Influence of etoposide and cyclophosphamide on the efficacy of cloxacillin and erythromycin in an experimental staphylococcal infection

Abstract

The effect of monocytopenia and granulocytopenia on the outgrowth of Staphylococcus aureus as well as on antibiotic efficacy was studied in an experimental thigh infection in mice. Pretreatment with etoposide reduced monocyte numbers in blood to 14% and those of granulocytes to 54% at the time of infection. Monocytopenia did not affect the proliferation of bacteria in the infected thigh or the reduction of bacterial numbers after treatment with cloxacillin or erythromycin. Pretreatment with cyclophosphamide reduced monocyte numbers to 15% and granulocyte numbers to 3%. This resulted in a marked increase in the number of bacteria at the site of infection and a decrease in the efficacy of antibiotic treatment.Cytostatic drugs have several effects that can impair host resistance (3), but the decrease in the number of circulating granulocytes is probably one of the most important factors, since it promotes infections and reduces the efficacy of the antibiotic treatment applied. Previous work has shown that in an experimental infection in irradiated mice, the outgrowth of bacteria is inversely related to the number of granulocytes in peripheral blood (4,8). Moreover, the efficacy of antibiotics is adversely affected by granulocytopenia. Although it is generally thought that monocytes do not play a major role in the defense against acute infections, the lack of experimental evidence led us to undertake the present study to compare the effects of two cytostatic drugs-etoposide, which induces monocytopenia, and cyclophosphamide, which induces both granulocytopenia and monocytopenia-on the antibiotic efficacy of cloxacillin and erythromycin in an experimental infection with Staphylococcus aureus.Etoposide , which was kindly donated by Bristol Myers (Weesp, The Netherlands), was dissolved in a specified vehicle and further diluted in phosphate-buffered saline (PBS; pH 7.2). The vehicle without etoposide was prepared by our hospital pharmacy according to the prescription of the manufacturer. Standard solutions of cyclophosphamide (Montedison, Rotterdam, The Netherlands) were prepared in PBS.A strain of S. aureus that was isolated from clinical material and that was serum resistant was stored in brain heart infusion broth (Oxoid Ltd., Basingstoke, England) at -70°C in a suspension containing about 109 bacteria per ml. Just before the start of each experiment, a vial of this suspension was rapidly thawed at 37°C. Cloxacillin (MIC, 0.25 ,ug/ml; 90.5% activity; Beecham, Amstelveen, The Netherlands) and erythromycin (MIC, 0.25 ,ug/ml; 98.0% activity; Abbott N.V., Amstelveen, The Netherlands) were dissolved in PBS.Short-term growth experiments were performed in vitro as described elsewhere (1). Male specific-pathogen-free Swiss mice (weight, 20 to 30 g) were used. Monocytopenia was induced by injecting a dose of 16 mg of etoposide per kg into a tail vein on days 1 and 3. Control animals received the * Corresponding author. same volume of vehicle alone. To induce granulocytopenia and monocytopenia, cyclophosphamide was injected i...

Etoposide Attenuates Zymosan-Induced Shock in Mice

“…Activated macrophages produce excessive amounts of TNF-a locally, underlaying different destructive processes in internal organs [17,18]. Etoposide is a cytostatic drug, known to deplete the monocyte/macrophage population in mice and rabbits [19,20]. It has recently been demonstrated that etoposide has a beneficial effect in collagen-induced arthritis.…”

Neutropenia induced in outbred mice by a simplified low-dose cyclophosphamide regimen: characterization and applicability to diverse experimental models of infectious diseases

“…sepsis) and allows close quantification of the intrinsic efficacy of antibiotics. Previous research on animal infection models using irradiated mice showed that bacterial growth is inversely related to the number of granulocytes in peripheral blood [ 21 , 22 ], and other authors demonstrated with the thigh infection model that there was a significant difference in CFU numbers at the site of infection between mice treated with CPM (250 mg/kg) and non-neutropenic mice [ 23 ].…”

Confocal laser scanning microscopic observation of glycocalyx production by Staphylococcus aureus in mouse skin: does S. aureus generally produce a biofilm on damaged skin?

“…As mice are well defended by PMNs against S. aureus invasion, 17 the animals in our previous studies 6,7 were made neutropenic by intraperitoneal administration of Cy 18 to reduce neutrophilic infiltration. Recently, we reported that a combination of roxithromycin and imipenem was a potentially effective treatment for S. aureus biofilm‐associated skin infections as roxithromycin can induce the invasion of PMNs into the biofilm 19 .…”