To see the other types of publications on this topic, follow the link: Polymyxin E.
Journal articles on the topic 'Polymyxin E'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Polymyxin E.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Choi, Soo-Keun, Soo-Young Park, Rumi Kim, Seong-Bin Kim, Choong-Hwan Lee, Jihyun F. Kim, and Seung-Hwan Park. "Identification of a Polymyxin Synthetase Gene Cluster of Paenibacillus polymyxa and Heterologous Expression of the Gene in Bacillus subtilis." Journal of Bacteriology 191, no. 10 (May 15, 2009): 3350–58. http://dx.doi.org/10.1128/jb.01728-08.
Full textAbstract:
ABSTRACT Polymyxin, a long-known peptide antibiotic, has recently been reintroduced in clinical practice because it is sometimes the only available antibiotic for the treatment of multidrug-resistant gram-negative pathogenic bacteria. Lack of information on the biosynthetic genes of polymyxin, however, has limited the study of structure-function relationships and the development of improved polymyxins. During whole genome sequencing of Paenibacillus polymyxa E681, a plant growth-promoting rhizobacterium, we identified a gene cluster encoding polymyxin synthetase. Here, we report the complete sequence of the gene cluster and its function in polymyxin biosynthesis. The gene cluster spanning the 40.6-kb region consists of five open reading frames, designated pmxA, pmxB, pmxC, pmxD, and pmxE. The pmxC and pmxD genes are similar to genes that encode transport proteins, while pmxA, pmxB, and pmxE encode polymyxin synthetases. The insertional disruption of pmxE led to a loss of the ability to produce polymyxin. Introduction of the pmx gene cluster into the amyE locus of the Bacillus subtilis chromosome resulted in the production of polymyxin in the presence of extracellularly added l-2,4-diaminobutyric acid. Taken together, our findings demonstrate that the pmx gene cluster is responsible for polymyxin biosynthesis.
2
Lenhard, Bulman, Tsuji, and Kaye. "Shifting Gears: The Future of Polymyxin Antibiotics." Antibiotics 8, no. 2 (April 12, 2019): 42. http://dx.doi.org/10.3390/antibiotics8020042.
Full textAbstract:
The manuscripts contained in this special edition of Antibiotics represent a current review of the polymyxins as well as highlights from the 3rd International Polymyxin Conference, which was held in Madrid, Spain, April 25 to 26, 2018. The role of the polymyxin antibiotics has evolved over time based on the availability of alternative agents. After high rates of nephrotoxicity caused the drug class to fall out of favor, polymyxins were once against utilized in the 21st century to combat drug-resistant pathogens. However, the introduction of safer agents with activity against drug-resistant organisms has brought the future utility of polymyxins into question. The present review investigates the future niche of polymyxins by evaluating currently available and future treatment options for difficult-to-treat pathogens. The introduction of ceftazidime-avibactam, meropenem-vaborbactam and plazomicin are likely to decrease polymyxin utilization for infections caused by Enterobacteriaceae. Similarly, the availability of ceftolozane-tazobactam will reduce the use of polymyxins to counter multidrug-resistant Pseudomonas aeruginosa. In contrast, polymyxins will likely continue be an important option for combatting carbapenem-resistant Acinetobacter baumannii until better options become commercially available. Measuring polymyxin concentrations in patients and individualizing therapy may be a future strategy to optimize clinical outcomes while minimizing nephrotoxicity. Inhaled polymyxins will continue to be an adjunctive option for pulmonary infections but further clinical trials are needed to clarify the efficacy of inhaled polymyxins. Lastly, safer polymyxin analogs will potentially be an important addition to the antimicrobial armamentarium.
3
Dai, Chongshan, Yang Wang, Gaurav Sharma, Jianzhong Shen, Tony Velkov, and Xilong Xiao. "Polymyxins–Curcumin Combination Antimicrobial Therapy: Safety Implications and Efficacy for Infection Treatment." Antioxidants 9, no. 6 (June 9, 2020): 506. http://dx.doi.org/10.3390/antiox9060506.
Full textAbstract:
The emergence of antimicrobial resistance in Gram-negative bacteria poses a huge health challenge. The therapeutic use of polymyxins (i.e., colistin and polymyxin B) is commonplace due to high efficacy and limiting treatment options for multidrug-resistant Gram-negative bacterial infections. Nephrotoxicity and neurotoxicity are the major dose-limiting factors that limit the therapeutic window of polymyxins; nephrotoxicity is a complication in up to ~60% of patients. The emergence of polymyxin-resistant strains or polymyxin heteroresistance is also a limiting factor. These caveats have catalyzed the search for polymyxin combinations that synergistically kill polymyxin-susceptible and resistant organisms and/or minimize the unwanted side effects. Curcumin—an FDA-approved natural product—exerts many pharmacological activities. Recent studies showed that polymyxins–curcumin combinations showed a synergistically inhibitory effect on the growth of bacteria (e.g., Gram-positive and Gram-negative bacteria) in vitro. Moreover, curcumin co-administration ameliorated colistin-induced nephrotoxicity and neurotoxicity by inhibiting oxidative stress, mitochondrial dysfunction, inflammation and apoptosis. In this review, we summarize the current knowledge-base of polymyxins–curcumin combination therapy and discuss the underlying mechanisms. For the clinical translation of this combination to become a reality, further research is required to develop novel polymyxins–curcumin formulations with optimized pharmacokinetics and dosage regimens.
4
Yun, Bo, Mohammad A. K. Azad, Cameron J. Nowell, Roger L. Nation, Philip E. Thompson, Kade D. Roberts, Tony Velkov, and Jian Li. "Cellular Uptake and Localization of Polymyxins in Renal Tubular Cells Using Rationally Designed Fluorescent Probes." Antimicrobial Agents and Chemotherapy 59, no. 12 (September 21, 2015): 7489–96. http://dx.doi.org/10.1128/aac.01216-15.
Full textAbstract:
ABSTRACTPolymyxins are cyclic lipopeptide antibiotics that serve as a last line of defense against Gram-negative bacterial superbugs. However, the extensive accumulation of polymyxins in renal tubular cells can lead to nephrotoxicity, which is the major dose-limiting factor in clinical use. In order to gain further insights into the mechanism of polymyxin-induced nephrotoxicity, we have rationally designed novel fluorescent polymyxin probes to examine the localization of polymyxins in rat renal tubular (NRK-52E) cells. Our design strategy focused on incorporating a dansyl fluorophore at the hydrophobic centers of the polymyxin core structure. To this end, four novel regioselectively labeled monodansylated polymyxin B probes (MIPS-9541, MIPS-9542, MIPS-9543, and MIPS-9544) were designed, synthesized, and screened for their antimicrobial activities and apoptotic effects against rat kidney proximal tubular cells. On the basis of the assessment of antimicrobial activities, cellular uptake, and apoptotic effects on renal tubular cells, incorporation of a dansyl fluorophore at either position 6 or 7 (MIPS-9543 and MIPS-9544, respectively) of the polymyxin core structure appears to be an appropriate strategy for generating representative fluorescent polymyxin probes to be utilized in intracellular imaging and mechanistic studies. Furthermore, confocal imaging experiments utilizing these probes showed evidence of partial colocalization of the polymyxins with both the endoplasmic reticulum and mitochondria in rat renal tubular cells. Our results highlight the value of these new fluorescent polymyxin probes and provide further insights into the mechanism of polymyxin-induced nephrotoxicity.
5
Poirel, Laurent, Aurélie Jayol, and Patrice Nordmann. "Polymyxins: Antibacterial Activity, Susceptibility Testing, and Resistance Mechanisms Encoded by Plasmids or Chromosomes." Clinical Microbiology Reviews 30, no. 2 (March 8, 2017): 557–96. http://dx.doi.org/10.1128/cmr.00064-16.
Full textAbstract:
SUMMARY Polymyxins are well-established antibiotics that have recently regained significant interest as a consequence of the increasing incidence of infections due to multidrug-resistant Gram-negative bacteria. Colistin and polymyxin B are being seriously reconsidered as last-resort antibiotics in many areas where multidrug resistance is observed in clinical medicine. In parallel, the heavy use of polymyxins in veterinary medicine is currently being reconsidered due to increased reports of polymyxin-resistant bacteria. Susceptibility testing is challenging with polymyxins, and currently available techniques are presented here. Genotypic and phenotypic methods that provide relevant information for diagnostic laboratories are presented. This review also presents recent works in relation to recently identified mechanisms of polymyxin resistance, including chromosomally encoded resistance traits as well as the recently identified plasmid-encoded polymyxin resistance determinant MCR-1. Epidemiological features summarizing the current knowledge in that field are presented.
6
Barth, Natália, Vanessa B. Ribeiro, and Alexandre P. Zavascki. "In VitroActivity of Polymyxin B plus Imipenem, Meropenem, or Tigecycline against KPC-2-Producing Enterobacteriaceae with High MICs for These Antimicrobials." Antimicrobial Agents and Chemotherapy 59, no. 6 (March 23, 2015): 3596–97. http://dx.doi.org/10.1128/aac.00365-15.
Full textAbstract:
ABSTRACTWe evaluated thein vitroactivity of polymyxin B plus imipenem, meropenem, or tigecycline against six KPC-2-producingEnterobacteriaceaestrains with high MICs for these antimicrobial agents. Polymyxin B with carbapenems, especially meropenem, were the most active combinations forKlebsiella pneumoniaeandEnterobacter cloacaeregardless of the polymyxin B concentration used in the time-kill assay. This combination was also synergistic against twoSerratia marcescensstrains that are intrinsically resistant to polymyxins. Polymyxin B and tigecycline also presented synergistic activity in most experiments.
7
Cho, Hyejin, Atanu Naskar, Sohee Lee, Semi Kim, and Kwang-Sun Kim. "A New Surface Charge Neutralizing Nano-Adjuvant to Potentiate Polymyxins in Killing Mcr-1 Mediated Drug-Resistant Escherichia coli." Pharmaceutics 13, no. 2 (February 11, 2021): 250. http://dx.doi.org/10.3390/pharmaceutics13020250.
Full textAbstract:
Resistance to polymyxins when treating multidrug-resistant (MDR) Gram-negative bacterial infections limit therapeutic options. Here, we report the synthesis of a nickel (Ni) doped Zinc oxide (NZO) combined with black phosphorus (BP) (NZB) nanocomposite and its synergistic action with polymyxin B (PolB) against polymyxin-resistant Escherichia coli harboring mobilized colistin resistance (mcr-1) gene. NZB and PolB combination therapy expressed a specific and strong synergy against Mcr-1 expressing E. coli cells. The underlying mechanism of the synergy is the charge neutralization of the E. coli cell surface by NZB, resulting in a more feasible incorporation of PolB to E. coli. The synergistic concentration of NZB with PolB was proved biocompatible. Thus, the NZB is the first biocompatible nano-adjuvant to polymyxins against polymyxin-resistant E. coli cells, recognizing the physical status of bacteria instead of known adjuvants targeting cellular gene products. Therefore, NZB has the potential to revive polymyxins as leading last-resort antibiotics to combat polymyxin-resistant Gram-negative bacterial infections.
