Clinical Pharmacokinetics and Pharmacodynamics of Colistin

Abstract

In this review, we provide an updated summary on colistin pharmacokinetics and pharmacodynamics. Colistin is an old molecule that is frequently used as last-line treatment for infections caused by multidrug-resistant Gram-negative bacteria. Colistin is a decapeptide administered either as a prodrug, colistin methanesulfonate (CMS), when used intravenously, or as colistin sulfate when used orally. Because colistin binds to laboratory materials, many experimental issues are raised and studies on colistin can be tricky. Due to its large molecular weight and its cationic properties at physiological pH, colistin passes through physiological membranes poorly and is mainly distributed within the extracellular space. Renal clearance of colistin is very low, but the dosing regimen should be adapted to the renal function of the patient because CMS is partly eliminated by the kidney. Therapeutic drug monitoring of colistin is warranted because the pharmacokinetics of colistin are very variable, and because its therapeutic window is narrow. Resistance of bacteria to colistin is increasing worldwide in parallel to its clinical and veterinary uses and a plasmid-mediated resistance mechanism (MCR-1) was recently described in animals and humans. In vitro, bacteria develop various resistance mechanisms rapidly when exposed to colistin. The use of a loading dose might reduce the emergence of resistance but the use of colistin in combination also seems necessary.

Antimicrobial Therapy for Infections Caused by Carbapenem-Resistant Gram-Negative Bacteria

“…Carbapenemase producing 내성 균주는 plasmid를 통하여 다른 균주로 내성을 전달할 수가 있어 의료 관련 감 염에서 심각한 문제가 되고 있다 [5,6]. [12,13]. 따라서 치료 실패 및 내성 발현을…”

“…막기 위하여 다양한 항생제와 병용해서 투여하려는 실험 연 구와 시도가 이루어져 왔으며 carbapenems, sulbactam, tigecycline, rifampicin, fosfomycin, glycopeptides와 실험실적으로 상 승 효과가 있는 것으로 나타났다[9,13,18,19].하지만 실제 임 상에서 이러한 병용요법의 효과가 명확하게 증명된 바는 없다. 카바페넴 내성 그람음성균을 대상으로 한 22개의 임상연구를 대상으로 한 분석에서 colistin 단일요법이 colistin/carbapenem, colistin/tigecycline, colistin/aminoglycoside, or colistin/fosfomycin 병합요법보다 사망률이 높다고 나왔으나 저자들은 대부분의 연구가 후향적 관찰 연구였다는 근거로 병합요법을 표준 치 료로 받아들이기에는 부족하다는 의견을 제시하였다[20].…”

The global distribution and spread of the mobilized colistin resistance gene mcr-1

“…Within China, nearly half (45%) of positive isolates stem from Shandong province ( Figure 1B). The vast majority of mcr-1 positive isolates belong to Escherichia coli (411), but the dataset also comprises mcr-1 positive isolates from another seven bacterial species: Salmonella enterica (29), Klebsiella pneumoniae (8), Escherichia fergusonii (2), Kluyvera ascorbata (2), Citrobacter braakii (2), Cronobacter sakazakii (1) and Klebsiella aerogenes (1) ( Figure 1A). The majority of isolates for which sampling dates were available (80%), were collected between 2012 and 2016, with the oldest available isolates dating back to 2008 ( Figure 1C).…”

“…Colistin was largely abandoned as a treatment for bacterial infections in the 1970s due to its high toxicity and low renal clearance, but has been reintroduced in recent years as an antibiotic of 'last resort' against multi-drug-resistant (MDR) infections 1 . It is therefore alarming that the prevalence of resistance to colistin has become a significant concern, following the identification of plasmid-mediated colistin resistance conferred by the mcr-1 gene in late 2015 2 .…”

Intra-Vesical Colistin for Pseudomonas aeruginosa Urinary Tract Infections

“…Colistin is an antibiotic belonging to the polymyxin group which was discovered in 1949 by Koyama et al and made available in the form of a less toxic prodrug, colistimethate sodium. It was later largely abandoned due to its nephrotoxicity [4] . This toxicity together with the need to tackle MDR-GNB has led to topical routes of administration, such as intrathecal and intraventricular, as well as by inhalation.…”