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In vitro activity of LY146032 against gram-positive bacteria
M Silva1, N V Jacobus, S L Gorbach
1Department of Community Health, Tufts University School of Medicine, Boston, MA 02111.
Abstract:
The activity of LY146032 (LY) was evaluated against 269 clinical isolates: 150 Staphylococcus spp. (Staph), 45 enterococci, 51 Clostridium spp., and 23 peptostreptococci. LY was compared to penicillin, metronidazole, imipenem, clindamycin, oxacillin, ciprofloxacin, vancomycin, and ampicillin. LY and oxacillin were tested against Staph by microdilution in cation-supplemented Mueller-Hinton broth (CSMHB), and in unsupplemented Mueller-Hinton broth (MHB). For LY, the MIC 90s in CSMHB were 16-32 dilutions lower. Among the Staph, the MIC 90s for LY, vancomycin, and ciprofloxacin were 4 micrograms/ml, 4 micrograms/ml, and 2 micrograms/ml respectively. The MIC 90s for enterococci by agar dilution were as follows: LY 8 micrograms/ml; ampicillin 4 micrograms/ml; imipenem 4 micrograms/ml; vancomycin 4 micrograms/ml; and ciprofloxacin 2 micrograms/ml. Clindamycin and penicillin were the most effective drugs against peptostreptococci and Clostridia spp., but LY was the most active drug against Clostridium difficile. The bactericidal activity of LY was determined by 24-hr time-kill curves in MHB. These showed a bactericidal effect against enterococci, and a bacteriostatic effect against three of four strains of Staph. Synergy was demonstrated against enterococci and Staph when LY was tested with aztreonam, ceftriaxone, or tobramycin. LY is a promising new agent against gram-positive bacteria, including methicillin resistant strains of staphylococci and enterococci.
Insights
LY146032 (LY) shows potent activity against gram-positive bacteria, including resistant strains. This new agent demonstrates efficacy against Staphylococcus and enterococci, with synergistic effects when combined with other antibiotics.
Area of Science:
- Microbiology
- Infectious Diseases
- Pharmacology
Background:
- Gram-positive bacterial infections pose significant challenges due to rising antimicrobial resistance.
- Novel therapeutic agents are crucial for combating infections caused by resistant pathogens like Staphylococcus and Enterococcus species.
Purpose of the Study:
- To evaluate the in vitro activity of LY146032 (LY) against a panel of clinical isolates of gram-positive bacteria.
- To compare the efficacy of LY against common antibiotics and assess its bactericidal and synergistic potential.
Main Methods:
- MICs were determined for LY146032 against 269 clinical isolates including Staphylococcus, Enterococcus, Clostridium, and Peptostreptococcus species.
- Broth microdilution and agar dilution methods were employed, with testing in cation-supplemented Mueller-Hinton broth (CSMHB) and unsupplemented Mueller-Hinton broth (MHB).
- Time-kill curves assessed bactericidal activity, and synergy was evaluated in combination with aztreonam, ceftriaxone, or tobramycin.
Main Results:
- LY146032 exhibited potent activity against Staphylococcus spp. and enterococci, with MIC90 values comparable or superior to vancomycin and ciprofloxacin.
- LY demonstrated significant activity against Clostridium difficile and showed a concentration-dependent reduction in bacterial viability.
- Synergistic effects were observed when LY was combined with aztreonam, ceftriaxone, or tobramycin against enterococci and Staphylococcus.
Conclusions:
- LY146032 is a promising new antimicrobial agent with broad-spectrum activity against clinically relevant gram-positive bacteria.
- Its efficacy extends to methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) strains.
- The demonstrated bactericidal and synergistic potential of LY146032 warrants further investigation for clinical applications.