Abstract
MRX-I is a potent oxazolidinone antibiotic against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), penicillin-intermediate S. pneumoniae (PISP), and vancomycin-resistant enterococci (VRE). In this study, the in vivo efficacy of orally administered MRX-I was evaluated using linezolid as a comparator. MRX-I showed the same or better efficacy than linezolid in both systemic and local infection models against the tested strains.
TEXT
MRX-I is a new oxazolidinone antibacterial agent developed by MicuRx Pharmaceuticals, Inc. (Shanghai, China), with the same core structure as linezolid (Fig. 1). In vitro studies by another group demonstrated that MRX-I had potent antibacterial activity, with a spectrum that includes aerobic Gram-positive isolates, such as methicillin-resistant staphylococci (methicillin-resistant Staphylococcus aureus [MRSA] and methicillin-resistant Staphylococcus epidermidis [MRSE]), penicillin-nonsusceptible Streptococcus pneumoniae (penicillin-intermediate S. pneumoniae [PISP] and penicillin-resistant S. pneumoniae [PRSP]), and vancomycin-resistant enterococci (VRE). MRX-I demonstrated comparable or slightly higher activity than linezolid and was active against enterococci resistant to both vancomycin and teicoplanin. In addition, MRX-I exhibited bactericidal activities against staphylococci and streptococci but was bacteriostatic against enterococci (D.-M. Zhu, Y.-Y. Zhang, and W. Wang, unpublished data). In this study, the potent in vitro activities of MRX-I against staphylococci, streptococci, and enterococci were confirmed in our laboratory. Next, the in vivo efficacy of MRX-I was evaluated in mouse systemic and local infection models, using linezolid as the reference agent, as it is the only commercially available oxazolidinone. All in vivo experiment procedures were approved by the Animal Research Committee of the Institute of Medicinal Biotechnology.
FIG 1.
Structures of MRX-I {(5S)-5-[(isoxazole-3-amino)methyl]-3-[(2, 3, 5-trifluoro-4-(4-oxo-2,3-dihydropyridine-1)phenyl]-2-oxazolidione; C18H15F3N4O4; molecular weight [MW], 408.33} and linezolid {(S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-acetamide; C16H20FN3O4; MW, 337.35}.
MIC and MBC determinations.
MIC and minimal bactericidal concentration (MBC) determinations were conducted by the agar dilution method and broth macrodilution method, respectively, according to CLSI/NCCLS recommendations (1, 2), using linezolid, vancomycin, and teicoplanin as the reference agents. The test isolates included methicillin-susceptible staphylococci (methicillin-susceptible S. aureus [MSSA] and methicillin-susceptible S. epidermidis [MSSE]), methicillin-resistant staphylococci (MRSA and MRSE), penicillin-susceptible S. pneumoniae (PSSP), penicillin-intermediate S. pneumoniae (PISP), penicillin-resistant S. pneumoniae (PRSP), vancomycin-susceptible enterococci (VSE), vancomycin-resistant enterococci (VRE), and Streptococcus pyogenes. As shown in Table 1, MRX-I demonstrated potent activities against staphylococci, streptococci, and enterococci, including antibiotic-resistant isolates such as MRSA, MRSE, PISP, PRSP, and VRE. The activity of MRX-I was similar to (for S. aureus, S. pneumoniae, S. pyogenes, Enterococcus faecalis, and Enterococcus faecium) or slightly higher than (for S. epidermidis) that of linezolid. MRX-I was bacteriostatic against enterococci (MBC/MICs, >32 μg/ml for most of the isolates) but showed very weak bactericidal activities against staphylococci (MBC/MIC range, 8 to 32 μg/ml for most of the isolates) and some streptococci (MBC/MIC, 8 μg/ml for 4 out of 14 isolates), as well as relatively high bactericidal activities against 10 out of 14 streptococcal isolates (MBC/MICs, 2 to 4 μg/ml).
TABLE 1.
