[Therapeutic study on biofilm of the urinary tract using a severely complicated bladder model (biofilm model of the urinary tract)--experimental study using an automatic simulator of urinary antimicrobial agent concentration, and clinical study].

For the purpose of conducting a therapeutic study on biofilm of the urinary tract, we devised a computer-controlled severely complicated bladder model (biofilm model of the urinary tract) enabling us to simulate the time-course of the concentration of antimicrobial agents in the urine. Using this model, we investigated clarithromycin (CAM), which has been reported to have anti-biofilm action, at concentrations close to its urinary levels at the time of clinical use in order to predict its effect on biofilm of the urinary tract. On the basis of those experimental results, we also conducted a clinical examination. The following results were obtained. 1. The action of ciprofloxacin (CPFX, MIC: 8 micrograms/ml) alone, which shows anti-P. aeruginosa activity, caused apparent elimination of P. aeruginosa from the model. However, regrowth of the microbes occurred when CPFX was removed from the bladder model. Moreover, the biofilm was not eliminated by the antimicrobial action of CPFX, and this was surmised to be the cause of the regrowth. 2. CAM (MIC: above 128 micrograms/ml), which has no anti-P. aeruginosa activity, was similarly tested as anti-biofilm agent when added alone to the biofilm model. The P. aeruginosa recovered to its initial concentration within 48 hours, but the biofilm disappeared due to the action of CAM. 3. The combined action of CPFX and CAM caused microbial elimination from the bladder model without microbial regrowth, even after these antimicrobial agents were removed from the bladder model. After the action of CPFX and CAM, the biofilm disappeared, and no microbial adherence was noted. 4. Measurement of time-course of the alginate content, which is the main component of P. aeruginosa biofilm, in the presence of CAM found that the alginate content decreased below the limit of detection after day 5. 5. The clinical study of complicated urinary tract infection revealed the microbial elimination rate and the efficacy rate to be higher in the combined CPFX-CAM administration group than in the CPFX-only administration group. 6. Based on the above results, we surmise that the combined use of an antimicrobial agent which is active against the causative microbe and anti-biofilm agent such as CAM will show some degree of efficacy in eliminating biofilm of the urinary tract.