Chronic granulomatous disease: uptake and intracellular activity of fosfomycin in granulocytes.
In chronic granulomatous disease (CGD) polymorphonuclear leukocytes (PMN) are unable to kill phagocytized catalase-positive bacteria. Therefore, patients with CGD are prone to infections and dependent on antimicrobial agents able to penetrate PMN membranes and to act intracellularly. Owing to their good lipid solubility, trimethoprim/sulfamethoxazole and rifampicin passively diffuse the membrane. In contrast, fosfomycin is transported actively into the cell. In normal PMN, it reaches cellular-to-extracellular ratios of 1.83 after 15 min, in CGD-PMN 2.18 after 30 min. At concentrations between 16 and 200 mg/liter, fosfomycin was able to kill staphylococci surviving within CGD-PMN, thus compensating for the bactericidal deficiency in CGD. A combination of low concentrations of fosfomycin (8 mg/liter) plus rifampicin (0.06 mg/liter) was more effective at the intracellular level than either agent alone. Apart from a stimulation of PMN-chemiluminescence of yet unknown significance, the agent did not interfere with other neutrophil functions. Clinical investigations are indicated to study whether fosfomycin can be added to the small number of antibiotics useful in CGD.
D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001424:Bacterial Infections / Q000188:drug therapy; D001693:Biological Transport, Active; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D005260:Female; D005578:Fosfomycin / Q000378:metabolism* / Q000627:therapeutic use; D006098:Granulocytes / Q000378:metabolism*; D006105:Granulomatous Disease, Chronic / Q000150:complications / Q000378:metabolism*; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism; D010406:Penicillins / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D012293:Rifampin / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects; D013420:Sulfamethoxazole / Q000378:metabolism; D014295:Trimethoprim / Q000378:metabolism
D000900:Anti-Bacterial Agents; D010406:Penicillins; D005578:Fosfomycin; D014295:Trimethoprim; D013420:Sulfamethoxazole; D012293:Rifampin