Abstract
Biapenem is a carbapenem being developed in combination with RPX7009, a new inhibitor of serine β-lactamases. Biapenem was tested alone and in combination with fixed concentrations of RPX7009 by agar dilution against 377 recent isolates of anaerobes. A separate panel of 27 isolates of Bacteroides spp. with decreased susceptibility or resistance to imipenem was also tested. Comparator drugs included meropenem, piperacillin-tazobactam, ampicillin-sulbactam, cefoxitin, ceftazidime, metronidazole, clindamycin, and tigecycline plus imipenem, doripenem, and ertapenem for the 27 selected strains. For recent consecutive strains of Bacteroides species, the MIC90 for biapenem-RPX7009 was 1 μg/ml, with a MIC90 of 4 μg/ml for meropenem. Other Bacteroides fragilis group species showed a MIC90 of 0.5 μg/ml for both agents. The MIC90s for biapenem-RPX7009 were 0.25 μg/ml for Prevotella spp., 0.125 μg/ml for Fusobacterium nucleatum and Fusobacterium necrophorum, 2 μg/ml for Fusobacterium mortiferum, 0.5 μg/ml for Fusobacterium varium, ≤0.5 μg/ml for Gram-positive cocci and rods, and 0.03 to 8 μg/ml for clostridia. Against 5 B. fragilis strains harboring a known metallo-beta-lactamase, biapenem-RPX7009 MICs were comparable to those of other carbapenems (≥32 μg/ml). Against Bacteroides strains with an imipenem MIC of 2 μg/ml, biapenem-RPX7009 had MICs of 0.5 to 2 μg/ml, with MICs of 0.5 to 32 μg/ml for meropenem, doripenem, and ertapenem. For strains with an imipenem MIC of 4 μg/ml, the MICs for biapenem-RPX7009 were 4 to 16 μg/ml, with MICs of 8 to >32 μg/ml for meropenem, doripenem, and ertapenem. The inhibitor RPX7009 had no antimicrobial activity when tested alone, and it showed little or no potentiation of biapenem versus anaerobes. Biapenem-RPX7009 showed activity comparable to that of imipenem and was superior to meropenem, doripenem, and ertapenem against imipenem-nonsusceptible Bacteroides spp.
INTRODUCTION
Biapenem is a carbapenem with a broad spectrum of activity against Gram-positive and Gram-negative aerobes and anaerobes and with a methyl group on the 1-beta position which confers stability against dehydropeptidase I (1, 2), and it appears to be more stable to hydrolysis by the CcrA enzyme than imipenem or meropenem (3). Its in vitro activity against anaerobes was the subject of a number of studies in the 1990s, around the time of its development (1, 4–10). Biapenem was approved for clinical use in Japan in 2001 and was launched in 2002. It was studied clinically against intra-abdominal infections (11) and was found to be equivalent to imipenem. Scant data have been published regarding biapenem's activity against contemporary anaerobic isolates.
Carbapenem resistance in anaerobic bacteria is rare, although strains of Bacteroides spp. with class B zinc metallo-beta-lactamases (cfiA or ccrA) have been reported (12). Although not all cfiA-positive Bacteroides fragilis strains are resistant to carbapenems, they all have the possibility of becoming resistant to this group of antibiotics by acquisition of an appropriate insertion (IS) element for full expression of the cfiA gene, leading to possible treatment failure (12). RPX7009 is a new serine beta-lactamase inhibitor that has been combined with biapenem to enhance its spectrum against carbapenemase-producing bacteria, including KPC-producing isolates. No prior studies have reported RPX7009's activity against anaerobes or the effect of its potential combination with biapenem. Consequently, we studied the effects of three different fixed concentrations of RPX7009 (2, 4, and 8 μg/ml) on the activity of biapenem against 377 recent isolates of anaerobes. In addition, we studied the activity of biapenem alone and in combination with RPX7009 against 27 isolates of Bacteroides spp. with various levels of known resistance to imipenem.
MATERIALS AND METHODS
Bacterial strains.
The organisms were recovered from recent clinical samples (2009–2011) from humans, mostly from intra-abdominal sources. Some Prevotella species came from respiratory sources, and some Gram-positive cocci came from skin and soft tissue infections. Isolates were identified by standard methods (13, 14) and stored in 20% skim milk at −70°C. They were taken from the freezer and transferred at least twice on blood agar to ensure purity and good growth.
In addition to the recent clinical samples, a separate panel of strains from our collection that exhibited diminished imipenem susceptibility was tested. These strains were as follows: for B. fragilis, 10 strains with imipenem MICs of 1 to 4 μg/ml and 5 strains with MICs of >32 μg/ml; for Parabacteroides, 7 strains (4 Parabacteroides distasonis strains and 3 Parabacteroides goldsteinii strains) with imipenem MICs of 1 to 8 μg/ml; 1 strain each of Bacteroides caccae (imipenem MIC, 16 μg/ml), Bacteroides ovatus (imipenem MIC, 2 μg/ml), and Bacteroides thetaiotaomicron (imipenem MIC, 4 μg/ml); and 2 strains of Bacteroides uniformis (imipenem MICs, 4 and 8 μg/ml).
Drugs tested.
Biapenem and RPX7009 (Rempex Pharmaceuticals, San Diego, CA) were tested alone and in combination. Comparator drugs were meropenem, piperacillin-tazobactam, ampicillin-sulbactam, cefoxitin, ceftazidime, metronidazole, clindamycin, and tigecycline (Sigma, St. Louis, MO, or USP, Rockville, MD) and were reconstituted according to the manufacturers' instructions. Additionally, 27 selected strains which showed either diminished imipenem susceptibility or imipenem resistance were also tested against imipenem, doripenem, and ertapenem.
MICs were determined using the agar dilution method according to CLSI guidelines (15). Biapenem was tested at concentrations of 0.03 to 32 μg/ml, RPX7009 at 0.125 to 128 μg/ml, and comparator agents at various concentrations from 0.03 to 128 μg/ml. Biapenem was tested alone and in combination with a fixed concentration of RPX7009 (2, 4, or 8 μg/ml). Quality control strains included B. fragilis ATCC 25285, Clostridium difficile ATCC 700057, Klebsiella pneumonia BAA-1705 (a KPC-positive strain), and Escherichia coli ATCC 25922. The MIC was defined as the lowest concentration that yielded no visible growth or a major reduction in growth compared to the growth control.
