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Pharmacotherapy Jan 2019The polymyxin antibiotics colistin (polymyxin E) and polymyxin B became available in the 1950s and thus did not undergo contemporary drug development procedures. Their...
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...
The polymyxin antibiotics colistin (polymyxin E) and polymyxin B became available in the 1950s and thus did not undergo contemporary drug development procedures. Their clinical use has recently resurged, assuming an important role as salvage therapy for otherwise untreatable gram-negative infections. Since their reintroduction into the clinic, significant confusion remains due to the existence of several different conventions used to describe doses of the polymyxins, differences in their formulations, outdated product information, and uncertainties about susceptibility testing that has led to lack of clarity on how to optimally utilize and dose colistin and polymyxin B. We report consensus therapeutic guidelines for agent selection and dosing of the polymyxin antibiotics for optimal use in adult patients, as endorsed by the American College of Clinical Pharmacy (ACCP), Infectious Diseases Society of America (IDSA), International Society of Anti-Infective Pharmacology (ISAP), Society for Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). The European Society for Clinical Microbiology and Infectious Diseases (ESCMID) endorses this document as a consensus statement. The overall conclusions in the document are endorsed by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). We established a diverse international expert panel to make therapeutic recommendations regarding the pharmacokinetic and pharmacodynamic properties of the drugs and pharmacokinetic targets, polymyxin agent selection, dosing, dosage adjustment and monitoring of colistin and polymyxin B, use of polymyxin-based combination therapy, intrathecal therapy, inhalation therapy, toxicity, and prevention of renal failure. The treatment guidelines provide the first ever consensus recommendations for colistin and polymyxin B therapy that are intended to guide optimal clinical use.
Topics: Adult; Anti-Bacterial Agents; Colistin; Dose-Response Relationship, Drug; Gram-Negative Bacterial Infections; Humans; Polymyxin B; Salvage Therapy
PubMed: 30710469
DOI: 10.1002/phar.2209 -
International Journal of Antimicrobial... Dec 2016The polymyxin antibiotics [colistin and polymyxin B (PMB)] are increasingly used as a last-line option for the treatment of infections caused by extensively... (Review)
Review
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.
Topics: Acute Kidney Injury; Anti-Bacterial Agents; Colistin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Polymyxin B
PubMed: 27793510
DOI: 10.1016/j.ijantimicag.2016.09.010 -
Critical Care (London, England) Feb 2023Sepsis and septic shock remain drivers for morbidity and mortality in critical illness. The clinical picture of patients presenting with these syndromes evolves rapidly... (Review)
Review
Sepsis and septic shock remain drivers for morbidity and mortality in critical illness. The clinical picture of patients presenting with these syndromes evolves rapidly and may be characterised by: (a) microbial host invasion, (b) establishment of an infection focus, (c) opsonisation of bacterial products (e.g. lipopolysaccharide), (d) recognition of pathogens resulting in an immune response, (e) cellular and humoral effects of circulating pathogen and pathogen products, (f) immunodysregulation and endocrine effects of cytokines, (g) endothelial and organ damage, and (h) organ crosstalk and multiple organ dysfunction. Each step may be a potential target for a specific therapeutic approach. At various stages, extracorporeal therapies may target circulating molecules for removal. In sequence, we could consider: (a) pathogen removal from the circulation with affinity binders and cartridges (specific), (b) circulating endotoxin removal by haemoperfusion with polymyxin B adsorbers (specific), (c) cytokine removal by haemoperfusion with sorbent cartridges or adsorbing membranes (non-specific), (d) extracorporeal organ support with different techniques for respiratory and cardiac support (CO removal or extracorporeal membrane oxygenation), and renal support (haemofiltration, haemodialysis, or ultrafiltration). The sequence of events and the use of different techniques at different points for specific targets will likely require trials with endpoints other than mortality. Instead, the primary objectives should be to achieve the desired action by using extracorporeal therapy at a specific point.