MICs and MBC/MICs of MRX-I and the reference agents against staphylococci, streptococci, and enterococci
| Strain (resistance type) | MIC (μg/ml) of: |
MBC/MIC of: |
||||||
|---|---|---|---|---|---|---|---|---|
| MRX-I | Linezolid | Vancomycin | Teicoplanin | MRX-I | Linezolid | Vancomycin | Teicoplanin | |
| S. aureus ATCC 29213 (MSSA) | 1 | 1 | 1 | 0.5 | 32 | 32 | 4 | 4 |
| S. aureus ATCC BAA-977 (MSSA) | 2 | 2 | 2 | 0.5 | >32 | >32 | 1 | 8 |
| S. aureus ATCC 13709 (MSSA) | 2 | 2 | 1 | 1 | 32 | 32 | 2 | 16 |
| S. aureus ATCC 33591 (MRSA) | 2 | 2 | 1 | 0.5 | 8 | 16 | 2 | 4 |
| S. aureus ATCC 700698 (MRSA) | 2 | 2 | 2 | 4 | >32 | >32 | 2 | 4 |
| S. aureus ATCC 700788 (MRSA) | 2 | 2 | 4 | 4 | 16 | 16 | 2 | 2 |
| S. aureus ATCC BAA-976 (MRSA) | 2 | 2 | 2 | 1 | 32 | >32 | 4 | 8 |
| S. aureus ATCC BAA-1708 (MRSA) | 2 | 2 | 2 | 0.5 | 32 | 32 | 2 | 16 |
| S. aureus Mu50 (MRSA/VISA) | 2 | 2 | 4 | 4 | 8 | >32 | 4 | 4 |
| S. aureus 15 (MSSA) | 2 | 2 | 1 | 0.25 | 32 | >32 | 2 | 8 |
| S. aureus 0802 (MSSA) | 0.5 | 2 | 2 | 4 | 32 | >32 | 4 | 2 |
| S. aureus 0605 (MSSA) | 2 | 2 | 2 | 0.5 | 8 | >32 | 4 | 4 |
| S. aureus 0850 (MRSA) | 1 | 1 | 1 | 0.5 | 32 | 32 | 8 | 4 |
| S. epidermidis ATCC 12228 (MSSE) | 0.5 | 1 | 2 | 2 | >32 | >32 | 4 | 4 |
| S. epidermidis 0833 (MSSE) | 0.5 | 1 | 2 | 1 | >32 | 32 | 16 | 4 |
| S. epidermidis 0925 (MRSE) | 0.25 | 1 | 4 | 8 | 16 | 8 | 8 | 4 |
| S. epidermidis 0934 (MRSE) | 0.5 | 1 | 2 | 4 | 32 | >32 | 2 | 2 |
| S. pneumoniae ATCC 6301 (PSSP) | 1 | 0.5 | 0.5 | 0.12 | 4 | 8 | 1 | 1 |
| S. pneumoniae ATCC 10813 (PSSP) | 1 | 1 | 1 | 0.25 | 8 | 2 | 1 | 2 |
| S. pneumoniae ATCC 51915 (PRSP) | 1 | 0.5 | 4 | 4 | 4 | 4 | 1 | 2 |
| S. pneumoniae ATCC 49619 (PISP) | 1 | 1 | 0.25 | 0.03 | 8 | 2 | 1 | 2 |
| S. pneumoniae ATCC 51916 (PISP) | 1 | 0.5 | 0.5 | 0.06 | 2 | 4 | 1 | 2 |
| S. pneumoniae 0806 (PSSP) | 2 | 2 | 0.5 | 0.06 | 2 | 2 | 1 | 2 |
| S. pneumoniae 0809 (PSSP) | 1 | 0.5 | 0.125 | 0.03 | 2 | 2 | 4 | 2 |
