Infections with Gram negative bacilli resistant to all antibiotics except colistin have become increasingly common. This is a worldwide problem, with substantial issues being noted in South America and Asia. No new antibiotic classes with activity against these resistant Gram negative organisms are likely to be commercially available in the next 5 years. Yet, the pharmacokinetics (PK) of the only remaining antibiotic option, colistin, were studied in the 1960s when many of the modern principles of antibiotic dosing were not known. The Product Information of the drug suggests dosing regimens which may not be optimal for the management of serious infections. Furthermore, many patients with multiply resistant Gram negative infections are critically ill requiring renal replacement therapy and the Product Information gives no recommendations for dosing in this scenario. Although most physicians refer to """"""""colistin"""""""", the only form available for intravenous use is sodium colistin methanesulfonate (CMS). In the body, CMS is partially hydrolyzed to colistin. CMS and colistin differ in their antibacterial and PK characteristics. We were the first to develop HPLC assays which can separately measure both CMS and colistin.
We aim to measure the levels of CMS and generated colistin in plasma in all patients and at the site of infection in patients with pneumonia (lung epithelial lining fluid) in a multicenter cohort of 238 patients. We will also measure the clearance of CMS and colistin in those patients in the cohort who are undergoing dialysis or continuous renal replacement therapy. We will determine outcome of these patients and correlate outcome with pharmacodynamic parameters such as the ratio of area under the plasma concentration-time curve:minimal inhibitory concentration (MIC) or peak concentration:MIC. The primary outcome measures will be bacteriologic and clinical response. Mathematical modeling techniques such as Monte Carlo simulation will be used to integrate the PK/PD and outcome data in order to establish optimal dosing regimens. Resistance or intolerance to CMS/colistin leaves physicians with no antibiotic options - therefore, we will secondarily explore the relationships between PK, treatment duration and patient characteristics on resistance to colistin or advent of toxicity.
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