Feb THE JAPANESE JOURNAL OF ANTIBIOTICS ,4 2,4 2,4 2,3,4 2,3,4 2,3, ,3, Garenoxacin GRNX Levofloxacin LV

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1 Feb THE JAPANESE JOURNAL OF ANTIBIOTICS ,4 2,4 2,4 2,3,4 2,3,4 2,3, ,3, Garenoxacin GRNX Levofloxacin LVFX Sitafloxacin STFX Moxifloxacin MFLX Pharmacokinetics-Pharmacodynamics PK-PD GRNX LVFX STFX 9 Streptococcus pneumoniae 15 Streptococcus pyogenes 14 Streptococcus agalactiae 19 Methicillin-susceptible Staphylococcus aureus MSSA 24 Escherichia coli 35 Haemophilus influenzae 17 Klebsiella pneumoniae 14 Pseudomonas aeruginosa 31 Moraxella catarrhalis 11 LVFX S. pneumoniae S. pyogenes S. agalactiae MSSA MIC μg/ml E. coli GRNX LVFX STFX MFLX MIC μg/ml PK-PD f AUC/MIC S. pneumoniae % E. coli % CLcr S. pneumoniae S. pyogenes S. agalactiae LVFX MSSA LVFX STFX 3 GRNX, LVFX, STFX

2 28 28 THE JAPANESE JOURNAL OF ANTIBIOTICS 69 1 Feb ,2 Levofloxacin LVFX Moxifloxacin MFLX Garenoxacin GRNX Sitafloxacin STFX MFLX GRNX STFX 3 Prevotella Fusobacterium JANIS % % 13.1% 3.4% 9 Pharmacokinetics-Pharmacodynamics PK-PD 10 PK-PD f 11 PK-PD f AUC/MIC f Cmax/MIC PK-PD f AUC/MIC LVFX GRNX STFX MFLX PK-PD Monte Carlo simulation; MCS PK MIC PK-PD PK-PD

3 Feb THE JAPANESE JOURNAL OF ANTIBIOTICS Streptococcus pneumoniae 15 Streptococcus pyogenes 14 Streptococcus agalactiae 19 Methicillin-susceptible Staphylococcus aureus MSSA 24 4 Escherichia coli 35 Haemophilus influenzae 17 Klebsiella pneumoniae 14 Pseudomonas aeruginosa 31 1 Moraxella catarrhalis 11 β ESBL E. coli MIC Clinical and Laboratory Standards Institute CLSI 13 GRNX LVFX MFLX STFX 4 MIC 50 MIC μg/ml 12 AUC Dose F/CL GRNX LVFX STFX MFLX 75% 19 30% 20 39% 16 50% 21 f % PK-PD GRNX MFLX 400 mg 1 1 LVFX 500 mg 1 1 STFX 100 mg 1 1 PK-PD f AUC 0 24h /MIC f dose/clcr/ MIC 30 MSSA PK-PD CLcr ml/ min MCS MFLX CLcr 3. PK-PD MCS MCS Oracle Crystal Ball CL/ F 5,000 CLcr TANIGAWARA 16 STFX CLcr 75 ml/min 1. 2 S. pneumoniae MIC 50 /MIC 90 GRNX STFX 0.03/0.06 μg/ml MFLX 0.12/0.25 μg/ml LVFX 1/2 μg/ml S. pyogenes STFX 0.03/0.06 μg/ml GRNX 0.06/0.25 μg/ ml S. agalactiae STFX 0.06/0.5 μg/ml GRNX 0.06/2 μg/ml MSSA MIC 50 /MIC 90 STFX 0.03/0.25 μg/ml GRNX 0.03/1 μg/ml MFLX 0.06/2 μg/ml LVFX MIC

