In vitro activity of sitafloxacin (STFX) and various oral antimicrobial agents against bacterial isolates recovered from clinial specimens between January and December 2012, at different healthcare facilities in Japan was evaluated. A total of 1,620 isolates including aerobi and anaerobic organisms were available for the susceptibility testing using the microbroth dilution methods recommended by Clinical and Laboratory Standards Institute.

The minimum inhibitory concentration of STFX at which 90% of isolates (MIC₉₀) was 0.5𝜇g/mL for methicillin-susceptible Staphylococcus aureus and was 2 times lower than that of garenoxaciin (GRNX), 4 times lower than that of moxifloxacin (MFLX), and 16 times lower than that of levofloxacin (LVFX). STFX inhibited the growth of all the isolates of Streptococcus pneumoniae at 0.06𝜇g/mL or less. The MIC₉₀ of STFX was 0.03𝜇g/mL and was 2 times lower than that GRNX, 8 times lower than that of MFLX, and 32 times lower than that of LVFX. The MIC₉₀ of STFX was 2𝜇g/ML for Enterococcus faecalis, and was 4 times lower than that of GRNX, 8 times lower than that of MFLX, and 32 times lower than that of LVFX. The MIC₉₀ of STFX for Escherichia coli was 2𝜇g/mL, and the MIC₉₀s of other 10 species of Enterobacteriaceae which were the lowest values of quinolones tested ranged from 0.03 to 1𝜇g/mL. The MIC₉₀ of STFX for Pseudomonas aeruginosa isolates recovered from urinary infections was 4𝜇g/mL and was 32 times lower than those of GRNX, MFLX, LVFX. The MIC₉₀ of STFX for P. aeruginosa isolates recovered from respiratory infections was 4𝜇g/mL and was 8 to 16 times lower than those of GRNX, MFLX, and LVFX. STFX inhibited the growth of all the isolates of Haemophilus influenzae at 0.004𝜇g/mL or less, and was 4 times lower than that of GRNX, 16 times lower than thatof MFLX, and 8 times lower than that of LVFX. The MIC₉₀ of STFX was 0.015𝜇g/mL for Moraxella catarrhalis, and was equal to that of GRNX, 4 times lower than those of MFLX and LVFX. The MIC₉₀s of STFX ranged from 0.03 to 0.25𝜇g/mL for all the species of anaerobic bacteria and were the lowest values of all the antimicrobial agents tested.

In conclusion, the activity of STFX against Gram-positive cocci was comparable or superior to those of GRNX, MFLX and LVFX. STFX showed the most potent activity against Gram-negative bacteria and anaerobic bacteria of all the antimicrobial agents tested in this study.

From October 2006 to September 2007, we collected the specimen from 356 patients with lower respiratory tract infections in 14 institutions in Japan, and investigated the susceptibilities of isolated bacteria to various antibacterial agents and patients’ characteristics. Of 414 strains that were isolated from specimen (mainly from sputum) and assumed to be bacteria causing in infection, 407 strains were examined. The isolated bacteria were: Staphylococcus aureus 64, Streptococcus pneumoniae 96, Haemophilus influenzae 87, Pseudomonas aeruginosa (non-mucoid) 52, P. aeruginosa (mucoid) 11, Klebsiella pneumoniae 20, and Moraxella catarrhalis 44.

