Abstract
In vitro activities of DA-7867, a novel oxazolidinone, were compared to those of linezolid and commonly used antimicrobials. DA-7867 had the lowest MIC for 90% of the aerobic gram-positive bacterial strains tested, ≤0.25 μg/ml, and it was more potent than linezolid.
Increased antimicrobial resistance in gram-positive cocci, particularly staphylococci, enterococci, and pneumococci, has become a problem in recent years (11, 20). The introduction of oxazolidinones to clinical practice represents an important advance in the therapy of infections due to these gram-positive bacteria (3). Linezolid has been reported to be mainly potent against gram-positive anaerobes, with no useful activity against gram-negative anaerobes (4, 16). Significantly, the mode of action of oxazolidinone is specific, and no cross-resistance between it and other antimicrobial agents has been observed (7).
DA-7867 (Dong-A Pharmaceutical Co., Yongin, Korea) is a new hetero-ring-substituted pyridine-containing oxazolidinone, (S)-[N-3-(4-(2-(1-methyl-5-tetrazolyl)-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide, which was selected from among several candidate chemicals (Fig. 1). An animal study showed that it has potential for the treatment of infections of the skin, soft tissue, and the respiratory tract (T. Lee, D. Kim, J. Cho, S. Choi, W. Im, and J. Rhee, Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-1314, 2002).
FIG. 1.
Structure of DA-7867.
In vitro studies had shown that DA-7867 was more potent than linezolid against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), penicillin-resistant Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis (W. Im, T. Lee, J. Cho, S. Choi, and J. Rhee, Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-1311, 2002; S. Choi, T. Lee, W. Im, J. Cho, D. Kim, J. Rhee, and W. Kim, Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-1313, 2002). However, the number of isolates tested was limited, and in vitro activities against coagulase-negative staphylococci, group A and B streptococci, and anaerobic bacteria have not been determined.
In this study, we compared the in vitro activities of DA-7867 against major aerobic gram-positive pathogens, gram-negative respiratory pathogens, and anaerobic bacteria with those of linezolid and other antimicrobial agents.
(This study was presented in part at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, Calif., 27 to 30 September 2002 [K. Lee et al., abstr. F-1312, 2002].)
Bacterial strains were isolated in 2000 and 2001 from patients at a Korean tertiary-care hospital. The species were identified by conventional methods and by using either the ID 32 GN or the ATB 32A system (bioMérieux, Marcy-l'Etoile, France).
Antimicrobial susceptibility was determined as recommended by the NCCLS (13, 14). The antimicrobial agents used were linezolid (Dong-A Pharmaceutical Co.), erythromycin, tetracycline, penicillin G (Sigma Chemical Co., St. Louis, Mo.), clindamycin (Korea Upjohn, Seoul, Korea), trimethoprim, sulfamethoxazole (Dong Wha Pharmaceutical Co., Seoul, Korea), levofloxacin (Daiichi Pharmaceutical Co., Tokyo, Japan), ampicillin, chloramphenicol (Chong Kun Dang Pharmaceutical Co., Seoul, Korea), sulbactam (Pfizer Korea, Seoul, Korea), cefotaxime (Handok Pharmaceutical Co., Seoul, Korea), metronidazole (Choongwae Pharmaceutical Co., Seoul, Korea), and vancomycin (Daewoong Pharmaceutical Co., Seoul, Korea). An anaerobic chamber (Forma Scientific, Marietta, Ohio) was used for anaerobic incubation, and American Type Culture Collection strains of S. aureus (29213), Enterococcus faecalis (29212), S. pneumoniae (49619), H. influenzae (49247), Bacteroides fragilis (25285), and B. thetaiotaomicron (29741) were used as controls. The linezolid breakpoint was used for DA-7867, for which the breakpoint has not yet been defined. For M. catarrhalis, the criteria for staphylococci were applied.
In many Korean hospitals, the proportion of MRSA was around 70% (9). In this study, all staphylococci were inhibited by DA-7867 at 0.25 μg/ml and linezolid at 2 μg/ml (Table 1). The activity of linezolid was similar to those reported previously (1, 6, 8). The MIC of DA-7867 for 90% of the staphylococcal strains tested (MIC90) was eightfold lower than that of linezolid. All MRSA strains were susceptible to DA-7867 and linezolid, but the majority were resistant to erythromycin, clindamycin, gentamicin, levofloxacin, and tetracycline.
