Activity of gatifloxacin alone or in combination with pyrimethamine or gamma interferon against Toxoplasma gondii.
The activity of gatifloxacin against Toxoplasma gondii, either alone or in combination with pyrimethamine or gamma interferon (IFN-gamma), was examined in vitro and in vivo. In vitro, gatifloxacin significantly inhibited intracellular replication of tachyzoites of the RH strain with a 50% inhibitory concentration of 0.21 microg/ml at 48 h after addition of the drug to the cultures. Toxicity for host cells was not observed at this concentration. A synergistic effect (combination indices < 0.5) was demonstrated in vitro following 48 h of treatment with the combination of gatifloxacin and pyrimethamine (1:1 ratio). Doses of gatifloxacin of 100 and 200 mg/kg of body weight/day administered orally to mice for 10 days resulted in significant (P values of 0.056 and <0.0001, respectively) prolongation in time to death following infection with a lethal inoculum of tachyzoites. A dose of 400 mg/kg resulted in 20% survival (P = 0.0001). Mortality was 100% in untreated control mice and in mice treated with 25 or 50 mg/kg/day. Treatment of infected mice with a combination of gatifloxacin at 200 mg/kg/day and pyrimethamine at 12.5 mg/kg/day resulted in 85% survival, whereas 100 and 80% of mice treated with gatifloxacin alone or pyrimethamine alone, respectively, died (P < 0.0001). Moreover, a gatifloxacin dose of 200 mg/kg/day administered orally for 10 days plus 2 microg of recombinant murine IFN-gamma/day administered intraperitoneally for 10 days resulted in significant survival compared with IFN-gamma alone (P < 0.0001) or gatifloxacin alone (P < 0.007).
Khan
A A
AA
Department of Immunology and Infectious Diseases, Research Institute, Palo Alto Medical Foundation, Palo Alto, California 94301, USA.
Slifer
T R
TR
Araujo
F G
FG
Remington
J S
JS
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D024841:Fluoroquinolones; D000077734:Gatifloxacin; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D011739:Pyrimethamine / Q000494:pharmacology* / Q000627:therapeutic use; D011994:Recombinant Proteins; D014122:Toxoplasma / Q000187:drug effects*; D014123:Toxoplasmosis / Q000188:drug therapy / Q000382:microbiology
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D011994:Recombinant Proteins; D007371:Interferon-gamma; D000077734:Gatifloxacin; D011739:Pyrimethamine