously tribactams). Two publications (4, 9) have demonstrated that sanfetrinem possesses a broad spectrum of activity, which includes gram-negative and gram-positive aerobes and anaerobes, and exhibits high potency and stability against many β-lactamases. Quinupristin-dalfopristin is a semisynthetic injectable streptogramin with significant activity against gram-positive organisms and marked antianaerobic activity.
This study aimed to ascertain the current susceptibility pattern of these organisms in our hospital in order to detect trends and to evaluate the activities of the new agents. We compared the in vitro susceptibilities of recently isolated B. fragilis strains to both newer (moxifloxacin, trovafloxacin, sanfetrinem, and quinupristin-dalfopristin) and older antimicrobial agents (including β-lactam antibiotics, β-lactam–β-lactamase inhibitor combinations, and non-β-lactam agents).
(Part of this study was presented at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, Calif., 24 to 27 September 1998.)
The 218 clinical isolates of B. fragilis group bacteria isolated in 1997 tested included the following numbers of isolates: B. fragilis, 133; B. thetaiotaomicron, 39; B. uniformis, 26; B. caccae, 6; B. ovatus, 6; B. distasonis, 4; and B. vulgatus, 4. A group of 10 B. fragilis strains (collected from 1989 to 1997) resistant to imipenem (MICs, 16 to >256 μg/ml) were also tested. Strains were identified by using the Rapid ID 32A system (bioMérieux, Marcy l’Etoile, France). Sources included skin and soft tissue (44.4%), abdomen (43.1%), blood (8.2%), respiratory tract (1.8%), body fluid (1.4%), female genital tract (0.9%), and bone (0.5%) samples.
Antimicrobial agents were obtained from the following companies: trovafloxacin, ampicillin, and sulbactam, Pfizer, New York, N.Y.; moxifloxacin, Bayer, Barcelona, Spain; sanfetrinem, Glaxo Wellcome, Verona, Italy; quinupristin-dalfopristin and metronidazole, Rhône-Poulenc Rorer, Madrid, Spain; chloramphenicol, Zyma Farmacéutica, Barcelona, Spain; clindamycin, Pharmacia & Upjohn, Barcelona, Spain; cefoxitin and imipenem, Merck Sharp & Dohme, West Point, Pa.; ceftizoxime, amoxicillin, ticarcillin, and clavulanate, SmithKline Beecham Pharmaceuticals, Philadelphia, Pa.; cefminox, Tedec-Meiji Farma, Madrid, Spain; piperacillin and tazobactam, Wyeth Lederle, Pearl River, N.Y.
MICs were determined by the agar dilution method in accordance with National Committee for Clinical Laboratory Standards (NCCLS) guidelines (15).
The results of susceptibility testing are presented in Table 1. Trovafloxacin displayed high levels of activity against members of the B. fragilis group, with 92 and 95% of the strains susceptible at 1 and 2 μg/ml, respectively. The in vitro activity of moxifloxacin was comparable to that of trovafloxacin, with 94% of all strains inhibited at 4 μg/ml. Trovafloxacin was slightly more active against B. thetaiotaomicron and B. uniformis than was moxifloxacin. Sanfetrinem showed excellent activity, inhibiting 99.5% of the strains at 4 μg/ml. The sanfetrinem MICs for 50 and 90% of the strains tested (MIC50 and MIC90, respectively) were comparable to those of the carbapenems and lower than the MICs obtained with the other nine β-lactams tested. Overall, metronidazole and quinupristin-dalfopristin were the most active agents; both inhibited all strains at 2 μg/ml. For the cephamycins and piperacillin, there was variability in the susceptibility rates when MICs within 1 or 2 dilutions of the breakpoint were considered. Cefoxitin inhibited 70.6, 87.2, and 96.3% of the isolates at 16, 32, and 64 μg/ml, respectively. Within the group, B. fragilis strains were more susceptible to the cephalosporins tested than were the other species of the group. Cefoxitin and cefminox exhibited similar activities against B. fragilis strains, and ceftizoxime was markedly more active. In our hospital, the rate of resistance to clindamycin has remained at about 30 to 33% since 1994. We found one B. fragilis strain that was highly resistant to all of the β-lactam antibiotics, either alone or in combination with a β-lactamase inhibitor.