| S. pneumoniae 0810 (PISP) | 1 | 0.5 | 0.5 | 0.06 | 2 | 2 | 1 | 1 |
| S. pneumoniae 0613 (PRSP) | 2 | 2 | 0.5 | 0.06 | 4 | 2 | 1 | 1 |
| S. pneumoniae 1226 (PRSP) | 1 | 0.5 | 0.25 | 0.06 | 2 | 2 | 2 | 2 |
| S. pneumoniae 1263 (PRSP) | 2 | 1 | 0.5 | 0.06 | 4 | 2 | 1 | 1 |
| S. pyogenes ATCC 19615 | 2 | 1 | 0.5 | 0.06 | 8 | 4 | 8 | 8 |
| S. pyogenes ATCC 21546 | 2 | 1 | 1 | 0.125 | 4 | 8 | 1 | 1 |
| S. pyogenes 556 | 1 | 1 | 0.5 | 0.06 | 8 | 4 | 8 | 2 |
| E. faecalis ATCC 29212 (VSE) | 1 | 1 | 4 | 1 | >32 | >32 | >32 | >32 |
| E. faecalis ATCC 51188 (VSE) | 4 | 2 | 2 | 1 | >32 | >32 | >32 | 32 |
| E. faecalis ATCC 29302 (VSE) | 4 | 4 | 2 | 0.5 | >32 | >32 | >32 | >32 |
| E. faecalis ATCC 51299 (VRE) | 2 | 2 | 32 | 1 | >32 | >32 | —a | >32 |
| E. faecalis ATCC 51575 (VRE) | 2 | 1 | >128 | 1 | >32 | 32 | — | >32 |
| E. faecalis ATCC 700802 (VRE) | 2 | 2 | 64 | 1 | >32 | >32 | — | >32 |
| E. faecalis HH22 (HLGR-VSE) | 2 | 2 | 4 | 0.5 | >32 | >32 | >32 | >32 |
| E. faecalis 0910 (VSE) | 2 | 2 | 4 | 1 | >32 | >32 | >32 | >32 |
| E. faecalis 0911 (VSE) | 2 | 2 | 2 | 0.5 | >32 | >32 | >32 | >32 |
| E. faecalis EFL4041 (VRE) | 1 | 1 | 32 | 1 | >32 | >32 | — | >32 |
| E. faecalis 0909 (VRE) | 2 | 2 | >128 | >128 | >32 | >32 | — | — |
| E. faecium ATCC 19434 (VSE) | 4 | 2 | 2 | 1 | >32 | >32 | >32 | >32 |
| E. faecium ATCC 35667 (VSE) | 4 | 2 | 2 | 2 | >32 | >32 | >32 | >32 |
| E. faecium ATCC 700221 (VRE) | 2 | 2 | >128 | >128 | >32 | >32 | — | — |
| E. faecium ATCC 51559 (VRE) | 4 | 4 | >128 | >128 | >32 | >32 | — | — |
| E. faecium 0809 (VSE) | 2 | 2 | 2 | 0.5 | >32 | >32 | >32 | >32 |
| E. faecium 0810 (VSE) | 2 | 2 | 2 | 1 | >32 | >32 | >32 | >32 |
| E. faecium 0811 (VRE) | 2 | 2 | >128 | >128 | >32 | >32 | — | — |
| E. faecium 0830 (VRE) | 2 | 1 | >128 | 64 | >32 | >32 | — | — |
| E. faecium 0925 (VRE) | 2 | 2 | >128 | >128 | 32 | >32 | — | — |
−, fewer than 5 dilutions were used for viable colony counting due to the high MICs, and the MBCs were >128 μg/ml.
Mouse systemic infection model.