Topics: Humans; Endotoxins; Hemoperfusion; Polymyxin B; Sepsis; Shock, Septic; Extracorporeal Membrane Oxygenation
PubMed: 36750878
DOI: 10.1186/s13054-023-04310-2 -
Critical Care (London, England) May 2022Blood purification through the removal of plasma solutes by adsorption to beads of charcoal or resins contained in a cartridge (hemoperfusion) has a long and imperfect... (Review)
Review
BACKGROUND
Blood purification through the removal of plasma solutes by adsorption to beads of charcoal or resins contained in a cartridge (hemoperfusion) has a long and imperfect history. Developments in production and coating technology, however, have recently increased the biocompatibility of sorbents and have spurred renewed interest in hemoperfusion.
METHODS
We performed a narrative assessment of the literature with focus on the technology, characteristics, and principles of hemoperfusion. We assessed publications in ex vivo, animal, and human studies. We synthesized such literature in a technical and state-of-the-art summary.
RESULTS
Early hemoperfusion studies were hampered by bioincompatibility. Recent technology, however, has improved its safety. Hemoperfusion has been used with positive effects in chronic dialysis and chronic liver disease. It has also demonstrated extraction of a variety of toxins and drugs during episodes of overdose. Trials with endotoxin binding polymyxin B have shown mixed results in septic shock and are under active investigation. The role of non-selective hemoperfusion in sepsis or inflammation remains. Although new technologies have made sorbents more biocompatible, the research agenda in the field remains vast.
CONCLUSION
New sorbents markedly differ from those used in the past because of greater biocompatibility and safety. Initial studies of novel sorbent-based hemoperfusion show some promise in specific chronic conditions and some acute states. Systematic studies of novel sorbent-based hemoperfusion are now both necessary and justified.
Topics: Adsorption; Animals; Hemoperfusion; Humans; Polymyxin B; Sepsis; Shock, Septic
PubMed: 35549999
DOI: 10.1186/s13054-022-04009-w -
JAMA Oct 2018Polymyxin B hemoperfusion reduces blood endotoxin levels in sepsis. Endotoxin activity can be measured in blood with a rapid assay. Treating patients with septic shock... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Polymyxin B hemoperfusion reduces blood endotoxin levels in sepsis. Endotoxin activity can be measured in blood with a rapid assay. Treating patients with septic shock and elevated endotoxin activity using polymyxin B hemoperfusion may improve clinical outcomes.
OBJECTIVE
To test whether adding polymyxin B hemoperfusion to conventional medical therapy improves survival compared with conventional therapy alone among patients with septic shock and high endotoxin activity.
DESIGN, SETTING, AND PARTICIPANTS
Multicenter, randomized clinical trial involving 450 adult critically ill patients with septic shock and an endotoxin activity assay level of 0.60 or higher enrolled between September 2010 and June 2016 at 55 tertiary hospitals in North America. Last follow-up was June 2017.
INTERVENTIONS
Two polymyxin B hemoperfusion treatments (90-120 minutes) plus standard therapy completed within 24 hours of enrollment (n = 224 patients) or sham hemoperfusion plus standard therapy (n = 226 patients).
MAIN OUTCOMES AND MEASURES
The primary outcome was mortality at 28 days among all patients randomized (all participants) and among patients randomized with a multiple organ dysfunction score (MODS) of more than 9.
RESULTS
Among 450 eligible enrolled patients (mean age, 59.8 years; 177 [39.3%] women; mean APACHE II score 29.4 [range, 0-71 with higher scores indicating greater severity), 449 (99.8%) completed the study. Polymyxin B hemoperfusion was not associated with a significant difference in mortality at 28 days among all participants (treatment group, 84 of 223 [37.7%] vs sham group 78 of 226 [34.5%]; risk difference [RD], 3.2%; 95% CI, -5.7% to 12.0%; relative risk [RR], 1.09; 95% CI, 0.85-1.39; P = .49) or in the population with a MODS of more than 9 (treatment group, 65 of 146 [44.5%] vs sham, 65 of 148 [43.9%]; RD, 0.6%; 95% CI, -10.8% to 11.9%; RR, 1.01; 95% CI, 0.78-1.31; P = .92). Overall, 264 serious adverse events were reported (65.1% treatment group vs 57.3% sham group). The most frequent serious adverse events were worsening of sepsis (10.8% treatment group vs 9.1% sham group) and worsening of septic shock (6.6% treatment group vs 7.7% sham group).