RESULTS
Biapenem alone and in combination with RPX7009 showed excellent activity that was comparable to that of meropenem (Table 1). RPX7009 had no inhibitory activity against any strain tested, with all MICs being >128 μg/ml. The MIC90s for Gram-positive cocci and rods were ≤0.5 μg/ml. Finegoldia magna, Parvimonas micra, and Peptoniphilus harei isolates had a maximum biapenem and biapenem-RPX7009 MIC of 0.5 μg/ml, while 10 strains of Peptostreptococcus anaerobius had MIC50s of 0.5 μg/ml but MIC90s of 8 and 16 μg/ml for biapenem alone and biapenem-RPX 7009 (at 2 μg/ml), respectively. The MIC90 for Clostridium perfringens isolates was 0.06 μg/ml, and that for C. difficile was 8 μg/ml. For other Clostridium species, the MIC range was 0.125 to 4 μg/ml, depending on the species.
Table 1.
Comparative in vitro activities of biapenem, alone and in combination with RPX7009, and other antimicrobial agents against anaerobic bacteria
| Organism (no. of strains) and antimicrobial agent | MIC range (μg/ml) | MIC50 (μg/ml) | MIC90 (μg/ml) | % I or Ra |
|---|---|---|---|---|
| Gram-negative organisms | ||||
| Bacteroides fragilis (36) | ||||
| Biapenem | 0.125–>32 | 0.25 | 1 | 2.7 |
| Biapenem plus RPX7009 (2 μg/ml) | 0.125–>32 | 0.25 | 0.5 | |
| Biapenem plus RPX7009 (4 μg/ml) | 0.125–>32 | 0.25 | 0.5 | |
| Biapenem plus RPX7009 (8 μg/ml) | 0.125–>32 | 0.25 | 0.5 | |
| Meropenem | 0.125–>32 | 0.25 | 4 | 5.5 |
| Piperacillin-tazobactam | 0.125–>128 | 0.5 | 4 | 2.7 |
| Ampicillin-sulbactam | 0.5–>128 | 1 | 16 | 16.7 |
| Cefoxitin | 4–128 | 8 | 32 | 13.9 |
| Ceftazidime | 16–>128 | 64 | >128 | NA |
| Metronidazole | 0.5–2 | 1 | 2 | 0 |
| Clindamycin | ≤0.06–>128 | 0.5 | >128 | 16.7 |
| Tigecycline | 0.25–16 | 0.5 | 4 | 8.3 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| B. caccae (19) | ||||
| Biapenem | 0.125–1 | 0.25 | 0.5 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | 0.125–1 | 0.25 | 0.5 | |
| Biapenem plus RPX7009 (4 μg/ml) | 0.125–1 | 0.25 | 0.5 | |
| Biapenem plus RPX7009 (8 μg/ml) | 0.125–1 | 0.25 | 0.5 | |
| Meropenem | 0.06–2 | 0.25 | 1 | 0 |
| Piperacillin-tazobactam | ≤0.06–16 | 4 | 8 | 0 |
| Ampicillin-sulbactam | 0.5–16 | 2 | 8 | 2.7 |
| Cefoxitin | 4–128 | 16 | 32 | 26.3 |
| Ceftazidime | 32–>128 | 128 | >128 | NA |
| Metronidazole | 0.5–4 | 2 | 2 | 0 |
| Clindamycin | 0.5–>128 | 4 | >128 | 52.6 |
| Tigecycline | 0.125–32 | 4 | 16 | 42 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| B. ovatus (19) | ||||
| Biapenem | 0.25–1 | 0.5 | 1 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | 0.25–1 | 0.5 | 1 | |
| Biapenem plus RPX7009 (4 μg/ml) | 0.25–1 | 0.5 | 0.06 | |
| Biapenem plus RPX7009 (8 μg/ml) | 0.25–1 | 0.5 | 0.06 | |
| Meropenem | 0.25–2 | 0.25 | 1 | 0 |
| Piperacillin-tazobactam | 2–16 | 4 | 16 | 0 |
| Ampicillin-sulbactam | 0.5–16 | 2 | 16 | 10.5 |
| Cefoxitin | 16–128 | 32 | 64 | 52.6 |
| Ceftazidime | 128–>128 | >128 | >128 | NA |
| Metronidazole | 0.5–2 | 1 | 2 | 0 |
| Clindamycin | 0.5–>128 | 2 | >128 | 42.1 |
| Tigecycline | ≤0.06–16 | 1 | 8 | 10.5 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| B. thetaiotaomicron (18) | ||||
| Biapenem | 0.25–0.5 | 0.25 | 0.5 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | 0.25–0.5 | 0.25 | 0.5 | |
| Biapenem plus RPX7009 (4 μg/ml) | 0.25–0.5 | 0.25 | 0.5 | |
| Biapenem plus RPX7009 (8 μg/ml) | 0.25–0.5 | 0.25 | 0.5 | |
| Meropenem | 0.125–1 | 0.25 | 0.5 | 0 |
| Piperacillin-tazobactam | 4–32 | 16 | 16 | 0 |
| Ampicillin-sulbactam | 1–16 | 2 | 16 | 11.1 |
| Cefoxitin | 16–64 | 32 | 64 | 66.7 |
| Ceftazidime | >128–>128 | >128 | >128 | NA |
| Metronidazole | 0.25–2 | 2 | 2 | 0 |
| Clindamycin | 2–129 | 4 | >128 | 72.2 |
| Tigecycline | 0.125–32 | 4 | 32 | 33.3 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| B. vulgatus (10) | ||||
| Biapenem | 0.125–1 | 0.5 | 1 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | 0.125–1 | 0.25 | 1 | |
| Biapenem plus RPX7009 (4 μg/ml) | 0.125–1 | 0.5 | 1 | |
| Biapenem plus RPX7009 (8 μg/ml) | 0.125–1 | 0.25 | 1 | |
| Meropenem | 0.125–1 | 0.5 | 1 | 0 |
| Piperacillin-tazobactam | 0.25–8 | 1 | 4 | 0 |
| Ampicillin-sulbactam | 1–16 | 8 | 8 | 10 |
| Cefoxitin | 4–128 | 16 | 16 | 10 |
| Ceftazidime | 32–>128 | 128 | >128 | NA |
| Metronidazole | 0.5–1 | 1 | 1 | 0 |