The in vivo therapeutic efficacies of MRX-I and the comparator linezolid in the mouse systemic infection model were assessed with 5 strains of S. aureus, 3 strains of S. pneumoniae, 3 strains of E. faecalis, and 1 strain of S. pyogenes (Table 2). The experiment was carried out by a method adapted from the literature (3). For each isolate infection, 110 CD-1 ICR mice (body weight, 18 to 22 g) were allocated randomly into 11 groups with 5 regimens for each compound and 1 control group (10 mice per group, 5 males and 5 females). The mice were infected intraperitoneally with 0.5 ml of a bacterial suspension in 5% mucin (100% minimum lethal dose). At 1 h and 5 h postinfection, 5 dose levels of each compound were administered orally. The dose ranges of MRX-I were 4.0 to 16.0, 4.0 to 10.0, 0.41 to 16.0, 0.625 to 10.0, and 0.625 to 10.0 mg/kg of body weight for infections from S. aureus strains ATCC 29213, 15, ATCC 33591, 0850, and Mu50, respectively; 3.0 to 12.0, 12.6 to 32.0, and 6.6 to 20.0 mg/kg for infections from S. pneumoniae strains ATCC 49619, 0806, and 0613, respectively; 10.0 to 40.0, 4.0 to 12.0, and 2.5 to 20.0 mg/kg for infections from E. faecalis strains ATCC 29212, EFL4041, and HH22, respectively; and 5.0 to 20.0 mg/kg for S. pyogenes infections. The mortality in each group was recorded daily for 7 days, and the 50% effective dose (ED50) and 95% confidence limits were determined by Probit analysis (4). The MICs, ED50s, and 95% confidence limits of MRX-I and the reference compound are listed in Table 2. MRX-I demonstrated in vivo activities that were similar to or comparably higher than linezolid against aerobic Gram-positive bacteria. The ED50s of MRX-I against S. aureus ATCC 29213, 15, ATCC 33591, Mu50, and 0850 were 7.98, 5.74, 2.36, 2.50, and 3.71 mg/kg, respectively, which were similar to (for strains ATCC 29213, 15, and 0850) or significantly lower than (for strains ATCC 33591 and Mu50) those of linezolid (ED50s, 9.03, 5.86, 7.55, 5.35, and 3.63 mg/kg, respectively). MRX-I had high efficacy against S. pneumoniae ATCC 49619 (PISP) (ED50, 8.07 mg/kg), S. pneumoniae 0806 (PSSP) (ED50, 22.02 mg/kg), and S. pneumoniae 0613 (PRSP) (ED50, 10.46 mg/kg), which was comparable (P > 0.05) to that of linezolid (ED50s, 8.17, 16.78, and 9.33 mg/kg, respectively). The ED50s of MRX-I against E. faecalis ATCC 29212 (VSE), E. faecalis EFL4041 (VRE), and E. faecalis HH22 (HLGR-VSE) infections (14.11, 6.15, and 7.44 mg/kg, respectively) were similar to those of linezolid (13.42, 5.97, and 5.64 mg/kg, respectively). The therapeutic efficacy of MRX-I against S. pyogenes was high, with an ED50 of 8.86 mg/kg, which was comparable to that of linezolid (7.81 mg/kg).
TABLE 2.
In vivo efficacies of MRX-I and reference compound in mouse systemic infection
| Organism (resistance type) | Challenge dose (CFU/mouse) | MRX-I data |
Linezolid data |
P, MRX-I vs. linezolid | ||
|---|---|---|---|---|---|---|
| MIC (mg/liter) | ED50 (95% confidence interval) (mg/kg of body wt) | MIC (mg/liter) | ED50 (95% confidence interval) (mg/kg) | |||
| S. aureus ATCC 29213 (MSSA) | 2.1 × 105 | 1 | 7.98 (5.18–12.29) | 1 | 9.03 (7.09–11.50) | >0.05 |
| S. aureus 15 (MSSA) | 2.7 × 105 | 2 | 5.74 (4.15–7.94) | 2 | 5.86 (4.60–7.48) | >0.05 |
| S. aureus ATCC 33591 (MRSA) | 3.2 × 104 | 2 | 2.36 (1.56–3.57) | 2 | 7.55 (5.88–9.71) | <0.01 |
| S. aureus Mu50 (MRSA/VISA) | 2.1 × 105 | 2 | 2.50 (1.82–3.42) | 2 | 5.35 (4.02–7.12) | <0.01 |
| S. aureus 0850 (MRSA) | 1.3 × 104 | 1 | 3.71 (2.73–5.06) | 1 | 3.63 (2.33–5.67) | >0.05 |
| S. pneumoniae ATCC 49619 (PISP) | 8.8 × 105 | 1 | 8.07 (6.08–10.71) | 1 | 8.17 (6.48–10.31) | >0.05 |
| S. pneumoniae 0806 (PSSP) | 3.7 × 105 | 2 | 22.02 (18.41–26.34) | 2 | 16.78 (14.73–19.11) | >0.05 |
| S. pneumoniae 0613 (PRSP) | 3.2 × 105 | 2 | 10.46 (7.81–14.00) | 2 | 9.33 (7.06–12.34) | >0.05 |
| E. faecalis ATCC 29212 (VSE) | 3.3 × 106 | 1 | 14.11 (6.93–28.73) | 1 | 13.42 (9.26–19.45) | >0.05 |
| E. faecalis EFL4041 (VRE) | 7.5 × 107 | 1 | 6.15 (4.80–7.88) | 1 | 5.97 (4.73–7.54) | >0.05 |
| E. faecalis HH22 (HLGR-VSE) | 7.0 × 107 | 2 | 7.44 (6.04–9.15) | 2 | 5.64 (4.04–7.88) | >0.05 |
| S. pyogenes 556 | 3.3 × 106 | 1 | 8.86 (6.88–11.40) | 1 | 7.81 (6.04–10.11) | >0.05 |
Mouse thigh infection model.