CONCLUSIONS AND RELEVANCE
Among patients with septic shock and high endotoxin activity, polymyxin B hemoperfusion treatment plus conventional medical therapy compared with sham treatment plus conventional medical therapy did not reduce mortality at 28 days.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01046669.
Topics: APACHE; Adult; Aged; Anti-Bacterial Agents; Endotoxins; Female; Hospital Mortality; Humans; Male; Middle Aged; Polymyxin B; Shock, Septic; Survival Analysis
PubMed: 30304428
DOI: 10.1001/jama.2018.14618 -
Natural Product Reports Mar 2017Covering: 1975 up to the end of 2016The decline in the discovery and development of novel antibiotics has resulted in the emergence of bacteria that are resistant to... (Review)
Review
Covering: 1975 up to the end of 2016The decline in the discovery and development of novel antibiotics has resulted in the emergence of bacteria that are resistant to almost all available antibiotics. Currently, polymyxin B and E (colistin) are being used as the last-line therapy against life-threatening infections, unfortunately resistance to polymyxins in both the community and hospital setting is becoming more common. Octapeptins are structurally related non-ribosomal lipopeptide antibiotics that do not exhibit cross-resistance with polymyxins and have a broader spectrum of activity that includes Gram-positive bacteria. This makes them a precious and finite resource for the development of new antibiotics against these problematic polymyxin-resistant Gram-negative pathogens, in particular Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. This review surveys the progress in understanding octapeptin chemistry, mechanisms of antibacterial activity and biosynthesis. With the lack of cross-resistance and their broad antibacterial activity, the octapeptins represent ideal candidates for the development of a new generation of polymyxin-like lipopeptide antibiotics targeting polymyxin-resistant 'superbugs'.
Topics: Acinetobacter baumannii; Colistin; Drug Resistance, Bacterial; Humans; Klebsiella pneumoniae; Lipopeptides; Molecular Structure; Polymyxin B; Polymyxins; Pseudomonas aeruginosa
PubMed: 28180225
DOI: 10.1039/c6np00113k -
Advances in Experimental Medicine and... 2019Polymyxin B is an antibiotic that shows strong bactericidal activity against Gram-negative bacteria, by binding to and inactivating endotoxin. Systemic administration of... (Review)
Review
Polymyxin B is an antibiotic that shows strong bactericidal activity against Gram-negative bacteria, by binding to and inactivating endotoxin. Systemic administration of polymyxin B in humans is restricted because of its nephrotoxicity and neurotoxicity, and this compound was therefore considered a strong candidate ligand for the extracorporeal selective adsorption of circulating endotoxin in the blood. Toraymyxin® is a direct hemoperfusion column that uses polymyxin B attached to an insoluble carrier to bind endotoxin in the blood. In 1994, the Japanese National Health Insurance system approved the use of Toraymyxin for the treatment of endotoxemia and septic shock.In this chapter, we will review the development, clinical use, and efficacy of Toraymyxin, examine the structure of the Toraymyxin column, and comment on the current position of Toraymyxin in the treatment of severe sepsis and septic shock. We will also highlight some potential new applications of Toraymyxin for pulmonary diseases.