TABLE 1.
In vitro effectiveness of antimicrobial agents against the B. fragilis group
| Organism (no. of strains tested) and antimicrobial | MICa range | MIC50a | MIC90a | % Re-sistant strainsb | Organism (no. of strains tested) and antimicrobial | MICa range | MIC50a | MIC90a | % Re-sistant strainsb | |
|---|---|---|---|---|---|---|---|---|---|---|
| B. fragilis group (218) | ||||||||||
| Metronidazole | ≤0.06–2 | 0.5 | 1 | 0 | ||||||
| Chloramphenicol | 0.1–8 | 4 | 4 | 0 | ||||||
| Clindamycin | ≤0.06–>256 | 0.5 | >256 | 33.5 | ||||||
| Cefoxitin | ≤0.06–128 | 16 | 64 | 12.8 | ||||||
| Ceftizoxime | ≤0.06–>256 | 2 | 32 | 6.9 | ||||||
| Cefminox | ≤0.06–256 | 2 | 256 | 16.5 | ||||||
| Cefotetan | ≤0.06–>256 | 16 | 128 | 35.1 | ||||||
| Piperacillin | ≤0.06–>256 | 8 | 256 | 22.8 | ||||||
| Imipenem | ≤0.06–256 | 0.1 | 1 | 0.5 | ||||||
| Meropenem | ≤0.06–256 | 0.1 | 1 | 0.5 | ||||||
| Amoxicillin-clavulanate | ≤0.06–64 | 0.5 | 8 | 5 | ||||||
| Ampicillin-sulbactam | ≤0.06–256 | 1 | 8 | 0.5 | ||||||
| Ticarcillin-clavulanate | ≤0.06–256 | 0.5 | 8 | 0.5 | ||||||
| Piperacillin-tazobactam | 0.2–>256 | 4 | 16 | 0.5 | ||||||
| Sanfetrinemc | ≤0.06–256 | 0.1 | 1 | |||||||
| Quinupristin-dalfopristinc | ≤0.06–2 | 0.5 | 1 | |||||||
| Trovafloxacin | ≤0.06–8 | 0.2 | 1 | 1.8 | ||||||
| Moxifloxacinc | ≤0.06–32 | 0.5 | 2 | |||||||
| B. fragilis (133) | ||||||||||
| Metronidazole | ≤0.06–2 | 0.5 | 1 | 0 | ||||||
| Chloramphenicol | 0.1–4 | 2 | 4 | 0 | ||||||
| Clindamycin | ≤0.06–>256 | 0.5 | >256 | 32.8 | ||||||
| Cefoxitin | ≤0.06–128 | 16 | 32 | 9 | ||||||
| Ceftizoxime | ≤0.06–>256 | 2 | 16 | 0.8 | ||||||
| Cefminox | 0.2–256 | 1 | 64 | 10.5 | ||||||
| Cefotetan | ≤0.06–>256 | 8 | 128 | 12 | ||||||
| Piperacillin | ≤0.06–>256 | 4 | 128 | 14.3 | ||||||
| Imipenem | ≤0.06–256 | ≤0.06 | 0.5 | 0.8 | ||||||
| Meropenem | ≤0.06–256 | 0.1 | 1 | 0.8 | ||||||
| Amoxicillin-clavulanate | ≤0.06–64 | 0.5 | 4 | 2.3 | ||||||
| Ampicillin-sulbactam | ≤0.06–256 | 0.5 | 4 | 0.8 | ||||||
| Ticarcillin-clavulanate | ≤0.06–256 | 0.2 | 4 | 0.8 | ||||||
| Piperacillin-tazobactam | 0.2–>256 | 1 | 16 | 0.8 | ||||||
| Sanfetrinem | ≤0.06–256 | 0.1 | 0.5 | |||||||
| Quinupristin-dalfopristin | 0.1–2 | 0.5 | 1 | |||||||
| Trovafloxacin | ≤0.06–8 | 0.2 | 1 | 1.5 | ||||||
| Moxifloxacin | ≤0.06–32 | 0.2 | 1 | |||||||
| B. thetaiotaomicron (39) | ||||||||||
| Metronidazole | 0.1–2 | 0.5 | 1 | 0 | ||||||
| Chloramphenicol | 2–8 | 4 | 8 | 0 | ||||||
