Theoretical Studies on Antimicrobial Chemotherapy Employing aUrinary Tract Experimental Infection Model with an Automatic Antimicrobial Agent Urinary Concentration Simulator : Comparison with Clinical Results

Using a device for computer-controlled simulation of the pattern of change in the urinary concentrations of antimicrobial agents after their administration, experimental models of uncomplicated, moderately complicated and severely complicated urinary tract infections (UTI) were prepared. Employing those models, we investigated the usefulness of single-dose therapy in relation to uncomplicated cystitis. For moderately complicated UTI, we estimated the MIC breakpoints for antimicrobial agents, and we then considered whether or not it was possible to estimate the efficacy of an administration method even before its actual clinical application. In addition, we carried out fundamental studies in relation to therapeutic countermeasures for severely complicated UTI, which may involve the formation of a biofilm. Our results can be summarized as follows. 1. Theoretical Consideration of the Usefulness of Single-Dose Therapy for Uncomplicated Cystitis 1) Using the model of uncomplicated UTI, ofloxacin acted on the bacteria in the model bladder in accordance with the pattern of change in the urinary concentration of the drug when a single dose of 100 mg was administered. It was found that the bacteria were eradicated by an ofloxacin concentration of 4 μg/ml. 2) Ninety percent of the causative bacteria of uncomplicated cystitis are Escherichia coli, and most strains of those bacteria are sensitive to concentrations of 4 μg/ml or less (i. e., MIC distribu-tion) of oral preparations of new quinolone antimicrobial agents. It was thus surmised that excel-lent therapeutic results can be achieved by single-dose therapy for uncomplicated cystitis with these antimicrobial agents. 2. Antimicrobial Chemotherapy of Moderately Complicated UTI 1) The experimental breakpoint was obtained using the model of moderately complicated UTI. It was found that, when the administration method was the same, the value for the experimental breakpoint was almost the same as the clinical breakpoint calculated from the results of clinical therapy. 2) The relationship between the clinical breakpoint and the actual therapeutic results was inves-tigated. It was demonstrated that the microbial eradication rate increased in direct proportion to the degree to which the clinical breakpoint covered the MIC distribution of the causative microbe. The efficacy rate showed a similar tendency to increase as the degree of coverage of the MIC distri-bution increased. 3) On the basis of the findings described above, we proposed the following as a method for estimating an effective antimicrobial administration method. First, based on the antimicrobial potency (MIC distribution) shown by an antimicrobial agent in relation to the microbes isolated from the urinary tract, the drug concentration that will cover 70% or more of the isolates' MIC distribution prior to the start of clinical therapy should be determined. Then, using the authors' experimental model, an administration method which will yield that value as the experimental brea-kpoint should be identified. Finally, by carrying out clinical therapy through application of that administration method, we think that it should be possible to achieve satisfactory microbial eradica-tion and efficacy rates. 3. Therapeutic Studies of Severely Complicated UTI-Countermeasures for Biofilm-Forming Urinary Tract Microbes- 1) Ciprofloxacin showed antimicrobial activity against Pseudomonas aeruginosa even when em-ployed alone. This drug eradicated bacteria suspended in the model bladder, but when the drug was removed from the system, bacteria that were concealed inside the biofilm showed renewed growth. 2) Conversely, clarithromycin employed alone showed no antimicrobial activity against P. aer-uginosa, and introduction of this agent to the model bladder caused almost no change in the bacte-rial count therein. However, after clarithromycin acted on this system, it was found that the glycocalyx of the biofilm had disappeared. 3) Accordingly, when ciprofloxacin and clarithromycin were both introduced into the experimen-tal model, no regrowth of the P. aeruginosa was observed to occur even after the antimicrobial activity was removed from the system. It was surmised that the activity of clarithromycin resulted in elimination of the glycocalyx, thereby allowing the antimicrobial activity of ciprofloxacin to be expressed even against the bacterial cells in the biofilm. 4) Therefore, these studies provided experimental evidence that combined use of an anti-biofilm drug (such as clarithromycin) with an antimicrobial agent showing antimicrobial activity against the causative microbes will achieve a certain degree of therapeutic efficacy even in the treatment of severely complicated UTI. On the basis of the experimental results described above, the authors surmise that it should be possible to estimate a theoretically effective method for administration of antimicrobial agents for the treatment of clinical UTI cases by employing our in vitro experimental UTI models to carry out simulation studies and analyze the properties of antimicrobial agents under conditions that are close the actual clinical situation