| Clindamycin | ≤0.06–>128 | 0.25 | >128 | 40 |
| Tigecycline | 0.125–8 | 0.5 | 8 | 20 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Other Bacteroides spp. (20)b | ||||
| Biapenem | 0.25–2 | 0.5 | 1 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | 0.25–2 | 0.25 | 1 | |
| Biapenem plus RPX7009 (4 μg/ml) | 0.25–1 | 0.05 | 1 | |
| Biapenem plus RPX7009 (8 μg/ml) | 0.25–2 | 0.5 | 1 | |
| Meropenem | 0.125–32 | 0.5 | 1 | 5 |
| Piperacillin-tazobactam | ≤0.06–16 | 2 | 8 | 0 |
| Ampicillin-sulbactam | 1–32 | 4 | 16 | 50 |
| Cefoxitin | 4–64 | 16 | 64 | 25 |
| Ceftazidime | 16–>128 | >128 | >128 | NA |
| Metronidazole | 0.5–2 | 2 | 2 | 0 |
| Clindamycin | ≤0.06–>128 | 2 | >128 | 35 |
| Tigecycline | 0.125–32 | 0.5 | 8 | 25 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Parabacteroides spp. (23)c | ||||
| Biapenem | 0.25–2 | 1 | 2 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | 0.25–2 | 1 | 2 | |
| Biapenem plus RPX7009 (4 μg/ml) | 0.25–2 | 1 | 2 | |
| Biapenem plus RPX7009 (8 μg/ml) | 0.25–2 | 1 | 2 | |
| Meropenem | 0.25–16 | 1 | 8 | 21.7 |
| Piperacillin-tazobactam | 2–>128 | 4 | 16 | 4.3 |
| Ampicillin-sulbactam | 1–64 | 8 | 32 | 21.7 |
| Cefoxitin | 8–128 | 32 | 64 | 39.1 |
| Ceftazidime | 16–>128 | >128 | >128 | NA |
| Metronidazole | 0.5–2 | 1 | 2 | 0 |
| Clindamycin | ≤0.06–>128 | 4 | >128 | 39.1 |
| Tigecycline | 0.5–8 | 1 | 8 | 8.7 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Prevotella bivia (10) | ||||
| Biapenem | 0.125–0.25 | 0.25 | 0.25 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | 0.125–0.25 | 0.25 | 0.25 | |
| Biapenem plus RPX7009 (4 μg/ml) | 0.125–0.25 | 0.25 | 0.25 | |
| Biapenem plus RPX7009 (8 μg/ml) | 0.06–0.25 | 0.125 | 0.25 | |
| Meropenem | 0.06–0.25 | 0.125 | 0.125 | 0 |
| Piperacillin-tazobactam | ≤0.06 | ≤0.06 | ≤0.06 | 0 |
| Ampicillin-sulbactam | 0.125–4 | 2 | 4 | 0 |
| Cefoxitin | 2–4 | 2 | 4 | 0 |
| Ceftazidime | 2–>128 | 64 | >128 | NA |
| Metronidazole | 1–4 | 2 | 4 | 0 |
| Clindamycin | ≤0.06–>128 | >128 | >128 | 70 |
| Tigecycline | ≤0.06–0.125 | ≤0.06 | ≤0.06 | 0 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Prevotella buccae (10) | ||||
| Biapenem | 0.06–0.25 | 0.125 | 0.25 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | 0.06–0.25 | 0.125 | 0.25 | |
| Biapenem plus RPX7009 (4 μg/ml) | 0.06–0.25 | 0.06 | 0.25 | |
| Biapenem plus RPX7009 (8 μg/ml) | 0.06–0.25 | 0.06 | 0.25 | |
| Meropenem | ≤0.03–0.5 | 0.06 | 0.25 | 0 |
| Piperacillin-tazobactam | ≤0.06–4 | ≤0.06 | 2 | 0 |
| Ampicillin-sulbactam | 0.125–4 | 0.125 | 2 | 0 |
| Cefoxitin | 1–16 | 1 | 4 | 0 |
| Ceftazidime | 2–>128 | 32 | 128 | NA |
| Metronidazole | 0.25–1 | 1 | 1 | 0 |
| Clindamycin | ≤0.06–>128 | ≤0.06 | >128 | 20 |
| Tigecycline | ≤0.06–4 | 0.125 | 0.5 | 0 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Prevotella melaninogenica (10) | ||||
| Biapenem | ≤0.03–0.25 | 0.06 | 0.125 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | ≤0.03–0.25 | 0.125 | 0.125 | |
| Biapenem plus RPX7009 (4 μg/ml) | ≤0.03–0.25 | 0.06 | 0.25 | |
| Biapenem plus RPX7009 (8 μg/ml) | ≤0.03–0.25 | 0.06 | 0.125 | |
| Meropenem | ≤0.03–0.25 | 0.06 | 0.25 | 0 |
| Piperacillin-tazobactam | ≤0.06 | ≤0.06 | ≤0.06 | 0 |
| Ampicillin-sulbactam | 0.125–4 | 1 | 1 | 0 |
| Cefoxitin | 1–8 | 2 | 4 | 0 |
| Ceftazidime | 1–64 | 16 | 32 | NA |
| Metronidazole | 0.5–2 | 1 | 2 | 0 |
| Clindamycin | ≤0.06–>128 | ≤0.06 | >128 | 40 |
| Tigecycline | ≤0.06 | ≤0.06 | ≤0.06 | 0 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Prevotella oralis (10) | ||||
| Biapenem | ≤0.03–0.25 | ≤0.03 | 0.125 | |
| Biapenem plus RPX7009 (2 μg/ml) | ≤0.03–0.25 | ≤0.03 | 0.125 | |
| Biapenem plus RPX7009 (4 μg/ml) | ≤0.03–0.25 | ≤0.03 | 0.125 | |
| Biapenem plus RPX7009 (8 μg/ml) | ≤0.03–0.25 | ≤0.03 | 0.125 | |
| Meropenem | ≤0.03–0.25 | ≤0.03 | 0.06 | 0 |
| Piperacillin-tazobactam | ≤0.06 | ≤0.06 | ≤0.06 | 0 |
| Ampicillin-sulbactam | ≤0.06–1 | ≤0.06 | 0.125 | 0 |
| Cefoxitin | 0.25–2 | 2 | 2 | 0 |
| Ceftazidime | 0.5–>128 | 4 | 8 | NA |
| Metronidazole | 0.06–1 | 0.125 | 0.5 | 0 |
| Clindamycin | ≤0.06–>128 | ≤0.06 | >128 | 30 |
| Tigecycline | ≤0.06 | ≤0.06 | ≤0.06 | 0 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Fusobacterium necrophorum (10) | ||||
