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LY146032, alone and in combination with gentamicin, for the treatment of enterococcal pyelonephritis in the rat model
F L Sapico1, V J Ginunas, H N Canawati
1Department of Medicine, Rancho Los Amigos Medical Center, Downey, California 90242.
Abstract:
The in vivo and in vitro activity of LY146032 against Streptococcus faecalis GK was examined. The following MICs and MBCs in micrograms per milliliter were obtained: ampicillin, 0.8 and 1.5; vancomycin, 0.8 and 50; gentamicin, 12 and 25; and LY146032, 0.8 and 6. A time-kill-curve study involving approximately 10(6) organisms per ml showed a drop in the number of organisms of almost 2 log10 in the tube containing LY146032 (2 micrograms/ml) plus gentamicin (4 micrograms/ml) compared with bacterial numbers for the control at 4 h of incubation. However, regrowth was observed at 24 and 48 h, and no in vitro synergism was observed with the combination. A sample (1 ml) of overnight growth of this enterococcal strain at a concentration of 10(7) was then injected intravenously into 184 male Wistar rats weighing about 100 g each. After 12 days, 10 rats were sacrificed and the remaining ones were randomized into four treatment groups: (i) untreated control, (ii) LY146032 (3 mg) given subcutaneously, (iii) gentamicin (0.8 mg) given intramuscularly, and (iv) LY146032 plus gentamicin at the same dosages as when the drugs were used singly. The rats received antibiotics for 4 weeks twice daily, and approximately 10 rats in each group were sacrificed for quantitative kidney cultures at 1, 2, 4, and 6 weeks after the start of therapy. At the end of the 4- and 6-week periods, significantly better results were obtained with the combination of LY146032 plus gentamicin than with no treatment or treatment with single antibiotics.
Insights
This study investigated the antibiotic LY146032 against Streptococcus faecalis. The combination of LY146032 and gentamicin showed improved in vivo results in rats, despite no observed in vitro synergy.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Streptococcus faecalis (enterococci) are significant pathogens.
- Antibiotic resistance in enterococci necessitates novel therapeutic strategies.
- LY146032 is a novel antibiotic agent with potential activity against Gram-positive bacteria.
Purpose of the Study:
- To evaluate the in vitro and in vivo activity of LY146032 against Streptococcus faecalis.
- To assess the efficacy of LY146032 alone and in combination with gentamicin in a rat model of enterococcal infection.
Main Methods:
- In vitro susceptibility testing (MICs, MBCs, time-kill curves) of LY146032 and gentamicin against Streptococcus faecalis.
- Establishment of a rat model by intravenous injection of Streptococcus faecalis.
- Randomized controlled trial with four treatment groups: untreated, LY146032 alone, gentamicin alone, and combination therapy.
- Quantitative kidney cultures performed at multiple time points to assess bacterial burden.
Main Results:
- LY146032 demonstrated potent in vitro activity (MIC: 0.8 µg/ml, MBC: 6 µg/ml) against Streptococcus faecalis.
- In vitro combination of LY146032 and gentamicin showed rapid bacterial killing but no synergy, with observed regrowth.
- In vivo, the combination of LY146032 and gentamicin significantly reduced bacterial load in rat kidneys compared to monotherapy or no treatment at 4 and 6 weeks.
Conclusions:
- LY146032 exhibits promising in vitro and in vivo activity against Streptococcus faecalis.
- The combination of LY146032 and gentamicin demonstrates superior in vivo efficacy in a rat model, suggesting potential therapeutic benefit.
- Further investigation into the mechanisms of in vivo synergy and optimal dosing is warranted.