Therapeutic Specification of the Last Resort Polymyxins: An Intelligent Approach (original) (raw)
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Pharmacokinetics and pharmacodynamics of ‘old’ polymyxins: what is new?
Diagnostic Microbiology and Infectious Disease, 2012
'Old' colistin and polymyxin B are increasingly used as last-line therapy against multidrugresistant Gram-negative bacteria Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. For intravenous administration, colistin is dosed as its inactive prodrug colistin methanesulfonate (sodium), while polymyxin B is used as its sulfate (active antibacterial). Over the last decade significant progress has been made in understanding their chemistry, pharmacokinetics (PK) and pharmacodynamics (PD). The first scientifically based dosing suggestions are now available for colistin methanesulfonate to generate a desired target steadystate plasma concentration of formed colistin in various categories of critically-ill patients. As simply increasing polymyxin dosage regimens is not an option for optimizing their PK/PD due to nephrotoxicity, combination therapy with other antibiotics has great potential to maximize the efficacy of polymyxins while minimizing emergence of resistance. We must pursue rational approaches to the use of polymyxins and other existing antibiotics through the application of PK/ PD principles.
Pharmacokinetics/pharmacodynamics of colistin and polymyxin B: are we there yet?
Carolina Digital Repository (University of North Carolina at Chapel Hill), 2016
The polymyxin antibiotics [colistin and polymyxin B (PMB)] are increasingly used as a last-line option for the treatment of infections caused by extensively drug-resistant Gram-negative bacteria. Despite having similar structures and antibacterial activity in vitro, the two clinically available polymyxins have very different pharmacological properties, as colistin (polymyxin E) is intravenously administered to patients in the form of an inactive prodrug colistin methanesulphonate (sodium). This review will discuss recent progress in the pharmacokinetics/ pharmacodynamics and toxicity of colistin and PMB, the factors that affect their pharmacological profiles, and the challenges for the effective use of both polymyxins. Strategies are proposed for optimising their clinical utility based upon the recent pharmacological studies in vitro, in animals and patients. In the 'bad bugs, no drugs' era, polymyxins are a critically important component of the antibiotic armamentarium against difficult-to-treat Gram-negative 'superbugs'. Rational approaches to the use of polymyxins must be pursued to increase their effectiveness and to minimise resistance and toxicity.
Clinical Infectious Diseases, 2005
The emergence of multidrug-resistant gram-negative bacteria and the lack of new antibiotics to combat them have led to the revival of polymyxins, an old class of cationic, cyclic polypeptide antibiotics. Polymyxin B and polymyxin E (colistin) are the 2 polymyxins used in clinical practice. Most of the reintroduction of polymyxins during the last few years is related to colistin. The polymyxins are active against selected gram-negative bacteria, including Acinetobacter species, Pseudomonas aeruginosa, Klebsiella species, and Enterobacter species. These drugs have been used extensively worldwide for decades for local use. However, parenteral use of these drugs was abandoned ∼20 years ago in most countries, except for treatment of patients with cystic fibrosis, because of reports of common and serious nephrotoxicity and neurotoxicity. Recent studies of patients who received intravenous polymyxins for the treatment of serious P. aeruginosa and Acinetobacter baumannii infections of various types, including pneumonia, bacteremia, and urinary tract infections, have led to the conclusion that these antibiotics have acceptable effectiveness and considerably less toxicity than was reported in old studies.
Polymyxin Combinations: Pharmacokinetics and Pharmacodynamics for Rationale Use
Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 2015
Since their reintroduction into the clinic in the 1980s, the polymyxin antibiotics colistin-administered intravenously as an inactive prodrug, colistin methanesulfonate (CMS)-and polymyxin B have assumed an important role as salvage therapy for otherwise untreatable gram-negative infections. However, the emerging pharmacodynamic and pharmacokinetic data on CMS/colistin and polymyxin B indicate that polymyxin monotherapy is unlikely to generate plasma concentrations that are reliably efficacious. Additionally, regrowth and the emergence of resistance with monotherapy are commonly reported even when concentrations exceed those achieved clinically. Given this situation, polymyxin combination therapy, which is increasingly being used clinically, has been suggested as a possible means of increasing antimicrobial activity and reducing the development of resistance. Although considerable in vitro data support this view, investigations of polymyxin combination therapy in patients have only recently commenced. The currently available clinical data for polymyxin combinations are generally limited to retrospective analyses and small, low-powered, prospective studies using traditional dosage regimens that achieve low plasma concentrations. Considering the potential for rapid development of resistance to polymyxins, well-designed clinical trials that include higher-dose polymyxin regimens are urgently required to provide a more definitive answer regarding the role of polymyxin combination therapy compared with monotherapy. In this article, we provide an overview of key in vitro and clinical investigations examining CMS/colistin and polymyxin B combination therapy.