8
Jiang, Xukai, Kai Yang, Bing Yuan, Meiling Han, Yan Zhu, Kade D. Roberts, Nitin A. Patil, et al. "Molecular dynamics simulations informed by membrane lipidomics reveal the structure–interaction relationship of polymyxins with the lipid A-based outer membrane of Acinetobacter baumannii." Journal of Antimicrobial Chemotherapy 75, no. 12 (September 10, 2020): 3534–43. http://dx.doi.org/10.1093/jac/dkaa376.
Full textAbstract:
Abstract Background MDR bacteria represent an urgent threat to human health globally. Polymyxins are a last-line therapy against life-threatening Gram-negative ‘superbugs’, including Acinetobacter baumannii. Polymyxins exert antimicrobial activity primarily via permeabilizing the bacterial outer membrane (OM); however, the mechanism of interaction between polymyxins and the OM remains unclear at the atomic level. Methods We constructed a lipid A-based OM model of A. baumannii using quantitative membrane lipidomics data and employed all-atom molecular dynamics simulations with umbrella sampling techniques to elucidate the structure–interaction relationship and thermodynamics governing the penetration of polymyxins [B1 and E1 (i.e. colistin A) representing the two clinically used polymyxins] into the OM. Results Polymyxin B1 and colistin A bound to the A. baumannii OM by the initial electrostatic interactions between the Dab residues of polymyxins and the phosphates of lipid A, competitively displacing the cations from the headgroup region of the OM. Both polymyxin B1 and colistin A formed a unique folded conformation upon approaching the hydrophobic centre of the OM, consistent with previous experimental observations. Polymyxin penetration induced reorientation of the headgroups of the OM lipids near the penetration site and caused local membrane disorganization, thereby significantly increasing membrane permeability and promoting the subsequent penetration of polymyxin molecules into the OM and periplasmic space. Conclusions The thermodynamics governing the penetration of polymyxins through the outer leaflet of the A. baumannii OM were examined and novel structure–interaction relationship information was obtained at the atomic and membrane level. Our findings will facilitate the discovery of novel polymyxins against MDR Gram-negative pathogens.
9
Vaara, Martti, John Fox, Günther Loidl, Osmo Siikanen, Juha Apajalahti, Frank Hansen, Niels Frimodt-Møller, Junya Nagai, Mikihisa Takano, and Timo Vaara. "Novel Polymyxin Derivatives Carrying Only Three Positive Charges Are Effective Antibacterial Agents." Antimicrobial Agents and Chemotherapy 52, no. 9 (June 30, 2008): 3229–36. http://dx.doi.org/10.1128/aac.00405-08.
Full textAbstract:
ABSTRACT The lack of novel antibiotics against gram-negative bacteria has reinstated polymyxins as the drugs of last resort to treat serious infections caused by extremely multiresistant gram-negative organisms. However, polymyxins are nephrotoxic, and this feature may complicate therapy or even require its discontinuation. Like that of aminoglycosides, the nephrotoxicity of polymyxins might be related to the highly cationic nature of the molecule. Colistin and polymyxin B carry five positive charges. Here we show that novel polymyxin derivatives carrying only three positive charges are effective antibacterial agents. NAB739 has a cyclic peptide portion identical to that of polymyxin B, but in the linear portion of the peptide, it carries the threonyl-d-serinyl residue (no cationic charges) instead of the diaminobutyryl-threonyl-diaminobutyryl residue (two cationic charges). The MICs of NAB739 for 17 strains of Escherichia coli were identical, or very close, to those of polymyxin B. Furthermore, NAB739 was effective against other polymyxin-susceptible strains of Enterobacteriaceae and against Acinetobacter baumannii. At subinhibitory concentrations, it dramatically sensitized A. baumannii to low concentrations of antibiotics such as rifampin, clarithromycin, vancomycin, fusidic acid, and meropenem. NAB739 methanesulfonate was a prodrug analogous to colistin methanesulfonate. NAB740 was the most active derivative against Pseudomonas aeruginosa. NAB7061 (linear portion of the peptide, threonyl-aminobutyryl) lacked direct antibacterial activity but sensitized the targets to hydrophobic antibiotics by factors up to 2,000. The affinities of the NAB compounds for isolated rat kidney brush border membrane were significantly lower than that of polymyxin B.
10
Llobet, Enrique, Miguel A. Campos, Paloma Giménez, David Moranta, and José A. Bengoechea. "Analysis of the Networks Controlling the Antimicrobial-Peptide-Dependent Induction of Klebsiella pneumoniae Virulence Factors." Infection and Immunity 79, no. 9 (June 27, 2011): 3718–32. http://dx.doi.org/10.1128/iai.05226-11.
Full textAbstract:
ABSTRACTAntimicrobial peptides (APs) impose a threat to the survival of pathogens, and it is reasonable to postulate that bacteria have developed strategies to counteract them. Polymyxins are becoming the last resort to treat infections caused by multidrug-resistant Gram-negative bacteria and, similar to APs, they interact with the anionic lipopolysaccharide. Given that polymyxins and APs share the initial target, it is possible that bacterial defense mechanisms against polymyxins will be also effective against host APs. We sought to determine whether exposure to polymyxin will increaseKlebsiella pneumoniaeresistance to host APs. Indeed, exposure ofK. pneumoniaeto polymyxin induces cross-resistance not only to polymyxin itself but also to APs present in the airways. Polymyxin treatment upregulates the expression of the capsule polysaccharide operon and the loci required to modify the lipid A with aminoarabinose and palmitate with a concomitant increase in capsule and lipid A species containing such modifications. Moreover, these surface changes contribute to APs resistance and also to polymyxin-induced cross-resistance to APs. Bacterial loads of lipid A mutants in trachea and lungs of intranasally infected mice were lower than those of wild-type strain. PhoPQ, PmrAB, and the Rcs system govern polymyxin-induced transcriptional changes, and there is a cross talk between PhoPQ and the Rcs system. Our findings support the notion thatKlebsiellaactivates a defense program against APs that is controlled by three signaling systems. Therapeutic strategies directed to prevent the activation of this program could be a new approach worth exploring to facilitate the clearance of the pathogen from the airways.
11
Cheah, Soon-Ee, Jian Li, Brian T. Tsuji, Alan Forrest, Jürgen B. Bulitta, and Roger L. Nation. "Colistin and Polymyxin B Dosage Regimens against Acinetobacter baumannii: Differences in Activity and the Emergence of Resistance." Antimicrobial Agents and Chemotherapy 60, no. 7 (April 11, 2016): 3921–33. http://dx.doi.org/10.1128/aac.02927-15.
Full textAbstract:
ABSTRACTInfections caused by multidrug-resistantAcinetobacter baumanniiare a major public health problem, and polymyxins are often the last line of therapy for recalcitrant infections by such isolates. The pharmacokinetics of the two clinically used polymyxins, polymyxin B and colistin, differ considerably, since colistin is administered as an inactive prodrug that undergoes slow conversion to colistin. However, the impact of these substantial pharmacokinetic differences on bacterial killing and resistance emergence is poorly understood. We assessed clinically relevant polymyxin B and colistin dosage regimens against one reference and three clinicalA. baumanniistrains in a dynamic one-compartmentin vitromodel. A new mechanism-based pharmacodynamic model was developed to describe and predict the drug concentrations and viable counts of the total and resistant populations. Rapid attainment of target concentrations was shown to be critical for polymyxin-induced bacterial killing. All polymyxin B regimens achieved peak concentrations of at least 1 mg/liter within 1 h and caused ≥4 log10killing at 1 h. In contrast, the slow rise of colistin concentrations to 3 mg/liter over 48 h resulted in markedly reduced bacterial killing. A significant (4 to 6 log10CFU/ml) amplification of resistant bacterial populations was common to all dosage regimens. The developed mechanism-based model explained the observed bacterial killing, regrowth, and resistance. The model also implicated adaptive polymyxin resistance as a key driver of bacterial regrowth and predicted the amplification of preexisting, highly polymyxin-resistant bacterial populations following polymyxin treatment. Antibiotic combination therapies seem the most promising option for minimizing the emergence of polymyxin resistance.
12
Xu, Qingqing, Teng Xu, Yuan Zhuang, Xiaofen Liu, Ying Li, and Yijian Chen. "In Vivo Development of Polymyxin B Resistance in Klebsiella pneumoniae owing to a 42 bp Deletion in the Sequence of phoQ." BioMed Research International 2020 (April 22, 2020): 1–6. http://dx.doi.org/10.1155/2020/5868479.
Full textAbstract:
Polymyxins resistance has emerged worldwide and is threatening the treatment efficacy of multidrug resistant Klebsiella pneumoniae in humans and animals. In this research, we employed whole-genome sequencing (WGS) to investigate the polymyxin B resistance mechanism in selected polymyxin B-susceptible and polymyxin B-resistant K. pneumoniae, isolated from one patient of Huashan Hospital affiliated to Fudan University. The WGS results showed that the two K. pneumoniae all belong to ST11. The average nucleotide identity between the two K. pneumoniae was nearly 100%. No sense mutations of polymyxins resistance associated genes (pmrA, pmrB, phoP, mgrB) were observed in polymyxin B-resistant K. pneumonia (PRKP) compared to the polymyxin B-susceptible isolate. A 42 bp deletion was found in the sequence of phoQ in PRKP. The deletion of amino acid occurred on the periplasmic domain of PhoQ protein. We speculate that this is the domain that MgrB protein interact with the PhoQ protein and negatively regulate the PhoP/PhoQ system. qRT-PCR analysis revealed an overexpression of the pmrA (6.8-fold), pmrB (151.9-fold), pmrC (14.5-fold), pmrK (287.9-fold), phoP (14.5-fold), and phoQ (16.8-fold) genes in the polymyxin B-resistant isolate compared to the expression of the polymyxin B-susceptible K. pneumoniae isolate, suggesting that the phoQ deletion maybe responsible for the increased expression levels of those genes. In conclusion, this study identified a 42 bp deletion in the sequence of phoQ as being responsible for the overexpression of pmrCAB and pmrHFIJKLM operons, leading to resistance to polymyxin B.
13
Simar, Shelby, Diane Sibley, Deborah Ashcraft, and George Pankey. "Evaluation of the Rapid Polymyxin NP Test for Polymyxin B Resistance Detection Using Enterobacter cloacae and Enterobacter aerogenes Isolates." Journal of Clinical Microbiology 55, no. 10 (July 26, 2017): 3016–20. http://dx.doi.org/10.1128/jcm.00934-17.
