Clindamycin Effects on Experimental Ocular Toxoplasmosis in the Rabbit

Tabbara, Khalid F.; Nozik, Robert A.; O’Connor, G. Richard

doi:10.1001/archopht.1974.01010010252017

Cited by 52 publications

(20 citation statements)

References 9 publications

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“…Brief exposure of T. gondii to clindamycin alone had no effect on extracellular T. gondii and did not change the effect of the combination of sulfadiazine plus pyrimethamine or that of sulfadiazine as a single agent. This lack of effect of clindamycin on T. gondii is in contrast with in vivo results reported by others (1,7,10) and may be due to a need for more prolonged exposure of extracellular T. gondii to the antibiotic, the effect in vivo being due to a metabolite rather than to the parent compound, lack of penetration of clindamycin into mouse macrophages, which might be necessary for a sustained effect on T. gondii or an unrecognized artifact of this in vitro system. Clindamycin has been found to be actively transported into guinea pig alveolar macrophages (3), but whether clindamycin entered mouse peritoneal macrophages in our system was not determined.…”

Section: Resultscontrasting

confidence: 89%

“…Pyrimethamine and sulfadiazine were studied to determine whether the tnicromethod would demonstrate the inhibitory effects on 1. gondii that have been described clinically and for other in vitro and in vivo assay methods. Clindamycin was studied because of its efficacy in the treatment of toxoplasmosis in mouse and rabbit models (1,7,10), and metronidazole was studied because it is effective against another protozoan, Entamoeba histolytica. Sulfadoxine was studied because it has a half-life that is substantially longer than those of sulfadiazine and the triple sulfonamides and it is available in combination with pyrimethamine, which has a half-life of days.…”

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confidence: 99%

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New micromethod to study the effect of antimicrobial agents on Toxoplasma gondii: comparison of sulfadoxine and sulfadiazine individually and in combination with pyrimethamine and study of clindamycin, metronidazole, and cyclosporin A

Mack¹,

McLeod²

1984

Antimicrob Agents Chemother

108

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An in vitro method by which reagents, cells, and Toxoplasma gondii trophozoites are conserved (microniethod) was developed to quantitate the effect of antimicrobial agents on T. gondii. Sulfadoxine alone had no effect on T. gondii in vitro when evaluated with a macromethod, the new knicromethod, or visual inspection of Giemsa-stained preparations. Sulfadoxine combined with pyrimethamine inhibited T. gbndit more than did pyrimethamine alohe, but the combination of sulfadoxine plus pyrimethamine was slightly less active than was the combination of sulfadiazine plus pyrimethamine. Neither clindamycin nor metronidazole, alone or in combination with sulfadiazine or pyrimethamine and sulfadiazine, had any effect on intracellular T. gondii. Brief exposure (10 min before and during challenge) to elindamycin had no effect on extraceUular T. gondii when clindamycin was studied alone or with sulfadiazine or pyrimethamine plus sulfadiazine. Cyclosporin A inhibited T. gondii replication at concentrations of ca. -2 ,ug/ml.In vitro assays have been used to evaluate the effects of atitimicrobial agents on Toxoplasma gondii (2, 8, 9), but none of these methods have been designed to minimize the amounts of cells, T. gondii trophozoites, and reagents used. We developed such a system and then utilized this system to study the effects of a number of antimicrobial agents. Pyrimethamine and sulfadiazine were studied to determine whether the tnicromethod would demonstrate the inhibitory effects on 1. gondii that have been described clinically and for other in vitro and in vivo assay methods. Clindamycin was studied because of its efficacy in the treatment of toxoplasmosis in mouse and rabbit models (1, 7, 10), and metronidazole was studied because it is effective against another protozoan, Entamoeba histolytica. Sulfadoxine was studied because it has a half-life that is substantially longer than those of sulfadiazine and the triple sulfonamides and it is available in combination with pyrimethamine, which has a half-life of days. Cyclosporin A was studied because of its antimalarial effect in vitro and in vivo (11) (GIBCO, Grand Island, N.Y.) that contained 10% heatinactivated (60 tnin, 56°C) fetal calf serum (GIBCO), penicillin (100 U/ml), and streptomycin (100 ,ug/ml) (M199-FCS).(ii) Macromethod. A 0.5-ml amount of the cell suspension was placed into each well of 24-well plates (2 cm2; Linbro Scientific Inc., Hamden, Conn.) and four-chamber Lab-Tek slides (2 cm2; Miles, Naperville, Ill.) which were then * Corresponding author. incubated at 37°C for 1 to 4 h to permit macrophages to adhere. Nonadherent cells were then removed, and cultures were washed with Hanks balanced salt solution (GIBCO).(iii) Micromethod. A 0.1-ml amount of the cell suspension was placed into each well of 96-well plates (0.28 cm2; Linbro Scientific Inc.). Cultures were incubated for 1 to 4 h at 37°C before challenge. Nonadherent cells were not removed from the cultures because eliminating this step simplified performance of the assay and did not alter the resu...

