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Microorganisms
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Polymyxins: New Insights into An 'Old' Class of Antibiotics
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Polymyxins: New Insights into An 'Old' Class of Antibiotics

A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Antimicrobial Agents and Resistance".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 18809

Special Issue Editor

Dr. Andrea Kwa

E-Mail Website
Guest Editor
Duke-NUS Graduate Medical School Singapore, Program in Emerging Infectious Diseases, Singapore City, Singapore
Interests: critical care medicine; infectious diseases; antimicrobial resistance

Special Issue Information

Dear colleagues,

Polymyxins are polypeptide antibiotics that were developed in the 1940s, but fell into disfavor due to their high toxicity rates. Recently, polymyxins have regained significant interest as a consequence of the increasing incidence of infections due to multidrug-resistant Gram-negative bacteria. In this Special Issue, we invite you to send contributions that deal with recent advances in polymyxins that may include (but are not limited to) the following aspects:

  • Polymyxins mechanisms of resistance
  • Predictors for polymyxins resistant infections
  • In-vitro or In-vivo pharmacodynamics of polymyxins alone or polymyxin combinations against specific gram-negative bacilli
  • Polymyxins PK/PD
  • Outcomes of patients using polymyxins or polymyxins combinations against carbapenem-resistant gram-negative bacilli
  • New potential polymyxins-like compounds
  • Polymyxins toxicities
    • mechanisms of
    • clinical outcomes of
  • Use of polymyxins or polymyxins combinations in osteomyelitis, central nervous system infections, or biliary tract infections
  • Rational combinations of polymyxins with antibiotics or non-antibiotics
  • Employing TDM for polymyxins

Dr. Andrea Kwa
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Microorganisms is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (4 papers)

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Research

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12 pages, 1425 KiB  
Article
Combination of Colistin and Azidothymidine Demonstrates Synergistic Activity against Colistin-Resistant, Carbapenem-Resistant Klebsiella pneumoniae
by Ya-Ting Chang, Tsung-Ying Yang, Po-Liang Lu, Shang-Yi Lin, Liang-Chun Wang, Sheng-Fan Wang, Ya-Ju Hsieh and Sung-Pin Tseng
Microorganisms 2020, 8(12), 1964; https://doi.org/10.3390/microorganisms8121964 - 11 Dec 2020
Cited by 3 | Viewed by 2152
Abstract
Carbapenem-resistant Enterobacteriaceae (CRE) is listed as an urgent threat by the World Health Organization because of the limited therapeutic options, rapid evolution of resistance mechanisms, and worldwide dissemination. Colistin is a common backbone agent among the “last-resort” antibiotics for CRE; however, its emerging [...] Read more.
Carbapenem-resistant Enterobacteriaceae (CRE) is listed as an urgent threat by the World Health Organization because of the limited therapeutic options, rapid evolution of resistance mechanisms, and worldwide dissemination. Colistin is a common backbone agent among the “last-resort” antibiotics for CRE; however, its emerging resistance among CRE has taken the present dilemma to the next level. Azidothymidine (AZT), a thymidine analog used to treat human immunodeficiency virus/acquired immunodeficiency syndrome, has been known to possess antibacterial effects against Enterobacteriaceae. In this study, we investigated the combined effects of AZT and colistin in 40 clinical isolates of colistin-resistant, carbapenem-resistant K. pneumoniae (CCRKP). Eleven of the 40 isolates harbored Klebsiella pneumoniae carbapenemase. The in vitro checkerboard method and in vivo nematode killing assay both revealed synergistic activity between the two agents, with fractional inhibitory concentration indexes of ≤0.5 in every strain. Additionally, a significantly lower hazard ratio was observed for the nematodes treated with combination therapy (0.288; p < 0.0001) compared with either AZT or colistin treatment. Toxicity testing indicated potentially low toxicity of the combination therapy. Thus, the AZT–colistin combination could be a potentially favorable therapeutic option for treating CCRKP. Full article
(This article belongs to the Special Issue Polymyxins: New Insights into An 'Old' Class of Antibiotics)
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7 pages, 479 KiB  
Communication
Performance of Population Pharmacokinetic Models in Predicting Polymyxin B Exposures
by Vincent H. Tam, Lawrence S. Lee, Tat-Ming Ng, Tze-Peng Lim, Benjamin P. Z. Cherng, Hafeez Adewusi, Kim H. Hee, Ying Ding, Shimin Jasmine Chung, Li-Min Ling, Piotr Chlebicki, Andrea L. H. Kwa and David C. Lye
Microorganisms 2020, 8(11), 1814; https://doi.org/10.3390/microorganisms8111814 - 18 Nov 2020
Cited by 6 | Viewed by 2045
Abstract
Polymyxin B is the last line of defense in treating multidrug-resistant gram-negative bacterial infections. Dosing of polymyxin B is currently based on total body weight, and a substantial intersubject variability has been reported. We evaluated the performance of different population pharmacokinetic models to [...] Read more.
Polymyxin B is the last line of defense in treating multidrug-resistant gram-negative bacterial infections. Dosing of polymyxin B is currently based on total body weight, and a substantial intersubject variability has been reported. We evaluated the performance of different population pharmacokinetic models to predict polymyxin B exposures observed in individual patients. In a prospective observational study, standard dosing (mean 2.5 mg/kg daily) was administered in 13 adult patients. Serial blood samples were obtained at steady state, and plasma polymyxin B concentrations were determined by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The best-fit estimates of clearance and daily doses were used to derive the observed area under the curve (AUC) in concentration–time profiles. For comparison, 5 different population pharmacokinetic models of polymyxin B were conditioned using patient-specific dosing and demographic (if applicable) variables to predict polymyxin B AUC of the same patient. The predictive performance of the models was assessed by the coefficient of correlation, bias, and precision. The correlations between observed and predicted AUC in all 5 models examined were poor (r2 < 0.2). Nonetheless, the models were reasonable in capturing AUC variability in the patient population. Therapeutic drug monitoring currently remains the only viable approach to individualized dosing. Full article
(This article belongs to the Special Issue Polymyxins: New Insights into An 'Old' Class of Antibiotics)
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Review