Topics: Anti-Bacterial Agents; Endotoxemia; Endotoxins; Hemoperfusion; Humans; Polymyxin B; Sepsis; Shock, Septic
PubMed: 31364085
DOI: 10.1007/978-3-030-16373-0_19 -
Clinical Infectious Diseases : An... Jul 2014Colistin and polymyxin B have indistinguishable microbiological activity in vitro, but they differ in the form administered parenterally to patients. Polymyxin B is... (Review)
Review
Colistin and polymyxin B have indistinguishable microbiological activity in vitro, but they differ in the form administered parenterally to patients. Polymyxin B is administered directly as the active antibiotic, whereas colistin is administered as the inactive prodrug, colistin methanesulfonate (CMS). CMS must be converted to colistin in vivo, but this occurs slowly and incompletely. Here we summarize the key differences between parenteral CMS/colistin and polymyxin B, and highlight the clinical implications. We put forth the view that overall polymyxin B has superior clinical pharmacological properties compared with CMS/colistin. We propose that in countries such as the United States where parenteral products of both colistin and polymyxin B are available, prospective studies should be conducted to formally examine their relative efficacy and safety in various types of infections and patients. In the meantime, where clinicians have access to both polymyxins, they should carefully consider the relative merits of each in a given circumstance.
Topics: Administration, Intravenous; Anti-Bacterial Agents; Bacterial Infections; Clinical Trials as Topic; Colistin; Humans; Polymyxin B
PubMed: 24700659
DOI: 10.1093/cid/ciu213 -
The Medical Journal of Malaysia Oct 2018Polymyxin B and colistin (polymyxin E) were introduced in clinical practice to treat Gram-negative infections in 1950s but their parenteral use waned in 1970s due to... (Review)
Review
Polymyxin B and colistin (polymyxin E) were introduced in clinical practice to treat Gram-negative infections in 1950s but their parenteral use waned in 1970s due to toxicity concerns. Resurgence of polymyxins use in Malaysia began approximately in 2009 due to a lack of treatment options for MDR Gram negative superbugs such as Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. However, limited experience and a lack of widespread availability of up-to-date dosing guidelines could potentially result in incorrect use of these last resort antibiotics by managing doctors. The recent report of polymyxin resistant strains is also a cause of concern. Herein, we discuss the importance of preserving the efficacy of polymyxins in hospitals, the similarities and differences between polymyxin B and colistin, issues pertaining to current use of polymxyins and strategies to improve polymyxins' prescription. Polymyxins should only be used to treat significant infections, in optimum doses and if possible, in combination with other antibiotics.
Topics: Administration, Intravenous; Anti-Bacterial Agents; Colistin; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Polymyxin B
PubMed: 30350826
DOI: No ID Found -
BMC Infectious Diseases Oct 2021To investigate how to use polymyxin B rationally in order to produce the best efficacy and safety in patients with carbapenem-resistant gram-negative organisms (CRO)...
OBJECTIVE
To investigate how to use polymyxin B rationally in order to produce the best efficacy and safety in patients with carbapenem-resistant gram-negative organisms (CRO) infection.
METHODS
The clinical characteristics and microbiological results of 181 patients caused by CRO infection treated with polymyxin B in the First Affiliated Hospital from July 2018 to May 2020 were retrospectively analyzed. The bacterial clearance rate, clinical efficacy, adverse drug reactions and 28 days mortality were evaluated.
RESULTS
The overall effective rate of 181 patients was 49.72%, the total bacterial clearance rate was 42.0%, and the 28 day all-cause mortality rate was 59.1%. The effective rate and bacterial clearance rate in the group of less than 24 h from the isolation of CRO to the use of polymyxin B were significantly higher than those in the group of more than 24 h. Logistics multivariate regression analysis showed that the predictive factors for effective treatment of CRO with polymyxin B were APACHEII score, duration of polymyxin B treatment, combination of polymyxin B and other antibiotics, and bacterial clearance. 17 cases (9.36%) of acute kidney injury were considered as polymyxin B nephrotoxicity and 4 cases (23.5%) recovered after polymyxin B withdrawal. After 14 days of polymyxin B use, 3 cases of polymyxin B resistance appeared, and there were 2 cases of polymyxin B resistance in the daily dose 1.5 mg/kg/day group.
CONCLUSION
For CRO infection, the treatment of polymyxin B should be early, combined, optimal dose and duration of treatment, which can achieve better clinical efficacy and microbial reactions, and reduce the adverse reactions and drug resistance.
Topics: Anti-Bacterial Agents; Carbapenems; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Polymyxin B; Retrospective Studies
PubMed: 34607561
DOI: 10.1186/s12879-021-06719-y