%T MIC MIC. Pharmacokinetics PK: Cmax AUC T1/2 Pharmacodynamics PD: MIC: minimum inhibitory concentration time-killing-curve 1990.

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1 THE JAPANESE JOURNAL OF ANTIBIOTICS ( 55 ) ( 2 15 ) %T MIC MIC %T MIC 50%T MIC 1000 mg 3 3 /day Pharmacokinetics PK: Cmax AUC T1/2 Pharmacodynamics PD: MIC: minimum inhibitory concentration time-killing-curve 1990 in vivo PK/PD Cmax/MIC 24 AUC/MIC b - MIC Time above MIC% %T MIC 1) Cmax, AUC, T1/2 MIC 50, MIC 90 MIC Vd: CLt:

2 160( 56 ) THE JAPANESE JOURNAL OF ANTIBIOTICS 58 2 Apr. MIC 1,000 5,000 10,000 PK/PD 2,3) 2 10, mg (0.5 hr) 2 /day 500 mg (0.5 hr) 3 /day 1000 mg (0.5 hr) 2 /day 1000 mg (0.5 hr) 3 /day %T MIC 1 3 5) mg (3 hrs) 2 /day 500 mg (3 hrs) 3 /day 1000 mg (3 hrs) 2 /day 1000 mg (3 hrs) 3 /day ) 1. 4) 2. I. Two-compartment open model 4) 1 VdL CLt L/h f ) MIC

3 THE JAPANESE JOURNAL OF ANTIBIOTICS ( 57 ) 129 MIC 90 : 0.06 mg/ml 280 MIC 90 : 8 m g/ml MIC 3 10,000 MIC 10,000 MIC KUTI 2,3) %T MIC 10, 20, 30, 40, 50, 60, 70, 80, 90, 100% Target Attainment% (TA%) CRAIG 7) %T MIC 30% bacteriostatic responses 50% bactericidal responses TA30% TA50% 2) Crystal Ball 2000 II. %T MIC TA% 1. %T>MIC TA% %T MIC 30, %T MIC 50 TA% 1 0.5

4 162( 58 ) THE JAPANESE JOURNAL OF ANTIBIOTICS 58 2 Apr TA30% 100% TA50% 500 mg (0.5 hr) 2 /day: 99.6% 1000 mg (0.5 hr) 2 /day: 99.8% 500 mg (0.5 hr) 3 /day 1000 mg (0.5 hr) 3 /day 100% TA30% 100% TA30% 500 mg (0.5 hr) 2 /day: 70.1% 1000 mg (0.5 hr) 2 /day: 75.8%, 500 mg (0.5 hr) 3 /day: 78.7%, 1000 mg (0.5 hr) 3 /day: 84.2% TA50% 500 mg (0.5 hr) 2 /day: 26.5% 1000 mg (0.5 hr) 2 /day: 41.9%, 500 mg (0.5 hr) 3 /day: 65.5%, 1000 mg (0.5 hr) 3 /day: 72.1% 2. %T>MIC TA% %T MIC 30, %T MIC 50 TA% 1 0.5

5 THE JAPANESE JOURNAL OF ANTIBIOTICS ( 59 ) TA50% mg 3 /day mg 1000 mg 2 / day TA30%, TA50% 100% , 7 TA30% 500 mg (3 hrs) 2 /day: 78.3%, 500 mg (3 hrs) 3 /day: 81.1%, 1000 mg (3 hrs) 2 /day: 82.8%, 1000 mg (3 hrs) 3 /day: 91.1% TA50% 500 mg (3 hrs) 2 /day: 60.4%, 1000 mg (3 hrs) 2 /day: 69.6% 500 mg (3 hrs) 3 /day: 75.4% 1000 mg (3 hrs) 3 /day: 81.4% 3. %T>MIC TA% %T MIC 30, %T MIC 50 TA% 1 3

6 164( 60 ) THE JAPANESE JOURNAL OF ANTIBIOTICS 58 2 Apr. 4. %T>MIC TA% %T MIC 30, %T MIC 50 TA% %T MIC III. CRAIG 1 %T MIC ) WA.CRAIG et al. ICAAC Abstr A-91,1994

7 THE JAPANESE JOURNAL OF ANTIBIOTICS ( 61 ) %T MIC %T MIC 20 30% bacteriostatic effect ARIANO60 %T MIC 8) %T MIC 0 51% 30%, %T MIC 51 75% 63%, %T MIC % 80% ARIANO 50% %T MIC %T MIC 30% %T MIC 50% 50% %T MIC b - MIC 50 MIC 90 %T MIC MIC MIC 1,000 5,000 10,000 MIC %T MIC 30% 50% 2,3) KUTI 1000 mg /day 2000 mg /day MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) ,000 %T MIC TA% CRAIG 7) %T MIC 30% bacteriostatic responses 50% bactericidal responses 6 2) 1000 mg (3 hrs) 2 / day TA30%, TA50% TA30%, TA50% 1000 mg (3 hrs) 3 /day, 2000 mg (0.5 hr) 3 /day, 2000 mg (3 hrs) 3 /day KUTI 2,3) 4) MIC 6) TA% 10)