TABLE 1.
Antimicrobial activities of DA-7867 compared with those of other antibiotics against aerobic and anaerobic bacteria
| Organism(s) (no. of isolates tested) and antimicrobial agent | MIC (μg/ml)
|
% of isolatesd
|
||||
|---|---|---|---|---|---|---|
| Range | 50% of strains | 90% of strains | S | I | R | |
| Methicillin-susceptible Staphylococcus aureus (33) | ||||||
| DA-7867 | 0.12-0.25 | 0.25 | 0.25 | 100 | NAc | NA |
| Linezolid | 1-2 | 2 | 2 | 100 | NA | NA |
| Erythromycin | 0.12-128 | 0.25 | 64 | 79 | 0 | 21 |
| Clindamycin | ≤0.06->128 | ≤0.06 | ≤0.06 | 97 | 0 | 3 |
| Cotrimoxazole | ≤0.06-16 | ≤0.06 | 0.12 | 97 | NA | 3 |
| Gentamicin | ≤0.06-128 | ≤0.06 | 64 | 79 | 3 | 18 |
| Levofloxacin | 0.12-1 | 0.25 | 0.25 | 100 | 0 | 0 |
| Tetracycline | 0.12-128 | 0.25 | 32 | 79 | 0 | 21 |
| MRSA (30) | ||||||
| DA-7867 | 0.06-0.25 | 0.12 | 0.25 | 100 | NA | NA |
| Linezolid | 1-2 | 2 | 2 | 100 | NA | NA |
| Erythromycin | 0.5->128 | >128 | >128 | 7 | 0 | 93 |
| Clindamycin | ≤0.06->128 | >128 | >128 | 10 | 0 | 90 |
| Cotrimoxazole | ≤0.06-128 | 0.12 | 64 | 83 | NA | 17 |
| Gentamicin | 0.25->128 | 128 | >128 | 7 | 0 | 93 |
| Levofloxacin | 0.5->128 | >128 | >128 | 7 | 0 | 93 |
| Tetracycline | 0.5-128 | 64 | 128 | 13 | 0 | 87 |
| Methicillin-susceptible coagulase-negative staphylococci (22) | ||||||
| DA-7867 | 0.06-0.25 | 0.12 | 0.12 | 100 | NA | NA |
| Linezolid | 0.5-2 | 1 | 1 | 100 | NA | NA |
| Erythromycin | ≤0.06-128 | 0.12 | 32 | 77 | 0 | 23 |
| Clindamycin | ≤0.06->128 | ≤0.06 | 0.12 | 96 | 0 | 4 |
| Cotrimoxazole | ≤0.06-8 | 0.12 | 8 | 82 | NA | 18 |
| Gentamicin | ≤0.06-64 | 1 | 4 | 96 | 0 | 4 |
| Levofloxacin | 0.06-8 | 0.25 | 1 | 91 | 0 | 9 |
| Tetracycline | ≤0.06-128 | 0.25 | 64 | 64 | 5 | 32 |
| Methicillin-resistant coagulase-negative staphylococci (29) | ||||||
| DA-7867 | ≤0.03-0.25 | 0.12 | 0.25 | 100 | NA | NA |
| Linezolid | 0.25-2 | 1 | 2 | 100 | NA | NA |
| Erythromycin | 0.25->128 | >128 | >128 | 14 | 0 | 86 |
| Clindamycin | ≤0.06->128 | >128 | >128 | 45 | 3 | 52 |
| Cotrimoxazole | ≤0.06-8 | 2 | 8 | 55 | NA | 45 |
| Gentamicin | ≤0.06-128 | 32 | 128 | 24 | 14 | 62 |
| Levofloxacin | 0.12-32 | 0.5 | 8 | 52 | 10 | 38 |
| Tetracycline | 0.25->128 | 2 | 64 | 62 | 3 | 35 |
| Vancomycin-susceptible Enterococcus faecalis (49) | ||||||
| DA-7867 | ≤0.06-0.12 | 0.12 | 0.12 | 100 | 0 | 0 |
| Linezolid | 0.5-2 | 1 | 2 | 100 | 0 | 0 |
| Ampicillin | 0.25-4 | 0.5 | 2 | 100 | NA | 0 |
| Erythromycin | ≤0.12->128 | >128 | >128 | 12 | 8 | 80 |
| Levofloxacin | 1-64 | 2 | 64 | 61 | 0 | 39 |
| Tetracycline | 0.5->128 | 64 | 128 | 12 | 4 | 84 |