| Clindamycin | 0.1–>256 | 2 | >256 | 35.9 | ||||||
| Cefoxitin | 4–128 | 32 | 128 | 28.2 | ||||||
| Ceftizoxime | 1–>256 | 8 | 128 | 17.9 | ||||||
| Cefminox | 0.5–256 | 16 | 128 | 35.9 | ||||||
| Cefotetan | 4–>256 | 64 | 128 | 74.4 | ||||||
| Piperacillin | 2–>256 | 64 | >256 | 43.6 | ||||||
| Imipenem | ≤0.06–1 | 0.2 | 1 | 0 |
| Meropenem | ≤0.06–4 | 0.2 | 2 | 0 |
| Amoxicillin-clavulanate | 0.1–32 | 2 | 8 | 5.1 |
| Ampicillin-sulbactam | 0.5–16 | 2 | 16 | 0 |
| Ticarcillin-clavulanate | 0.1–32 | 2 | 16 | 0 |
| Piperacillin-tazobactam | 1–32 | 16 | 16 | 0 |
| Sanfetrinem | ≤0.06–1 | 0.2 | 1 | |
| Quinupristin-dalfopristin | ≤0.06–2 | 0.5 | 2 | |
| Trovafloxacin | ≤0.06–8 | 0.5 | 2 | 0 |
| Moxifloxacin | ≤0.06–32 | 1 | 8 | |
| B. uniformis (26) | ||||
| Metronidazole | 0.1–2 | 0.5 | 1 | 0 |
| Chloramphenicol | 2–8 | 4 | 8 | 0 |
| Clindamycin | 0.1–>256 | 2 | >256 | 38.5 |
| Cefoxitin | 0.2–32 | 8 | 32 | 0 |
| Ceftizoxime | 0.5–128 | 4 | 128 | 11.5 |
| Cefminox | 0.5–64 | 4 | 64 | 15.4 |
| Cefotetan | 0.5–128 | 32 | 128 | 46.2 |
| Piperacillin | 1–>256 | 16 | >256 | 23.1 |
| Imipenem | ≤0.06–1 | 0.1 | 0.5 | 0 |
| Meropenem | ≤0.06–1 | 0.2 | 0.5 | 0 |
| Amoxicillin-clavulanate | 0.5–64 | 1 | 16 | 7.7 |
| Ampicillin-sulbactam | 0.5–16 | 1 | 8 | 0 |
| Ticarcillin-clavulanate | ≤0.06–16 | 1 | 16 | 0 |
| Piperacillin-tazobactam | 1–16 | 8 | 16 | 0 |
| Sanfetrinem | ≤0.06–1 | 0.1 | 1 | |
| Quinupristin-dalfopristin | ≤0.06–2 | 0.5 | 2 | |
| Trovafloxacin | 0.1–4 | 0.5 | 4 | 0 |
| Moxifloxacin | 0.1–32 | 1 | 8 | |
| Imipenem-resistant B. fragilis (10) | ||||
| Metronidazole | 0.25–2 | 0.5 | 2 | 0 |
| Chloramphenicol | 2–4 | 4 | 4 | 0 |
| Clindamycin | 0.25–>256 | >256 | >256 | 60 |
| Cefoxitin | 32–128 | 128 | 128 | 90 |
| Ceftizoxime | 64–>256 | >256 | >256 | 90 |
| Cefminox | 16–256 | 128 | 256 | 90 |
| Cefotetan | 32–>256 | 128 | 256 | 90 |
| Piperacillin | 32–>256 | >256 | >256 | 90 |
| Imipenem | 16–>256 | 256 | >256 | 100 |
| Meropenem | 256–>256 | 256 | >256 | 100 |
| Amoxicillin-clavulanate | 16–64 | 64 | 64 | 100 |
| Ampicillin-sulbactam | 32–>256 | >256 | >256 | 100 |
| Ticarcillin-clavulanate | 64–>256 | >256 | >256 | 100 |
| Piperacillin-tazobactam | 16–>256 | >256 | >256 | 90 |
| Sanfetrinem | 32–256 | 256 | 256 | |
| Quinupristin-dalfopristin | 0.2–1 | 0.5 | 1 | |
| Trovafloxacin | 0.1–4 | 0.2 | 2 | 0 |
| Moxifloxacin | 0.1–4 | 0.2 | 4 |
MICs are given in micrograms per milliliter.