Full textAbstract:
ABSTRACT Polymyxin resistance is an increasing problem worldwide. Currently, determining susceptibility to polymyxins is problematic and lengthy. Polymyxins diffuse poorly into agar, potentially giving inaccurate disk diffusion and Etest results. A rapid screening test (2 h) for the detection of polymyxin resistance in Enterobacteriaceae , developed by P. Nordmann and L. Poirel (rapid polymyxin NP test) in 2016, detects glucose metabolization in the presence of polymyxin E (PE) and PB via pH-induced color change. The sensitivity and specificity were 99.3 and 95.4%, respectively, with results obtained in ≤2 h. Our goal was to evaluate this test using PB against larger numbers of Enterobacter . A total of 143 nonduplicate Enterobacter isolates (102 E. cloacae complex, 41 E. aerogenes ) were tested, including 136 collected from Ochsner Health System patients from March to May 2016 and 7 previously determined PB-resistant E. cloacae isolates from JMI Laboratories. MICs were determined via broth microdilution. For the rapid polymyxin NP test, a color change from orange to yellow is positive; a weak/no color change is deemed negative after 4 h. Of 143 Enterobacter isolates, 25 were determined to be PB resistant by broth microdilution (MIC > 2 μg/ml), including all 7 JMI isolates. Of these 25, 7 were positive by the rapid polymyxin NP test (included 3/7 JMI isolates). All 118 isolates determined to be PB susceptible by broth microdilution were NP test negative. The sensitivity and specificity for the rapid polymyxin NP test were 25 and 100%, respectively, compared to broth microdilution. Although the rapid polymyxin NP test is a much faster method (2 to 4 h) for polymyxin resistance determination compared to broth microdilution (16 to 20 h), our study indicates that it may be subject to limitations when testing Enterobacter .
14
Yu, Zhiliang, Wangrong Qin, Jianxun Lin, Shisong Fang, and Juanping Qiu. "Antibacterial Mechanisms of Polymyxin and Bacterial Resistance." BioMed Research International 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/679109.
Full textAbstract:
Multidrug resistance in pathogens is an increasingly significant threat for human health. Indeed, some strains are resistant to almost all currently available antibiotics, leaving very limited choices for antimicrobial clinical therapy. In many such cases, polymyxins are the last option available, although their use increases the risk of developing resistant strains. This review mainly aims to discuss advances in unraveling the mechanisms of antibacterial activity of polymyxins and bacterial tolerance together with the description of polymyxin structure, synthesis, and structural modification. These are expected to help researchers not only develop a series of new polymyxin derivatives necessary for future medical care, but also optimize the clinical use of polymyxins with minimal resistance development.
15
Sampson, Timothy R., Xiang Liu, Max R. Schroeder, Colleen S. Kraft, Eileen M. Burd, and David S. Weiss. "Rapid Killing of Acinetobacter baumannii by Polymyxins Is Mediated by a Hydroxyl Radical Death Pathway." Antimicrobial Agents and Chemotherapy 56, no. 11 (August 20, 2012): 5642–49. http://dx.doi.org/10.1128/aac.00756-12.
Full textAbstract:
ABSTRACTAcinetobacter baumanniiis an opportunistic pathogen that is a cause of clinically significant nosocomial infections. Increasingly, clinical isolates ofA. baumanniiare extensively resistant to numerous antibiotics, and the use of polymyxin antibiotics against these infections is often the final treatment option. Historically, the polymyxins have been thought to kill bacteria through membrane lysis. Here, we present an alternative mechanism based on data demonstrating that polymyxins induce rapid cell death through hydroxyl radical production. Supporting this notion, we found that inhibition of radical production delays the ability of polymyxins to killA. baumannii. Notably, we demonstrate that this mechanism of killing occurs in multidrug-resistant clinical isolates ofA. baumanniiand that this response is not induced in a polymyxin-resistant isolate. This study is the first to demonstrate that polymyxins induce rapid killing ofA. baumanniiand other Gram-negatives through hydroxyl radical production. This significantly augments our understanding of the mechanism of polymyxin action, which is critical knowledge toward the development of adjunctive therapies, particularly given the increasing necessity for treatment with these antibiotics in the clinical setting.
16
Iudin, Dmitrii, Natalia Zashikhina, Elena Demyanova, Viktor Korzhikov-Vlakh, Elena Shcherbakova, Roman Boroznjak, Irina Tarasenko, et al. "Polypeptide Self-Assembled Nanoparticles as Delivery Systems for Polymyxins B and E." Pharmaceutics 12, no. 9 (September 11, 2020): 868. http://dx.doi.org/10.3390/pharmaceutics12090868.
Full textAbstract:
Polymyxins are peptide antibiotics that are highly efficient against many multidrug resistant pathogens. However, the poor stability of polymyxins in the bloodstream requires the administration of high drug doses that, in turn, can lead to polymyxin toxicity. Consequently, different delivery systems have been considered for polymyxins to overcome these obstacles. In this work, we report the development of polymyxin delivery systems based on nanoparticles obtained from the self-assembly of amphiphilic random poly(l-glutamic acid-co-d-phenylalanine). These P(Glu-co-dPhe) nanoparticles were characterized in terms of their size, surface charge, stability, cytotoxicity, and uptake by macrophages. The encapsulation efficiency and drug loading into P(Glu-co-dPhe) nanoparticles were determined for both polymyxin B and E. The release kinetics of polymyxins B and E from nanoformulations was studied and compared in buffer solution and human blood plasma. The release mechanisms were analyzed using a number of mathematical models. The minimal inhibitory concentrations of the nanoformulations were established and compared with those determined for the free antibiotics.
17
Dubashynskaya, Natallia V., and Yury A. Skorik. "Polymyxin Delivery Systems: Recent Advances and Challenges." Pharmaceuticals 13, no. 5 (April 29, 2020): 83. http://dx.doi.org/10.3390/ph13050083.
Full textAbstract:
Polymyxins are vital antibiotics for the treatment of multiresistant Gram-negative ESKAPE pathogen infections. However, their clinical value is limited by their high nephrotoxicity and neurotoxicity, as well as their poor permeability and absorption in the gastrointestinal tract. This review focuses on various polymyxin delivery systems that improve polymyxin bioavailability and reduce drug toxicity through targeted and controlled release. Currently, the most suitable systems for improving oral, inhalation, and parenteral polymyxin delivery are polymer particles, liposomes, and conjugates, while gels, polymer fibers, and membranes are attractive materials for topical administration of polymyxin for the treatment of infected wounds and burns. In general, the application of these systems protects polymyxin molecules from the negative effects of both physiological and pathological factors while achieving higher concentrations at the target site and reducing dosage and toxicity. Improving the properties of polymyxin will be of great interest to researchers who are focused on developing antimicrobial drugs that show increased efficacy and safety.
18
Nation, Roger, Maria Rigatto, Diego Falci, and Alexandre Zavascki. "Polymyxin Acute Kidney Injury: Dosing and Other Strategies to Reduce Toxicity." Antibiotics 8, no. 1 (March 14, 2019): 24. http://dx.doi.org/10.3390/antibiotics8010024.
Full textAbstract:
Polymyxins are valuable antimicrobials for the management of multidrug-resistant Gram-negative bacteria; however, nephrotoxicity associated with these drugs is a very common side effect that occurs during treatment. This article briefly reviews nephrotoxic mechanisms and risk factors for polymyxin-associated acute kidney injury (AKI) and discusses dosing strategies that may mitigate kidney damage without compromising antimicrobial activity. Polymyxins have a very narrow therapeutic window and patients requiring treatment with these drugs are frequently severely ill and have multiple comorbidities, which increases the risk of AKI. Notably, there is a significant overlap between therapeutic and toxic plasma polymyxin concentrations that substantially complicates dose selection. Recent dosing protocols for both colistin and polymyxin B have been developed and may help fine tune dose adjustment of these antibiotics. Minimizing exposure to modifiable risk factors, such as other nephrotoxic agents, is strongly recommended. The dose should be carefully selected, particularly in high-risk patients. The administration of oxidative stress-reducing drugs is a promising strategy to ameliorate polymyxin-associated AKI, but still requires support from clinical studies.
19
Park, Soo-Young, Soo-Keun Choi, Jihoon Kim, Tae-Kwang Oh, and Seung-Hwan Park. "Efficient Production of Polymyxin in the Surrogate Host Bacillus subtilis by Introducing a ForeignectBGene and Disrupting theabrBGene." Applied and Environmental Microbiology 78, no. 12 (March 30, 2012): 4194–99. http://dx.doi.org/10.1128/aem.07912-11.
Full textAbstract:
ABSTRACTIn our previous study,Bacillus subtilisstrain BSK3S, containing a polymyxin biosynthetic gene cluster fromPaenibacillus polymyxa, could produce polymyxin only in the presence of exogenously addedl-2,4-diaminobutyric acid (Dab). The dependence of polymyxin production on exogenous Dab was removed by introducing anectBgene encoding the diaminobutyrate synthase ofP. polymyxainto BSK3S (resulting in strain BSK4). We found, by observing the complete inhibition of polymyxin synthesis when thespo0Agene was knocked out (strain BSK4-0A), that Spo0A is indispensable for the production of polymyxin. Interestingly, theabrB-spo0Adouble-knockout mutant, BSK4-0A-rB, and the singleabrBmutant, BSK4-rB, showed 1.7- and 2.3-fold increases, respectively, in polymyxin production over that of BSK4. These results coincided with the transcription levels ofpmxAin the strains observed by quantitative real-time PCR (qRT-PCR). The AbrB protein was shown to bind directly to the upstream region ofpmxA, indicating that AbrB directly inhibits the transcription of polymyxin biosynthetic genes. The BSK4-rB strain, producing high levels of polymyxin, will be useful for the development and production of novel polymyxin derivatives.
20
Huang, Jiayuan, Chen Li, Jiangning Song, Tony Velkov, Lushan Wang, Yan Zhu, and Jian Li. "Regulating polymyxin resistance in Gram-negative bacteria: roles of two-component systems PhoPQ and PmrAB." Future Microbiology 15, no. 6 (April 2020): 445–59. http://dx.doi.org/10.2217/fmb-2019-0322.
Full textAbstract:
Polymyxins (polymyxin B and colistin) are last-line antibiotics against multidrug-resistant Gram-negative pathogens. Polymyxin resistance is increasing worldwide, with resistance most commonly regulated by two-component systems such as PmrAB and PhoPQ. This review discusses the regulatory mechanisms of PhoPQ and PmrAB in mediating polymyxin resistance, from receiving an external stimulus through to activation of genes responsible for lipid A modifications. By analyzing the reported nonsynonymous substitutions in each two-component system, we identified the domains that are critical for polymyxin resistance. Notably, for PmrB 71% of resistance-conferring nonsynonymous mutations occurred in the HAMP (present in histidine kinases, adenylate cyclases, methyl accepting proteins and phosphatase) linker and DHp (dimerization and histidine phosphotransfer) domains. These results enhance our understanding of the regulatory mechanisms underpinning polymyxin resistance and may assist with the development of new strategies to minimize resistance emergence.