| Vancomycin | 1-2 | 2 | 2 | 100 | 0 | 0 |
| Teicoplanin | ≤0.12-1 | 0.25 | 0.5 | 100 | 0 | 0 |
| Vancomycin-resistant E. faecalis (10) | ||||||
| DA-7867 | ≤0.06-0.12 | ≤0.06 | 0.12 | 100 | 0 | 0 |
| Linezolid | 0.5-2 | 1 | 1 | 100 | 0 | 0 |
| Ampicillin | 0.5-4 | 2 | 4 | 100 | NA | 0 |
| Erythromycin | >128 | >128 | >128 | 0 | 0 | 100 |
| Levofloxacin | 16-64 | 64 | 64 | 0 | 0 | 100 |
| Tetracycline | 16-64 | 32 | 64 | 0 | 0 | 100 |
| Vancomycin | >128 | >128 | >128 | 0 | 0 | 100 |
| Teicoplanin | 64->128 | >128 | >128 | 0 | 0 | 100 |
| Vancomycin-susceptible E. faecium (29) | ||||||
| DA-7867 | ≤0.06-0.12 | 0.12 | 0.12 | 100 | 0 | 0 |
| Linezolid | 0.5-2 | 2 | 2 | 100 | 0 | 0 |
| Ampicillin | 1->128 | >128 | >128 | 3 | NA | 97 |
| Erythromycin | ≤0.12->128 | >128 | >128 | 3 | 7 | 90 |
| Levofloxacin | 1-128 | 64 | 128 | 7 | 0 | 93 |
| Tetracycline | ≤0.12-64 | 0.5 | 8 | 90 | 7 | 3 |
| Vancomycin | 0.5-4 | 0.5 | 1 | 100 | 0 | 0 |
| Teicoplanin | 0.25-1 | 0.5 | 1 | 100 | 0 | 0 |
| Vancomycin-resistant E. faecium (30) | ||||||
| DA-7867 | ≤0.06-0.12 | 0.12 | 0.12 | 100 | 0 | 0 |
| Linezolid | 0.5-2 | 2 | 2 | 100 | 0 | 0 |
| Ampicillin | 16->128 | >128 | >128 | 0 | NA | 100 |
| Erythromycin | 64->128 | >128 | >128 | 0 | 0 | 100 |
| Levofloxacin | 8-128 | 64 | 128 | 0 | 0 | 100 |
| Tetracycline | ≤0.12-32 | 0.25 | 1 | 90 | 0 | 10 |
| Vancomycin | >128 | >128 | >128 | 0 | 0 | 100 |
| Teicoplanin | 4->128 | 64 | 128 | 3 | 13 | 84 |
| Streptococcus pneumoniae (22) | ||||||
| DA-7867 | ≤0.008-0.12 | 0.03 | 0.03 | 100 | NA | NA |
| Linezolid | 0.5-2 | 1 | 1 | 100 | NA | NA |
| Penicillin G | 0.03-2 | 1 | 2 | 14 | 63 | 23 |
| Cefotaxime | ≤0.008-2 | 1 | 2 | 36 | 50 | 14 |
| Clindamycin | ≤0.06->128 | >128 | >128 | 27 | 0 | 73 |
| Erythromycin | 0.12->128 | 128 | 128 | 5 | 0 | 95 |
| Cotrimoxazole | 0.5-64 | 8 | 32 | 36 | 0 | 64 |
| Levofloxacin | 8-128 | 64 | 128 | 0 | 0 | 100 |
| Tetracycline | 8-64 | 16 | 32 | 0 | 0 | 100 |
| Streptococcus pyogenes (15) | ||||||
| DA-7867 | ≤0.008-0.12 | 0.06 | 0.12 | 100 | NA | NA |
| Linezolid | 0.25-1 | 0.5 | 1 | 100 | NA | NA |
| Penicillin G | ≤0.008-0.015 | ≤0.008 | ≤0.008 | 100 | NA | NA |
| Cefotaxime | ≤0.008-0.015 | ≤0.008 | 0.015 | 100 | 0 | 0 |
| Clindamycin | ≤0.06 | ≤0.06 | ≤0.06 | 100 | 0 | 0 |
| Erythromycin | 0.12->128 | 0.12 | 16 | 87 | 0 | 13 |
| Levofloxacin | 0.12-2 | 0.5 | 1 | 100 | 0 | 0 |
| Streptococcus agalactiae (15) | ||||||
| DA-7867 | ≤0.008-0.12 | 0.06 | 0.12 | 100 | NA | NA |
| Linezolid | 0.015-1 | 0.5 | 1 | 100 | NA | NA |
| Penicillin G | 0.015-0.06 | 0.03 | 0.06 | 100 | NA | NA |
