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1 446 JULY 2012.. 2010 .. 2010 12 .. PK-PD .. 2012 .. 4 . 2012 4 60 .. VOL. 60 NO. 4 447.. I 448. II 448. 1 448. 2 450. 3 450. 4 452. III PK-PD 453. 1 453. 2 454. 3 455. 4 456. 5 456. 6 PK-PD 456. IV 457. 1 457. 2 458. 3 458. 1 458. 2 458. 4 458. V 459. 1 459. 1 459. 2 459. 3 459. 2 460. 1 460. 2 461. 3 461. 3 462. 1 462. 2 462. 3 462. 4 462. 1 462. 448 JULY 2012.. I .. NDM-1 1 .. I .. II . Executive Summary 1 . 2 .. 3 LPS . 4 . 5 in vitro in vivo . 1 . E Bacillus colistinus . 1950 1 .. 2 4 1 . 5 7 B 1 .. VOL. 60 NO. 4 449. Taina Litwak 2007. Reproduced with permission. 1. 8 . Polymyxin .. lipopolysaccharide LPS . LPS .. 450 JULY 2012. 1. 2. 9 10 .. MIC g/mL .. CLSI 2 4 8. 2 4. EUCAST 4 8. 2 4. 2 4.. 2 .. 1 .. 2 CLSI Clinical and Laboratory Standards Institute MIC Minimum Inhibitory Concentration 2 g! mL . 4 g! mL 8 g! mL 2 g! mL 4 g! mL 9 EUCAST European Committee on Antimicrobial Susceptibility Testing.

2 MIC 2 g! mL 4 g! mL 4 g! mL 8 g! mL . 10 . 2 2007 2008 3,480 11 .. MIC 4 g! mL . NDM-1 KPC Klebsiella pneumoniae carbapenemase . 12 14 NDM-1 KPC .. 2007 2008 . 139 . 49 15 .. 3 . 16 21 Ko 214 . 17 . 20,21 . LPS LPS . 22 23 24,25 . 26 27 LPS Lipid A . VOL. 60 NO. 4 451. n 1,732 . n 561 . n 515 . n 119 . n 108 . n 31 . 2. 5. 1. 2. 4. 8. 16. 6. 16.. MIC ( g/mL). 2. 11 . 10. 8. ATCC 19606. Isolate 6. 6. Log10 CFU/mL. 4. 2. 0. 0 2 4 6 8 10. g/mL . 3. 30 . 2 g/mL . 101 102 CFU/mL .. Moffatt LPS . 23 . 28 29 LPS .. 30 33 Li . 1 10 g! mL 30 . 8 10 g! mL . 3 .. 28,34 .. 452 JULY 2012. 3. in vitro . No. RFP 28 . RFP IPM 35 . IPM IPM 44 . IPM 47 . MEPM MEPM 8/8 45 . MEPM 46 . TOB 49 . MINO IPM 90% 51 . VCM 54 . TEIC 55 . TGC 50 .. RFP IPM MEPM TOB . MINO VCM TEIC TGC . 4. in vivo .. No. RFP IPM 56 .. RFP 57 . LPS . RFP 58 .. RFP 60 .. TOB 49 .. IPM 59.

3 RFP TOB IPM . 4 . in vitro in vivo 3 4 .. in vitro 28,35 43 36,44 47 . 48,49 36 36,50 52 . 53 54,55 3 .. 37 BC .. Gordon 39 . 54,55 . in vitro in vivo . 48,49 . 49 56 63 . 4 . in vitro .. 57 .. VOL. 60 NO. 4 453. 5. I . 1 . 1 . IU 2 . 5 mg/kg/ 15 150 mg/ . Coly-Mycin M Parenteral /kg/ 2 4 60 kg 150 300 mg/ . JHP Pharmaceuticals LLC 1 mL 450 900 1. 5% 1 2 .. 60 kg 100 / 200 . 5 / . /kg/ 1 3 60 kg 300 600 . 60 kg / 100 / 1. Colomycin Injection 100 3 6 200 / . Forest Laboratories UK Ltd . 200 1 3 1 2 3 .. 1 50 mL 30 .. 5% 5% .. 200 / . I /kg mg/kg 60 kg 900 / .. 50 mL 1 2 30 1 5 . 15 /kg/ . 1 . 2 . 1 mg 3 1 mg .. III PK-PD. Executive Summary 1 5 mg! kg! 1 2 4 . 300 600 1 3 .. 2 PK-PD AUC! MIC Cmax! MIC . MSW Mutant Selection Window .. 1 .. 64,65 5 . I .. 6 .. 454 JULY 2012. 6.. 64 67 66 . 1 1 . CL-M . / . mg/kg/ 1. / / 1. % % .. % . 76 100 5 2 4 100 4 6 3 100.