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Section: Resultscontrasting

confidence: 89%

mentioning

confidence: 99%

New micromethod to study the effect of antimicrobial agents on Toxoplasma gondii: comparison of sulfadoxine and sulfadiazine individually and in combination with pyrimethamine and study of clindamycin, metronidazole, and cyclosporin A

Mack¹,

McLeod²

1984

Antimicrob Agents Chemother

108

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“…In a rabbit model, injection of tachyzoites into the suprachoroidal space resulted in outer retinal lesions and localized foci of retinal pigment epitheliosis within 48 h. This suggests the crossing of the parasite through the RPE-Bruchs membrane barrier from the choroid to the retina (27). Histopathological examination of the eyes of patients with toxoplasma-induced retinochoroiditis revealed the presence of free tachyzoites and cysts in the RPE and the retina (9,19,24).…”

mentioning

confidence: 99%

Toxoplasma gondii Infection Induces Gene Expression and Secretion of Interleukin 1 (IL-1), IL-6, Granulocyte-Macrophage Colony-Stimulating Factor, and Intercellular Adhesion Molecule 1 by Human Retinal Pigment Epithelial Cells

2000

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We have used human retinal pigment epithelial (HRPE) cultures to investigate the primary cellular responses of retinal resident cells to intracellular Toxoplasma gondii replication. At 4 days postinoculation, when all of the cells were infected, the secretion of interleukin 1␤ (IL-1␤), IL-6, granulocyte-macrophage colonystimulating factor (GM-CSF), and intercellular adhesion molecule 1 (ICAM-1) was augmented by 23-, 10-, 8-, and 5-fold, respectively, over the control. Northern and reverse transcriptase PCR analyses showed significant upregulation of steady-state levels of mRNA for IL-1␤, IL-6, GM-CSF, and ICAM-1. The secretion of these molecules by HRPE cells may play a critical immunoregulatory role in the pathophysiological processes associated with T. gondii-induced retinochoroiditis.Retinochoroiditis caused by Toxoplasma gondii during ocular toxoplasmosis results in inflammation and disorganization of the retina, occasionally leading to severe loss of vision (11,20,23,30). The intensity of damage to the retina and choroid depends on the severity of the infection and the associated inflammatory reaction (11,13,20). Inflammatory cells, predominantly macrophages and lymphocytes, infiltrate the retina, the subretinal space, and the vitreous (6,11,20). In the severe form of T. gondii-induced uveitis, destruction of large segments of the outer retina and pigment epithelium is observed (6, 9, 13, 24). Within the retina, lysosomal and other autolytic enzymes released by inflammatory cells are thought to contribute to the pathogenic mechanisms of retinal tissue damage (6, 11).Retinal pigment epithelium (RPE), an integral part of the neuroretina in the posterior pole of the eye, acts as a barrier between the highly vascularized choroid and the retina with a complex architecture of neuronal cells (2, 31). In addition to its role in the transport of metabolites between retina and choroid, the RPE phagocytose the shed outer segments of retinal rods and cones (2, 31). Many of these activities of the RPE are essential for the structural and functional integrity of the retina and choroid. The RPE, because of its critical location and physiological activities, is constantly subjected to contact with various infectious agents and inflammatory mediators (12,14).Tachyzoites of T. gondii injected into the peritonial cavities of mice were thought to reach the retina via both choroidal and retinal circulation (8,21,26). In a rabbit model, injection of tachyzoites into the suprachoroidal space resulted in outer retinal lesions and localized foci of retinal pigment epitheliosis within 48 h. This suggests the crossing of the parasite through the RPE-Bruchs membrane barrier from the choroid to the retina (27). Histopathological examination of the eyes of patients with toxoplasma-induced retinochoroiditis revealed the presence of free tachyzoites and cysts in the RPE and the retina (9,19,24). Hence, studies of the mechanisms of T. gondii replication within retinal cells and the responses of the host cells to parasite invasion would be ...