| Cefotaxime | ≤0.008-0.06 | 0.06 | 0.06 | 100 | 0 | 0 |
| Clindamycin | ≤0.06->128 | ≤0.06 | 128 | 73 | 0 | 27 |
| Erythromycin | ≤0.06->128 | ≤0.06 | >128 | 87 | 0 | 13 |
| Levofloxacin | 0.25-0.5 | 0.5 | 0.5 | 100 | 0 | 0 |
| Moraxella catarrhalis (24) | ||||||
| DA-7867 | 0.25-8 | 0.5 | 0.5 | 96 | NA | NA |
| Linezolid | 2-32 | 4 | 4 | 96 | NA | NA |
| Penicillin G | 0.015-32 | 8 | 16 | 9 | NA | 91 |
| Cefaclor | 0.25-16 | 1 | 8 | 96 | 4 | 0 |
| Clindamycin | ≤0.06-32 | 0.5 | 2 | 70 | 25 | 4 |
| Erythromycin | ≤0.06-64 | 0.12 | 0.5 | 91 | 0 | 9 |
| Cotrimoxazole | 0.12-8 | 0.25 | 1 | 96 | NA | 4 |
| Levofloxacin | 0.015-0.25 | 0.06 | 0.06 | 100 | 0 | 0 |
| Tetracycline | ≤0.06-16 | 0.25 | 0.5 | 91 | 0 | 9 |
| Gentamicin | ≤0.06-0.25 | 0.12 | 0.25 | 100 | 0 | 0 |
| Haemophilus influenzae (24) | ||||||
| DA-7867 | 0.25-4 | 2 | 2 | NA | NA | NA |
| Linezolid | 2-8 | 8 | 8 | NA | NA | NA |
| Ampicillin | 0.25->128 | 32 | >128 | 21 | 0 | 79 |
| Ampicillin-sulbactam | 0.25-8 | 2 | 8 | 58 | NA | 42 |
| Cefaclor | 1-64 | 8 | 32 | 50 | 29 | 21 |
| Cefuroxime | 0.25-32 | 1 | 8 | 84 | 8 | 8 |
| Cefotaxime | ≤0.008-1 | 0.03 | 0.06 | 100 | NA | NA |
| Azithromycin | 0.5-4 | 2 | 4 | 100 | NA | NA |
| Cotrimoxazole | 0.25-32 | 16 | 32 | 17 | 4 | 79 |
| Levofloxacin | 0.03-1 | 0.03 | 0.06 | 100 | NA | NA |
| Tetracycline | 0.12-8 | 0.5 | 8 | 71 | 4 | 25 |
| Peptostreptococcus spp. (56) | ||||||
| DA-7867 | ≤0.06-2 | ≤0.06 | 0.12 | NA | NA | NA |
| Linezolid | 0.5-8 | 1 | 2 | NA | NA | NA |
| Ampicillin | ≤0.06-32 | 0.25 | 16 | 75 | 0 | 25 |
| Ampicillin-sulbactam | ≤0.06-16 | 0.25 | 16 | 89 | 11 | 0 |
| Piperacillin | ≤0.06-32 | 0.25 | 16 | 100 | 0 | 0 |
| Piperacillin-tazobactam | ≤0.06-32 | 0.12 | 16 | 100 | 0 | 0 |
| Cefoxitin | ≤0.06-16 | 0.5 | 8 | 100 | 0 | 0 |
| Cefotetan | ≤0.06-128 | 1 | 64 | 77 | 4 | 20 |
| Imipenem | ≤0.06-2 | ≤0.06 | 2 | 100 | 0 | 0 |
| Clindamycin | ≤0.06->128 | 0.5 | 64 | 75 | 4 | 21 |
| Metronidazole | 0.25-32 | 2 | 16 | 84 | 14 | 2 |
| Chloramphenicol | 1-64 | 2 | 4 | 95 | 0 | 5 |
| Clostridium perfringens (17) | ||||||
| DA-7867 | 0.12 | 0.12 | 0.12 | NA | NA | NA |
| Linezolid | 2 | 2 | 2 | NA | NA | NA |
| Ampicillin | ≤0.06-0.12 | ≤0.06 | 0.12 | 100 | 0 | 0 |
| Ampicillin-sulbactam | ≤0.06-0.12 | ≤0.06 | 0.12 | 100 | 0 | 0 |
| Piperacillin | ≤0.06-0.5 | 0.25 | 0.5 | 100 | 0 | 0 |
| Piperacillin-tazobactam | ≤0.06-1 | 0.25 | 0.5 | 100 | 0 | 0 |
| Cefoxitin | 0.12-2 | 1 | 2 | 100 | 0 | 0 |
| Cefotetan | ≤0.06-2 | 1 | 2 | 100 | 0 | 0 |
| Imipenem | ≤0.06-0.12 | ≤0.06 | 0.12 | 100 | 0 | 0 |
| Clindamycin | ≤0.06-4 | 2 | 4 | 53 | 47 | 0 |
