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Experimental Therapeutics

In Vivo Efficacy of a Novel Oxazolidinone Compound in Two Mouse Models of Infection

Charles J. Gill, George K. Abruzzo, Amy M. Flattery, Andrew S. Misura, Ken Bartizal, Emily J. Hickey
Charles J. Gill
Department of Infectious Diseases, Merck Research Laboratories, Rahway, New Jersey 07065
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  • For correspondence: charles_gill@merck.com
George K. Abruzzo
Department of Infectious Diseases, Merck Research Laboratories, Rahway, New Jersey 07065
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Amy M. Flattery
Department of Infectious Diseases, Merck Research Laboratories, Rahway, New Jersey 07065
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Andrew S. Misura
Department of Infectious Diseases, Merck Research Laboratories, Rahway, New Jersey 07065
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Ken Bartizal
Department of Infectious Diseases, Merck Research Laboratories, Rahway, New Jersey 07065
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Emily J. Hickey
Department of Infectious Diseases, Merck Research Laboratories, Rahway, New Jersey 07065
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DOI: 10.1128/AAC.01567-06
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  • FIG. 1.
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    FIG. 1.

    Efficacy of AM 7359 and linezolid (Lin) against an MRSA COL strain in a localized infection model. DBA/2 mice (five per group) were challenged intramuscularly with 3.6 × 108 CFU of MRSA in a 0.2-ml inoculum and treated p.o. three times a day for 1 day and once a day for 5 days or i.v. three times a day for 1 day and once a day for 1 day.

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    FIG. 2.

    Efficacy of AM 7359 and linezolid against an LMRSA strain in a localized infection model. C3H mice (five per group) were challenged intramuscularly with 109 CFU of LMRSA in a 0.2-ml inoculum and treated p.o. three times a day for 1 day and once a day for 5 days.

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  • TABLE 1.

    Comparative efficacies of AM 7359 and linezolid against MSSA Smith in an organ burden assay

    Compound (mode of administration) and MIC (μg/ml)Dose (mg/kg/day)% MortalityaLog CFU/g of kidneyb (% eradication)Reduction (SD)c
    AM 7359 (p.o.), 0.1252503.11* (0) 5.23 (0.58)
    12.505.41* (0) 2.93 (0.59)
    6.2505.71* (0) 2.63 (0.80)
    3.1208.60 (0)−0.26 (0.37)
    Linezolid (p.o.), 2.02502.27* (100) 6.07 (0.04)
    12.505.63* (0) 2.71 (0.37)
    6.2506.90* (0) 1.44 (0.59)
    3.1208.87 (0)−0.53 (0.10)
    AM 7359 (i.v.), 0.1252503.81* (0) 4.59 (0.15)
    12.503.94* (0) 4.46 (0.16)
    6.2506.37* (0) 2.03 (0.61)
    3.1208.34 (0)0.06 (0.15)
    Linezolid (i.v.), 2.02504.13* (0) 4.27 (0.70)
    12.506.96* (0) 1.44 (1.62)
    6.2508.52 (0)−0.12 (0.20)
    3.1208.67 (0)−0.27 (0.11)
    Control (distilled H2O; p.o.)208.34 (0)
    Control (distilled H2O; i.v.)08.40 (0)
    • ↵ a Calculated as the number dead divided by the total number in the group.

    • ↵ b *, significant reduction compared to sham-treated control as determined by Student's t test.

    • ↵ c Reduction in log number of CFU compared to sham-treated control. Significant reductions are shown in bold. SD, standard deviation of results for the four mice per group.

  • TABLE 2.

    ED99 of AM 7359 and linezolid in mouse efficacy models

    Model (organism)ED99 (mg/kg) (95% CI) of:
    AM 7359Linezolid
    p.o.i.v.p.o.i.v.
    Kidney (MSSA)a4.9 (3.1-7.6)6.3 (4.2-9.5)7.0 (5.3-9.2)12 (7.8-18.5)
    Thigh (MRSA)b4.2 (2.8-6.1)5.6 (2.3-∞)5.2 (4.2-6.6)6.9 (4.5-∞)
    Thigh (LMRSA)10.2 (4.3-24)NTa85 (50.2-∞)NT
    • ↵ a Values are based on mice receiving a single dose 15 min postchallenge; therefore, ED99 values are equal to the total mg/kg/day given each mouse.

    • ↵ b Orally dosed mice received a total of eight doses in 5 days and i.v. dosed mice a total of four doses in 24 h; therefore, the ED99 values represent the value of each individual dose given in each model.

    • c NT, not tested.

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In Vivo Efficacy of a Novel Oxazolidinone Compound in Two Mouse Models of Infection
Charles J. Gill, George K. Abruzzo, Amy M. Flattery, Andrew S. Misura, Ken Bartizal, Emily J. Hickey
Antimicrobial Agents and Chemotherapy Aug 2007, 51 (9) 3434-3436; DOI: 10.1128/AAC.01567-06

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In Vivo Efficacy of a Novel Oxazolidinone Compound in Two Mouse Models of Infection
Charles J. Gill, George K. Abruzzo, Amy M. Flattery, Andrew S. Misura, Ken Bartizal, Emily J. Hickey
Antimicrobial Agents and Chemotherapy Aug 2007, 51 (9) 3434-3436; DOI: 10.1128/AAC.01567-06
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KEYWORDS

Anti-Bacterial Agents
oxazolidinones
staphylococcal infections

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