4 30 30 THE JAPANESE JOURNAL OF ANTIBIOTICS 69 1 Feb

5 Feb THE JAPANESE JOURNAL OF ANTIBIOTICS

6 32 32 THE JAPANESE JOURNAL OF ANTIBIOTICS 69 1 Feb S. pyogenes S. agalactiae MSSA MIC μg/ml 16 μg/ ml 8 μg/ml K. pneumoniae H. influenzae MIC E. coli MIC 90 GRNX 16 μg/ml LVFX MFLX 16 μg/ml P. aeruginosa MIC 90 STFX 0.5 μg/ml GRNX LVFX MFLX 4 μg/ml M. catarrhalis MIC 50 /MIC 90 GRNX STFX 0.015/ μg/ml LVFX MFLX 0.12/0.12 μg/ml 2. PK-PD PK-PD 30 MSSA GRNX LVFX STFX MFLX S. pneumoniae 100%, 86.9%, 100%, 100% S. pyogenes 93.9%, 67.5%, 94.6%, 78.6% S. agalactiae 60.5%, 47.6%, 59.9%, 58.7% MSSA 73.4%, 50.1%, 76.2%, 70.0% GRNX STFX 4 GRNX LVFX STFX MFLX 82.0% 63.0% 82.7% 76.8% LVFX E. coli 66.2% STFX 65.7% GRNX 65.1% LVFX 1. PK-PD 1 PK-PD

7 Feb THE JAPANESE JOURNAL OF ANTIBIOTICS MFLX 52.1% 6 H. influenzae STFX 94.7% GRNX LVFX MFLX % K. pneumoniae 93% GRNX LVFX 92.8% STFX 91.7% MFLX 20.5% M. catarrhalis K. pneumoniae GRNX STFX LVFX 100% 99% 91% MFLX 61.2% P. aeruginosa 6% PK-PD 20 ml/min LVFX 69.1% STFX 49.6% M. catarrhalis 80% CLcr 50 ml/min GRNX 200 mg/ STFX 50 mg/ LVFX 250 mg/ GRNX PK-PD LVFX PK-PD 3. PK-PD PK-PD GRNX STFX LVFX MCS 2 GRNX 400 mg/ STFX 100 mg/ LVFX 500 mg/ S. pneumoniae, S. pyogenes, S. agalactiae, MSSA LVFX CLcr 80 ml/min 80% GRNX STFX E. coli H. influenzae 80% K. pneumoniae CLcr 120 ml/min STFX 80% P. aeruginosa LVFX STFX CLcr 4 GRNX, LVFX, STFX, MFLX MCS PK-PD 3 GRNX, LVFX, STFX 9 S. pneumoniae S. pyogenes MSSA LVFX S. agalactiae LVFX MFLX 22 S. pneumoniae

8 34 34 THE JAPANESE JOURNAL OF ANTIBIOTICS 69 1 Feb PK-PD ml/ min PK-PD GRNX 400 mg 1 / GRNX 200 mg 1 / STFX 100 mg 1 / STFX 50 mg 1 / LVFX 500 mg 1 / LVFX 250 mg 1 /

9 Feb THE JAPANESE JOURNAL OF ANTIBIOTICS GRNX LVFX MFLX MIC μg/ml 1 MCS GRNX 400 mg 1 / MFLX 400 mg 1 / PK-PD 100% LVFX 500 mg 1 / 84.8% GRNX 100%, MFLX 100%, LVFX 86.9% 2014 JANIS 3.4% 9 KIMURA 23 S. agalactiae K. pneumoniae H. influenzae M. catarrhalis MIC 50 MIC 90 E. coli ESBL 24 S. pneumoniae H. influenzae M. catarrhalis K. pneumoniae Staphylococcus aureus 25 S. pneumoniae MCS GRNX STFX MFLX 100% LVFX 86.9%