| Metronidazole | 4-16 | 16 | 16 | 41 | 59 | 0 |
| Chloramphenicol | 2-4 | 4 | 4 | 100 | 0 | 0 |
| Vancomycin | 0.5-1 | 0.5 | 1 | NA | NA | NA |
| Clostridium difficile (15) | ||||||
| DA-7867 | ≤0.06-0.25 | 0.12 | 0.25 | NA | NA | NA |
| Linezolid | 0.5-4 | 2 | 2 | NA | NA | NA |
| Ampicillin | 0.5-2 | 0.5 | 1 | 73 | 20 | 7 |
| Ampicillin-sulbactam | 0.5-2 | 0.5 | 1 | 100 | 0 | 0 |
| Piperacillin | 2-8 | 2 | 8 | 100 | 0 | 0 |
| Piperacillin-tazobactam | 2-8 | 2 | 8 | 100 | 0 | 0 |
| Cefoxitin | 128->128 | 128 | 128 | 0 | 0 | 100 |
| Cefotetan | 16-32 | 32 | 32 | 27 | 73 | 0 |
| Imipenem | 4-16 | 8 | 8 | 13 | 80 | 7 |
| Clindamycin | 1->128 | >128 | >128 | 7 | 7 | 87 |
| Metronidazole | 1-4 | 4 | 4 | 100 | 0 | 0 |
| Chloramphenicol | 2-32 | 8 | 32 | 33 | 27 | 40 |
| Vancomycin | 0.25-2 | 0.5 | 1 | NA | NA | NA |
| Other Clostridium spp. (10) | ||||||
| DA-7867 | ≤0.06-1 | 0.12 | 0.5 | NA | NA | NA |
| Linezolid | 0.5-8 | 2 | 8 | NA | NA | NA |
| Ampicillin | 0.12->128 | 0.5 | 32 | 50 | 20 | 30 |
| Ampicillin-sulbactam | 0.12-16 | 0.25 | 1 | 90 | 10 | 0 |
| Piperacillin | 0.5->256 | 1 | 32 | 90 | 0 | 10 |
| Piperacillin-tazobactam | 0.5-16 | 2 | 16 | 100 | 0 | 0 |
| Cefoxitin | 0.5-128 | 8 | 64 | 50 | 30 | 20 |
| Cefotetan | 0.5->128 | 16 | >128 | 70 | 10 | 20 |
| Imipenem | ≤0.06-2 | 0.5 | 2 | 100 | 0 | 0 |
| Clindamycin | ≤0.06->128 | 2 | >128 | 50 | 0 | 50 |
| Metronidazole | 1->128 | 32 | 64 | 30 | 10 | 60 |
| Chloramphenicol | 0.5-16 | 4 | 8 | 90 | 10 | 0 |
| Vancomycin | 0.5->16 | 2 | 16 | NA | NA | NA |
| Other anaerobic gram-positive rodsa (14) | ||||||
| DA-7867 | ≤0.06 | ≤0.06 | ≤0.06 | NA | NA | NA |
| Linezolid | 0.25-1 | 1 | 1 | NA | NA | NA |
| Ampicillin | ≤0.06-4 | 0.25 | 4 | 71 | 7 | 21 |
| Ampicillin-sulbactam | ≤0.06-4 | 0.25 | 4 | 100 | 0 | 0 |
| Piperacillin | ≤0.06-32 | 2 | 16 | 100 | 0 | 0 |
| Piperacillin-tazobactam | ≤0.06-32 | 0.5 | 16 | 100 | 0 | 0 |
| Cefoxitin | ≤0.06-128 | 4 | 32 | 79 | 14 | 7 |
| Cefotetan | 0.5-128 | 4 | 64 | 57 | 21 | 21 |
| Imipenem | ≤0.06-2 | ≤0.06 | 1 | 100 | 0 | 0 |
| Clindamycin | ≤0.06->128 | ≤0.06 | >128 | 79 | 0 | 21 |
| Metronidazole | 0.5->128 | 32 | >128 | 36 | 7 | 57 |
| Chloramphenicol | 0.5-4 | 2 | 4 | 100 | 0 | 0 |
| Vancomycin | 0.5-1 | 1 | 1 | NA | NA | NA |
| Bacteroides fragilis (34) | ||||||
| DA-7867 | 1-2 | 1 | 2 | NA | NA | NA |
| Linezolid | 4 | 4 | 4 | NA | NA | NA |
| Ampicillin-sulbactam | 0.5-16 | 1 | 8 | 94 | 6 | 0 |
| Piperacillin | 4->256 | 32 | >256 | 59 | 3 | 38 |
| Piperacillin-tazobactam | 0.06-8 | 2 | 4 | 100 | 0 | 0 |
| Cefoxitin | 4->128 | 8 | 32 | 88 | 3 | 9 |
