[Prerequisites for enhancement of the efficacy of fosfomycin by glucose-6-phosphate in treatment of experimentally infected animals (author's transl)].
In chemotherapy of otherwise fatally infected mice (intraperitoneally) the effective dose50 (ED50) of fosfomycin (2 single doses, subcutaneous application 1 and 6 h post infect.) was decreased significantly by supplementing the antibiotic solution with 100 mg glucose-6-phosphate (G-6-P) per kg animal and per injection if also the MIC of the infecting strain (Klebsiella oxytoca and K. aerogenes II) was lowered by addition of G-6-P (25 mg/l) to the nutrient medium (Table 1 and 2). With strains not exhibiting any influence on the MIC no such effect was observed (Table 1). From this it is concluded that the enhancement of antimicrobial activity of fosfomycin in vivo is based on the same mechanism as in vitro. This mechanism is the initiation of a second route of transportation into the bacterial cell (7), the hexose-6-phosphate transport system that apparently is inducible not only in vitro but also in vivo. Blood levels of G-6-P sufficient or above to induce this system in vitro (5 mg/l) were being held with doses of 100 mg/kg body weight in dogs during 70 to 120 min (Fig. 3) and 45 to 70 min (Fig. 4) when applied subcutaneously or intravenously respectively. These periods of contact area adequate to induce a considerable decrease of the MIC. With the strain used (K. oxytoca) the MIC of 128 mg/l was lowered by contact with G-6-P during 60 or 120 min to 16 or 8 mg/l respectively (Fig. 5). For full induction of the hexose-6-phosphate system resulting in a MIC of 2 mg/l however, 8 h were necessary. From the above findings it is concluded that clinical studies are necessary. As G-6-P is a (short-lived) physiological product of cell metabolism and nontoxic such studies are justifiable in cases where therapeutic use of fosfomycin can be regarded as an indication.
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001692:Biological Transport; D004285:Dogs; D004357:Drug Synergism; D005578:Fosfomycin / Q000627:therapeutic use*; D019298:Glucose-6-Phosphate; D005958:Glucosephosphates / Q000097:blood / Q000494:pharmacology*; D006600:Hexosephosphates / Q000378:metabolism; D007709:Klebsiella / Q000187:drug effects; D007710:Klebsiella Infections / Q000188:drug therapy*; D007711:Klebsiella pneumoniae / Q000187:drug effects; D008297:Male; D051379:Mice; D011512:Proteus Infections / Q000188:drug therapy*; D011513:Proteus mirabilis / Q000187:drug effects
D000900:Anti-Bacterial Agents; D005958:Glucosephosphates; D006600:Hexosephosphates; D005578:Fosfomycin; D019298:Glucose-6-Phosphate
Voraussetzungen für die Wirkungssteigerung von Fosfomycin durch Glukose-6-Phosphat in der Therapie von tierexperimentellen Infektionen.