[Susceptibility of clinically-isolated bacteria strains to respiratory quinolones and evaluation of antimicrobial agent efficacy by Monte Carlo simulation].

Respiratory quinolones (RQs) are broad-spectrum antimicrobial agents used for the treatment of a wide variety of community-acquired and nosocomial infections. However, bacterial resistance to quinolones has been on the increase. In this study, we investigated the predicted efficacy of RQs for various strains of 9 bacterial species clinically isolated at our university hospital using the Monte Carlo simulation (MCS) method based on pharmacokinetics/pharmacodynamics modeling. In addition, the influence of the patients' renal function on the efficacy of RQs was evaluated. We surveyed antimicrobial susceptibility testing of 9 bacterial species (n = number of strains) [Streptococcus pneumoniae (n = 15), Streptococcus pyogenes (n = 14), Streptococcus agalactiae (n = 19), methicillin-susceptible Staphylococcus aureus (MSSA) (n = 24), Escherichia coli (n = 35), Haemophilus influenzae (n = 17), Klebsiella pneumoniae (n = 14), Pseudomonas aeruginosa (n = 31), and Moraxella catarrhalis (n = 11)] to 4 RQs [garenoxacin (GRNX), levofloxacin (LVFX), sitafloxacin (STFX), and moxifloxacin (MFLX)]. We found that compared with the other RQs, Gram-positive cocci was most resistant to LVFX, and that the minimum inhibitory concentration (MIC90) values for S. pneumoniae, S. pyogenes, S. agalactiae, and MSSA were high (2, 16, > 16, and 8 µg/mL, respectively). In regard to Gram-negative rods, the susceptibility of E. coli to RQs was found to be decreased, with the MIC90 values of GRNX, LVFX, STFX, and MFLX being > 16, 16, 1, and 16 µg/mL, respectively. MCS revealed that the target attainment rate of the area under the unbound concentration-time curve divided by the MIC90 (ƒ · AUC/MIC ratio), against S. pneumoniae was 86.9-100%, but against E. coli was low (52.1-66.2%). The ƒ · AUC/MIC target attainment rate of LVFX against S. pneumoniae, S. pyogenes, and S. agalactiae tended to decrease due to increased creatinine clearance, and that of LVFX and STFX against MSSA also tended to decrease. The findings of this study suggest that the drug susceptibility distribution of each RQ varies, even within the same bacterial species, and that the expected efficacy also varies between the drugs. Moreover, the influence of the patient's renal function on the efficacy differed among the 3 renal excretory drugs (GRNX, LVFX, and STFX), thus suggesting that the efficacy also differs. In conclusion, the findings of this study show that for the administration of RQs, it is desirable to select agents in consideration of surveyed sensitivity within the population and the pharmacokinetic characteristics.

Assessment of airway sensitization potential of inhaled trimellitic anhydride by monitoring the elicitation phase in a mouse model.

While several skin sensitization tests have been developed and are available as regulatory toxicity tests at present, no such tests for the airway have been established. We have been developing an animal model by introducing an elicitation phase into the mouse IgE test (MIGET) for assessment of agricultural chemicals with airway sensitization potential. In the current study, trimellitic anhydride (TMA), a representative low molecular weight (LMW) airway sensitizer, was examined for its sensitization potential in our mouse model. Mice were epicutaneously sensitized to TMA on Days 0 and 7, followed by an inhalation challenge with TMA dust at high or low concentration on Day 14. Groups of different sensitization route including inhalation were established for comparison of effectiveness of immunization. Non-sensitized animals challenged with TMA dust served as controls. An ovalbumin-sensitized and -challenged animals constituted a reference group (OVA). Enhanced pause (Penh) was measured as an indicator of airflow disturbance by using a restrained flow whole body plethysmograph. The high TMA concentration group exhibited an augmented Penh, elevated IgE values, and pronounced influx of eosinophils into their BAL fluid and minor infiltration of inflammatory cells including eosinophils into the lung. The low TMA concentration group also exhibited elevated IgE values and a less frequent occurrence of minor lung inflammation, but these were not accompanied by any positive responses in Penh and BAL fluid. Almost all mice in the other immunization route groups exhibited negative responses for any parameter examined. The OVA group showed no changes in breathing pattern during the inhalation challenge despite presenting a high total serum IgE value. These results suggest that this mouse model may be useful for assessment of airway sensitization potential of agrochemicals, but by way of epicutaneous sensitization.