| Cefotetan | 2->128 | 8 | 128 | 82 | 0 | 18 |
| Imipenem | ≤0.06-2 | 0.25 | 0.5 | 100 | 0 | 0 |
| Clindamycin | 0.5->128 | >128 | >128 | 35 | 6 | 59 |
| Metronidazole | 2-8 | 4 | 8 | 100 | 0 | 0 |
| Chloramphenicol | 4-8 | 4 | 8 | 100 | 0 | 0 |
| B. thetaiotaomicron (15) | ||||||
| DA-7867 | 1-8 | 2 | 4 | NA | NA | NA |
| Linezolid | 4-8 | 4 | 8 | NA | NA | NA |
| Ampicillin-sulbactam | 1-64 | 2 | 32 | 80 | 7 | 13 |
| Piperacillin | 16->256 | 64 | >256 | 27 | 33 | 40 |
| Piperacillin-tazobactam | 4->256 | 16 | 16 | 93 | 0 | 7 |
| Cefoxitin | 8-64 | 16 | 32 | 53 | 40 | 7 |
| Cefotetan | 8->128 | 128 | >128 | 7 | 20 | 73 |
| Imipenem | 0.12-16 | 0.5 | 4 | 93 | 0 | 7 |
| Clindamycin | 4->128 | >128 | >128 | 0 | 20 | 80 |
| Metronidazole | 2-8 | 2 | 4 | 100 | 0 | 0 |
| Chloramphenicol | 4-8 | 8 | 8 | 100 | 0 | 0 |
| Other Bacteroides spp. (11) | ||||||
| DA-7867 | 0.5-4 | 2 | 2 | NA | NA | NA |
| Linezolid | 2-4 | 4 | 4 | NA | NA | NA |
| Ampicillin-sulbactam | 0.5-32 | 8 | 16 | 64 | 27 | 9 |
| Piperacillin | 8->256 | >256 | >256 | 27 | 9 | 64 |
| Piperacillin-tazobactam | 2-128 | 4 | 128 | 82 | 0 | 18 |
| Cefoxitin | 4-64 | 16 | 32 | 64 | 27 | 9 |
| Cefotetan | 16->128 | 32 | 128 | 18 | 36 | 45 |
| Imipenem | 0.25-2 | 0.5 | 1 | 100 | 0 | 0 |
| Clindamycin | ≤0.12->128 | >128 | >128 | 27 | 0 | 73 |
| Metronidazole | 1-4 | 4 | 4 | 100 | 0 | 0 |
| Chloramphenicol | 4-8 | 8 | 8 | 100 | 0 | 0 |
| Other anaerobic gram-negative rodsb (27) | ||||||
| DA-7867 | ≤0.06-2 | 0.25 | 1 | NA | NA | NA |
| Linezolid | 0.5-8 | 2 | 8 | NA | NA | NA |
| Ampicillin-sulbactam | ≤0.06-4 | 1 | 4 | 100 | 0 | 0 |
| Piperacillin | 0.06->256 | 16 | 128 | 67 | 22 | 11 |
| Piperacillin-tazobactam | ≤0.06-16 | ≤0.06 | 4 | 100 | 0 | 0 |
| Cefoxitin | ≤0.06-16 | 1 | 8 | 100 | 0 | 0 |
| Cefotetan | ≤0.06-64 | 4 | 32 | 67 | 30 | 4 |
| Imipenem | ≤0.06-2 | ≤0.06 | 2 | 100 | 0 | 0 |
| Clindamycin | ≤0.06->128 | ≤0.06 | >128 | 70 | 4 | 26 |
| Metronidazole | ≤0.12-8 | 2 | 8 | 100 | 0 | 0 |
| Chloramphenicol | 1-8 | 2 | 4 | 100 | 0 | 0 |
Four Eubacterium spp., three Bifidobacterium spp., four Actinomyces spp., and three Propionibacterium acnes strains.
Nineteen Prevotella and Porphyromonas spp. and eight Fusobacterium spp.
NA, not applicable.
S, susceptible; I, intermediate; R, resistant.
VRE have become prevalent in Korea (17). All enterococci, including VRE, were inhibited by DA-7867 at 0.12 μg/ml and by linezolid at 2 μg/ml, which is also in agreement with prior reports (5, 18) (Table 1). The MIC90 of DA-7867 was 16-fold lower than that of linezolid.
