788 Correspondence 1ID 1992; 165 (April)

100 D------O-O---o-----O-----o Clarithromycin-Minocycline is Synergistic in a Murine 'l\ , Model of Toxoplasmosis ~,\ - ...- NOTREATMI' 80 •• b , -_e- C200mllki/daylOclays ~§' ~ II ""'c, :::g: ~~+M·SO " >0 60 ~ \ c Colleagues-Although clarithromycin, a 6-o-methyl derivative ~CI: II , of erythromycin, has been shown to be active against Toxo­ "'~ I•. , O--i:l-----e 40 I, plasma gondii both in vitro and in vivo [1-3], relatively high ~~ I, ffig I .-e concentrations are necessary to achieve significant protection. ll. ',.------~----_e 20 •, In repeated experiments in our laboratory, concentrations of \ , clarithromycin as high as 300 mg/kg/day protected ~30% ofthe 0 5 10 15 20 25 30 infected mice. We recognize that this may not necessarily pre­ DAYS AFTER INFECTION dict a relative lack ofefficacy in humans, as the pharmacokinet­ ics in mice and humans may differ considerably. Results of a Figure 1. Activity ofclarithromycin (C) and minocycline (M) alone or in combination in treatment of murine toxoplasmosis. Downloaded from https://academic.oup.com/jid/article/165/4/788/816554 by guest on 29 September 2021 trial in AIDS patients with toxoplasmic encephalitis revealed that treatment with the combination clarithromycin-pyrimetha­ mine resulted in total or partial resolution of brain lesions on Treatment with 200 mg/kg clarithromycin combined with 50 computed tomography and striking clinical responses [4], sug­ mg/kg minocycline for 10 days resulted in lOO% survival ofmice gesting that the activity ofclarithromycin against T. gondii may infected with a lethal inoculum of cysts (figure 1). These mice have been potentiated by combination with pyrimethamine. Re­ did not show any signs of acute toxoplasmosis and were alive cent studies in our laboratory to determine the activity ofclar­ and well after 50 days of infection, when the experiment was ithromycin in combination with other drugs revealed that the terminated. However, cysts of T. gondii were present in their combination of clarithromycin with either pyrimethamine or brains. All untreated mice died (100% mortality) by day 13 of sulfadiazine is synergistic (unpublished data). Because ofreports infection; the survival rate of mice treated with clarithromycin indicating that the tetracycline analog minocycline also has ac­ alone was 20% and ofmice treated with minocycline alone was tivity against T. gondii [I, 5], we examined the activity of the 50%.Similar results were obtained in two separate experiments. combination clarithromycin-minocycline in the treatment of We conclude that the above results revealed remarkable syn­ murine toxoplasmosis. ergism of the combination clarithrornycin-rninocycline for the Clarithromycin (Abbott Laboratories, lot 134-974-AX) was treatment of murine toxoplasmosis. dissolved in PBS (pH 6.8), and the solution was sonicated just before oral administration to mice. Minocycline (Lederle Labo­ Fausto G. Araujo, Philippe Prokocimer, ratories, Pearl River, NY; lot 798) was dissolved in distilled and Jack S. Remington water, and appropriate concentrations were prepared in polyeth­ Department ofImmunology and Infectious Diseases. ylene glycol 200 (J. T. Baker, Phillipsburg, NJ) and adminis­ Research Institute. Palo Alto Medical Foundation, and tered orally with clarithromycin. Cysts of T. gondii were col­ Department ofMedicine, Stanford University School ofMedicine. lected from the brains ofmice chronically infected with the C56 California; Pharmaceutical Products Research and Development, strain and used to infect mice. Each animal received 10 cysts Abbott Laboratories. North Chicago. Illinois administered orally. Treatment with each drug alone or in com­ bination was initiated 3 days after infection and continued for References 10 days. Mice were examined daily for signs ofacute toxoplas­ mosis, and those dying during the experiment were examined I. Chang HR. Comte R. Piguet PF. Pechere JC Activity of minocycline for the presence ofT. gondii tachyzoites in their peritoneal fluid. against Toxoplasma gondii infection in mice. J Antimicrob Chemother 1991;27:639-45. Surviving mice were examined for the presence ofT. gondii cysts 2. Chang HR, Pechere JC In vitro effects offour macrolides (roxithromy­ in their brains. cin, spiramycin, azithromycin [CP-62993], and A-56268) on Toxo­ plasma gondii. Antimicrob Agents Chemother 1988;32:524-9. 3. Chang HR. Rudareanu FC, Pechere JC Activity ofA-56268 (TE-031). a new macrolide. against Toxoplasma gondii in mice. J Antimicrob Che­ Grant support: National Institutes of Health (AI-04717, AI-30230). mother 1988;22:359-61. Reprints or correspondence: Dr. Jack S. Remington, Department of Im­ 4. Fernandez-Martin JC, Leport C, Morlat P, Meyohas MC, Chauvin JP. munology and Infectious Diseases, Research Institute, Palo Alto Medical Vilde JL. Pyrimetharnine-clarithromycin combination for therapy of Foundation, Palo Alto, CA 94301. acute toxoplasma encephalitis in patients with AIDS. Antimicrob Agents Chemother 1991;35:2049-52. The Journal of Infectious Diseases 1992;165:788 © 1992 by The University ofChicago. All rights reserved. 5. Tabbara KF, Sakuragi S, O'Connor GR. Minocycline in the chemother­ 0022-1899/92/6504-0043$01.00 apy of murine toxoplasmosis. Parasitology 1982;84:297-302.