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Polymyxin pharmacology

Thien B Tran, Tony Velkov, Roger L Nation, Alan Forrest, Brian T Tsuji, Phillip J Bergen, Jian Li
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...
December 2016: International Journal of Antimicrobial Agents
Sherif M Sabry Hassan, Magdy F Youakim, Ayman Abou Elenein Rizk, Charity Thomann, Zulfiqar Ahmad
AIMS: Although once a common antibiotic, polymyxin E fell out of favor after reports of its nephrotoxicity. However, recent concerns with gram-negative bacteria, which are resistant to multiple antibiotics, have resulted in increased interest in polymyxin E. Silybin is a known antihepatotoxic drug and may have potential for protecting the kidney from polymyxin E. Therefore, the aim of the current study was to evaluate whether silybin affected the damages produced by polymyxin E on the rat kidney...
August 30, 2016: Neurourology and Urodynamics
Kade D Roberts, Mohammad A K Azad, Jiping Wang, Andrew S Horne, Philip E Thompson, Roger L Nation, Tony Velkov, Jian Li
Polymyxin B and colistin are currently used as a 'last-line' treatment for multidrug-resistant Gram-negative bacteria. However very little is known about the pharmacological differences between polymyxin B1, polymyxin B2, colistin A, colistin B, the major cyclic lipopeptides components present in polymyxin B and colistin products. Here, we report on the in vitro and in vivo antimicrobial activity and toxicity of these major lipopeptide components. All four lipopeptides had comparable MICs (<0.125-4 mg/L) against a panel of clinical Gram-negative isolates...
November 13, 2015: ACS Infectious Diseases
Henrietta Abodakpi, Jie Gohlke, Kai-Tai Chang, Diana S-L Chow, Vincent H Tam
To enhance our understanding of the pharmacological properties of polymyxin B, serum protein binding for polymyxin B1, B2, and B3 and for isoleucine-polymyxin B1 was evaluated. Using equilibrium dialysis and ultrafiltration, comparable protein binding was found in all 4 components of polymyxin B (92% to 99%). Protein binding in human serum was further assessed using a functional assay, the results of which were in general agreement with previous findings (approximately 90%).
November 2015: Antimicrobial Agents and Chemotherapy
Mohammad A K Azad, Kade D Roberts, Heidi H Yu, Boyin Liu, Alice V Schofield, Simon A James, Daryl L Howard, Roger L Nation, Kelly Rogers, Martin D de Jonge, Philip E Thompson, Jing Fu, Tony Velkov, Jian Li
Polymyxin is the last-line therapy against Gram-negative 'superbugs'; however, dose-limiting nephrotoxicity can occur in up to 60% of patients after intravenous administration. Understanding the accumulation and concentration of polymyxin within renal tubular cells is essential for the development of novel strategies to ameliorate its nephrotoxicity and to develop safer, new polymyxins. We designed and synthesized a novel dual-modality iodine-labeled fluorescent probe for quantitative mapping of polymyxin in kidney proximal tubular cells...
February 3, 2015: Analytical Chemistry
Bruna Feltrin Antoniazzi, Carine Weber Pires, Carmela Rampazzo Bresolin, Rita Niederauer Weiss, Juliana Rodrigues Praetzel
Guedes-Pinto paste is the filling material most employed in Brazil for endodontic treatment of deciduous teeth; however, the Rifocort® ointment has been removed. Thus, the aim of this study was to investigate the antimicrobial potential of filling pastes, by proposing three new pharmacological associations to replace Rifocort® ointment with drugs of already established antimicrobial power: Nebacetin® ointment, 2% Chlorhexidine Gluconate gel, and Maxitrol® ointment. A paste composed of Iodoform, Rifocort® ointment and Camphorated Paramonochlorophenol (CPC) was employed as the gold standard (G1)...
2015: Brazilian Oral Research
Roger L Nation, Jian Li, Otto Cars, William Couet, Michael N Dudley, Keith S Kaye, Johan W Mouton, David L Paterson, Vincent H Tam, Ursula Theuretzbacher, Brian T Tsuji, John D Turnidge
In the face of diminishing therapeutic options for the treatment of infections caused by multidrug-resistant, Gram-negative 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 affecting the safe and effective use of polymyxins, identify the gaps in knowledge, and set priorities for future research...
