fortimicin-a-sulfate and Pseudomonas-Infections

KW-2228, a mutationally modified recombinant human granulocyte colony-stimulating factor (rhG-CSF), possesses some excellent properties such as high specific activity in stimulating granulocyte colony-formation in vitro, great biological stability in plasma, good pharmacokinetic profile and high potency in granulopoiesis in normal mice in vivo. Recently, the application of G-CSF against infectious diseases has been considered, and some animal experiments have been carried out to support such an application on human infectious diseases. In this paper, we examined combination effect of KW-2228 with various chemotherapeutic drugs in experimental infectious in mice. A combination effect of KW-2228 with ceftazidime (CAZ) was evaluated in a systemic infection with Pseudomonas aeruginosa in normal mice. Combination effects of KW-2228 with CAZ, astromicin and amphotericin B were also evaluated in experimental systemic infections caused by P. aeruginosa, Serratia marcescens and Candida albicans in immunosuppressed mice treated with cyclophosphamide. Synergistic effects were generally observed at KW-2228 doses from 1 to 5 micrograms per mouse with all combinations. We concluded that combination therapies of KW-2228 with various chemotherapeutic drugs in experimental infections in mice showed that it should be effective in normal and immunosuppressed host. These results of our laboratory studies suggest that KW-2228 in combination with antibiotics would be useful in the clinical treatment of microbial infections. Recently, clinical efficacy studies of KW-2228 have been initiated in Japan.

Topics: Aminoglycosides; Amphotericin B; Animals; Anti-Bacterial Agents; Candidiasis; Ceftazidime; Drug Therapy, Combination; Granulocyte Colony-Stimulating Factor; Male; Mice; Mice, Inbred Strains; Neutropenia; Pseudomonas Infections; Recombinant Proteins; Serratia Infections

A modified recombinant human granulocyte colony-stimulating factor (rhG-CSF), KW-2228, has some excellent properties such as high specific activity in stimulating granulocyte colony-formation in vitro, great biological stability in plasma, good pharmacokinetic profile and high potency in granulopoiesis in normal mice in vivo. Recently, the application of G-CSF against infectious diseases has been considered, and some animal experiments have been carried out to support its clinical applications. Patients with underlying diseases such as leukemia and cancer often have recurrent infections because of reduced numbers or functions of neutrophils, which mediate an early stage of host defense. In out present study, we established a new method to evaluate in vivo potency of G-CSF in colon 26 tumor-bearing mice. By using the method, we examined combination effects of KW-2228 with aminoglycoside antibiotics against a systemic infection caused by Pseudomonas aeruginosa. KW-2228 (1 microgram/mouse/day) was administered (s.c.) once a day for 4 days before the bacterial infection was introduced in colon 26 tumor-bearing mice receiving cyclophosphamide 3 days after the transplantation of tumor. Antibiotics were administered (s.c.) 2 hours after the introduction of the bacterial infection. ED50 of gentamicin (GM) alone and that of the combination with KW-2228 were 40.7 mg/kg and 3.6 mg/kg, respectively. ED50 of astromicin (ASTM) alone and that of the combination with KW-2228 were 386 mg/kg and 17.8 mg/kg, respectively. Thus the combination therapy of KW-2228 with GM or ASTM exhibited excellent protective effects in comparison to the treatment with antibiotic alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Cyclophosphamide; Drug Therapy, Combination; Gentamicins; Granulocyte Colony-Stimulating Factor; Male; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neoplasms, Experimental; Neutropenia; Pseudomonas Infections; Recombinant Proteins

The optimal dosing regimens and combination effects of gentamicin (GM), or astromicin (ASTM) and piperacillin (PIPC) against P. aeruginosa in a mouse thigh infection model were studied. Therapeutic efficacy of the single regimen and duration of a postantibiotic effect (PAE) of GM and ASTM were dose dependent, but those of PIPC were dose independent. The optimal dosing of GM or ASTM with the same total daily dose was less frequent, but that of PIPC was frequent. Initial killing (the delta log bacteria changed at 2 hour after starting of the therapy) was the main significant pharmacokinetic and pharmacodynamic parameter determining efficacy for GM, whereas the time that serum levels exceeded the minimum inhibitory concentration (T greater than MIC) was the major parameter for PIPC. The optimal synergistic combinations of GM or ASTM plus PIPC in various dosing intervals with the same total daily dose were observed in the less frequent regimens of GM or ASTM and the frequent regimen of PIPC. The differences of therapeutic efficacy were observed in twice a day regimens of GM or ASTM plus PIPC in three dosing schedules (GM or ASTM before PIPC, with PIPC simultaneously, after PIPC). The effect of GM or ASTM after PIPC exposure was inferior to that of the other dosing regimens. These findings suggest that it may be possible to use the optimal regimens of aminoglycosides and beta-lactams against clinical P. aeruginosa infections in humans. Further careful, controlled clinical trials are needed.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Gentamicins; Mice; Mice, Inbred ICR; Piperacillin; Pseudomonas Infections

