Pharmacodynamics of dose-escalated ‘front-loading’ polymyxin B regimens against polymyxin-resistant mcr-1-harbouring Escherichia coli

Smith, Nicholas M.; Bulman, Zackery P.; Sieron, Arthur; Bulitta, Jürgen B.; Holden, Patricia N.; Nation, Roger L.; Li, Jian; Wright, Gerard D.; Tsuji, Brian T.

doi:10.1093/jac/dkx121

Cited by 14 publications

(16 citation statements)

References 23 publications

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“…The stability of polymyxin resistance additionally suggests that the administration of polymyxin antibiotics to mcr-1- harboring organisms is unlikely to have a collateral impact to potentiate high levels of polymyxin resistance such as have been described for polymyxin-induced chromosomal mutations in mgrB or pmrAB ( 16 , 17 ). The effect of polymyxin monotherapy on polymyxin-susceptible Enterobacteriaceae , where high levels of resistance almost always emerge, is in stark contrast to the stable, low-level polymyxin resistance observed in mcr-1- harboring organisms ( 18 ). This may also support the use of short-duration polymyxin B regimens that can generate concentrations above the MIC.…”

Section: Observationmentioning

confidence: 90%

Polymyxin Combinations Combat Escherichia coli Harboring mcr-1 and bla _NDM-5 : Preparation for a Postantibiotic Era

Bulman

Chen

Walsh

et al. 2017

mBio

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The rapid increase of carbapenem resistance in Gram-negative bacteria has resurrected the importance of the polymyxin antibiotics. The recent discovery of plasmid-mediated polymyxin resistance (mcr-1) in carbapenem-resistant Enterobacteriaceae serves as an important indicator that the golden era of antibiotics is under serious threat. We assessed the bacterial killing of 15 different FDA-approved antibiotics alone and in combination with polymyxin B in time-killing experiments against Escherichia coli MCR1_NJ, the first reported isolate in the United States to coharbor mcr-1 and a New Delhi metallo-β-lactamase gene (blaNDM-5). The most promising regimens were advanced to the hollow-fiber infection model (HFIM), where human pharmacokinetics for polymyxin B, aztreonam, and amikacin were simulated over 240 h. Exposure to polymyxin B monotherapy was accompanied by MCR1_NJ regrowth but not resistance amplification (polymyxin B MIC from 0 to 240 h [MIC0h to MIC240h] of 4 mg/liter), whereas amikacin monotherapy caused regrowth and simultaneous resistance amplification (amikacin MIC0h of 4 mg/liter versus MIC240h of >64 mg/liter). No MCR1_NJ colonies were observed for any of the aztreonam-containing regimens after 72 h. However, HFIM cartridges for both aztreonam monotherapy and the polymyxin B-plus-aztreonam regimen were remarkably turbid, and the presence of long, filamentous MCR1_NJ cells was evident in scanning electron microscopy, suggestive of a nonreplicating persister (NRP) phenotype. In contrast, the 3-drug combination of polymyxin B, aztreonam, and amikacin provided complete eradication (>8-log10 CFU/ml reduction) with suppression of resistance and prevention of NRP formation. This is the first comprehensive pharmacokinetic/pharmacodynamic study to evaluate triple-drug combinations for polymyxin- and carbapenem-resistant E. coli coproducing MCR-1 and NDM-5 and will aid in the preparation for a so-called “postantibiotic” era.

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Section: Observationmentioning

confidence: 90%

Polymyxin Combinations Combat Escherichia coli Harboring mcr-1 and bla _NDM-5 : Preparation for a Postantibiotic Era

Bulman

Chen

Walsh

et al. 2017

mBio

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“…[106][107][108][109] With the recent report of mobile colistin resistance genes, 16-18, 110, 111 the presence of heteroresistance, 19 and the association between colistin resistance and increased risk of in-hospital mortality, 106 there is mounting support for strategies to optimize polymyxins therapeutically including combination therapy. 41,[111][112][113] There is a mechanism-based rationale for using polymyxins in combination with other antimicrobials that display synergy with a membrane permeabilizer (such as the polymyxins) allowing for increased concentrations of companion antibacterial agents that have intracellular targets. 109,[114][115][116] Unfortunately, the clinical literature on combination therapy versus monotherapy is difficult to interpret due to limitations in many studies.…”