| Biapenem | ≤0.03–0.125 | 0.06 | 0.125 | |
| Biapenem plus RPX7009 (2 μg/ml) | ≤0.03–0.125 | 0.125 | 0.125 | |
| Biapenem plus RPX7009 (4 μg/ml) | ≤0.03–0.125 | 0.125 | 0.125 | |
| Biapenem plus RPX7009 (8 μg/ml) | ≤0.03–0.125 | 0.06 | 0.125 | |
| Meropenem | ≤0.03 | ≤0.03 | ≤0.03 | 0 |
| Piperacillin-tazobactam | ≤0.06 | ≤0.06 | ≤0.06 | 0 |
| Ampicillin-sulbactam | ≤0.06–0.25 | 0.125 | 0.125 | 0 |
| Cefoxitin | 025–0.5 | 0.5 | 0.5 | 0 |
| Ceftazidime | 0.5–1 | 1 | 1 | NA |
| Metronidazole | 0.25–0.5 | 0.25 | 0.5 | 0 |
| Clindamycin | ≤0.06 | ≤0.06 | ≤0.06 | 0 |
| Tigecycline | ≤0.06 | ≤0.06 | ≤0.06 | 0 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Fusobacterium nucleatum (11) | ||||
| Biapenem | ≤0.03–0.125 | 0.06 | 0.125 | |
| Biapenem plus RPX7009 (2 μg/ml) | ≤0.03–0.125 | 0.06 | 0.125 | |
| Biapenem plus RPX7009 (4 μg/ml) | ≤0.03–0.125 | 0.06 | 0.125 | |
| Biapenem plus RPX7009 (8 μg/ml) | ≤0.03–0.125 | ≤0.03 | 0.125 | |
| Meropenem | ≤0.03–0.06 | ≤0.03 | 0.06 | |
| Piperacillin-tazobactam | ≤0.06 | ≤0.06 | 0.06 | 0 |
| Ampicillin-sulbactam | ≤0.06–0.125 | ≤0.06 | 0.125 | 0 |
| Cefoxitin | 0.125–1 | 0.25 | 0.5 | 0 |
| Ceftazidime | 1–8 | 4 | 4 | NA |
| Metronidazole | ≤0.03–0.25 | 0.06 | 0.25 | 0 |
| Clindamycin | ≤0.06–0.125 | 0.06 | 0.125 | 0 |
| Tigecycline | ≤0.06–0.25 | ≤0.06 | 0.25 | 0 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Fusobacterium mortiferum (10) | ||||
| Biapenem | 1–4 | 2 | 2 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | 1–4 | 1 | 1 | |
| Biapenem plus RPX7009 (4 μg/ml) | 1–2 | 1 | 1 | |
| Biapenem plus RPX7009 (8 μg/ml) | 1–4 | 1 | 1 | |
| Meropenem | 0.25–0.5 | 0.5 | 0.5 | 0 |
| Piperacillin-tazobactam | 0.25–4 | 1 | 1 | 0 |
| Ampicillin-sulbactam | 1–8 | 1 | 8 | 0 |
| Cefoxitin | 4–8 | 8 | 8 | 0 |
| Ceftazidime | 1,280–>128 | >128 | >128 | NA |
| Metronidazole | 0.5–2 | 0.5 | 1 | 0 |
| Clindamycin | ≤0.06–0.125 | ≤0.06 | 0.125 | 0 |
| Tigecycline | 0.125–0.5 | 0.25 | 0.5 | 0 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Fusobacterium varium (11) | ||||
| Biapenem | ≤0.03–2 | 0.25 | 0.5 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | ≤0.03–2 | 0.25 | 0.25 | |
| Biapenem plus RPX7009 (4 μg/ml) | ≤0.03–2 | 0.25 | 0.5 | |
| Biapenem plus RPX7009 (8 μg/ml) | ≤0.03–2 | 0.25 | 0.5 | |
| Meropenem | ≤0.03–0.25 | 0.125 | 0.125 | 0 |
| Piperacillin-tazobactam | ≤0.06–4 | 2 | 4 | 0 |
| Ampicillin-sulbactam | 0.125–4 | 1 | 2 | 0 |
| Cefoxitin | 0.25–8 | 4 | 8 | 0 |
| Ceftazidime | 1–32 | 8 | 16 | NA |
| Metronidazole | 0.25–1 | 0.5 | 1 | 0 |
| Clindamycin | ≤0.06–32 | 4 | 8 | 63.6 |
| Tigecycline | 0.125–0.25 | 0.25 | 0.25 | 0 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Porphyromonas species (10)d | ||||
| Biapenem | ≤0.03–0.06 | 0.06 | 0.06 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | ≤0.03–0.125 | 0.06 | 0.06 | |
| Biapenem plus RPX7009 (4 μg/ml) | ≤0.03–0.25 | ≤0.03 | 0.06 | |
| Biapenem plus RPX7009 (8 μg/ml) | ≤0.03–0.125 | ≤0.03 | 0.06 | |
| Meropenem | ≤0.03–0.125 | ≤0.03 | ≤0.03 | |
| Piperacillin-tazobactam | ≤0.06 | ≤0.06 | ≤0.06 | 0 |
| Ampicillin-sulbactam | ≤0.06–2 | ≤0.06 | 1 | 0 |
| Cefoxitin | 0.25–2 | 0.5 | 1 | 0 |
| Ceftazidime | 0.25–32 | 0.5 | 8 | NA |
| Metronidazole | 0.125–2 | 0.25 | 1 | 0 |
| Clindamycin | ≤0.06–>128 | ≤0.06 | 1 | 10 |
| Tigecycline | ≤0.06–0.5 | ≤0.06 | ≤0.06 | 0 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Veillonella species (10) | ||||
| Biapenem | ≤0.03–1 | 0.5 | 1 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | 0.06–4 | 0.5 | 4 | |
| Biapenem plus RPX7009 (4 μg/ml) | ≤0.03–4 | 0.125 | 1 | |
| Biapenem plus RPX7009 (8 μg/ml) | ≤0.03–2 | 0.25 | 2 | |
| Meropenem | ≤0.03–0.25 | ≤0.03 | ≤0.03 | 0 |
| Piperacillin-tazobactam | 0.25–4 | 2 | 4 | 0 |
| Ampicillin-sulbactam | ≤0.06–2 | 0.5 | 1 | 0 |
| Cefoxitin | 0.25–8 | 4 | 4 | 0 |
| Ceftazidime | 2–32 | 8 | 32 | NA |
| Metronidazole | 0.25–8 | 2 | 4 | 0 |
| Clindamycin | ≤0.06–0.125 | ≤0.06 | ≤0.06 | 0 |
| Tigecycline | ≤0.06–0.5 | 0.25 | 0.5 | 0 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Bilophila wadsworthia (10) | ||||
| Biapenem | 1–>32 | 32 | >32 | 90 |
| Biapenem plus RPX7009 (2 μg/ml) | 0.5–>32 | 32 | >32 | |
| Biapenem plus RPX7009 (4 μg/ml) | 2–>32 | 32 | >32 | |