The therapeutic efficacies of MRX-I and linezolid in mouse thigh infections caused by S. aureus ATCC 29213 (MSSA) and clinical isolate S. aureus 0605 (MSSA) were evaluated with CD-1 ICR mice (body weight, 23 to 27 g; 10 mice per group, half males, half females) by previously published methods, with modifications (5, 6). The mice were immunocompromised using cyclophosphamide (150 mg/kg of body weight/day for 3 days) (7) prior to infection by right thigh intramuscular injection of 0.1 ml bacterial suspension in saline (challenge dose, 4.2 × 105 CFU/mouse for S. aureus ATCC 29213, 4.6 × 104 CFU/mouse for S. aureus 0605). Five different doses (5.0, 10.0, 20.0, 40.0, and 80.0 mg/kg) of MRX-I and the reference compound linezolid were orally administered twice, at 2 h and 6 h after infection, respectively. The mice were sacrificed at 24 h postinfection, and the right thigh muscles were removed aseptically. The muscles were weighed and homogenized in saline (0.1 g tissue to 1 ml final volume), and the viable colony counts were determined by spreading 0.1 ml properly diluted homogenates onto nutrient agar plates and incubating them at 35°C for 48 h. The log10 CFU/g thigh was calculated thereafter, and the statistical significance was determined by SPSS 13.0. The lower detection limit was 2 log10 CFU/g, which corresponded to the lowest dilution of muscle tissue of 10−1 that avoided significant drug carryover. The results are shown in Table 3. MRX-I and linezolid exhibited dose-dependent efficacy in mouse thigh infections by S. aureus isolates used in the study, with thigh colony counts that were significantly lower (P < 0.01) than those of the corresponding controls for most of the tested doses. Challenging the neutropenic mice with 4.2 × 105 CFU/mouse of S. aureus ATCC 29213 or 4.6 × 104 CFU/mouse of S. aureus 0605 resulted in colony counts of 8.14 and 8.06 log10 CFU/g thigh at 24 h postinfection, respectively. The administrations of MRX-I and the reference compound linezolid at 2 h and 6 h postinfection significantly lowered the thigh colony counts. MRX-I treatments of 5.0 to 80.0 mg/kg resulted in 0.95 to 3.37 log10 CFU/g thigh reductions for S. aureus ATCC 29213 infection and 2.45 to 4.53 log10 CFU/g thigh reductions for S. aureus 0605 infection in comparison to the controls. The thigh colony counts with MRX-I treatments were generally not significantly different (P > 0.05) from the corresponding values for the linezolid treatments (4.41 to 7.19 log10 CFU/g thigh of MRX-I versus 4.44 to 7.09 log10 CFU/g thigh of linezolid for S. aureus ATCC 29213 at 5.0- to 80.0-mg/kg dose levels, and 3.53 to 5.59 log10 CFU/g thigh of MRX-I versus 3.57 to 4.55 log10 CFU/g thigh of linezolid for S. aureus 0605 at 10.0- to 80.0-mg/kg dose levels).
TABLE 3.