10 36 36 THE JAPANESE JOURNAL OF ANTIBIOTICS 69 1 Feb S. pneumoniae MIC LVFX 5 90% MFLX M. catarrhalis K. pneumoniae 61.2% 20.5% S. pneumoniae H. influenzae M. catarrhalis MFLX LVFX 2008 E. coli Enterococcus faecalis S. agalactiae K. pneumoniae P. aeruginosa E. coli 90% % 27 E. coli PK-PD % S. agalactiae % P. aeruginosa 0 5.7% JAID/JSC 2014 E. coli 20% 6 PK-PD 70% LVFX 28 PAI BMI 40 kg/m 2 LVFX PK LVFX CLcr LUQUE kg, BMI: 56.2 kg/m 2, CLcr: 78 ml/min LVFX mg LVFX MFLX kg BMI: kg/m 2 MFLX 31 GRNX 60 kg 100 kg Cmax AUC mg 14 CKD

11 Feb THE JAPANESE JOURNAL OF ANTIBIOTICS CLcr 50 ml/min 1 STFX CLcr 50 ml/min 1 50 mg LVFX CLcr ml/min 500 mg mg CLcr 20 ml/ min 500 mg mg 2 1 GRNX 40 kg CLcr 30 ml/min 200 mg GRNX STFX LVFX MCS CLcr 50 ml/min LVFX PK-PD CLcr 50 ml/min S. pneumoniae E. coli 6 GRNX PK-PD GRNX 40 kg CLcr 30 ml/min Antimicrobial stewardship 1 BALL, P.: Quinolone generations: natural history or natural selection? J. Antimicrob. Chemother. 46: 17 24, ZHANEL, G. G.; S. FONTAINE, H. ADAM, et al.: A review of new fluoroquinolones: Focus on their use in respiratory tract infections. Treat. Respir. Med. 5: , STEIN, G. E. & E. J. GOLDSTEIN: Fluoroquinolones and anaerobes. Clin. Infect. Dis. 42: , LIEBETRAU, A.; A. C. RODLOFF & J. BEHRA- MIELLET: In vitro activities of a new des-fluoro 6 quinolone, garenoxacin, against clinical anaerobic bacteria. Antimicrob. Agents Chemother. 47: , KEATING, G. M.: Sitafloxacin: in bacterial infections. Drugs 71: , GOETTSCH, W.; W. VAN PELT & N. NAGELKERKE: Increasing resistance to fluoroquinolones in Escherichia coli from urinary tract infections in the Netherlands. J. Antimicrob. Chemother. 46: , CHEN, D. K.; A. MCGEER, J. C. DE AZAVEDO, et al.: Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. N. Engl. J. Med. 341: , DAVIDSON, R.; R. CAVALCANTI, J. L. BRUNTON, et al.: Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N. Engl. J. Med. 346: , JANIS report/2014/3/1/ken_open_report_ pdf