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25 pages, 3208 KiB  
Review
Nebulized Colistin in Ventilator-Associated Pneumonia and Tracheobronchitis: Historical Background, Pharmacokinetics and Perspectives
by Yinggang Zhu, Antoine Monsel, Jason A. Roberts, Konstantinos Pontikis, Olivier Mimoz, Jordi Rello, Jieming Qu, Jean-Jacques Rouby and on behalf of the European Investigator Network for Nebulized Antibiotics in Ventilator-Associated Pneumonia (ENAVAP)
Microorganisms 2021, 9(6), 1154; https://doi.org/10.3390/microorganisms9061154 - 27 May 2021
Cited by 68 | Viewed by 6693
Abstract
Clinical evidence suggests that nebulized colistimethate sodium (CMS) has benefits for treating lower respiratory tract infections caused by multidrug-resistant Gram-negative bacteria (GNB). Colistin is positively charged, while CMS is negatively charged, and both have a high molecular mass and are hydrophilic. These physico-chemical [...] Read more.
Clinical evidence suggests that nebulized colistimethate sodium (CMS) has benefits for treating lower respiratory tract infections caused by multidrug-resistant Gram-negative bacteria (GNB). Colistin is positively charged, while CMS is negatively charged, and both have a high molecular mass and are hydrophilic. These physico-chemical characteristics impair crossing of the alveolo-capillary membrane but enable the disruption of the bacterial wall of GNB and the aggregation of the circulating lipopolysaccharide. Intravenous CMS is rapidly cleared by glomerular filtration and tubular excretion, and 20–25% is spontaneously hydrolyzed to colistin. Urine colistin is substantially reabsorbed by tubular cells and eliminated by biliary excretion. Colistin is a concentration-dependent antibiotic with post-antibiotic and inoculum effects. As CMS conversion to colistin is slower than its renal clearance, intravenous administration can lead to low plasma and lung colistin concentrations that risk treatment failure. Following nebulization of high doses, colistin (200,000 international units/24h) lung tissue concentrations are > five times minimum inhibitory concentration (MIC) of GNB in regions with multiple foci of bronchopneumonia and in the range of MIC breakpoints in regions with confluent pneumonia. Future research should include: (1) experimental studies using lung microdialysis to assess the PK/PD in the interstitial fluid of the lung following nebulization of high doses of colistin; (2) superiority multicenter randomized controlled trials comparing nebulized and intravenous CMS in patients with pandrug-resistant GNB ventilator-associated pneumonia and ventilator-associated tracheobronchitis; (3) non-inferiority multicenter randomized controlled trials comparing nebulized CMS to intravenous new cephalosporines/ß-lactamase inhibitors in patients with extensive drug-resistant GNB ventilator-associated pneumonia and ventilator-associated tracheobronchitis. Full article
(This article belongs to the Special Issue Polymyxins: New Insights into An 'Old' Class of Antibiotics)
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12 pages, 259 KiB  
Review
Colistin Update on Its Mechanism of Action and Resistance, Present and Future Challenges
by Ferdinando F. Andrade, Daniela Silva, Acácio Rodrigues and Cidália Pina-Vaz
Microorganisms 2020, 8(11), 1716; https://doi.org/10.3390/microorganisms8111716 - 2 Nov 2020
Cited by 117 | Viewed by 7100
Abstract
Colistin has been extensively used since the middle of the last century in animals, particularly in swine, for the control of enteric infections. Colistin is presently considered the last line of defense against human infections caused by multidrug-resistant Gram-negative organisms such as carbapenemase-producer [...] Read more.
Colistin has been extensively used since the middle of the last century in animals, particularly in swine, for the control of enteric infections. Colistin is presently considered the last line of defense against human infections caused by multidrug-resistant Gram-negative organisms such as carbapenemase-producer Enterobacterales, Acinetobacter baumanni, and Pseudomonas aeruginosa. Transferable bacterial resistance like mcr-genes was reported in isolates from both humans and animals. Researchers actively seek strategies to reduce colistin resistance. The definition of guidelines for colistin therapy in veterinary and human medicine is thus crucial. The ban of colistin use in swine as a growth promoter and for prophylactic purposes, and the implementation of sustainable measures in farm animals for the prevention of infections, would help to avoid resistance and should be encouraged. Colistin resistance in the human–animal–environment interface stresses the relevance of the One Health approach to achieve its effective control. Such measures should be addressed in a cooperative way, with efforts from multiple disciplines and with consensus among doctors, veterinary surgeons, and environment professionals. A revision of the mechanism of colistin action, resistance, animal and human use, as well as colistin susceptibility evaluation is debated here. Full article
(This article belongs to the Special Issue Polymyxins: New Insights into An 'Old' Class of Antibiotics)
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