8 166( 62 ) THE JAPANESE JOURNAL OF ANTIBIOTICS 58 2 Apr. 9) KUTI CRAIg 7) %T MIC 30% bacteriostatic responses 50% bactericidal responses TA30% TA50% 2) 500 mg (0.5 hr) 2 / day TA30%, TA50% 100% 500 mg (0.5 hr) 2 /day 500 mg (0.5 hr) 2 /day 1000 mg (0.5 hr) 2 /day 500 mg (0.5 hr) 3 /day 1000 mg (0.5 hr) 3 /day TA30%, TA50% %T MIC 50% %T MIC 500 mg (0.5 hr) 3 /day 1000 mg (0.5 hr) 3 /day TA% %T MIC TA% TA% 3 TA30%, TA50% 1 1 MIC 500 mg (0.5 hr) 2 /day %T MIC 50% 50 %T MIC 500 mg (0.5 hr, 3 hrs) 3 /day 1000 mg (0.5 hr, 3 hrs) 3 /day %T MIC TA% 1000 mg 3 /day MIC MIC Empiric

9 THE JAPANESE JOURNAL OF ANTIBIOTICS ( 63 ) 1) CRAIG, W. A.: Pharmacokinetic/pharmacodynamic parameters: Rationale for antibacterial dosing of mice and Men. Clinical Infectious Disease 26: 1 12, ) KUTI, J. L.; P. DANDEKAR, C. H. NIGHTINGALE & D. P. NICOLAU: Use of monte carlo simulation to design an optimized pharmacodynamic dosing strategy for meropenem. J. Clin. Pharmacol. 43: , ) KUTI, J. L.; C. H. NIGHTINGALE & D. P. NICOLAU: Optimizing pharmacodynamic target attainment using the MYSTIC antibiogram: Data collected in north America in Antimicrobial. Agents Chemotherapy. 48 7: , ) Meropenem Chemotherapy 40 (S-1): , ) JARURATANASIRIKUL, S. & S. SRIWIRIYAJAN: Comparison of the pharmacodynamics of meropenem in healthy volunteers following administration by intermittent infusion or bolus injection. J. Antimicrob. Chemother. 52: , ) Meropenem 2002 Jpn. J. Antibiotics 57 (1): , ) WALKER, M. R.; D. ANDES, W. A. CRAIG, et al.: Pharmacodynamic activities of meropenem in animal infection model. ICAAC Abstr A-91, ) ARIANO, R. E.; A. NYHLEN, J. P. DONNELLY, D. S. SITAR, G. K. M. HARDING & S. A. ZELENITSKY: Pharmacokinetics and pharmacodynamics of meropenem in febrile neutropenic patients with bacteremia. The Annals of Pharmacotherapy 39: 32 38, 9) LEROY, A.; J. P. FILLASTRE, I. ETIENNE, F. BORSA-LEBAS & G. HUMBERT: Pharmacokinetics of meropenem in subjects with renal insufficiency. Eur. J. Clin. Pharmacol. 42 (5): , ) KUTI, J. L.; S. KOTAPATI, C. H. NIGHTINGALE, D. P. NICOLAU: Evaluation of Pharmacodynamic Target Attainment Between Healthy Subject and Patients Data Using Monte Carlo Simulation. ICAAC Abstr A-9, 2003 THE COMPARISON OF OPTIMIZED PHARMACODYNAMIC DOSING STRATEGY FOR MEROPENEM USING MONTE CARLO SIMULATION HIROSHIGE MIKAMO Division of Anaerobe Research, Life Science Research Center, Gifu University KYOICHI TOTSUKA Department of Infectious Diseases, Tokyo Women s Medical University Monte Carlo simulation was enmloyed to determine pharmacodynamic target attainment rates for several meropenem dosage regimens against E. coli and P. aeruginosa populations. Percent Time above MIC (%T MIC) exposures for several meropenem dosage regimens were simulated for 10,000 subjects. Variability in pharmacokinetic parameters and MIC distributions were derived from studies in healthy volunteers and the injection antibiotics include of Meropenem susceptibility test surveillance program. The probabilities of attaining bacteriostatic responses (30%T MIC) and bactericidal responses (50%T MIC) exposures were high for all dosage regimens against populations of E. coli. Against P. aeruginosa, the 1000mg 3.0 infusion q8 dosage regimen provided the hightest target attainment rates. Further study of these dosage recommendations in clinical trials is suggested.