The Lancet Infectious Diseases, 2015
In the face of diminishing therapeutic options for the treatment of infections caused by multidrug-resistant, Gramnegative bacteria, clinicians are increasingly using colistin and polymyxin B. These antibiotics became available clinically in the 1950s, when understanding of antimicrobial pharmacology and regulatory requirements for approval of drugs was substantially less than today. At the 1st International Conference on Polymyxins in Prato, Italy, 2013, participants discussed a set of key objectives that were developed to explore the factors aff ecting the safe and eff ective use of polymyxins, identify the gaps in knowledge, and set priorities for future research. Participants identifi ed several factors that aff ect the optimum use of polymyxins, including: confusion caused by several diff erent conventions used to describe doses of colistin; an absence of appropriate pharmacopoeial standards for polymyxins; outdated and diverse product information; and uncertainties about susceptibility testing and breakpoints. High-priority areas for research included: better defi nition of the eff ectiveness of polymyxin-based combination therapy compared with monotherapy via well designed, randomised controlled trials; examination of the relative merits of colistin versus polymyxin B for various types of infection; investigation of pharmacokinetics in special patient populations; and defi nition of the role of nebulised polymyxins alone or in combination with intravenous polymyxins for the treatment of pneumonia. The key areas identifi ed provide a roadmap for action regarding the continued use of polymyxins, and are intended to help with the eff ective and safe use of these important, last-line antibiotics.
Frontiers in Pharmacology, 2022
The latest PK/PD findings have demonstrated negligible efficacy of intravenous polymyxins against pulmonary infections. We investigated pharmacokinetic/pharmacodynamic (PK/ PD)-based breakpoints of polymyxin B for bloodstream infections and the rationality of the recent withdrawal of polymyxin susceptibility breakpoints by the CLSI. Polymyxin B pharmacokinetic data were obtained from a phase I clinical trial in healthy Chinese subjects and population pharmacokinetic parameters were employed to determine the exposure of polymyxin B at steady state. MICs of 1,431 recent clinical isolates of Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae collected from across China were determined. Monte-Carlo simulations were performed for various dosing regimens (0.42-1.5 mg/kg/12 h via 1 or 2-h infusion). The probability of target attainment, PK/PD breakpoints and cumulative fraction of response were determined for each bacterial species. MIC 90 of polymyxin B was 1 mg/L for P. aeruginosa and 0.5 mg/L for A. baumannii and K. pneumoniae. With the recommended polymyxin B dose of 1.5-2.5 mg/kg/day, the PK/PD susceptible breakpoints for P. aeruginosa, A. baumannii and K. pneumoniae were 2, 1 and 1 mg/L respectively for bloodstream infection. For Chinese patients, polymyxin B dosing regimens of 0.75-1.5 mg/kg/12 h for P. aeruginosa and 1-1.5 mg/kg/12 h for A. baumannii and K. pneumoniae were appropriate. Breakpoint determination should consider the antimicrobial PK/PD at infection site and delivery route. The recent withdrawal of polymyxin susceptible breakpoint by CLSI primarily based on poor efficacy against lung infections needs to be reconsidered for bloodstream infections.
Optimizing Polymyxin Combinations Against Resistant Gram-Negative Bacteria
Infectious diseases and therapy, 2015
Polymyxin combination therapy is increasingly used clinically. However, systematic investigations of such combinations are a relatively recent phenomenon. The emerging pharmacodynamic (PD) and pharmacokinetic (PK) data on CMS/colistin and polymyxin B suggest that caution is required with monotherapy. Given this situation, polymyxin combination therapy has been suggested as a possible way to increase bacterial killing and reduce the development of resistance. Considerable in vitro data have been generated in support of this view, particularly recent studies utilizing dynamic models. However, most existing animal data are of poor quality with major shortcomings in study design, while clinical data are generally limited to retrospective analysis and small, low-power, prospective studies. This article provides an overview of clinical and preclinical investigations of CMS/colistin and polymyxin B combination therapy.
Comparative Pharmacokinetic Profiling of Different Polymyxin B Components
Polymyxin B is increasingly used as a treatment of last resort for multidrug-resistant Gram-negative infections. Despite being available as a mixture of several structurally related analogues, the properties are commonly reported as an aggregate of the individual components. We compared the pharmacokinetics of individual polymyxin B components in an animal model and in humans. There were no considerable differences observed in the pharmacokinetics among major components of polymyxin B. Combining different components for pharmacokinetic analysis appeared reasonable.