In vivo efficacies of MRX-I and reference compound in mouse thigh infection
| Dose (mg/kg) by strain (resistance type) and drug type (MIC) | Log CFU/thigh ± SD (n = 10) | Log reduction from control |
P value vs: |
|
|---|---|---|---|---|
| Control | Linezolid at the same dose | |||
| S. aureus ATCC 29213 (MSSA) (4.2 × 105 CFU/mouse) | ||||
| MRX-I (MIC, 1 mg/liter) | ||||
| 5 | 7.19 ± 0.66 | 0.95 | >0.05 | >0.05 |
| 10 | 4.85 ± 0.94 | 3.29 | <0.01 | >0.05 |
| 20 | 4.81 ± 1.13 | 3.33 | <0.01 | >0.05 |
| 40 | 4.72 ± 0.78 | 3.42 | <0.01 | >0.05 |
| 80 | 4.41 ± 0.43 | 3.73 | <0.01 | >0.05 |
| Linezolid (MIC, 1 mg/liter) | ||||
| 5 | 7.09 ± 1.46 | 1.05 | >0.05 | |
| 10 | 5.45 ± 1.37 | 2.69 | <0.01 | |
| 20 | 5.32 ± 1.39 | 2.82 | <0.01 | |
| 40 | 4.50 ± 0.47 | 3.64 | <0.01 | |
| 80 | 4.44 ± 1.27 | 3.70 | <0.01 | |
| Control | 8.14 ± 0.55 | |||
| S. aureus 0605 (MSSA) (4.6 × 104 CFU/mouse) | ||||
| MRX-I (MIC, 2 mg/liter) | ||||
| 5 | 5.61 ± 1.68 | 2.45 | <0.01 | <0.01 |
| 10 | 5.59 ± 1.70 | 2.47 | <0.01 | >0.05 |
| 20 | 4.46 ± 1.44 | 3.60 | <0.01 | >0.05 |
| 40 | 3.93 ± 0.62 | 4.13 | <0.01 | >0.05 |
| 80 | 3.53 ± 0.75 | 4.53 | <0.01 | >0.05 |
| Linezolid (MIC, 2 mg/liter) | ||||
| 5 | 7.86 ± 0.77 | 0.20 | >0.05 | |
| 10 | 4.55 ± 1.45 | 3.51 | <0.01 | |
| 20 | 3.99 ± 1.55 | 4.07 | <0.01 | |
| 40 | 3.66 ± 0.49 | 4.40 | <0.01 | |
| 80 | 3.57 ± 1.59 | 4.49 | <0.01 | |
| Control | 8.06 ± 0.41 | |||
In conclusion, the in vitro activity of MRX-I was confirmed by MIC and MBC determinations, and the in vivo therapeutic efficacies of MRX-I were evaluated using animal models of mouse systemic and mouse neutropenic thigh infections. The MIC results (Table 1) demonstrated that MRX-I had activity that was comparable to or slightly higher than that of linezolid and was active against antibiotic-resistant isolates such as MRSA, MRSE, PISP, PRSP, and VRE. MBC determinations (Table 1) indicated that MRX-I was a bacteriostatic agent against enterococci but a very weak bactericidal agent against staphylococci and some streptococci (4 out of 14 isolates), as well as a relatively strong bactericidal agent against most streptococci (10 out of 14 isolates).
The results from mouse systemic infections (Table 2) mirrored the results of in vitro studies. MRX-I demonstrated relatively potent antibacterial activities against Gram-positive isolates (including antibiotic-resistant isolates of MRSA, vancomycin-intermediate S. aureus [VISA], PRSP, PISP, VRE, and high-level gentamicin-resistant VSE [HLGR-VSE]), which were similar to or higher than those of linezolid. The results from the mouse thigh infection model (Table 3) further verified the aforementioned conclusions. MRX-I and linezolid showed similar efficacies against mouse neutropenic thigh infections by S. aureus ATCC 29213 (standard MSSA) and S. aureus 0605 (clinical MSSA). The comparable to higher activity of MRX-I than that of linezolid against Gram-positive organisms (including the clinically important isolates of MRSA, VISA, PRSP, PISP, VRE, and HLGR-VSE) supports further clinical evaluations of MRX-I.
ACKNOWLEDGMENTS
We thank Barbara E. Murray, University of Texas Health Science Center, for her kindness in donating E. faecalis HH22.
This work was supported by the National Natural Science Foundation of China (grant no. 30901876 and 81273427) and the National Mega-project for Innovative Drugs (grant no. 2012ZX09301002-001 and 2012ZX09301002-005), People's Republic of China.
H. Yuan and M. F. Gordeev are currently employed by MicuRx Pharmaceuticals, Inc., Shanghai, People's Republic of China, and MicuRx Pharmaceuticals, Inc., Hayward, CA, respectively.
Footnotes
Published ahead of print 6 January 2014
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