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“…Ce modèle a permis de montrer l'efficacité de la clindamycine et de la minocycline dans la toxoplasmose oculaire (Rollins et al, 1982 ;Tabbara et al, 1974), mais l'extrapolation à l'homme reste difficile, du fait de notre méconnaissance de la pharmacocinétique de ces médicaments dans l'oeil, aussi bien chez l'animal que chez l'homme.…”

Section: -Rongeurs : Souris Rat Cobayeunclassified

Modèles expérimentaux de Toxoplasmose. Applications Pharmacologiques

et al. 1995

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Summary : EXPERIMENTAL MODELS OF TOXOPLASMOSIS. PHARMACOLO-GICAL APPLICATIONSToxoplasma gondii is an ubiquitous protozoan parasite causing severe or life-threatening infections in immunocompromised patients and in congenitally infected infants. Animal models have been extensively used to describe the pathology of infection and to identify new effective drugs for the treatment of congenital infections, chrorioretinitis and toxoplasmic encephalitis. Although inherent differences between man and animal can reduce the relevance of data obtained experimentally, animal models have greatly improved our knowledge on the various aspects of toxoplasmosis. Toxoplasma infection can be easily obtained in most laboratory animais, with exception of rats which are partially resistant. According to the strain used, the resulting infection may be acute, subacute or chronic, and can be monitored either by the survival of animais, the histopathological examination of lesions or, preferably, by titration of parasites in infected tissues using subinoculation to mice or tissue culture. This latter method has proved particularly useful to describe the kinetics of infection in host tissues and to assess the efficacy of drugs, according to their pharmacokinetics and tissue distribution.The relevance of results obtained in animal models of congenital toxoplasmosis and of chrorioretinitis is more questionable, due to the marked differences between the mode of infection in humans and in animais. Experiments performed in primates provided valuable informations for the management of therapy of congenital toxoplasmosis but were of limited interest for ocular toxoplasmosis. The pathogeny of toxoplasmic encephalitis is still poorly understood, and no experimental model is fully satisfactory to produce focal encephalitic lesions as observed in immunocompromised humans. Acute infections with highly virulent strains induce disseminated infection with major pulmonary and brain involvement, and thus can be used to assess the efficacity of drugs in these tissues. Direct inoculation of tachyzoites into brain tissue can induce focal encephalitis but this model is of difficult use for large scale studies. Although cellular immunity is mainly responsible for the control of toxoplasmosis at the chronic stage, administration of immunosuppressive drugs does not usually resuit in focal brain reactivation; such reactivation can only be obtained using antibodies against CD8 and CD4 Τ lymphocytes or interferon gamma. Another expe rimental approach is the use of genetically immunodeficient ani mais : these models are of limited interest for pharmacological research since infection of nude or Τ depleted mice usually results Résumé :Toxoplasma

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Clindamycin Effects on Experimental Ocular Toxoplasmosis in the Rabbit

Cited by 52 publications

References 9 publications

New micromethod to study the effect of antimicrobial agents on Toxoplasma gondii: comparison of sulfadoxine and sulfadiazine individually and in combination with pyrimethamine and study of clindamycin, metronidazole, and cyclosporin A

New micromethod to study the effect of antimicrobial agents on Toxoplasma gondii: comparison of sulfadoxine and sulfadiazine individually and in combination with pyrimethamine and study of clindamycin, metronidazole, and cyclosporin A

Toxoplasma gondii Infection Induces Gene Expression and Secretion of Interleukin 1 (IL-1), IL-6, Granulocyte-Macrophage Colony-Stimulating Factor, and Intercellular Adhesion Molecule 1 by Human Retinal Pigment Epithelial Cells

Modèles expérimentaux de Toxoplasmose. Applications Pharmacologiques

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