Of 64 S. aureus strains, those with 2𝜇g/ml or less of MIC of oxacillin (methicillinsusceptible S. aureus: MSSA) and those with 4𝜇g/ml or more of MIC of oxacillin (methicillinresistant S. aureus: MRSA) were 27 (42.2%) and 37 (57.8%) strains, respectively. Against MSSA, imipenem had the most potent antibacterial activity and inhibited the growth of all strains at 0.063𝜇g/ml or less. Against MRSA, vancomycin and linezolid showed the most potent activity and inhibited the growth of all the strains at 1𝜇g/ml. Carbapenems showed the most potent activities against S. pneumoniae and in particular, panipenem inhibited the growth of all the strains at 0.063𝜇g/ml or less. Imipenem and faropenem also had a preferable activity and inhibited the growth of all the strains at 0.125 and 0.5𝜇g/ml, respectively. In contrast, there were high-resistant strains (MIC: over 128𝜇g/ml) for erythromycin (45.8%) and clindamycin (20.8%). Against H. influenzae, levofloxacin showed the most potent activity and its MIC₉₀ was 0.063𝜇g/ml or less. Meropenem showed the most potent activity against P. aeruginosa (mucoid) and its MIC₉₀ was 0.5𝜇g/ml. Against P. aeruginosa (non-mucoid), tobramycin had the most potent activity and its MIC₉₀ was 2𝜇g/ml. Against K. pneumoniae, cefozopran was the most potent activity and inhibited the growth of all the strains at 0.063𝜇g/ml or less. Also, all the antibacterial agents except ampicillin generally showed a potent activity against M. catarrhalis and the MIC₉₀ of them were 2𝜇g/ml or less.

The approximately half the number (50.6%) of the patients with respiratory infection were aged 70 years or older. Bacterial pneumonia and chronic bronchitis accounted for 49.2% and 28.1% of all the respiratory infections, respectively. The bacteria frequently isolated from the patients with bacterial pneumonia were S. pneumoniae (29.2%), S. aureus (20.8%), and H. influenzae (12.9%). H. influenzae (25.0%) and P. aeruginosa (21.7%) also were frequently isolated from the patients with chronic bronchitis. Before the antibacterial agent administration, the bacteria frequently isolated from the patients were S. pneumoniae (27.5%) and H. influenzae (22.5%). The bacteria frequently isolated from the patients treated with macrolides was P. aeruginosa, and its isolation frequently was 39.4%.

Population pharmacokinetic analysis was conducted on cefditoren pivoxil (CDTR-PI, Brand name: MEIACT, Meiji Seika Pharma Co., Ltd.), a third generation oral antibiotic, using plasma concentrations of cefditoren (CDTR, total number of sampling points: 578) obtained from pediatric patients (153 subjects, dose: 5.62±1.62 mg/kg) after CDTR-PI administration as well as demographic data of those subjects. NONMEM (Ver. VI Level 2.0) was used as software. The first-orer confitional estimation (FOCE) method without interaction was employed as algorithm. A one-compartment model with first-order absorption was used as pharmacokinetic model. As the result of analysis, the following population pharmacokinetic parameters were obtained for CDTR.

Population mean parameters: ka (hr^-1)=0.527, CL/F (L/hr/kg)=-0.474×Scr+0.82, Vd/F (L/kg)=0.77, Tlag (hr)=0.282×(1+0.435×NAT) (NAT: 0=Japan, 1=USA, interindividual variability: ω(ka)=17.23%, ω(CL/F)=33.02%, ω(Vd/F)=86.66%, intraindividual residual variability: σ=0.428𝜇g/mL.

Bayes estimation was carried out for each subject using the final model to calculate secondary parameters such as C_max, T_max, AUC, and t_1/2. C_max and AUC increased significantly with dose. However, T_max was approximately 2 hours and t_1/2 was approximately 1 hour at any dose level, showing no significant dose-dependent changes. When CDTR-PI was administered orally to a child, a significant increase was noted in plasma CDTR concentrations, suggesting high efficacy. In addition, pharmacokinetics of CDTR were simulated in patients with renal impairment using the final model. As a result, a delay in T_max and increases in AUC, C_max, and t_1/2 were presumed with increased Scr, and the degrees of such increases were also quantitatively estimated.

As mentioned above, the population pharmacokinetic parameters of CDTR were obtained, which is sure contribute to simulation of its plasma concentrations in patients with various backgrounds and to speculation of its efficacy and safety.