21
Azad, Mohammad A. K., Jesmin Akter, Kelly L. Rogers, Roger L. Nation, Tony Velkov, and Jian Li. "Major Pathways of Polymyxin-Induced Apoptosis in Rat Kidney Proximal Tubular Cells." Antimicrobial Agents and Chemotherapy 59, no. 4 (January 26, 2015): 2136–43. http://dx.doi.org/10.1128/aac.04869-14.
Full textAbstract:
ABSTRACTIdentifying the pathways involved in the apoptotic cell death that is associated with polymyxin-induced nephrotoxicity is crucial for the development of strategies to ameliorate this dose-limiting side effect and for the development of novel safer polymyxins. The primary aim of this study was to identify the major pathways which lead to polymyxin-induced apoptosis in cultured rat kidney proximal tubular cells (NRK-52E). Caspase-3, -8, and -9 were activated by polymyxin B treatment in a concentration-dependent manner. Concentration- and time-dependent expression of FasL and deformation of mitochondrial morphology were revealed following polymyxin B treatment. The proportion of cells with filamentous mitochondria (regular morphology) following an 8-h treatment with 1.0 mM polymyxin B was 56.2% ± 9.7% (n= 3). This was decreased to 30.7% ± 7.5% when the polymyxin B concentration was increased to 2.0 mM. The mitochondrial membrane potential (Δψm) decreased to 14.1% ± 2.9% in the cells treated with 1.0 mM polymyxin B for 24 h (n= 3) compared to that in the untreated control group. Concomitantly, concentration- and time-dependent production of mitochondrial superoxide was also observed. This study is the first to have demonstrated that polymyxin-induced apoptosis is mediated through both the death receptor and mitochondrial pathways in cultured renal tubular cells. It provides key information not only for the amelioration of polymyxin-induced nephrotoxicity but also for the discovery of novel safer polymyxin-like antibiotics against Gram-negative “superbugs.”
22
Jayol, Aurélie, Véronique Dubois, Laurent Poirel, and Patrice Nordmann. "Rapid Detection of Polymyxin-Resistant Enterobacteriaceae from Blood Cultures." Journal of Clinical Microbiology 54, no. 9 (June 15, 2016): 2273–77. http://dx.doi.org/10.1128/jcm.00918-16.
Full textAbstract:
Enterobacterial strains resistant to polymyxins are being increasingly reported worldwide. The conventional methods for detection of colistin-resistant isolates such as broth microdilution remain time-consuming (24 to 48 h), and methods such as disc diffusion and Etest are not reliable. Recently, the rapid polymyxin NP test was developed for rapid identification of polymyxin-resistantEnterobacteriaceae. This test is based on the detection of glucose metabolism related to bacterial growth in the presence of a defined concentration of colistin (or polymyxin B). The formation of acid metabolites is evidenced by a color change of a pH indicator (red phenol) in less than 2 h. In this study, the polymyxin NP test was evaluated for detection of colistin-resistantEnterobacteriaceaedirectly from blood cultures. The test was performed with 73 blood culture sets (either spiked or clinical blood cultures) with various enterobacterial species. The test exhibited excellent discrimination between polymyxin-resistant and polymyxin-susceptible enterobacterial isolates, and results are obtained from blood cultures within 4 h. It is easy to perform and requires neither subculture nor a centrifugation step. This test is rapid, specific, and sensitive and allows early identification of polymyxin-resistantEnterobacteriaceaedirectly from blood cultures.
23
Gallardo-Godoy, Alejandra, Karl Hansford, Craig Muldoon, Bernd Becker, Alysha Elliott, Johnny Huang, Ruby Pelingon, Mark Butler, Mark Blaskovich, and Matthew Cooper. "Structure-Function Studies of Polymyxin B Lipononapeptides." Molecules 24, no. 3 (February 2, 2019): 553. http://dx.doi.org/10.3390/molecules24030553.
Full textAbstract:
The emerging threat of infections caused by highly drug-resistant bacteria has prompted a resurgence in the use of the lipodecapeptide antibiotics polymyxin B and colistin as last resort therapies. Given the emergence of resistance to these drugs, there has also been a renewed interest in the development of next generation polymyxins with improved therapeutic indices and spectra of action. We report structure-activity studies of 36 polymyxin lipononapeptides structurally characterised by an exocyclic FA-Thr2-Dab3 lipodipeptide motif instead of the native FA-Dab1-Thr2-Dab3 tripeptide motif found in polymyxin B, removing one of the positively charged residues believed to contribute to nephrotoxicity. The compounds were prepared by solid phase synthesis using an on-resin cyclisation approach, varying the fatty acid and the residues at position 2 (P2), P3 and P4, then assessing antimicrobial potency against a panel of Gram-negative bacteria, including polymyxin-resistant strains. Pairwise comparison of N-acyl nonapeptide and decapeptide analogues possessing different fatty acids demonstrated that antimicrobial potency is strongly influenced by the N-terminal L-Dab-1 residue, contingent upon the fatty acid. This study highlights that antimicrobial potency may be retained upon truncation of the N-terminal L-Dab-1 residue of the native exocyclic lipotripeptide motif found in polymyxin B. The strategy may aid in the design of next generation polymyxins.
24
Dubrovskaya, Yanina, Ting-Yi Chen, Marco R. Scipione, Diana Esaian, Michael S. Phillips, John Papadopoulos, and Sapna A. Mehta. "Risk Factors for Treatment Failure of Polymyxin B Monotherapy for Carbapenem-Resistant Klebsiella pneumoniae Infections." Antimicrobial Agents and Chemotherapy 57, no. 11 (August 19, 2013): 5394–97. http://dx.doi.org/10.1128/aac.00510-13.
Full textAbstract:
ABSTRACTPolymyxins are reserved for salvage therapy of infections caused by carbapenem-resistantKlebsiella pneumoniae(CRKP). Though synergy has been demonstrated for the combination of polymyxins with carbapenems or tigecycline,in vitrosynergy tests are nonstandardized, and the clinical effect of synergy remains unclear. This study describes outcomes for patients with CRKP infections who were treated with polymyxin B monotherapy. We retrospectively reviewed the medical records of patients with CRKP infections who received polymyxin B monotherapy from 2007 to 2011. Clinical, microbiology, and antimicrobial treatment data were collected. Risk factors for treatment failure were identified by logistic regression. Forty patients were included in the analysis. Twenty-nine of 40 (73%) patients achieved clinical cure as defined by clinician-documented improvement in signs and symptoms of infections, and 17/32 (53%) patients with follow-up culture data achieved microbiological cure. End-of-treatment mortality was 10%, and 30-day mortality was 28%. In a multivariate analysis, baseline renal insufficiency was associated with a 6.0-fold increase in clinical failure after adjusting for septic shock (odds ratio [OR] = 6.0; 95% confidence interval [CI] = 1.22 to 29.59). Breakthrough infections with organisms intrinsically resistant to polymyxins occurred in 3 patients during the treatment. Eighteen of 40 (45%) patients developed a new CRKP infection a median of 23 days after initial polymyxin B treatment, and 3 of these 18 infections were polymyxin resistant. The clinical cure rate achieved in this retrospective study was 73% of patients with CRKP infections treated with polymyxin B monotherapy. Baseline renal insufficiency was a risk factor for treatment failure after adjusting for septic shock. Breakthrough infections with organisms intrinsically resistant to polymyxin B and development of resistance to polymyxin B in subsequent CRKP isolates are of concern.
25
Hasan, Md Jahidul, Raihan Rabbani, and Sitesh C. Bachar. "Evaluation of the Therapeutic Effectiveness of Polymyxin B Versus Colistin in Carbapenem-resistanct Klebsiella pneumoniae-Associated Bacteremia." Dhaka University Journal of Pharmaceutical Sciences 18, no. 2 (September 22, 2019): 209–15. http://dx.doi.org/10.3329/dujps.v18i2.43263.
Full textAbstract:
Polymyxins are the last resort antibiotics for treating carbapenem-resistance Klebsiella pneumoniae (CR-Kp)-associated bacteremia. The main aim of this study was to demonstrate the therapeutic effectiveness of polymyxin B versus colistin in the treatment of CR-Kp-associated Bacteremia. This 12-month long cross-sectional study was conducted on 54 and 47 patients suffering from CR-Kp-associated Bacteremia, and residing into two separate groups, they were treated with polymyxin B and colistin, respectively. After 5 day-treatment, the microbiological eradication rate was found 96.30% (52; n=54) in polymyxin B group and 87.23% (41; n=47) in colistin group. In the 30-day mortality rate-comparison, 51.03% more death was found in colistin group (34.04 %, n= 47) than the polymyxin B group (16.67 %, n= 54). In this study, Polymyxin B showed superior therapeutic potentiality with less number of secondary infections and 30-day mortality rate in CR-Kp-associated bacteremia than colistin.
Dhaka Univ. J. Pharm. Sci. 18(2): 209-215, 2019 (December)
26
Bouvier, Maxime, Mustafa Sadek, Stefano Pomponio, Fernando D’Emidio, Laurent Poirel, and Patrice Nordmann. "RapidResa Polymyxin Acinetobacter NP® Test for Rapid Detection of Polymyxin Resistance in Acinetobacter baumannii." Antibiotics 10, no. 5 (May 11, 2021): 558. http://dx.doi.org/10.3390/antibiotics10050558.
Full textAbstract:
A homemade and culture-based test, relying on the visual detection of the reduction of the resazurin reagent (a cell viability indicator), has been developed for the rapid detection of polymyxin resistance in Acinetobacter baumannii. Here, we evaluated the industrial version of this test, the RapidResa Polymyxin Acinetobacter NP® test (Liofilchem, Italy). A well-characterized panel of 68 clinical A. baumannii strains (36 polymyxin-susceptible, 26 polymyxin-resistant A. baumannii, and 6 colistin-heteroresistant isolates) of worldwide origin was tested. All the colistin-susceptible A. baumannii isolates gave negative results according to the RapidResa Polymyxin Acinetobacter NP® test, except for a single isolate that gave a false-positive result. Out of the 26 colistin-resistant A. baumannii strains, 25 were correctly identified as colistin resistant using the RapidResa Polymyxin Acinetobacter NP® test. Only a single colistin-resistant A. baumannii strain gave a false-negative result. Additionally, the six colistin-heteroresistant isolates tested gave positive results. Altogether, the sensitivity and the specificity of the test were found to be 96% and 97%, respectively. The turn-around-time of this easy-to-perform test was 3-4h, which showed excellent reliability for identification of polymyxin resistance in A. baumannii. The RapidResa Polymyxin Acinetobacter NP® test allows a rapid differentiation between polymyxin-susceptible and -resistant A. baumannii isolates, which may contribute to optimization of the use of polymyxins for treating infections due to multidrug-resistant A. baumannii.
27
Azad, Mohammad A. K., Ben A. Finnin, Anima Poudyal, Kathryn Davis, Jinhua Li, Prue A. Hill, Roger L. Nation, Tony Velkov, and Jian Li. "Polymyxin B Induces Apoptosis in Kidney Proximal Tubular Cells." Antimicrobial Agents and Chemotherapy 57, no. 9 (June 24, 2013): 4329–35. http://dx.doi.org/10.1128/aac.02587-12.