The participation of tumor necrosis factor (TNF) and lipopolysaccharide (LPS) in Pseudomonas aeruginosa (Pa) infection was examined. The lethal challenge of Pa or TNF and LPS injection could be prevented by pretreatment with anti-TNF antibody, polymyxin B, ONO 1078, or Shosaiko-to. The combined effects of TNF and LPS may be deeply related to the lethality of Pa infection. The activities of leukotriene(LT) C4/D4/E4 or platelet activating factor (PAF) were also related to the lethality of Pa infection, probably due to the subsequently produced TNF which acts in combination with LPS. Activating the host defence mechanism with biological response modifiers like Chinese medicines was effective against Pa infection. One mechanism could involve an activity as an LT inhibitor or PAF antagonist. Following the administration of TNF and/or LPS, the serum levels of arachidonic cascade products underwent various changes. With a combination of TNF and LPS, there was a synergistic increment of prostaglandins, thromboxane, and LT. Following pretreatment with Shosaiko-to, suppression of LTs was dominant even with the combination of TNF and LPS, which might be related to the lethality of the infection or combined TNF with LPS.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Antibodies; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arachidonic Acid; Arachidonic Acids; Cephamycins; Chromones; Drug Synergism; Drugs, Chinese Herbal; Female; Leukotriene Antagonists; Leukotriene E4; Lipopolysaccharides; Mice; Mice, Inbred Strains; Platelet Activating Factor; Polymyxin B; Pseudomonas Infections; Recombinant Proteins; SRS-A; Tumor Necrosis Factor-alpha

Combination therapy of antibiotics and human intravenous gamma immunoglobulin (IgG) prepared for intravenous use is widely applied to control severe infectious diseases. To evaluate the antimicrobial activity of astromicin (ASTM, Fortimicin), the combination effect of ASTM with IgG was investigated in vitro and in mice with experimental infection (i.p.) with Pseudomonas aeruginosa BMH No. 1. Sulfonated IgG (Venilon, VL), and plasmin-treated IgG (Venoglobulin, VG) were administered (i.v., 42 mg/kg) 90 minutes before the infection, and ASTM was administered (s.c.) 60 minutes after the infection. Polyethyleneglycol-treated IgG (Venoglobulin-I, VG-I) was administered (i.v., 42 mg/kg) 90 minutes before or 60 minutes after the infection. ED50 of ASTM alone and that of combination with VL were 31.0 mg/kg and 24.2 mg/kg, respectively. ED50 of ASTM alone and that of combination with VG were 38.9 mg/kg and 15.5 mg/kg, respectively (P less than 0.05). When VG-I was administered prophylactically, ED50 of ASTM alone and that of combination were 51.5 mg/kg and 13.6 mg/kg, respectively (P less than 0.05). When VG-I was administered simultaneously with ASTM at 60 minutes after the infection, ED50 of ASTM alone and that of combination were 28.5 mg/kg and 15.5 mg/kg, respectively (P less than 0.05). Prophylactic effect of VG-I in immunosuppressed mice treated with cyclophosphamide (250 mg/kg, i.p., 4 days before infection) was also examined. ED50 of ASTM alone and that of combination were 126.1 mg/kg and 46.1 mg/kg, respectively (P less than 0.05). VG-I also enhanced in vitro synergistic bactericidal activity of ASTM and fresh mouse serum.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Drug Therapy, Combination; Escherichia coli Infections; gamma-Globulins; Injections, Intravenous; Male; Mice; Pseudomonas Infections

Astromicin (ASTM, Fortimicin) is a pseudodisaccharide aminoglycoside antibiotic. The ASTM exhibited excellent activity against Gram-positive and Gram-negative bacteria but was only weakly active against Pseudomonas aeruginosa. In vitro synergistical activities of ASTM combined with beta-lactam antibiotics have been reported against P. aeruginosa previously. In this paper, we investigated the in vivo combination efficacies of ASTM and beta-lactam antibiotics (latamoxef (LMOX), cefoperazone (CPZ), piperacillin (PIPC) and cefsulodin (CFS) against experimental infection with P. aeruginosa in both normal and immunosuppressed mice. In normal mice, the combination of ASTM with these beta-lactam antibiotics produced significantly greater protective effects than the single use of individual antibiotics against both strains of P. aeruginosa BMH No. 1 and E-2. In mice immunosuppressed with cyclophosphamide, the combination of ASTM with LMOX or CFS also exhibited synergistic protective effects against P. aeruginosa BMH No. 1, but PIPC and CPZ did not. From the above results, the combination therapy of ASTM with beta-lactam antibiotics appeared to be effective against experimental infections with P. aeruginosa in mice.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; beta-Lactams; Drug Synergism; Drug Therapy, Combination; Immune Tolerance; Male; Mice; Pseudomonas aeruginosa; Pseudomonas Infections

Synergistic activity of astromicin and an antipseudomonal beta-lactam antibiotic such as piperacillin, cefsulodin or carbenicillin against Pseudomonas aeruginosa was demonstrated in vitro and in vivo. Synergy in vitro was observed more often when astromicin was combined with piperacillin or cefsulodin than when it was combined with carbenicillin. The combination of astromicin with piperacillin showed a bactericidal activity against Pseudomonas aeruginosa at a bacteriostatic concentration of each antibiotic alone. The synergy observed in vitro was reproduced against experimental mouse infections, and the astromicin-piperacillin or cefsulodin combination produced significantly greater protective effects than the single use of individual antibiotics.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; beta-Lactams; Drug Synergism; Male; Mice; Mice, Inbred Strains; Pseudomonas aeruginosa; Pseudomonas Infections