MICs (in micrograms per milliliter) from the NCCLS for resistant isolates are as follows: metronidazole and chloramphenicol, ≥32; clindamycin and trovafloxacin, ≥8; cefoxitin, cefminox, and cefotetan, ≥64; piperacillin and ceftizoxime, ≥128; imipenem and meropenem, ≥16; amoxicillin-clavulanate, ≥16-28; ampicillin-sulbactam, ≥32-16; ticarcillin-clavulanate, ≥128-2; piperacillin-tazobactam, ≥128-4.
Breakpoints for sanfetrinem, moxifloxacin, and quinupristin-dalfopristin are not currently provided by the NCCLS for anaerobes.
Metronidazole and chloramphenicol were uniformly effective against all of the imipenem-resistant isolates tested. Six of these strains were also highly resistant to clindamycin. Trovafloxacin and moxifloxacin showed excellent activity against imipenem-resistant strains. Quinupristin-dalfopristin inhibited these strains at a concentration of ≤1 μg/ml, while sanfetrinem yielded high MICs (range, 32 to 256 μg/ml).
In general, with the old antibiotics, our results are similar to those found in other studies in Spain (6, 12) and other countries (1, 10, 13, 18, 19). Resistance to the carbapenems and β-lactam–β-lactamase inhibitor combinations has been detected in our hospital since 1989 but with a very low incidence (0.5 to 1.5%). Several researchers have reported low rates of resistance to imipenem (1, 10, 18, 20). By comparing the results of this study with those of previous susceptibility studies reported by our group for isolates recovered between 1979 and 1995 (7, 8), we found that there were no significant changes in the overall susceptibility patterns during the last 5 years.
Our results confirm the previous finding that quinupristin-dalfopristin has good in vitro activity against B. fragilis group organisms (16), although the quinupristin-dalfopristin MICs we obtained were slightly lower than those reported by Appelbaum et al. (3). Sanfetrinem appears to have excellent activity against B. fragilis group bacteria, as described previously by Di Modugno et al. (9) for B. fragilis strains. Our study shows high activity of trovafloxacin and moxifloxaxcin against B. fragilis group isolates, including those resistant to imipenem. Other studies (17, 20) have yielded values similar to ours for trovafloxacin. Several investigators (2, 11, 14) have also reported excellent activity of moxifloxacin against the B. fragilis group.Moxifloxacin and trovafloxacin MICs for B. fragilis strains were lower than those seen for B. thetaiotaomicron and B. uniformis strains, as reported elsewhere (2, 17, 20).
There are geographic variations and changes over time in the susceptibilities of B. fragilis group organisms to different antimicrobials. The increased incidence among B. fragilis group bacteria to some antimicrobial agents, such as clindamycin or cephamycins, and the emergence of resistance to imipenem and β-lactam–β-lactamase inhibitor combinations require periodic susceptibility studies and the development of new broad-spectrum drugs. Given the excellent in vitro activity of trovafloxacin and moxifloxacin and their broad spectrum of activity, we suggest that both of them be considered as single agents in the treatment and prophylaxis of mixed aerobic-anaerobic infections involving B. fragilis group organisms. This study also confirms the excellent in vitro activity of sanfetrinem and quinupristin-dalfopristin against the B. fragilis group. Both the quinolones tested and the new streptogramin may play a potential role in the treatment of infections caused by imipenem-resistant B. fragilis strains and would also be a therapeutic option for patients allergic to β-lactams. Clinical studies will determine the therapeutic efficacy of the new agents tested. As it is not known whether resistant strains will emerge during therapy, B. fragilis group bacteria should be periodically monitored for the emergence of resistance to these new drugs.
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