Full textAbstract:
ABSTRACTThe nephrotoxicity of polymyxins is a major dose-limiting factor for treatment of infections caused by multidrug-resistant Gram-negative pathogens. The mechanism(s) of polymyxin-induced nephrotoxicity is not clear. This study aimed to investigate polymyxin B-induced apoptosis in kidney proximal tubular cells. Polymyxin B-induced apoptosis in NRK-52E cells was examined by caspase activation, DNA breakage, and translocation of membrane phosphatidylserine using Red-VAD-FMK [Val-Ala-Asp(O-Me) fluoromethyl ketone] staining, a terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, and double staining with annexin V-propidium iodide (PI). The concentration dependence (50% effective concentration [EC50]) and time course for polymyxin B-induced apoptosis were measured in NRK-52E and HK-2 cells by fluorescence-activated cell sorting (FACS) with annexin V and PI. Polymyxin B-induced apoptosis in NRK-52E cells was confirmed by positive labeling from Red-VAD-FMK staining, TUNEL assay, and annexin V-PI double staining. The EC50(95% confidence interval [CI]) of polymyxin B for the NRK-52E cells was 1.05 (0.91 to 1.22) mM and was 0.35 (0.29 to 0.42) mM for HK-2 cells. At lower concentrations of polymyxin B, minimal apoptosis was observed, followed by a sharp rise in the apoptotic index at higher concentrations in both cell lines. After treatment of NRK-52E cells with 2.0 mM polymyxin B, the percentage of apoptotic cells (mean ± standard deviation [SD]) was 10.9% ± 4.69% at 6 h and reached plateau (>80%) at 24 h, whereas treatment with 0.5 mM polymyxin B for 24 h led to 93.6% ± 5.57% of HK-2 cells in apoptosis. Understanding the mechanism of polymyxin B-induced apoptosis will provide important information for discovering less nephrotoxic polymyxin-like lipopeptides.
28
Malott, Rebecca J., Barbara R. Steen-Kinnaird, Tracy D. Lee, and David P. Speert. "Identification of Hopanoid Biosynthesis Genes Involved in Polymyxin Resistance in Burkholderia multivorans." Antimicrobial Agents and Chemotherapy 56, no. 1 (October 17, 2011): 464–71. http://dx.doi.org/10.1128/aac.00602-11.
Full textAbstract:
ABSTRACTA major challenge to clinical therapy ofBurkholderia cepaciacomplex (Bcc) pulmonary infections is their innate resistance to a broad range of antimicrobials, including polycationic agents such as aminoglycosides, polymyxins, and cationic peptides. To identify genetic loci associated with this phenotype, a transposon mutant library was constructed inB. multivoransATCC 17616 and screened for increased susceptibility to polymyxin B. Compared to the parent strain, mutant 26D7 exhibited 8- and 16-fold increases in susceptibility to polymyxin B and colistin, respectively. Genetic analysis of mutant 26D7 indicated that the transposon inserted into open reading frame (ORF) Bmul_2133, part of a putative hopanoid biosynthesis gene cluster. A strain with a mutation in another ORF in this cluster, Bmul_2134, was constructed and named RMI19. Mutant RMI19 also had increased polymyxin susceptibility. Hopanoids are analogues of eukaryotic sterols involved in membrane stability and barrier function. Strains with mutations in Bmul_2133 and Bmul_2134 showed increased permeability to 1-N-phenylnaphthylamine in the presence of increasing concentrations of polymyxin, suggesting that the putative hopanoid biosynthesis genes are involved in stabilizing outer membrane permeability, contributing to polymyxin resistance. Results from a dansyl-polymyxin binding assay demonstrated that polymyxin B does not bind well to the parent or mutant strains, suggesting that Bmul_2133 and Bmul_2134 contribute to polymyxin B resistance by a mechanism that is independent of lipopolysaccharide (LPS) binding. Through this work, we propose a role for hopanoid biosynthesis as part of the multiple antimicrobial resistance phenotype in Bcc bacteria.
29
Schurek, Kristen N., Jorge L. M. Sampaio, Carlos R. V. Kiffer, Sumiko Sinto, Caio M. F. Mendes, and Robert E. W. Hancock. "Involvement of pmrAB and phoPQ in Polymyxin B Adaptation and Inducible Resistance in Non-Cystic Fibrosis Clinical Isolates of Pseudomonas aeruginosa." Antimicrobial Agents and Chemotherapy 53, no. 10 (July 27, 2009): 4345–51. http://dx.doi.org/10.1128/aac.01267-08.
Full textAbstract:
ABSTRACT During investigation of susceptibility testing methods for polymyxins, 24 multidrug-resistant clinical isolates of Pseudomonas aeruginosa were observed to have a distinct, reproducible phenotype in which skipped wells were observed during broth microdilution testing for polymyxin B. Possible mechanisms underlying this phenotype were investigated. The effects of various concentrations of polymyxin B on growth, the expression of resistance genes, and outer-membrane permeability were observed. Real-time PCR was performed to compare the expression, in response to selected concentrations of polymyxin B, of genes related to the PhoP-PhoQ and PmrA-PmrB two-component regulatory systems in polymyxin B-susceptible isolate PAO1, polymyxin B-resistant isolate 9BR, and two isolates (19BR and 213BR) exhibiting the skipped-well phenotype. 19BR and 213BR appeared to have similar basal levels of expression compared to that of PAO1 for phoQ, arnB, and PA4773 (from the pmrAB operon), and in contrast, 9BR had 52- and 280-fold higher expression of arnB and PA4773, respectively. The expression of arnB and PA4773 increased in response to polymyxin B in a concentration-dependent manner for 9BR but not for 19BR and 213BR. For these isolates, expression was significantly increased for arnB and PA4773, as well as phoQ, only upon exposure to 2 μg/ml polymyxin B but not at a lower concentration of 0.125 μg/ml. The sequencing of the pmrAB and phoPQ operons for all three isolates revealed a number of unique mutations compared to that for PAO1. 1-N-phenylnaphthylamine (NPN) was used to study the effect of preincubation with polymyxin B on the self-promoted uptake of polymyxin B across the outer membrane. The preincubation of cells with 2 μg/ml polymyxin B affected baseline membrane permeability in 19BR and 213BR and also resulted in a reduced rate of NPN uptake in these isolates and in PAO1 but not in 9BR. The results presented here suggest that the skipped-well isolates have the ability to adapt to specific concentrations of polymyxin B, inducing known polymyxin B resistance genes involved in generating alterations in the outer membrane.
30
Tsuji, Brian T., Cornelia B. Landersdorfer, Justin R. Lenhard, Soon-Ee Cheah, Visanu Thamlikitkul, Gauri G. Rao, Patricia N. Holden, et al. "Paradoxical Effect of Polymyxin B: High Drug Exposure Amplifies Resistance in Acinetobacter baumannii." Antimicrobial Agents and Chemotherapy 60, no. 7 (April 11, 2016): 3913–20. http://dx.doi.org/10.1128/aac.02831-15.
Full textAbstract:
ABSTRACTAdministering polymyxin antibiotics in a traditional fashion may be ineffective against Gram-negative ESKAPE (Enterococcus faecium,Staphylococcus aureus,Klebsiella pneumoniae,Acinetobacter baumannii,Pseudomonas aeruginosa, andEnterobacterspecies) pathogens. Here, we explored increasing the dose intensity of polymyxin B against two strains ofAcinetobacter baumanniiin the hollow-fiber infection model. The following dosage regimens were simulated for polymyxin B (t1/2= 8 h): non-loading dose (1.43 mg/kg of body weight every 12 h [q12h]), loading dose (2.22 mg/kg q12h for 1 dose and then 1.43 mg/kg q12h), front-loading dose (3.33 mg/kg q12h for 1 dose followed by 1.43 mg/kg q12h), burst (5.53 mg/kg for 1 dose), and supraburst (18.4 mg/kg for 1 dose). Against bothA. baumanniiisolates, a rapid initial decline in the total population was observed within the first 6 h of polymyxin exposure, whereby greater polymyxin B exposure resulted in greater maximal killing of −1.25, −1.43, −2.84, −2.84, and −3.40 log10CFU/ml within the first 6 h. Unexpectedly, we observed a paradoxical effect whereby higher polymyxin B exposures dramatically increased resistant subpopulations that grew on agar containing up to 10 mg/liter of polymyxin B over 336 h. High drug exposure also proliferated polymyxin-dependent growth. A cost-benefit pharmacokinetic/pharmacodynamic relationship between 24-h killing and 336-h resistance was explored. The intersecting point, where the benefit of bacterial killing was equal to the cost of resistance, was anfAUC0–24(area under the concentration-time curve from 0 to 24 h for the free, unbound fraction of drug) of 38.5 mg · h/liter for polymyxin B. Increasing the dose intensity of polymyxin B resulted in amplification of resistance, highlighting the need to utilize polymyxins as part of a combination against high-bacterial-densityA. baumanniiinfections.
31
Maria Dantas de Maio Carrilho, Claudia, Thalita Bento Talizin, Camila R. Lopes, Isabella Patruceli Azevedo, Kesia Paes, Leticia Maria Alves da Silva, Cintia Magalhaes Carvalho Grion, Lucienne Tibery Queiroz Cardoso, Karine Maria Boll, and Eduardo Alexandrino Servolo Medeiros. "2293. Revival of Polymyxins: A Single-Center Historical Cohort of Critically Ill Patients in Brazil." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S786. http://dx.doi.org/10.1093/ofid/ofz360.1971.
Full textAbstract:
Abstract Background The epidemiological scenario of multidrug-resistant bacteria has brought polymyxins back to medical prescriptions, as they are last-line therapy against carbapenem-resistant bacteria. There is a lack of knowledge of which is the best way to use this drug, especially in critically ill patients. We aimed to evaluate polymyxin use in an intensive care unit (ICU) in a university hospital and to describe its epidemiological characteristics. Methods This historical cohort included all consecutive patients who used polymyxins to treat ventilator-associated pneumonia from January 1, 2017 to January 31, 2018, during hospitalization in an ICU from a public university hospital, endemic for carbapenem-resistant bacteria, in Londrina, Brazil. Microbiological processing for diagnosis followed the guidelines from the Clinical and Laboratory Standards Institute (CLSI). Statistical analyses were performed using MedCalc for Windows, version 18.9 (MedCalc Software, Ostend, Belgium) and significance level adopted was 0.05. Results There were 179 patients; median of age was 57 years (IQR: 40.0 - 70.75). Polymyxin B was the most prescribed polymyxin (97.2%). Most of the patients had comorbidities (72.6%). Age was higher in the group of patients who died (60.0 vs. 36.5 years, P < 0.0001). Comorbidities prevalence was higher in non-survivors (80.7% vs. 38.2%, P < 0.0001). Sequential Organ Failure Assessment (SOFA) score on polymyxin prescribing day was higher in non-survivors (8.0 vs. 7.0, P = 0.0093), as well as Simplified Acute Physiology Score 3 (SAPS 3) score (70.7 vs. 59.35, P = 0.0003). Thirty-day mortality was 43%. Analysis of 14-day survival showed a higher mortality for patients who had sepsis (Log-rank test, P = 0.0284) and septic shock (Log-rank test, P = 0.0065). Acinetobacter baumannii was the most common etiologic agent, in 125 samples (73.9%), with 97.6% of resistance to carbapenem and 5.6% of resistance to polymyxins. Conclusion Polymyxin B was the most prescribed polymyxin. Age was higher in non-survivors, as well as comorbidities prevalence, SOFA and SAPS 3 scores. Patients with sepsis and septic shock showed a 14-day higher mortality. Acinetobacter baumannii was the most isolated agent. Carbapenem resistance was high. Disclosures All authors: No reported disclosures.