February 2015: Lancet Infectious Diseases
H Nimenya, A Delaunois, D La Duong, S Bloden, J Defour, B Nicks, M Ansay
During the treatment of fish diseases, drugs which inhibit the nitrification process can cause acute ammonia toxicity. The same phenomenon can occur when fish are put into a tank without active cultures of nitrifying bacteria. The purpose of this study was to quantify the inhibitory effects of 15 pharmacological agents, which are often used as therapeutic agents in ichthyopathology, on ammonia removal and nitrate production in a simple closed aquatic system. The experiments were conducted in polyethylene bags containing activated biofilters and synthetic water solutions, held in a water bath...
January 1999: Alternatives to Laboratory Animals: ATLA
Patrick M Honoré, Rita Jacobs, Olivier Joannes-Boyau, Stijn Lochy, Willem Boer, Elisabeth De Waele, Viola Van Gorp, Jouke De Regt, Vincent Collin, Herbert D Spapen
Polymyxins are 'old' antimicrobials which were abandoned for almost 30 years because of significant renal and neurological toxicity. However, the alarming rise in multiresistant Gram-negative bacterial infections worldwide has revived interest in these 'forgotten' agents. Colistin (polymyxin E) is one of the main antibiotics of this class. It is most often administered as the prodrug colistimethate sodium. Doses for treatment of systemic infections in adults range between 3 and 9 million IU per day. Colistin is increasingly used to treat pneumonia and bacteremia in critically ill patients...
2014: Blood Purification
Rebecca J Malott, Chia-Hung Wu, Tracy D Lee, Trevor J Hird, Nathan F Dalleska, James E A Zlosnik, Dianne K Newman, David P Speert
Burkholderia cepacia complex (Bcc) pulmonary infections in people living with cystic fibrosis (CF) are difficult to treat because of the extreme intrinsic resistance of most isolates to a broad range of antimicrobials. Fosmidomycin is an antibacterial and antiparasitic agent that disrupts the isoprenoid biosynthesis pathway, a precursor to hopanoid biosynthesis. Hopanoids are involved in membrane stability and contribute to polymyxin resistance in Bcc bacteria. Checkerboard MIC assays determined that although isolates of the Bcc species B...
September 2014: Antimicrobial Agents and Chemotherapy
Roger L Nation, Tony Velkov, Jian Li
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...
July 1, 2014: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Zakuan Z Deris, James D Swarbrick, Kade D Roberts, Mohammad A K Azad, Jesmin Akter, Andrew S Horne, Roger L Nation, Kelly L Rogers, Phillip E Thompson, Tony Velkov, Jian Li
The dry antibiotic development pipeline coupled with the emergence of multidrug resistant Gram-negative 'superbugs' has driven the revival of the polymyxin lipopeptide antibiotics. Polymyxin resistance implies a total lack of antibiotics for the treatment of life-threatening infections. The lack of molecular imaging probes that possess native polymyxin-like antibacterial activity is a barrier to understanding the resistance mechanisms and the development of a new generation of polymyxin lipopeptides. Here we report the regioselective modification of the polymyxin B core scaffold at the N-terminus with the dansyl fluorophore to generate an active probe that mimics polymyxin B pharmacologically...
April 16, 2014: Bioconjugate Chemistry
Charlotte Sahlberg Bang, Annica Kinnunen, Marie Karlsson, Anna Önnberg, Bo Söderquist, Katarina Persson
BACKGROUND: Nitric oxide (NO) is produced as part of the host immune response to bacterial infections, including urinary tract infections. The enzyme flavohemoglobin, coded by the hmp gene, is involved in protecting bacterial cells from the toxic effects of NO and represents a potentially interesting target for development of novel treatment concepts against resistant uropathogenic bacteria. The aim of the present study was to investigate if the in vitro antibacterial effects of NO can be enhanced by pharmacological modulation of the enzyme flavohemoglobin...
2014: BMC Microbiology
Mia Gisselbaek, Jérôme Pugin, Gordana Pavlovic
Sepsis and its complications remain the principal cause of death in intensive care units, and is associated with high costs. Protocolized care of septic shock has however lately been associated with decreased death rates, but to date there is still no specific treatment for sepsis. Pharmacologic therapies aiming at blocking the action of bacterial endotoxin or its receptor have been largely disappointing. Epuration of circulating endotoxin using hemoadsorption on polymyxin columns is a new treatment in septic shock showing encouraging preliminary results...