| Biapenem plus RPX7009 (8 μg/ml) | 1–>32 | 32 | >32 | |
| Meropenem | 0.06–>32 | 32 | >32 | 60 |
| Piperacillin-tazobactam | 16–>128 | 32 | >128 | 40 |
| Ampicillin-sulbactam | 8–>128 | 5 | >128 | 50 |
| Cefoxitin | 64–>128 | 128 | >128 | 100 |
| Ceftazidime | 32–>128 | 128 | >128 | NA |
| Metronidazole | 0.06–0.5 | 0.125 | 0.25 | 0 |
| Clindamycin | 0.5–>128 | 0.5 | 2 | 30 |
| Tigecycline | 0.5–1 | 0.5 | 0.5 | 0 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Gram-positive organisms | ||||
| Finegoldia magna (10) | ||||
| Biapenem | 0.125–0.25 | 0.125 | 0.125 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | 0.25–0.25 | 0.25 | 0.25 | |
| Biapenem plus RPX7009 (4 μg/ml) | 0.125–0.25 | 0.125 | 0.125 | |
| Biapenem plus RPX7009 (8 μg/ml) | 0.125–0.25 | 0.125 | 0.125 | |
| Meropenem | 0.06–0.125 | 0.06 | 0.125 | 0 |
| Piperacillin-tazobactam | 0.125–0.5 | 0.125 | 0.25 | 0 |
| Ampicillin-sulbactam | 0.25–0.5 | 0.25 | 0.25 | 0 |
| Cefoxitin | 0.5–2 | 1 | 1 | 0 |
| Ceftazidime | 16–64 | 32 | 64 | NA |
| Metronidazole | 0.25–1 | 0.5 | 1 | 0 |
| Clindamycin | 0.125–>128 | 0.5 | >128 | 30 |
| Tigecycline | 0.125–0.5 | 0.25 | 0.25 | 0 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Parvimonas micra (10) | ||||
| Biapenem | ≤0.03–0.5 | 0.125 | 0.5 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | 0.06–0.5 | 0.125 | 0.25 | |
| Biapenem plus RPX7009 (4 μg/ml) | 0.06–0.25 | 0.125 | 0.25 | |
| Biapenem plus RPX7009 (8 μg/ml) | ≤0.03–0.5 | 0.125 | 0.5 | |
| Meropenem | ≤0.03–0.25 | 0.06 | 0.25 | 0 |
| Piperacillin-tazobactam | ≤0.06–0.125 | ≤0.06 | 0.125 | 0 |
| Ampicillin-sulbactam | ≤0.06–0.5 | 0.125 | 0.5 | 0 |
| Cefoxitin | 0.25–4 | 1 | 4 | 0 |
| Ceftazidime | 0.5–32 | 2 | 4 | NA |
| Metronidazole | 0.06–0.5 | 0.25 | 0.5 | 0 |
| Clindamycin | ≤0.06–32 | 0.25 | 0.5 | 10 |
| Tigecycline | ≤0.06–0.125 | ≤0.06 | ≤0.06 | 0 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Peptoniphilus harei (10) | ||||
| Biapenem | <0.03–0.125 | ≤0.03 | 0.125 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | <0.03–0.125 | ≤0.03 | 0.125 | |
| Biapenem plus RPX7009 (4 μg/ml) | <0.03–0.125 | ≤0.03 | 0.125 | |
| Biapenem plus RPX7009 (8 μg/ml) | <0.03–0.125 | ≤0.03 | 0.125 | |
| Meropenem | ≤0.03 | ≤0.03 | ≤0.03 | 0 |
| Piperacillin-tazobactam | ≤0.06 | ≤0.06 | ≤0.06 | 0 |
| Ampicillin-sulbactam | ≤0.06–0.25 | 0.125 | 0.25 | 0 |
| Cefoxitin | 0.125–0.5 | 0.25 | 0.5 | 0 |
| Ceftazidime | 0.5–1 | 1 | 1 | NA |
| Metronidazole | 0.125–2 | 0.5 | 2 | 0 |
| Clindamycin | 0.125–>128 | 1 | >128 | 20 |
| Tigecycline | ≤0.06–0.125 | ≤0.06 | 0.125 | 0 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Peptostreptococcus anaerobius (10) | ||||
| Biapenem | 0.25–8 | 0.5 | 8 | 20 |
| Biapenem plus RPX7009 (2 μg/ml) | 0.25–16 | 0.5 | 16 | |
| Biapenem plus RPX7009 (4 μg/ml) | 0.25–8 | 0.5 | 8 | |
| Biapenem plus RPX7009 (8 μg/ml) | 0.25–8 | 0.5 | 8 | |
| Meropenem | 0.25–8 | 0.5 | 4 | 10 |
| Piperacillin-tazobactam | 0.25–16 | 0.25 | 16 | |
| Ampicillin-sulbactam | 0.125–16 | 0.25 | 16 | 20 |
| Cefoxitin | 0.5–16 | 1 | 16 | |
| Ceftazidime | 2–64 | 8 | 64 | NA |
| Metronidazole | 0.5–1 | 0.5 | 1 | 0 |
| Clindamycin | ≤0.06–0.25 | 0.125 | 0.25 | 0 |
| Tigecycline | ≤0.06 | ≤0.06 | ≤0.06 | 0 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Clostridium difficile (10) | ||||
| Biapenem | 4–16 | 8 | 8 | 70 |
| Biapenem plus RPX7009 (2 μg/ml) | 4–16 | 8 | 8 | |
| Biapenem plus RPX7009 (4 μg/ml) | 4–16 | 8 | 16 | |
| Biapenem plus RPX7009 (8 μg/ml) | 4–16 | 8 | 8 | |
| Meropenem | 1–4 | 2 | 4 | 0 |
| Piperacillin-tazobactam | 8–16 | 8 | 16 | 0 |
| Ampicillin-sulbactam | 2–4 | 2 | 4 | 0 |
| Cefoxitin | 128–>128 | 128 | >128 | 100 |
| Ceftazidime | >128–>128 | >128 | >128 | 100 |
| Metronidazole | 0.5–2 | 1 | 2 | 0 |
| Clindamycin | 8–>128 | 8 | >128 | 100 |
| Tigecycline | ≤0.06–0.125 | 0.125 | 0.125 | 0 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Clostridium clostridioforme group (10)e | ||||
| Biapenem | 0.25–4 | 1 | 4 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | 0.25–4 | 1 | 4 | |
| Biapenem plus RPX7009 (4 μg/ml) | 0.25–4 | 1 | 4 | |
| Biapenem plus RPX7009 (8 μg/ml) | 0.25–4 | 1 | 4 | |
| Meropenem | 0.25–4 | 0.5 | 2 | 0 |
| Piperacillin-tazobactam | ≤0.06–16 | 4 | 8 | 0 |
| Ampicillin-sulbactam | 0.5–2 | 1 | 2 | 0 |