32
Arroyo, Luis A., Carmen M. Herrera, Lucia Fernandez, Jessica V. Hankins, M. Stephen Trent, and Robert E. W. Hancock. "ThepmrCABOperon Mediates Polymyxin Resistance inAcinetobacter baumanniiATCC 17978 and Clinical Isolates through Phosphoethanolamine Modification of Lipid A." Antimicrobial Agents and Chemotherapy 55, no. 8 (June 6, 2011): 3743–51. http://dx.doi.org/10.1128/aac.00256-11.
Full textAbstract:
ABSTRACTThe emergence of multidrug resistance amongAcinetobacter baumanniiis leading to an increasing dependence on the use of polymyxins as last-hope antibiotics. Here, we utilized genetic and biochemical methods to define the involvement of thepmrCABoperon in polymyxin resistance in this organism. Sequence analysis of 16 polymyxin B-resistant strains, including 6 spontaneous mutants derived from strain ATCC 17978 and 10 clinical isolates from diverse sources, revealed that they had independent mutations in thepmrBgene, encoding a sensor kinase, or in the response regulator PmrA. Knockout of thepmrBgene in two mutants and two clinical isolates led to a decrease in the polymyxin B susceptibility of these strains, which could be restored with the clonedpmrABgenes from the mutants but not from the wild type. Reverse transcription-quantitative PCR (RT-qPCR) analysis also showed a correlation between the expression ofpmrCand polymyxin B resistance. Characterization of lipid A species from the mutant strains, by thin-layer chromatography and mass spectrometry, indicated that the addition of phosphoethanolamine to lipid A correlated with resistance. This addition is performed inSalmonella entericaserovar Typhimurium by the product of thepmrCgene, which is a homolog of thepmrCgene fromAcinetobacter. Knockout of this gene in the mutant R2 [pmrB(T235I)] reversed resistance as well as phosphoethanolamine modification of lipid A. These results demonstrate that specific alterations in the sequence of thepmrCABoperon are responsible for resistance to polymyxins inA. baumannii.
33
Falagas, Matthew E., Patra K. Koletsi, Petros Kopterides, and Argyris Michalopoulos. "Risk Factors for Isolation of Strains Susceptible Only to Polymyxin among Patients with Pseudomonas aeruginosa Bacteremia." Antimicrobial Agents and Chemotherapy 50, no. 7 (July 2006): 2541–43. http://dx.doi.org/10.1128/aac.00224-06.
Full textAbstract:
ABSTRACT We conducted a case-control study to identify risk factors associated with the isolation of Pseudomonas aeruginosa strains susceptible only to polymyxin from blood by comparing data between 16 patients with blood isolates that were susceptible only to polymyxins and 40 patients with blood isolates that were susceptible to carbapenems. The multivariable analysis showed that exposure to carbapenems was associated with the development of P. aeruginosa bacteremia susceptible only to polymyxin (odds ratio, 9.0; 95% confidence interval, 2.4 to 34.3; P = 0.001).
34
Yu, Zhiliang, Chenglin Guo, and Juanping Qiu. "Precursor Amino Acids Inhibit Polymyxin E Biosynthesis inPaenibacillus polymyxa, Probably by Affecting the Expression of Polymyxin E Biosynthesis-Associated Genes." BioMed Research International 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/690830.
Full textAbstract:
Polymyxin E belongs to cationic polypeptide antibiotic bearing four types of direct precursor amino acids including L-2,4-diaminobutyric acid (L-Dab), L-Leu, D-Leu, and L-Thr. The objective of this study is to evaluate the effect of addition of precursor amino acids during fermentation on polymyxin E biosynthesis inPaenibacillus polymyxa. The results showed that, after 35 h fermentation, addition of direct precursor amino acids to certain concentration significantly inhibited polymyxin E production and affected the expression of genes involved in its biosynthesis. L-Dab repressed the expression of polymyxin synthetase genespmxAandpmxE, as well as 2,4-diaminobutyrate aminotransferase geneectB; both L-Leu and D-Leu repressed thepmxAexpression. In addition, L-Thr affected the expression of not onlypmxA, but also regulatory genesspo0AandabrB. As L-Dab precursor, L-Asp repressed the expression ofectB,pmxA, andpmxE. Moreover, it affected the expression ofspo0AandabrB. In contrast, L-Phe, a nonprecursor amino acid, had no obvious effect on polymyxin E biosynthesis and those biosynthesis-related genes expression. Taken together, our data demonstrated that addition of precursor amino acids during fermentation will inhibit polymyxin E production probably by affecting the expression of its biosynthesis-related genes.
35
Barrow, Kaddy, and Dong H. Kwon. "Alterations in Two-Component Regulatory Systems of phoPQ and pmrAB Are Associated with Polymyxin B Resistance in Clinical Isolates of Pseudomonas aeruginosa." Antimicrobial Agents and Chemotherapy 53, no. 12 (September 14, 2009): 5150–54. http://dx.doi.org/10.1128/aac.00893-09.
Full textAbstract:
ABSTRACT Polymyxins are often the only option to treat acquired multidrug-resistant Pseudomonas aeruginosa. Polymyxin susceptibility in P. aeruginosa PAO1 is associated with the lipopolysaccharide structure that is determined by arnBCADTEF and modulated by phoPQ and pmrAB. We examined five clonally unrelated clinical isolates of polymyxin B-resistant P. aeruginosa to investigate the molecular basis of polymyxin resistance. All isolates grew with 4 μg/ml polymyxin B (MIC, 8 μg/ml), whereas P. aeruginosa PAO1 grew with 0.25 μg/ml polymyxin B (MIC, 0.5 μg/ml). The resistant isolates were converted to susceptible ones (the MICs fell from 8 to 0.5 μg/ml) following the introduction of phoPQ (four isolates) and pmrAB (one isolate), which had been cloned from strain PAO1. DNA sequence analysis revealed that a single-nucleotide substitution in three isolates replaced a single amino acid of PhoQ, the deletion of 17 nucleotides in one isolate truncated the protein of PhoQ, and two nucleotide substitutions in one isolate replaced two amino acids of PmrB. The involvement of these amino acid substitutions or the truncated protein of PhoQ and PmrB in polymyxin B resistance was confirmed using strain PAO1 lacking phoPQ or pmrAB that was transformed by phoPQ or pmrAB containing the amino acid substitutions or the truncated protein. The resistant clinical isolates were sensitized by the inactivation of arnBCADTEF (the MICs fell from 8 to 0.5 μg/ml). These results suggest that polymyxin B resistance among clinical isolates of P. aeruginosa is associated with alterations in two-component regulatory systems of phoPQ or pmrAB.
36
Vaara, Martti. "Polymyxin Derivatives that Sensitize Gram-Negative Bacteria to Other Antibiotics." Molecules 24, no. 2 (January 11, 2019): 249. http://dx.doi.org/10.3390/molecules24020249.
Full textAbstract:
Polymyxins (polymyxin B (PMB) and polymyxin E (colistin)) are cyclic lipodecapeptide antibiotics, highly basic due to five free amino groups, and rapidly bactericidal against Gram-negative bacteria, such as the majority of Enterobacteriaceae as well as Acinetobacter baumannii and Pseudomonas aeruginosa. Their clinical use was abandoned in the 1960s because of nephrotoxicity and because better-tolerated drugs belonging to other antibiotic classes were introduced. Now, due to the global dissemination of extremely-drug resistant Gram-negative bacterial strains, polymyxins have resurged as the last-line drugs against those strains. Novel derivatives that are less toxic and/or more effective at tolerable doses are currently under preclinical development and their properties have recently been described in several extensive reviews. Other derivatives lack any direct bactericidal activity but damage the outermost permeability barrier, the outer membrane, of the target bacteria and make it more permeable to many other antibiotics. This review describes the properties of three thus far best-characterized “permeabilizer” derivatives, i.e., the classic permeabilizer polymyxin B nonapeptide (PMBN), NAB7061, and SPR741/NAB741, a compound that recently successfully passed the clinical phase 1. Also, a few other permeabilizer compounds are brought up.
37
Vaara, Martti, Timo Vaara, Janis Kuka, Eduards Sevostjanovs, Solveiga Grinberga, Maija Dambrova, and Edgars Liepinsh. "Excretion of the Polymyxin Derivative NAB739 in Murine Urine." Antibiotics 9, no. 4 (March 27, 2020): 143. http://dx.doi.org/10.3390/antibiotics9040143.
Full textAbstract:
Extremely multiresistant strains of Enterobacteriaceae are emerging and spreading at a worrisome pace. Polymyxins are used as the last-resort therapy against such strains, in spite of their nephrotoxicity. We have previously shown that novel polymyxin derivatives NAB739 and NAB815 are less nephrotoxic in cynomolgus monkeys than polymyxin B and are therapeutic in murine Escherichia coli pyelonephritis at doses only one-tenth of that needed for polymyxin B. Here we evaluated whether the increased efficacy is due to increased excretion of NAB739 in urine. Mice were treated with NAB739 and polymyxin B four times subcutaneously at doses of 0.25, 0.5, 1, 2, and 4 mg/kg. In plasma, a clear dose–response relationship was observed. The linearity of Cmax with the dose was 0.9987 for NAB739 and 0.975 for polymyxin B. After administration of NAB739 at a dose of 0.25 mg/kg, its plasma concentrations at all tested time points were above 0.5 µg/mL while after administration at a dose of 0.5 mg/kg its plasma concentrations exceeded 1 µg/mL. The Cmax of NAB739 in plasma was up to 1.5-times higher after single (first) administration and up to two-times higher after the last administration when compared to polymyxin B. Polymyxin B was not detected in urine samples even when administered at 4 mg/kg. In contrast, the concentration of NAB739 in urine after single administration at a dose of 0.25 mg/kg was above 1 µg/mL and after administration of 0.5 mg/kg its average urine concentration exceeded 2 µg/mL. At the NAB739 dose of 4 mg/kg, the urinary concentrations were higher than 35 µg/mL. These differences explain our previous finding that NAB739 is much more efficacious than polymyxin B in the therapy of murine E. coli pyelonephritis.
