신대체 요법(CRRT or IHD)받는 환자에서의 colistin 용량

Colistin(Colistimethate)

1. Pharmacokinetic data

Vd	Healthy volunteer	Colistimethate	8.92 L
		Colistin	12.4 L
	Critically ill	Colistimethate	5.3 to 13.5 L
		Colistin	7.2 to 189 L
Protein binding	50%
Metabolism	Colistimethate sodium (inactive prodrug) ⇨ 가수분해 ⇨ colistin (active form)
Half-life elimination	-	Colistimethate	2 to 3 hours
	Critically ill(Adults)	Colistimethate	2.3 hours
		Colistin	14.4 hours
Excretion	Urine(colistin이 다시 colistimethate sodium으로 변하여 제거됨)
Target PK/PD paramter	Area under the plasma concentration-time curve across 24 hours at steady state (AUCss,24 hr) of ~50 mg · hour/L is required that equates to a target average steady-state plasma concentration (Css,avg) of ~2 mg/L for total drug.

2. RRT(Renal Replacement Therapy)받는 환자에서의 용량 조절

Does Renal Replacement Therapy Have Implications for Selection of Intravenous CMS Dosage Regimens?

We recommend that to target a plasma colistin Css,avg of 2 mg/L in a patient on intermittent hemodialysis (IHD), the following dosing schedule be utilized: On a nondialysis day, administer a CMS dose of 130 mg CBA/day (~3.95 million IU/day). On a dialysis day, administer a supplemental dose of CMS 40 mg CBA (~1.2 million IU) or 50 mg CBA (~1.6 million IU) for a 3- or 4-hour IHD session, respectively. If possible, the supplement to the baseline (nondialysis) daily dose should be administered with the next regular dose, after the dialysis session has ended. Conduct IHD sessions as late as possible within a CMS dosage interval to minimize the amount of CMS and formed colistin lost to the extracorporeal system.

We recommend that to target a plasma colistin Css,avg of 2 mg/L in patients prescribed sustained low-efficiency dialysis (SLED) that 10% of the CMS dose be added to the baseline daily dose per 1 hour of SLED.

We recommend that for patients prescribed continuous renal replacement therapy (CRRT), for a plasma colistin Css,avg of 2 mg/L, to administer CBA 440 mg/day (~13.3 million IU/day). This equates to 220 mg CBA every 12 hours (~6.65 million IU every 12 hours).

👍 Colistin methanesulfonate & colistin은 간헐적 혹은 지속적 신대체요법에 의해 효과적으로 제거된다. 각각의 신대체요법마다 시간당 약 10%씩 colistin이 제거된다고 알려져있으며 이로인해 신기능이 정상일 때보다 더 많은 유지용량이 요구될 수 있다.

예를 들어 CRRT(지속적 신대체 요법)을 받는 환자를 생각해보자.

CrCl ~0 mL/min이라고 가정하였을 때 기저 colistin 요구량은 65 mg q12h(130 mg/day)이다. 시간당 10%씩 감소되기 때문에 보충선량은 10% of the baseline dose per hour × 24 hours이 된다. (130 mg/day의 10% X 24 hr = 312 mg)

따라서 기저용량(130 mg/day)와 추가 용량(약 310 mg/day)를 합하여 440 mg/day가 추천되는 것이다.

3. CVVHDF를 받는 환자에서의 혈중 colistin/colistimethate 농도

대상 환자

Traditionally, reduced daily doses of colistin methanesulphonate (CMS) in critically ill patients receiving continuous venovenous haemodiafiltration (CVVHDF) have resulted in suboptimal colistin concentrations.

The necessity of a loading dose (LD) at treatment initiation has been proposed. A LD of 9 million IU (MU) [ca. 270 mg of colistin base activity (CBA)] was administrated with a maintenance dose of 4.5 MU (ca. 140 mg CBA) every 12 h (q12h) to eight critically ill patients receiving renal replacement therapy.

Blood samples were collected immediately before and at different time intervals after the LD and the fourth dose, whilst pre-filter and post-filter blood samples were also collected. CMS and colistin concentrations were determined using an LC-MS/MS assay.

Median maximum observed concentrations after the LD were 22.1 mg/L for CMS and 1.55 mg/L for colistin, whereas during maintenance dosing the corresponding values were 12.6 mg/L and 1.72 mg/L, respectively.

CVVHDF clearance was determined as 2.98 L/h for colistin, equivalent to 62% of total apparent colistin clearance in CVVHDF patients.

Both CMS and colistin were cleared by CVVHDF. Application of a LD of 9 MU CMS resulted in more rapid achievement of the target colistin concentration.

Following implementation of a predicted pharmacokinetic model on plasma CMS/colistin concentrations, a LD of 12 MU CMS appears more appropriate, whilst a CMS maintenance dosage of at least 6.5-7.5 MU q12h(200-230 mg q12h) is suggested in patients undergoing CVVHDF.

However, further clinical studies are warranted to assess the safety of a LD of 12 MU CMS in patients receiving CVVHDF.

reference:

1) Lexicomp

2) 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.

3) Karaiskos, Ilias, et al. "Challenge for higher colistin dosage in critically ill patients receiving continuous venovenous haemodiafiltration." International journal of antimicrobial agents 48.3 (2016): 337-341.