| Cefoxitin | 4–16 | 16 | 16 | 0 |
| Ceftazidime | 16–>128 | 32 | >128 | NA |
| Metronidazole | 0.06–0.5 | 0.06 | 0.25 | 0 |
| Clindamycin | ≤0.06–>128 | 0.5 | 32 | 20 |
| Tigecycline | ≤0.06–0.125 | ≤0.06 | ≤0.06 | 0 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Clostridium innocuum (10) | ||||
| Biapenem | 2–4 | 2 | 4 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | 2–4 | 2 | 4 | |
| Biapenem plus RPX7009 (4 μg/ml) | 2–4 | 2 | 4 | |
| Biapenem plus RPX7009 (8 μg/ml) | 2–4 | 2 | 4 | |
| Meropenem | 1–2 | 1 | 2 | 0 |
| Piperacillin-tazobactam | 1–4 | 2 | 2 | 0 |
| Ampicillin-sulbactam | 0.25–0.5 | 0.25 | 0.5 | 0 |
| Cefoxitin | 32–128 | 64 | 128 | 100 |
| Ceftazidime | 64–>128 | 128 | 128 | NA |
| Metronidazole | 0.5–16 | 1 | 4 | 10 |
| Clindamycin | 0.25–>128 | 1 | 2 | 10 |
| Tigecycline | ≤0.06 | ≤0.06 | ≤0.06 | 0 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Clostridium perfringens (10) | ||||
| Biapenem | ≤0.03–0.125 | 0.06 | 0.06 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | ≤0.03–0.125 | 0.06 | 0.06 | |
| Biapenem plus RPX7009 (4 μg/ml) | ≤0.03–0.125 | 0.06 | 0.06 | |
| Biapenem plus RPX7009 (8 μg/ml) | ≤0.03–0.125 | 0.06 | 0.06 | |
| Meropenem | ≤0.03 | ≤0.03 | ≤0.03 | 0 |
| Piperacillin-tazobactam | ≤0.06–1 | 0.125 | 1 | 0 |
| Ampicillin-sulbactam | ≤0.060–0.5 | 0.125 | 0.25 | 0 |
| Cefoxitin | 1–2 | 2 | 2 | 0 |
| Ceftazidime | 4–8 | 8 | 8 | NA |
| Metronidazole | 1–2 | 1 | 2 | 0 |
| Clindamycin | ≤0.06–16 | 1 | 2 | 10 |
| Tigecycline | 0.125–4 | 4 | 4 | 0 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Clostridium ramosum (10) | ||||
| Biapenem | 1–2 | 1 | 2 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | 1–2 | 1 | 1 | |
| Biapenem plus RPX7009 (4 μg/ml) | 1–2 | 1 | 2 | |
| Biapenem plus RPX7009 (8 μg/ml) | 1–2 | 1 | 1 | |
| Meropenem | 0.5–1 | 1 | 1 | 0 |
| Piperacillin-tazobactam | ≤0.06–0.125 | ≤0.06 | 0.125 | 0 |
| Ampicillin-sulbactam | ≤0.06–0.5 | 0.125 | 0.25 | 0 |
| Cefoxitin | 4–16 | 8 | 8 | 0 |
| Ceftazidime | 4–8 | 8 | 8 | NA |
| Metronidazole | 0.5–16 | 1 | 1 | 10 |
| Clindamycin | 2–4 | 4 | 4 | 90 |
| Tigecycline | 0.125–0.25 | 0.125 | 0.25 | 0 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Clostridium species (10)f | ||||
| Biapenem | 0.125–1 | 0.25 | 1 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | 0.125–1 | 0.25 | 1 | |
| Biapenem plus RPX7009 (4 μg/ml) | 0.125–1 | 0.25 | 1 | |
| Biapenem plus RPX7009 (8 μg/ml) | 0.125–1 | 0.25 | 1 | |
| Meropenem | 0.06–0.5 | 0.125 | 0.5 | 0 |
| Piperacillin-tazobactam | 0.125–2 | 0.5 | 2 | 0 |
| Ampicillin-sulbactam | ≤0.06–1 | 0.25 | 1 | 0 |
| Cefoxitin | 0.25–8 | 4 | 8 | 0 |
| Ceftazidime | 0.5–>128 | 8 | >128 | NA |
| Metronidazole | 0.125–2 | 0.5 | 1 | 0 |
| Clindamycin | ≤0.06–8 | 1 | 8 | 20 |
| Tigecycline | ≤0.06–0.5 | ≤0.06 | 0.25 | 0 |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Eggerthella lenta (10) | ||||
| Biapenem | 0.5–0.5 | 0.5 | 0.5 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | 0.5–0.5 | 0.5 | 0.5 | |
| Biapenem plus RPX7009 (4 μg/ml) | 0.5–0.5 | 0.5 | 0.5 | |
| Biapenem plus RPX7009 (8 μg/ml) | 0.5–0.5 | 0.5 | 0.5 | |
| Meropenem | 1–2 | 1 | 2 | 0 |
| Piperacillin-tazobactam | 16–64 | 32 | 32 | 10 |
| Ampicillin-sulbactam | 2–4 | 2 | 2 | 0 |
| Cefoxitin | 8–16 | 8 | 8 | 0 |
| Ceftazidime | >128–>128 | >128 | >128 | NA |
| Metronidazole | 0.5–1 | 0.5 | 0.5 | 0 |
| Clindamycin | 0.25–0.5 | 0.25 | 0.25 | 0 |
| Tigecycline | 0.5–0.5 | 0.5 | 0.5 | |
| RPX7009 | >128–>128 | >128 | >128 | NA |
| Non-spore-forming Gram-positive rods (10)g | ||||
| Biapenem | 0.06–0.5 | 0.06 | 0.5 | 0 |
| Biapenem plus RPX7009 (2 μg/ml) | 0.06–0.5 | 0.06 | 0.5 | |
| Biapenem plus RPX7009 (4 μg/ml) | 0.06–0.5 | 0.125 | 0.5 | |
| Biapenem plus RPX7009 (8 μg/ml) | 0.06–0.5 | 0.06 | 0.5 | |
| Meropenem | ≤0.03–0.25 | 0.06 | 0.25 | 0 |
| Piperacillin-tazobactam | ≤0.06–1 | ≤0.06 | 0.25 | 0 |
| Ampicillin-sulbactam | ≤0.06–0.5 | 0.25 | 0.5 | 0 |
| Cefoxitin | 0.125–16 | 2 | 8 | 0 |
| Ceftazidime | 0.25–32 | 8 | 32 | NA |
| Metronidazole | 0.25–>32 | 1 | 2 | 10 |
| Clindamycin | ≤0.06–>128 | ≤0.06 | 2 | 10 |
| Tigecycline | 0.125–0.5 | 0.125 | 0.5 | 0 |
| RPX7009 | >128–>128 | >128 | >128 |
I, intermediate; R, resistant; NA, not available.