38
Dmitrieva, N. V., I. N. Petukhova, Z. V. Grigorievskaya, N. S. Bagirova, I. V. Тereshchenko, and E. D. Grigorievsky. "POLYMIXIN IN ONCOLOGY CLINICAL PRACTICE." Siberian journal of oncology 17, no. 3 (July 4, 2018): 88–93. http://dx.doi.org/10.21294/1814-4861-2018-17-3-88-93.
Full textAbstract:
The purpose of the study was to present data on polymixin-based antibiotics with activity against infections caused by multidrug- resistant Gram-negative bacteria, such as Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa.Material and methods. The review includes data from clinical as well as in vitro studies for the period 1998–2017. The search for relevant sources was carried out in the Medline, Cochrane Library, Elibrary and other databases.Results. The analysis of the data showed the presence of synergism and additive activity of polymyxin in combination with carbapenems, rifampicin and azithromycin. However, experimental data showed no direct positive correlation between combination of polymyxim and azithromycin/ rifampicin. In clinical studies, in hospital-acquired pneumonia, including ventilator-associated pneumonia, the clinical response rate of polymyxin B combined with other antibiotics ranged from 38 % to 88 %. High nephro-and neurotoxicity of polymyxin observed in previous studies can be explained by a lack of understanding of its toxicodynamics or the use of an incorrect dose.Conclusion. Polymyxin B in combination with other antibiotics is a promising treatment against infectious complications caused by multidrug resistant Gram-negative bacteria.
39
Mostardeiro, Marcelo M., Carlos A. P. Pereira, Alexandre R. Marra, Jose O. M. Pestana, and Luis Fernando A. Camargo. "Nephrotoxicity and Efficacy Assessment of Polymyxin Use in 92 Transplant Patients." Antimicrobial Agents and Chemotherapy 57, no. 3 (January 7, 2013): 1442–46. http://dx.doi.org/10.1128/aac.01329-12.
Full textAbstract:
ABSTRACTPolymyxins are old antimicrobials, discontinued for many years because of nephrotoxicity and neurotoxicity reports and reintroduced recently due to the increasing frequency of multiresistant Gram-negative bacterial infections. There are very few data related to toxicity and efficacy from transplanted patients, the major subjects of this study. All solid-organ-transplanted patients from our institution during January 2001 to December 2007 who used polymyxins were retrospectively assessed for nephrotoxicity and treatment efficacy. Microbiological and clinical cure rates were 100% and 77.2%, respectively. Only transplant patients subjected to at least 72 h of intravenous polymyxin were entered in the study. Overall, 92 transplant patients were included, and the nephrotoxicity rate was 32.6%. Multivariate analysis showed a statistically significant association between duration of polymyxin treatment (P= 0.037; odds ratio [OR], 1.06; 95% confidence interval [CI], 1.00 to 1.12) and significant renal dysfunction. Polymyxin use is associated with very high rates of significant decrease in renal function; therefore, polymyxin must be used only when no other option is available and for as briefly as possible in the solid organ transplant setting.
40
Li, Mengyao, Su Mon Aye, Maizbha Uddin Ahmed, Mei-Ling Han, Chen Li, Jiangning Song, John D. Boyce, et al. "Pan-transcriptomic analysis identified common differentially expressed genes of Acinetobacter baumannii in response to polymyxin treatments." Molecular Omics 16, no. 4 (2020): 327–38. http://dx.doi.org/10.1039/d0mo00015a.
Full textAbstract:
Our pan-transcriptomic study for polymyxin-treated A. baumannii identified that the remodelled outer membrane, up-regulated efflux pumps and down-regulated fatty acid biosynthesis might be essential for early responses to polymyxins in A. baumannii.
41
Nang, Sue C., Faye C. Morris, Michael J. McDonald, Mei-Ling Han, Jiping Wang, Richard A. Strugnell, Tony Velkov, and Jian Li. "Fitness cost of mcr-1-mediated polymyxin resistance in Klebsiella pneumoniae." Journal of Antimicrobial Chemotherapy 73, no. 6 (March 5, 2018): 1604–10. http://dx.doi.org/10.1093/jac/dky061.
Full textAbstract:
Abstract Objectives The discovery of mobile colistin resistance mcr-1, a plasmid-borne polymyxin resistance gene, highlights the potential for widespread resistance to the last-line polymyxins. In the present study, we investigated the impact of mcr-1 acquisition on polymyxin resistance and biological fitness in Klebsiella pneumoniae. Methods K. pneumoniae B5055 was used as the parental strain for the construction of strains carrying vector only (pBBR1MCS-5) and mcr-1 recombinant plasmids (pmcr-1). Plasmid stability was determined by serial passaging for 10 consecutive days in antibiotic-free LB broth, followed by patching on gentamicin-containing and antibiotic-free LB agar plates. Lipid A was analysed using LC–MS. The biological fitness was examined using an in vitro competition assay analysed with flow cytometry. The in vivo fitness cost of mcr-1 was evaluated in a neutropenic mouse thigh infection model. Results Increased polymyxin resistance was observed following acquisition of mcr-1 in K. pneumoniae B5055. The modification of lipid A with phosphoethanolamine following mcr-1 addition was demonstrated by lipid A profiling. The plasmid stability assay revealed the instability of the plasmid after acquiring mcr-1. Reduced in vitro biological fitness and in vivo growth were observed with the mcr-1-carrying K. pneumoniae strain. Conclusions Although mcr-1 confers a moderate level of polymyxin resistance, it is associated with a significant biological fitness cost in K. pneumoniae. This indicates that mcr-1-mediated resistance in K. pneumoniae could be attenuated by limiting the usage of polymyxins.
42
Yang, Baopeng, Chang Liu, Xiaolei Pan, Weixin Fu, Zheng Fan, Yongxin Jin, Fang Bai, Zhihui Cheng, and Weihui Wu. "Identification of Novel phoP-phoQ Regulated Genes that Contribute to Polymyxin B Tolerance in Pseudomonas aeruginosa." Microorganisms 9, no. 2 (February 9, 2021): 344. http://dx.doi.org/10.3390/microorganisms9020344.
Full textAbstract:
Polymyxin B and E (colistin) are the last resorts to treat multidrug-resistant Gram-negative pathogens. Pseudomonas aeruginosa is intrinsically resistant to a variety of antibiotics. The PhoP-PhoQ two-component regulatory system contributes to the resistance to polymyxins by regulating an arnBCADTEF-pmrE operon that encodes lipopolysaccharide modification enzymes. To identify additional PhoP-regulated genes that contribute to the tolerance to polymyxin B, we performed a chromatin immunoprecipitation sequencing (ChIP-Seq) assay and found novel PhoP binding sites on the chromosome. We further verified that PhoP directly controls the expression of PA14_46900, PA14_50740 and PA14_52340, and the operons of PA14_11970-PA14_11960 and PA14_52350-PA14_52370. Our results demonstrated that mutation of PA14_46900 increased the bacterial binding and susceptibility to polymyxin B. Meanwhile, mutation of PA14_11960 (papP), PA14_11970 (mpl), PA14_50740 (slyB), PA14_52350 (ppgS), and PA14_52370 (ppgH) reduced the bacterial survival rates and increased ethidium bromide influx under polymyxin B or Sodium dodecyl sulfate (SDS) treatment, indicating roles of these genes in maintaining membrane integrity in response to the stresses. By 1-N-phenylnaphthylamine (NPN) and propidium iodide (PI) staining assay, we found that papP and slyB are involved in maintaining outer membrane integrity, and mpl and ppgS-ppgH are involved in maintaining inner membrane integrity. Overall, our results reveal novel PhoP-PhoQ regulated genes that contribute to polymyxin B tolerance.
43
Conly, JM, and BL Johnston. "Colistin: The phoenix Arises." Canadian Journal of Infectious Diseases and Medical Microbiology 17, no. 5 (2006): 267–69. http://dx.doi.org/10.1155/2006/901873.
Full textAbstract:
The polymyxins were discovered in the 1940s and represent a group of closely related polypeptide antibiotics obtained fromBacillus polymyxa, which was originally isolated from soil (1,2). Although they have been used extensively worldwide in topical otic and ophthalmic solutions for decades, the intravenous formulations were gradually abandoned in most parts of the world in the early 1980s because of the reported high incidence of nephrotoxicity (3-5). As a result, the use of polymyxin preparations has been mainly restricted to the treatment of lung infections due to multidrug-resistant (MDR) gram-negative bacteria in patients with cystic fibrosis (6,7). The emergence of bacteria resistant to most classes of commercially available antibiotics and the shortage of novel antimicrobial agents with activity against gram-negative microorganisms have led to the reemergence of polymyxins as a valuable addition to the therapeutic armamentarium. It was thus considered timely to review colistin and its emerging role in managing infections due to MDR gram-negative bacteria.
44
Wickremasinghe, Hasini, Heidi H. Yu, Mohammad A. K. Azad, Jinxin Zhao, Phillip J. Bergen, Tony Velkov, Qi Tony Zhou, Yan Zhu, and Jian Li. "Clinically Relevant Concentrations of Polymyxin B and Meropenem Synergistically Kill Multidrug-Resistant Pseudomonas aeruginosa and Minimize Biofilm Formation." Antibiotics 10, no. 4 (April 8, 2021): 405. http://dx.doi.org/10.3390/antibiotics10040405.
Full textAbstract:
The emergence of antibiotic resistance has severely impaired the treatment of chronic respiratory infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa. Since the reintroduction of polymyxins as a last-line therapy against MDR Gram-negative bacteria, resistance to its monotherapy and recurrent infections continue to be reported and synergistic antibiotic combinations have been investigated. In this study, comprehensive in vitro microbiological evaluations including synergy panel screening, population analysis profiling, time-kill kinetics, anti-biofilm formation and membrane damage analysis studies were conducted to evaluate the combination of polymyxin B and meropenem against biofilm-producing, polymyxin-resistant MDR P. aeruginosa. Two phylogenetically unrelated MDR P. aeruginosa strains, FADDI-PA060 (MIC of polymyxin B [MICpolymyxin B], 64 mg/L; MICmeropenem, 64 mg/L) and FADDI-PA107 (MICpolymyxin B, 32 mg/L; MICmeropenem, 4 mg/L) were investigated. Genome sequencing identified 57 (FADDI-PA060) and 50 (FADDI-PA107) genes predicted to confer resistance to a variety of antimicrobials, as well as multiple virulence factors in each strain. The presence of resistance genes to a particular antibiotic class generally aligned with MIC results. For both strains, all monotherapies of polymyxin B failed with substantial regrowth and biofilm formation. The combination of polymyxin B (16 mg/L)/meropenem (16 mg/L) was most effective, enhancing initial bacterial killing of FADDI-PA060 by ~3 log10 CFU/mL, followed by a prolonged inhibition of regrowth for up to 24 h with a significant reduction in biofilm formation (* p < 0.05). Membrane integrity studies revealed a substantial increase in membrane depolarization and membrane permeability in the surviving cells. Against FADDI-PA107, planktonic and biofilm bacteria were completely eradicated. In summary, the combination of polymyxin B and meropenem demonstrated synergistic bacterial killing while reinstating the efficacy of two previously ineffective antibiotics against difficult-to-treat polymyxin-resistant MDR P. aeruginosa.