4 40 75 2 50 75 2 3 2 50. 25 40 1 50 1 2 1 25 33. 25 1 36 hr 30 1 36 hr 15. 1 . 30 .. 1 . 30 .. CVVH 2 48 25. CVVH 1 L/hr dialysis flow 1 50. rate . CVVHD 1 L/hr dialysis 5 2 100. flow rate . CL-M CVVH CVVHD . 1 1 100% .. Fatty acid (D ) L-Dab L-Thr (D) L-Dab (D, ) L-Dab (D ) L-Dab D-Leu L-Leu (D ) L-Dab (D ) L-Dab L-Thr -NH2 -NH2 -NH2 -NH2 -NH2.. Fatty acid (D ) L-Dab L-Thr (D ) L-Dab (D , ) L-Dab (D) L-Dab D-Leu L-Leu (D) L-Dab (D) L-Dab L-Thr -NH2 -NH2 -NH2 -NH2 -NH2. CH2 CH2 CH2 CH2 CH2. O S O O S O O S O O S O O S O. ONa ONa ONa ONa ONa 4.. Fatty acid A 6 . B 6 . Dab . Leu . Thr . 2 .. 4 . 3 . 5 .. 64,66,67 6 . VOL. 60 NO. 4 455.. 5.. 7. I .. Cmax tmax AUC0 AUC0 12 CLr fe0 24 t1/2 95% CI . g/mL hr g hr/mL g hr/mL L/hr/kg % hr Ro Rs . 3 .. Cmax tmax AUC0 AUC0 12 CLr fe0 24 t1/2 95% CI . g/mL hr g hr/mL g hr/mL L/hr/kg % hr Ro Rs . 3 . fe . n 14 n 13 mean SD tmax median range.

5 6. n 14 . g/mL . n 13 . 4 h . 2. 0. 0 4 8 12 16 20 24. (hr). 6. n 14 n 13 . SD . TDM Therapeutic Drug Monitoring .. 3 . 15 mean SD kg . 456 JULY 2012. 8. I .. 0 2 hr 2 4 hr 4 6 hr 6 12 hr 12 18 hr 18 24 hr g/mL 3 g/mL . 0 2 hr 2 4 hr 4 6 hr 6 12 hr 12 18 hr 18 24 hr g/mL 3 g/mL n 15 n 14 mean SD. ! kg mg! kg . 1 2 . 50 mL 30 7 . 6 68 tmax 2 Cmax mean SD . g! g! mL mL 5 t1!2 mean SD . hr . hr 5 . 8 69 . 4 . 14 . 70 900 ! 12 ! kg! Cmax mean SD g! mL, t1!2 hr 15 ! kg! t1!2 .. 5 . 1 . 1 100 1 4 1 g! mL . 25 71 VAP 13 1 . 200 1 3 2 BALF .. 72 .. 6 PK-PD . PK-PD . MIC Cmax! PK-PD AUC! MIC . 70 . PK-PD Cmax! MIC 73 . MIC AUC! . I . PK-PD . MIC Cmax! AUC! MIC . 2 3 . MPC Mutant Prevention Concentration . 74 70 MICs range 2 g! mL . MPCs range 32 128 g! mL 6 128 g! mL I . MSW Mutant Selection Window .. Bergen in vitro . VOL. 60 NO. 4 457. 9.. BUN CLcr.

6 CLcr . 10.. APACHE II .. ACE .. NSAIDs .. 1 8 hr 12 hr 24 hr . 8 hr 75 . 1 2 3 .. IV . Executive Summary 1 . 2 .. 3 3 . 4 BUN .. e-GFR.. 5 .. 1 .. 64 66 9 . 65 20 1 .. 458 JULY 2012. 11.. N No.. A. ba 3 2. 0%. A. ba 1 7 100% 7/7 29 2/7 82 . 0%. 1 .. A. ba 20 14. A. ba 28 6 0%. 45 98% 44/45 2% 1/45 83 . 0%. 40 . 1/17 . P. aer 10/A. ba 7 17 13/17 4/15 . 0%. VAP 14 84 . 1. 2. VAP . A. ba: Acinetobacter baumannii, K. pn: Klebsiella pneumoniae, P. aer: Pseudomonas aeruginosa 76,77 .. 78 . BUN . e-GFR 79 . 3 . NAG N-acetyl- -D- glucosaminidase 80 . 2 . 64,65,81 10 .. 3 . 1 . 64 .. 2 .. 11 . 4 .. VOL. 60 NO. 4 459. V . Executive Summary .. MDRP .. 1 . 2 . 3 BC .. 4 .. 5 . 6 3 5 BUN .. e-GFR . 7 . 8 10 14 . 1 . 1 .. 3 . 85 .. 2 .. 2 . BC .. ICT . 3 .. 76,86 90 12 13 . Markou 24 3 . 87 4 24 . 73 30 . Hachem 95 36 .. 76 55 31 p . 39 53 .. 60 70 . 88.