Bacteroides uniformis (8), Bacteroides cellulosilyticus (3), Bacteroides dorei (2), Bacteroides nordii (2), Bacteroides salyersae (1), Bacteroides stercoris (3), and Bacteroides xylanisolvens.
Parabacteroides distasonis (6), Parabacteroides goldsteinii (9), and Parabacteroides merdae (8).
Porphyromonas asaccharolytica (5), Porphyromonas gingivalis (2), Porphyromonas somerae (2), and Porphyromonas uenonis (1).
Clostridium bolteae (2), Clostridium citroniae (1), Clostridium hathewayi (1), and Clostridium clostridioforme (6).
Clostridium butyricum (3), Clostridium paraputrificum (2), Clostridium scindens (1), Clostridium sordellii (2), and Clostridium symbiosum (3).
Collinsella aerofaciens (1), Eubacterium limosum (2), Pseudoramibacter alactolyticum (2), Slackia exigua (2), Solobacterium moorei (1), and Varibaculum cambriense (1).
For 36 recent isolates of B. fragilis, the MIC90 was 1 μg/ml for biapenem and 0.5 μg/ml for biapenem-RPX7009, both of which were more active than meropenem (MIC90, 4 μg/ml). For B. caccae and B. thetaiotaomicron, the MIC90 for biapenem and biapenem-RPX7009 was 0.5 μg/ml. Other B. fragilis group species, including B. ovatus and Bacteroides vulgatus, showed a MIC90 of 1 μg/ml for both biapenem-RPX7009 and meropenem.
The MIC90 for biapenem-RPX7009 for Prevotella spp. was 0.25 μg/ml, and that for Fusobacterium nucleatum and Fusobacterium necrophorum was 0.125 μg/ml. Biapenem-RPX7009 activity was lower against Fusobacterium mortiferum and Fusobacterium varium, with MIC90s of 2 and 0.5 μg/ml, respectively. Most Bilophila strains were resistant to all beta-lactams, including biapenem-RPX7009 and control carbapenems.
Regarding the comparator agents, clindamycin resistance was found in 17% of B. fragilis isolates and 72% of B. thetaiotaomicron isolates. Resistance in other Bacteroides and Parabacteroides species ranged from 26% to 42%. Tigecycline resistance was found in 8.3% of B. fragilis isolates and 33.3% of B. thetaiotaomicron isolates. Ampicillin-sulbactam resistance varied from 3% for B. caccae to 11% for B. ovatus and B. thetaiotaomicron, 17% for B. fragilis, and 50% for other B. fragilis group species. Comparatively, there was very little piperacillin-tazobactam resistance among all the B. fragilis group species, with only 2.7% resistance in B. fragilis itself.
In a subset of clinical isolates of B. fragilis and Parabacteroides spp. with meropenem MICs of >2 μg/ml (range, 4 to 32 μg/ml), the MIC50s/MIC90s of biapenem and biapenem-RPX7009 were 2/8 and 2/8 μg/ml, respectively, for B. fragilis isolates and 2/2 and 2/2 μg/ml, respectively, for Parabacteroides isolates. The MIC results for the 27 selected B. fragilis group strains previously demonstrated to have diminished imipenem susceptibility are shown in Table 2. Against the five B. fragilis strains harboring a metallo-beta-lactamase, biapenem-RPX7009 MICs were comparable to those of the three comparator carbapenems (MICs of ≥32 μg/ml), and the strains also showed resistance to piperacillin-tazobactam, ampicillin-sulbactam, and cefoxitin. Against Bacteroides strains with an intermediate imipenem MIC of 2 μg/ml, biapenem-RPX7009 had MICs ranging from 0.5 to 2 μg/ml, while MICs for meropenem, doripenem, and ertapenem were 0.5 to 32 μg/ml. For strains with an imipenem MIC of 4 μg/ml, biapenem-RPX7009 had MICs of 4 to 16 μg/ml, while meropenem, doripenem, and ertapenem had 2- to 3-fold higher MICs of 8 to >32 μg/ml. One strain of P. distasonis was unusual, with a much higher MIC than that of the other Parabacteroides isolates.
Table 2.