45
Perez, Federico, Nadim G. El Chakhtoura, Mohamad Yasmin, and Robert A. Bonomo. "Polymyxins: To Combine or Not to Combine?" Antibiotics 8, no. 2 (April 10, 2019): 38. http://dx.doi.org/10.3390/antibiotics8020038.
Full textAbstract:
Polymyxins have been a mainstay for the treatment of extensively drug resistant (XDR) Gram-negative bacteria for the past two decades. Many questions regarding the clinical use of polymyxins have been answered, but whether the administration of polymyxins in combination with other antibiotics leads to better outcomes remains unknown. This review discusses the limitations of observational studies that suggest a benefit of combinations of colistin and carbapenems to treat infections caused by carbapenem-resistant Enterobacteriaceae (CRE), especially Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae, and summarizes the results of randomized controlled trials in which treatment with colistin in combination with meropenem or rifampin does not lead to better clinical outcomes than colisitn monotherapy in infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB). Although the introduction of new antibiotics makes it possible to treat certain strains of CRE and carbapenem-resistant P. aeruginosa (CRPA) with polymyxin-sparing regimens, the use of polymyxins is, for now, still necessary in CRAB and in CRE and CRPA harboring metallo-beta-lactamases. Therefore, strategies must be developed to optimize polymyxin-based treatments, informed by in vitro hollow fiber models, careful clinical observations, and high-quality evidence from appropriately designed trials.
46
Ouderkirk, John P., Jill A. Nord, Glenn S. Turett, and Jay Ward Kislak. "Polymyxin B Nephrotoxicity and Efficacy against Nosocomial Infections Caused by Multiresistant Gram-Negative Bacteria." Antimicrobial Agents and Chemotherapy 47, no. 8 (August 2003): 2659–62. http://dx.doi.org/10.1128/aac.47.8.2659-2662.2003.
Full textAbstract:
ABSTRACT Reported rates of nephrotoxicity associated with the systemic use of polymyxins have varied widely. The emergence of infections due to multiresistant gram-negative bacteria has necessitated the use of systemic polymyxin B once again for the treatment of such infections. We retrospectively investigated the rate of nephrotoxicity in patients receiving polymyxin B parenterally for the treatment of infections caused by multiresistant gram-negative bacteria from October 1999 to September 2000. Demographic and clinical information was obtained for 60 patients. Outcome measures of interest were renal toxicity and clinical and microbiologic efficacy. Renal failure developed in 14% of the patients, all of whom had normal baseline renal function. Development of renal failure was independent of the daily and cumulative doses of polymyxin B and the length of treatment but was significantly associated with older age (76 versus 59 years, P = 0.02). The overall mortality was 20%, but it increased to 57% in those who developed renal failure. The organism was cleared in 88% of the patients from whom repeat specimens were obtained. The use of polymyxin B to treat multiresistant gram-negative infections was highly effective and associated with a lower rate of nephrotoxicity than previously described.
47
Landman, David, Claudiu Georgescu, Don Antonio Martin, and John Quale. "Polymyxins Revisited." Clinical Microbiology Reviews 21, no. 3 (July 2008): 449–65. http://dx.doi.org/10.1128/cmr.00006-08.
Full textAbstract:
SUMMARY The global emergence of multidrug-resistant gram-negative bacilli has spurred a renewed interest in polymyxins. Once discarded due to concerns regarding nephrotoxicity and neurotoxicity, polymyxins now hold an important role in the antibiotic armamentarium. However, more reliable information is needed to determine the optimal dosing of these agents. Also, unanswered questions regarding in vitro testing remain, including questions regarding the reliability of automated systems and the establishment of appropriate breakpoints for defining susceptibility. Most contemporary clinical studies examining the use of these agents have involved patients with infections due to multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii strains. It has been reassuring that polymyxin therapy for resistant bacteria has resulted in clinical responses and toxicity rates similar to those for carbapenem therapy for susceptible isolates. While most surveillance studies demonstrated high rates of susceptibility, several reports noted the emergence of polymyxin-resistant nosocomial pathogens. Polymyxins have assumed an important antibiotic niche for therapy for hospital-acquired infections; further studies defining the optimal use of these agents will likely extend the duration of their clinical usefulness.
48
Pogue, Jason M., Ronald N. Jones, John S. Bradley, David Andes, Sujata M. Bhavnani, Michael Dudley, Robert K. Flamm, Keith A. Rodvold, and Paul G. Ambrose. "1534. Polymyxin Antimicrobial Susceptibility (AST) Testing and Breakpoints for P. aeruginosa, A. baumannii, and Enterobacteriaceae: Recommendations from the United States Committee on Antimicrobial Susceptibility Testing (USCAST)." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S559. http://dx.doi.org/10.1093/ofid/ofz360.1398.
Full textAbstract:
Abstract Background Polymyxins are important antimicrobial agents for the treatment of infections due to carbapenem-resistant and other multidrug-resistant organisms. Recently, the CLSI and EUCAST have set breakpoints for colistin (EUCAST and CLSI) and polymyxin B (CLSI) with slight differences in recommendations. However, there are issues unique to the polymyxin class that warrant additional guidances. Herein, we assess data related to breakpoint setting and make additional recommendations for polymyxin AST interpretive criteria. Methods Data sources included longitudinal (2011–2017) US surveillance reference broth microdilution (BMD) MIC distributions (128,573 isolates) for colistin and polymyxin B (PB), published data on accuracy of various AST methodologies, in vivo pharmacokinetic/pharmacodynamic (PK-PD) models, prior polymyxin guidelines and agency package insert dosing recommendations, and population PK-PD and toxicodynamic (TD) data. Epidemiological cut-off, PK-PD (and TD), and clinical data were all considered for susceptible (S) breakpoint determinations. Results Data demonstrate that the most commonly utilized AST methodologies (disk diffusion, Etest, and automated MIC susceptibility panels), as well as agar dilution testing cannot reliably detect resistance; and BMD is the preferred AST. Importantly, colistin S is a reliable surrogate for PB S with cross-S accuracy at > 99% of isolates in each pathogen group. Breakpoint recommendations can be found in the Table with emphasis on applying combination therapy. Key recommendations include an S breakpoint of ≤2 mg/L for each pathogen (both colistin and PB). However, based on a lack of preclinical efficacy in murine pneumonia models, PK/PD concerns, and poor clinical outcome data, we strongly suggest that no breakpoints are applied for pneumonia and that alternative therapies should be used where available. Additionally, due to a lack of significant renal excretion, PB will also have no S breakpoint recommendation for lower urinary tract infections. Conclusion The polymyxins have compromising characteristics that make them suboptimal antimicrobials when used alone, and additional caveats are required for AST breakpoint interpretive criteria and stewardship programs. Disclosures All authors: No reported disclosures.
49
Macesic, Nenad, Brian Nelson, Thomas H. Mcconville, Marla J. Giddins, Daniel A. Green, Stephania Stump, Angela Gomez-Simmonds, Medini K. Annavajhala, and Anne-Catrin Uhlemann. "Emergence of Polymyxin Resistance in Clinical Klebsiella pneumoniae Through Diverse Genetic Adaptations: A Genomic, Retrospective Cohort Study." Clinical Infectious Diseases 70, no. 10 (September 12, 2019): 2084–91. http://dx.doi.org/10.1093/cid/ciz623.
Full textAbstract:
Abstract Background Polymyxins are antimicrobials of last resort for the treatment of carbapenem-resistant Enterobacteriaceae, but resistance in 5% to >40% isolates has been reported. We conducted a genomic survey of clinical polymyxin-resistant (PR) Klebsiella pneumoniae to determine the molecular mechanisms of PR and the role of polymyxin exposure versus transmission in PR emergence. Methods We included 88 patients with PR K. pneumoniae from 2011–2018 and collected demographic, antimicrobial exposure, and infection data. Whole-genome sequencing was performed on 388 isolates, including 164 PR isolates. Variant calling and insertion sequence detection were performed, focusing on key genes associated with PR (mgrB, crrAB, phoPQ, and pmrAB). We conducted phylogenetic analyses of key K. pneumoniae multi-locus sequence types (ST258, ST17, ST307, and ST392). Results Polymyxin exposure was documented in 53/88 (60%) patients prior to PR detection. Through an analysis of key PR genes, we detected 129 individual variants and 72 unique variant combinations in PR isolates. This included multiple, distinct changes in 36% of patients with serial PR isolates. Insertion sequence disruption was limited to mgrB (P < .001). Polymyxin minimum inhibitory concentrations showed stepwise increases with the number of PR genes affected (P < .001). When clusters containing PR isolates in ≥2 patients were analyzed, 10/14 had multiple genetic events leading to PR. Conclusions Molecular mechanisms leading to PR in clinical K. pneumoniae isolates are remarkably heterogenous, even within clusters or individual patients. Polymyxin exposure with de novo PR emergence led to PR in the majority of patients, rather than transmission. Optimizing polymyxin use should be a key strategy in stopping the spread of PR.
50
Ishaque, Sadia, Ehsan Bari, Muhammad Shahzad Shamim, and Syed Faisal Mahmood. "Cerebrospinal Fluid Sterilization with Intrathecal Polymyxin in Addition to Parenteral Polymyxin in Nosocomial Acinetobacter Meningitis." Pakistan Journal of Medical and Health Sciences 15, no. 7 (July 26, 2021): 1550–52. http://dx.doi.org/10.53350/pjmhs211571550.
Full textAbstract:
Background: For the last few decades there has been a substantial concern regarding the increasing prevalence of multidrug resistant (MDR) Acinetobacter species in hospitals. Aim: To determine the outcomes with intrathecal polymyxins therapy in patients with multidrug resistant Acinetobacter species nosocomial meningitis. Place and duration of study: This Retrospective study was conducted in the Department of Infectious Diseases, Aga Khan University Hospital, Karachi Pakistan between 2010 and 2014. Methodology: Twenty six patients who developed post neurosurgical MDR Acinetobacter nosocomial meningitis age above 18 were included, while those with polymicrobial meningitis, and those patients who only received intravenous polymyxins were excluded. The primary outcome is ability and time to sterilize the cerebrospinal fluid Results: The mean age was 42.9±11.5 years. Cerebrospinal fluid sterilization was observed in 24 patients in a median of 4 days. One patient made complete recovery, 16 patients recovered with neurological deficits and five patients expired. A trend of early cerebrospinal fluid sterilization was observed in patients with continuous intrathecal therapy. The time to cerebrospinal fluid sterilization is similar with intrathecal colistin or polymyxin. Conclusion: Intrathecal polymyxins are safe and efficacious in the treatment of multidrug resistant nosocomial Acinetobacter species meningitis. Keywords: Intrathecal, Polymyxins, Multidrug resistant, Acinetobacter species, Nosocomial, Meningitis