In vivo study assessed meropenem and amikacin combination therapy against carbapenem-resistant and carbapenemase-producing Enterobacteriaceae strains.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE), especially for carbapenemase-producing Enterobacteriaceae (CPE), is an emerging cause that pose a significant threat to public health. However, efficient therapy has not been established. We assessed the antimicrobial efficacy of meropenem (MEPM) and amikacin (AMK) combination therapy. MATERIAL AND METHODS: Total eight isolates of Escherichia coli or Klebsiella pneumoniae, including CRE and/or CPE have carbapenemase genes were used. The relationship between phenotype and in vivo efficacy was assessed in neutropenic murine thigh infection model. Efficacy was determined using the change in bacterial density and survival rate. RESULTS: The combination therapy showed enhanced antimicrobial activities against CRE+/CPE+ and CRE+/CPE-K. pneumoniae isolates than MEPM monotherapy (0.63 ± 0.04 vs. 2.56 ± 0.24 ⊿log10 cfu/mL, p < 0.05; -1.05 ± 0.15 vs. -0.48 ± 0.30 ⊿log10 cfu/mL, p < 0.05). Likewise, the combination therapy showed enhanced antimicrobial activities against CRE+/CPE+ and CRE+/CPE-E. coli isolates than MEPM monotherapy (0.90 ± 0.68 vs. 1.86 ± 0.23 ⊿log10 cfu/mL, p < 0.05; -1.81 ± 0.06 vs. -0.88 ± 0.23 ⊿log10 cfu/mL, p < 0.05). Also, combination therapy group showed similar to higher survival rates in CRE + E. coli infection mice, compared to MEPM monotherapy group. CONCLUSION: Our results are the first supportive data to threat CRE infections with combination therapy of MEPM and AMK with in vivo model. The current results verify the promising utility of the combination therapy with MEPM and AMK against CRE isolates with a wide range of MEPM MICs.

Oral L-citrulline supplementation improves erectile function and penile structure in castrated rats.

OBJECTIVES: To investigate the efficacy of oral L-citrulline for erectile dysfunction and penile structure disruption in a rat model. METHODS: Male Wistar-ST rats aged 15 weeks were randomly divided into three groups as follows: sham-operated rats (control group), surgically castrated rats (castrated group) and surgically castrated rats subsequently treated with 2% L-citrulline water (castrated + L-citrulline). At 4 weeks postoperative, erectile function was assessed based on intracavernous pressure changes, followed by electrostimulation of cavernous nerves and calculation of maximum intracavernous pressure/mean arterial pressure. Penile structure was evaluated by Masson's trichrome staining and the smooth muscle-to-collagen ratio was calculated. The serum bioavailable testosterone, L-arginine, L-citrulline, N(G),N(G) -dimethylarginine and nitrogen oxide levels were evaluated. RESULTS: The bioavailable testosterone concentrations were decreased in the castrated and castrated + L-citrulline groups compared with the control group at 4 weeks after surgery. The intracavernous pressure-to-mean arterial pressure and smooth muscle-to-collagen ratios were significantly decreased in the castrated group compared with the control group, but significantly increased in the castrated + L-citrulline group compared with the castrated group. The serum L-citrulline, L-arginine and N(G),N(G)-dimethylarginine levels, and the L-arginine-to-N(G),N(G)-dimethylarginine ratios were significantly increased in the castrated +L-citrulline group compared with the castrated group. The serum nitrogen oxide levels were increased in the castrated + L-citrulline group compared with the castrated group. CONCLUSIONS: Oral L-citrulline can improve the erectile response to electric stimulation of cavernous nerve and penile structure in castrated rats.

Oral L-citrulline supplementation improves erectile function in rats with acute arteriogenic erectile dysfunction.

INTRODUCTION: Oral L-citrulline supplementation increases serum L-arginine levels more efficiently than L-arginine itself and increases nitric oxide (NO) production. AIM: To investigate whether oral L-citrulline supplementation improves erectile function in rats with acute arteriogenic erectile dysfunction (ED). METHODS: We divided 8-week-old male Wistar-ST rats into 3 groups: sham-operated rats (control group), arteriogenic ED rats who underwent ligation of both internal iliac arteries (ligation group), and arteriogenic ED rats receiving oral 2% L-citrulline water supplementation (citrulline group). Citrulline water was given to arteriogenic ED rats for 3 weeks from 1 week after surgery. Erectile function was evaluated by maximum intracavernous pressure/mean arterial pressure (ICP/MAP) ratios via cavernous nerve stimulation at 4 weeks after surgery. Then, the penises were resected, stained with Masson's trichrome, and observed microscopically. Serum nitrogen oxides (NOx) levels were measured by high-performance liquid chromatography. Bonferroni's multiple t-test was used for statistical analysis. MAIN OUTCOME MEASURES: The main outcome measures were changes in ICP/MAP, smooth muscle (SM)/collagen ratios, and NOx levels following L-citrulline supplementation. RESULTS: The ICP/MAP ratio in the ligation group was significantly lower than that in the control group (P<0.05), denoting ED. The ICP/MAP ratio of the citrulline group was significantly higher than that of the ligation group (P<0.05), indicating ED amelioration. Levels of NOx in the ligation group were significantly lower than in the control group (P<0.05), while those in the citrulline group were significantly higher than in the ligation group (P<0.05). SM/collagen ratios in the ligation group were significantly lower than in the control group (P<0.05), while ratios in the citrulline group were significantly higher than those in the ligation group (P<0.05). CONCLUSIONS: Oral L-citrulline supplementation improved ICP/MAP and SM/collagen ratios and increased NOx. Therefore, oral L-citrulline supplementation might be a useful novel therapy for acute arteriogenic ED.