Comparison of carbapenem and other beta-lactam activities against Bacteroides and Parabacteroides species with resistance or reduced susceptibility to imipenema
| Mechanism and organism | RMA strain no. | MIC(μg/ml) |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| BPM | BPM-RPX7009 | MRP | IMI | ERT | DOR | P-T | A-S | FOX | ||
| Metalloenzymes | ||||||||||
| B. fragilis | 5 strains | >32 | >32 | >32 | >32 | >32 | >32 | >128 | >128 | 128 |
| Reduced susceptibility to imipenem | ||||||||||
| B. fragilis | 9565 | 2 | 2 | 8 | 1 | 8 | 16 | 1 | 16 | 32 |
| 10155 | 1 | 1 | 8 | 2 | 16 | 16 | 1 | 16 | 32 | |
| 13778 | 0.5 | 0.5 | 0.5 | 2 | 1 | 0.5 | 1 | 32 | 8 | |
| 15507 | 0.5 | 0.25 | 0.25 | 2 | 0.5 | 0.5 | 1 | 32 | 8 | |
| 18818 | 1 | 1 | 4 | 2 | 4 | 8 | 1 | 16 | 32 | |
| 20361 | 2 | 4 | 16 | 2 | 16 | 32 | 16 | 32 | 32 | |
| 16214 | 8 | 8 | 32 | 4 | 32 | >32 | 32 | 64 | 32 | |
| 18473 | 8 | 4 | 8 | 4 | 16 | 8 | 32 | 32 | >128 | |
| 20772 | 4 | 4 | 32 | 4 | 32 | 32 | 32 | 64 | 64 | |
| 21925 | 16 | 16 | 16 | 4 | 16 | 16 | 0.25 | 8 | 128 | |
| Other Bacteroides species with reduced susceptibility to imipenem | ||||||||||
| B. caccae | 9815 | 1 | 2 | 1 | 16 | 2 | 1 | >128 | 128 | 64 |
| B. ovatus | 14124 | 2 | 2 | 4 | 2 | 8 | 4 | 8 | 16 | >128 |
| B. thetaiotaomicron | 14510 | 0.5 | 0.5 | 0.5 | 4 | 2 | 0.5 | 64 | 32 | 64 |
| B. uniformis | 14942 | 0.5 | 0.5 | 0.5 | 4 | 2 | 1 | 1 | 32 | 16 |
| 9853 | 1 | 1 | 1 | 8 | 4 | 1 | >128 | 128 | 32 | |
| Parabacteroides species with reduced susceptibility to imipenem | ||||||||||
| P. distasonis | 10265 | 1 | 1 | 1 | 1 | 4 | 2 | 8 | 32 | 64 |
| 11017 | 1 | 1 | 0.5 | 4 | 1 | 1 | 32 | 32 | 16 | |
| 19958 | 16 | 16 | 32 | 8 | >32 | 32 | 8 | 16 | 16 | |
| 9803 | 1 | 1 | 1 | 8 | 4 | 1 | >128 | 128 | 64 | |
| P. goldsteinii | 14939 | 1 | 2 | 8 | 2 | 8 | 4 | 8 | 8 | 64 |
| P. merdae | 16062 | 0.5 | 0.5 | 0.5 | 2 | 1 | 1 | 8 | 32 | 16 |
| 18260 | 1 | 1 | 0.5 | 4 | 1 | 1 | 4 | 16 | 64 | |
Abbreviations: RMA, R. M. Alden Research Lab culture collection; BPM, biapenem; BPM-7009, biapenem-RPX7009; MRP, meropenem; IMI, imipenem; ERT, ertapenem; DOR, doripenem; P-T, piperacillin-tazobactam; A-S, ampicillin-sulbactam; FOX, cefoxitin.
DISCUSSION
A number of studies from the 1990s established the activity of biapenem against a variety of anaerobic bacteria (1, 4–10). Using an agar dilution method with Wilkins-Chalgren agar supplemented with 5% horse blood, Catchpole et al. (1) studied 23 B. fragilis strains and found a MIC90 of 2 μg/ml (range, 0.25 to 4 μg/ml). One year later, Malanoski et al. (8) used unsupplemented Wilkins-Chalgren agar and reported a MIC90 of 0.5 μg/ml (range, 0.25 to 1 μg/ml) against 20 B fragilis strains. In more systematic studies, Aldridge et al. (4) used a broth microdilution method and studied 339 B. fragilis group isolates, including 176 strains of B. fragilis, and they found a MIC90 of 0.25 μg/ml (range, 0.12 to 2 μg/ml) for both groups. Since then, no English-language reports on biapenem's anaerobic activity have been published. Our results, obtained with contemporary isolates, show that biapenem has maintained an excellent activity against anaerobes that is generally equivalent to that of the other carbapenems studied.
Comparatively, clindamycin, cefoxitin, and tigecycline resistance was common in B. thetaiotaomicron isolates. For clindamycin, 72% of our B. thetaiotaomicron isolates were resistant, compared to 17% of B. fragilis strains, while resistance in other Bacteroides and Parabacteroides species ranged from 26% to 42%. A recent study from Canada (16) reported that 34% of 232 B. fragilis isolates and 78% of 49 B. thetaiotaomicron isolates, collected between 2010 and 2011, were resistant to clindamycin. Snydman et al. (17) studied 1,021 B. fragilis isolates collected between 2006 and 2009 from eight geographically distributed U.S. hospitals and found 30% resistance to clindamycin, with 43% resistance for 418 B. thetaiotaomicron isolates. Karlowsky et al. (16) also noted that 14% of B. fragilis isolates and 31% of B. thetaiotaomicron isolates were resistant to tigecycline, compared to 5% and 2%, respectively, in the work of Snydman et al. (17). In contrast, we found tigecycline resistance in 8.3% of B. fragilis isolates and 33.3% of B. thetaiotaomicron isolates. Ampicillin-sulbactam resistance varied by species of the B. fragilis group, from 3% for B. caccae to 11% for B. ovatus and B. thetaiotaomicron, 17% for B. fragilis, and 50% for other B. fragilis group species. We found very little piperacillin-tazobactam resistance among all the B. fragilis group species, with only 2.7% resistance in B. fragilis itself. Similarly, both Karlowsky et al. (16) and Snydman et al. (17) found 1% piperacillin-tazobactam resistance in B. fragilis isolates, with <1% resistance for B. thetaiotaomicron.
Biapenem and biapenem-RPX7009 showed excellent activity against clinical isolates of Gram-positive and Gram-negative anaerobes that was comparable to that of meropenem. RPX7009 showed no antimicrobial activity when tested alone, and overall, there was no significant effect of RPX7009 on biapenem activity against anaerobic bacteria. In some strains of the B. fragilis group and the Parabacteroides spp., biapenem alone or combined with RPX7009 was more active than imipenem or meropenem. This was particularly the case in the panel of recent isolates with meropenem MICs of >2 μg/ml, as well as for strains from the collection of isolates with reduced susceptibility to imipenem. These data suggest that biapenem-RPX7009 may be useful in the treatment of infections due to anaerobic bacteria. Further studies investigating the utility of this combination are warranted.
ACKNOWLEDGMENTS
This study was partially supported by a grant from Rempex Pharmaceuticals Inc., San Diego, CA.
We thank Eliza Leoncio for technical assistance and Judee H. Knight and Alice E. Goldstein for various forms of assistance.
Footnotes
Published ahead of print 25 March 2013
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