colistin guideline, 콜리스틴 가이드라인 (3) _ Susceptibility and Pharmacokinetics/Pharmacodynamic

 

 

Susceptibility and Pharmacokinetics/Pharmacodynamic

1. How Should Susceptibility Be Tested, and WhatAre the Minimum Inhibitory Concentration Break-points for the Polymyxins to Guide Therapy?
2. Is There a Recommended PK/PD TherapeuticTarget for Maximization of Efficacy for Colistinand Polymyxin B?

 

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1. How Should Susceptibility Be Tested, and WhatAre the Minimum Inhibitory Concentration Break-points for the Polymyxins to Guide Therapy?

 

- broth microdilution 방식을 권장

- Agar dilution, disk diffusion, andgradient diffusion는 CLSI-EUCAST에서 broth microdilution에 비해 high error rate 이므로 권장하지 않음

 

 

- 실제 임상에서는 colistin의 susceptibility는 일반적으로 볼 수 없다.

 

2. Is There a Recommended PK/PD TherapeuticTarget for Maximization of Efficacy for Colistinand Polymyxin B?

 

- PK/PD target ⇛ AUC(area under the plasme concentration) ⇛ ~50 mg·hour/L

  ⇛ 이를 위해 Css,avg(acerage steady-state concentration)를 ~2 mg/L를 target으로 함

  ⇛ 하기도 감염에서는 해당 target이 suboptimal

- polymyxin B에 대해서는 target AUCss,24hr에 대한 자료가 부족하므로 colistin의 target을 공유함

- colistin의 exposure은 maximal tolerable exposure로 사용할 것을 권고, 이는 현재 mouse thigh infection modeld을 사용 했을 때, MIC breakpoints에서 권장된 exposure에서 살균 효과가 나타났지만, systemic(not directly into the lung) 투여로 mouse lung infection model에서는 부족한 살균 효과를 보였기 때문

🖐 즉, tolerable 하다면 efficacy를 위해 증량 고려해 볼 수 있다는 의미로 받아들여짐

- MIC 이상의 농도에서 상당히 빠른 살균 작용이 나타남

- modest post-antibiotic effect (high concentration)

- 위에서 언급된 PK/PD exposure target은 polymyxin monotheray와 관련된 연구에서 도출되었음 ⇛ 따라서 monotherapy에서의 target으로만 적용 가능

- in vitro의 Hollow Fiber Infection Model 연구(high bacterial density of organism & in the absence of an immune system)에서 오히려 고용량의 colistin은 high level polymyxin resistance를 증폭시킨다는 역설적인 효과를 보임

- monotherapy에서 inoculum effect 효과 입증 : VAP or HAP처럼 inocula인 경우 살균 효과가 현저히 감소됨

 

* The inoculum effect (IE) is a laboratory phenomenon that is described as a significant increase in the minimal inhibitory concentration of an antibiotic when the number of organisms inoculated is increased. 

 

 

reference : 

(1) Tsuji, Brian T., et al. "International Consensus Guidelines for the Optimal Use of the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti‐infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP)." Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 39.1 (2019): 10-39.

(2) Brook, Itzhak. "Inoculum effect." Reviews of infectious diseases 11.3 (1989): 361-368.