12 38 38 THE JAPANESE JOURNAL OF ANTIBIOTICS 69 1 Feb CRAIG, W. A.: Does the dose matter? Clin. Infect. Dis. 33: S , CRAIG, W. A.: Protein binding: Do we ever learn? Antimicrob. Agents Chemother. 55: , ANDERSSON, M. I. & A. P. MACGOWAN: Development of the quinolones. J. Antimicrob. Chemother. 51 S1 : 1 11, Clinical and Laboratory Standards Institute: Performance standards for antimicrobial susceptibility testing; twenty-second informational supplement. CLSI document M100-S22, Wayne PA, TANIGAWARA, Y.; K. NOZAWA, H. TSUDA, et al.: Optimal dose finding of garenoxacin based on population pharmacokinetics/pharmacodynamics and Monte Carlo simulation. Eur. J. Clin. Pharmacol. 68: 39 53, Levofloxacin 500 mg 57 S , TANIGAWARA, Y.; M. KAKU, K. TOTSUKA, et al.: Population pharmacokinetics and pharmacodynamics of sitafloxacin in patients with community-acquired respiratory tract infections. J. Infect. Chemother. 19: , GUMBO, T.: New susceptibility breakpoints for first-line antituberculosis drugs based on antimicrobial pharmacokinetic/pharmacodynamic science and population pharmacokinetic variability. Antimicrob. Agents Chemother. 54: , SIMON, N.; E. SAMPOL & J. ALBANESE: Population pharmacokinetics of moxifloxacin in plasma and bronchial secretions in patients with severe bronchopneumonia. Clin. Pharmacol. Ther. 74: , VAN WART, S.; L. PHILLIPS, E. A. LUDWIG, et al.: Population pharmacokinetics and pharmacodynamics of garenoxacin in patients with community-acquired respiratory tract infections. Antimicrob. Agents Chemother. 48: , FREI, C. R.; N. P. WIEDERHOLD & D. S. BURGESS: Antimicrobial breakpoints for Gram-negative aerobic bacteria based on pharmacokineticpharmacodynamic models with Monte Carlo simulation. J. Antimicrob. Chemother. 61: , SIEFERT, H. M.; A. DOMDEY-BETTE, K. HENNINGER, et al.: Pharmacokinetics of the 8-methoxyquinolone, moxifloxacin: a comparison in humans and other mammalian species. J. Antimicrob. Chemother. 43: 69 76, Jpn. J. Antibiotics 63: 1 9, KIMURA, K.; N. NAGANO, Y. NAGANO, et al.: High frequency of fluoroquinolone- and macrolideresistant streptococci among clinically isolated group B streptococci with reduced penicillin susceptibility. J. Antimicrob. Chemother. 68: , NAKAMURA, T.; C. SHIMIZU, M. KASAHARA, et al.: Monte Carlo simulation for evaluation of the efficacy of carbapenems and new quinolones against ESBL-producing Escherichia coli. J. Infect. Chemother. 15: 13 17, YANAGIHARA, K.; J. KADOTA, N. AOKI, et al.: Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2010: General view of the pathogens antibacterial susceptibility. J. Infect. Chemother. 21: , : , POLSO, A. K.; J. L. LASSITER & J. L. NAGEL: Impact of hospital guideline for weight-based antimicrobial dosing in morbidly obese adults and comprehensive literature review: J. Clin. Pharm. Ther. 39: , 2014

13 Feb THE JAPANESE JOURNAL OF ANTIBIOTICS PAI, M. P.; P. COJUTTI & F. PEA: Levofloxacin dosing regimen in severely morbidly obese patients BMI 40 kg/m 2 should be guided by creatinine clearance estimates based on ideal body weight and optimized by therapeutic drug monitoring. Clin. Pharmacokinet. 53: , LUQUE, S.; S. GRAU, M. VALLE, et al.: Levofloxacin weight-adjusted dosing and pharmacokinetic disposition in a morbidly obese patient. J. Antimicrob. Chemother. 66: , KEES, M. G.; S. WEBER, F. KEES, et al.: Pharmacokinetics of moxifloxacin in plasma and tissue of morbidly obese patients. J. Antimicrob. Chemother. 66: , CKD 2012

14 40 40 THE JAPANESE JOURNAL OF ANTIBIOTICS 69 1 Feb Susceptibility of clinically-isolated bacteria strains to respiratory quinolones and evaluation of antimicrobial agent efficacy by Monte Carlo simulation TADASHI KOSAKA 1,4, YUKIJI YAMADA 2,4, TAKESHI KIMURA 2,4, MAI KODAMA 2,3,4, YUMIKO FUJITOMO 2,3,4, MASAKI NAKANISHI 2,3,4, TOSHIAKI KOMORI 2, KEISUKE SHIKATA 1 and NAOHISA FUJITA 2,3,4 1 Department of Pharmacy, 2 Department of Clinical Laboratory, 3 Division of Infectious Diseases, 4 Department of Infection Control, Kyoto Prefectural University of Medicine, Kyoto, Japan 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 MIC 90 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 MIC 90 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 MIC 90 f AUC/MIC ratio, against S. pneumoniae was %, but against E. coli was low %. The f 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.

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