December 11, 2013: Revue Médicale Suisse
Juan Wang, Xiaoran Feng, Youjia Zeng, Jinjin Fan, Juan Wu, Zhijian Li, Xinhui Liu, Rong Huang, Fengxian Huang, Xueqing Yu, Xiao Yang
BACKGROUND: Host cell autophagy is implicated in the control of intracellular pathogen. Escherichia coli (E.coli) is the most common organism caused single-germ enterobacterial peritonitis during peritoneal dialysis. In this study, we investigated autophagy of peritoneal mesothelial cells and its role in defense against E.coli. RESULTS: Autophagy in human peritoneal mesothelial cell line (HMrSV5) was induced by lipopolysaccharide (LPS) in a dose-dependent and time-dependent way, which was demonstrated by increased expression of Beclin-1 and light chain 3 (LC3)-II, the accumulation of punctate green fluorescent protein-LC3, and a higher number of monodansylcadaverine-labeled autophagic vacuoles...
2013: BMC Microbiology
Omar M El-Halfawy, Miguel A Valvano
The overall antibiotic resistance of a bacterial population results from the combination of a wide range of susceptibilities displayed by subsets of bacterial cells. Bacterial heteroresistance to antibiotics has been documented for several opportunistic Gram-negative bacteria, but the mechanism of heteroresistance is unclear. We use Burkholderia cenocepacia as a model opportunistic bacterium to investigate the implications of heterogeneity in the response to the antimicrobial peptide polymyxin B (PmB) and also other bactericidal antibiotics...
2013: PloS One
Zahra Kassamali, John C Rotschafer, Ronald N Jones, Randall A Prince, Larry H Danziger
We currently face a lack of new antimicrobial therapies in an era of increasingly common multidrug-resistant (MDR) bacteria. The polymyxins have become last-line treatments for patients with MDR bacterial infections. An increasing body of published literature has attempted to answer questions about dosing, pharmacology, and susceptibility testing of these drugs, yet each takes for granted purity and potency of the 2 available polymyxin products. In the case of polymyxin B, true potency may vary by as much as 40% from the content reported in prescribing information...
September 2013: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Tony Velkov, Kade D Roberts, Roger L Nation, Philip E Thompson, Jian Li
Increasing antibiotic resistance in Gram-negative bacteria, particularly in Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae, presents a global medical challenge. No new antibiotics will be available for these 'superbugs' in the near future due to the dry antibiotic discovery pipeline. Colistin and polymyxin B are increasingly used as the last-line therapeutic options for treatment of infections caused by multidrug-resistant Gram-negative bacteria. This article surveys the significant progress over the last decade in understanding polymyxin chemistry, mechanisms of antibacterial activity and resistance, structure-activity relationships and pharmacokinetics/pharmacodynamics...
June 2013: Future Microbiology
Lee Sun New, Tze Peng Lim, Jing Wen Oh, Gavin Jia Sheng Cheah, Andrea L Kwa, Eric Chun Yong Chan
With increasing multidrug resistance coupled to a poor development pipeline, clinicians are exploring antimicrobial combinations to improve treatment outcomes. In vitro hollow-fiber infection model (HFIM) is employed to simulate human in vivo drug clearance and investigate pharmacodynamic synergism of antibiotics. Our overarching aim was to optimize the HFIM-based pharmacokinetic (PK) assay by using rifampicin and polymyxin B as probe drugs. An ultrapressure liquid chromatography tandem mass spectrometry method was validated for the quantification of rifampicin and polymyxin B components...
February 2013: Analytical and Bioanalytical Chemistry
N Xiong, M T Brewer, K L Anderson, S A Carlson
This study assessed the involvement of lipopolysaccharide (LPS) in the non-typhoidal Salmonella encephalopathy (NTSE) caused by a unique isolate of Salmonella enterica serovar Saint-paul (SstpNPG). NTSE was prevented by genetic (deletion of murE) or pharmacologic (polymyxin) disruption of LPS on SstpNPG although the disruption of LPS did not deter brain penetration of the strain. This is the first study to demonstrate that LPS is involved in the manifestations of NTSE.
February 22, 2013: Veterinary Microbiology
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