The proportion of non-penicillin-susceptible S. pneumoniae has remained around 80% since the early 1990s in Korea (2). In this study, the MIC range of DA-7867 for pneumococci, most of which were nonsusceptible to penicillin G or cefotaxime, was ≤0.008 to 0.12 μg/ml and the MIC90 of DA-7867 was 32-fold lower than that of linezolid (Table 1). All isolates of S. pyogenes and S. agalactiae were inhibited by DA-7867 at ≤0.12 μg/ml. All of these isolates were susceptible to penicillin G, but the MIC90 of penicillin G was at least eightfold higher for S. agalactiae than for S. pyogenes. Similar results were reported previously (10). S. agalactiae strains with reduced susceptibility to penicillin G and cefotaxime have also been reported in Japan (12).
A high prevalence of β-lactamase-producing strains of M. catarrhalis and H. influenzae has been reported in Korea (8, 19). The MIC ranges of DA-7867 for M. catarrhalis and H. influenzae were 0.25 to 8 and 0.25 to 4 μg/ml, respectively, and the MIC90s of DA-7867 for these organisms were four- and eightfold lower than those of linezolid. It is interesting that most of the M. catarrhalis isolates tested were interpreted to be susceptible to DA-7867, while linezolid was reported to be only moderately potent (11).
Soft-tissue and intraabdominal-cavity infections are often due to multiple organisms, including aerobic and anaerobic bacteria. All of the peptostreptococci and anaerobic gram-positive bacilli were inhibited by DA-7867 at ≤2 μg/ml, and the MIC90 for peptostreptococci was 16-fold lower than that of linezolid (Table 1). One of the favorable characteristics of an antimicrobial agent is that it does not disturb intestinal flora (15). The MIC90s of DA-7867, 1 to 4 μg/ml, for anaerobic gram-negative bacilli were slightly lower than those of linezolid, 4 to 8 μg/ml. This suggests that DA-7867 and linezolid have similar effects on intestinal flora. Moreover, the higher activity of DA-7867 than linezolid against Clostridium difficile suggests that the use of this drug may not result in overgrowth of this organism in the intestine.
In conclusion, we found that DA-7867 is more potent than linezolid in vitro against aerobic and anaerobic gram-positive bacteria, including multidrug-resistant bacteria. No cross-resistances with oxacillin in staphylococci and with vancomycin in enterococci were observed. Further studies are warranted to determine the feasibility of developing DA-7867 as a therapeutic agent.
Acknowledgments
This study was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (01-PJ1-PG4-01PT01-0005).
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