7 460 JULY 2012. 12.. N No. 21 39 60 58% 37% . 27%, 58% . 0%. 6 14 20 25% 86 . UTI 4 8 12 83%. BSI 7 2 9 78%. P. aer 20/A. ba 6 26 73% 14% 3/21 . 87 . 0%. P. aer 19/A. ba 36 VCM AMPH-B 55 31% 0%. VAP 29 32%. 95 . 9 22%. UTI 10 20%. A. ba 28 23/ 2 MEPM SBT/ABPC 54 67% 8% 4/50 .. CPFX PIPC/CVA 2% 1/50 . 18 56% 89 . 15 60%. UTI 6 100%. P. aer AGs 121 72% . QLs 0%. 20 65%. 90 . 59 73%. 16 63%. UTI 13 85%. P. aer A. spp K. pn AGs 60 72% 11% 6/55 . Ent. spp E. coli S. malt CPFX 0%. 36 69% 96 . 6 67%. UTI 5 80%. P. aer 10 80% . 1 1 . 5 60%. 88 . 3 100%. UTI 1 100%. VAP A. ba 21 57% 24% 77 . VAP UTI BSI . VCM AMPH-B B MEPM SBT/ABPC / CPFX . PIPC/CVA / AGs QLs . P. aer: Pseudomonas aeruginosa, A. ba: Acinetobacter baumannii, : Klebsiella pneumoniae, A. spp: Acinetobacter spp, Ent. spp: Enterobacter spp, E. coli: Escherichia coli, S. malt: Stenotrophomonas maltophilia 38,91.

8 92 in vitro 50 . 10 14 .. 72 . 2 . 1 .. VOL. 60 NO. 4 461. 13.. N No.. P. aer 31 52% 23% 76 . UTI . A. ba P. aer S. malt . 258 79% 10% 26/251 . K. pn E. coli E. clo 97 . 36 83%. MEPM 162 83%. UTI A. ba P. aer S. malt . 14 86%. E. coli E. clo 98 . MEPM 57 68% 7% 4/57 .. 23 61%. 99 . 10 60%. P. aer AMK 13 62%. 92%. 36 100% 3%. BUN .. P. aer 100 .. 100%. AZT azlocillin CAZ 35 100 Ccr . IPM/CS CPFX BUN . UTI . MEPM CPFX AMK AZT CAZ IPM/CS . / . P. aer: Pseudomonas aeruginosa, A. ba: Acinetobacter baumannii, : Stenotrophomonas maltophilia, K. pn: Klebsiella pneumoniae, E. coli: Esch- erichia coli, E. clo: Enterobacter cloacae .. 2 .. BC . in vitro . 17,93 .. 3 . BALF . 72 .. 94 .. 77,86,89,90,95,96 12 . 97 101 13 . 462 JULY 2012. 56 100 86,89,90,96 . 88,102 .. 103 .. 2 4 mL . 2 50 100 1 2 . 2 100 200 1 2 .. 10 14 .. 3 . 1 .. 2 .. 3 .. 86,89,90,96 12.

9 Montero 121 . 13 11 85 . 3 23 . 90 . 13 .. 38,91 . BC . 104 . 2 .. 4 . 1 .. SSI .. 86,88 90,105,106 .. VOL. 60 NO. 4 463.. 1 1 COLISTIN . J Antibiotics 1950; 3: 457-8. 2 Li J, Nation R L, Milne R W, Turnidge J D, Coulthard K: Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria. Int J Antimicrob Agents 2005; 25: 11-25. 3 Li J, Nation R L, Turnidge J D, Milne R W, Coulthard K, Rayner C R, et al: Colistin: the reemerging antibiotic for multidrug-resistant Gram-negative bacterial infections. Lancet Infect Dis 2006; 6: 589-601. 4 Evans M E, Feola D J, Rapp R P: Polymyxin B sulfate and colistin: old antibiotics for emerging multiresistant gram-negative bacteria. Ann Pharmacother 1999; 33: 960-7. 5 Li J, Turnidge J, Milne R, Nation R L, Coulthard K: In vitro pharmacodynamic properties of colistin and colistin methanesulfonate against Pseudomonas aeruginosa isolates from patients with cystic fibrosis.

10 Antimicrob Agents Chemother 2001; 45: 781-5. 6 Owen R J, Li J, Nation R L, Spelman D: In vitro pharmacodynamics of colistin against Acinetobacter baumannii clinical isolates. J Antimicrob Chemother 2007; 59: 473-7. 7 Poudyal A, Howden B P, Bell J M, Gao W, Owen R J, Turnidge J D, et al: In vitro pharmacodynamics of colistin against multidrug-resistant Klebsiella pneumoniae. J Antimicrob Chemother 2008; 62: 1311-8. 8 Arnold T M, Forrest G N, Messmer K J: Polymyxin antibiotics for gram-negative infections. Am J Health-Syst Pharm 2007; 64: 819-26. 9 Clinical and Laboratory Standards Institute: Performance standards for antimicrobial susceptibility testing;. twenty-first informational supplements. CLSI document M100-S21. CLSI, Wayne, PA, 2011. 10 European Committee on Antimicrobial Susceptibility Testing (EUCAST). ! http:! ! clinical_breakpoints!