Section: Polymyxin Combinationsmentioning

confidence: 99%

“…Finally, polymyxin resistance is increasing worldwide with several recent reports of clinical failure and resistance emergence during monotherapy . With the recent report of mobile colistin resistance genes, the presence of heteroresistance, and the association between colistin resistance and increased risk of in‐hospital mortality, there is mounting support for strategies to optimize polymyxins therapeutically including combination therapy . There is a mechanism‐based rationale for using polymyxins in combination with other antimicrobials that display synergy with a membrane permeabilizer (such as the polymyxins) allowing for increased concentrations of companion antibacterial agents that have intracellular targets …”

Section: Clinical Questions and Recommendationsmentioning

confidence: 99%

International Consensus Guidelines for the Optimal Use of the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti‐infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP)

et al. 2019

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The polymyxin antibiotics colistin (polymyxin E) and polymyxin B became available in the 1950s and thus did not undergo contemporary drug development procedures. Their clinical use has recently resurged, assuming an important role as salvage therapy for otherwise untreatable gram‐negative infections. Since their reintroduction into the clinic, significant confusion remains due to the existence of several different conventions used to describe doses of the polymyxins, differences in their formulations, outdated product information, and uncertainties about susceptibility testing that has led to lack of clarity on how to optimally utilize and dose colistin and polymyxin B. We report consensus therapeutic guidelines for agent selection and dosing of the polymyxin antibiotics for optimal use in adult patients, as endorsed by the American College of Clinical Pharmacy (ACCP), Infectious Diseases Society of America (IDSA), International Society of Anti‐Infective Pharmacology (ISAP), Society for Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). The European Society for Clinical Microbiology and Infectious Diseases (ESCMID) endorses this document as a consensus statement. The overall conclusions in the document are endorsed by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). We established a diverse international expert panel to make therapeutic recommendations regarding the pharmacokinetic and pharmacodynamic properties of the drugs and pharmacokinetic targets, polymyxin agent selection, dosing, dosage adjustment and monitoring of colistin and polymyxin B, use of polymyxin‐based combination therapy, intrathecal therapy, inhalation therapy, toxicity, and prevention of renal failure. The treatment guidelines provide the first ever consensus recommendations for colistin and polymyxin B therapy that are intended to guide optimal clinical use.

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“…Наконец, во всем мире отмечается рост резистентности к полимиксинам, по крайней мере у энтеробактерий, согласно недавно опубликованным данным о клинической неэффективности и возникновении резистентности на фоне монотерапии [106][107][108][109]. Учитывая сообщения о находящихся на мобильных генетических элементах генах, отвечающих за резистентность к колистину [16-18, 110, 111], и взаимосвязь между устойчивостью к колистину и повышенным риском внутрибольничной летальности [106], необходимы стратегии оптимизации применения полимиксинов, включая использование комбинированной терапии [41,[111][112][113]. Есть обоснование для комбинации полимиксинов с другими антибиотиками с учетом механизма действия.…”

Section: применение полимиксинов в комбинациях с другими абunclassified

Review of the international consensus guidelines for the optimal use of the polymyxins

Елисеева

Azyzov

Зубарева

2019

CMAC

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Polymyxins are often the only agents that remain in vitro active against extensively resistant bacterial pathogens. However, the use of polymyxins is compromised by the number of unresolved issues, including the technical aspects of antimicrobial susceptibility testing, pharmacokinetic and pharmacodynamics parameters, optimal dosing regimens, and combined use with other antibiotics. All of the aspects of polymyxin use are discussed in detail in recently published «International consensus guidelines for the optimal use of the polymyxins», that was endorsed by the following professional societies: American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Antiinfective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP).

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Pharmacodynamics of dose-escalated ‘front-loading’ polymyxin B regimens against polymyxin-resistant mcr-1-harbouring Escherichia coli

Abstract: Manipulating initial dose intensity of polymyxin B was not able to overcome plasmid-mediated resistance due to mcr-1 in E. coli . This reinforces the need to develop new combinatorial strategies to combat these highly resistant Gram-negative bacteria.

Cited by 14 publications

References 23 publications

Polymyxin Combinations Combat Escherichia coli Harboring mcr-1 and bla _NDM-5 : Preparation for a Postantibiotic Era

Polymyxin Combinations Combat Escherichia coli Harboring mcr-1 and bla _NDM-5 : Preparation for a Postantibiotic Era

Review of the international consensus guidelines for the optimal use of the polymyxins

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Pharmacodynamics of dose-escalated ‘front-loading’ polymyxin B regimens against polymyxin-resistant mcr-1-harbouring Escherichia coli

Abstract: Manipulating initial dose intensity of polymyxin B was not able to overcome plasmid-mediated resistance due to mcr-1 in E. coli . This reinforces the need to develop new combinatorial strategies to combat these highly resistant Gram-negative bacteria.

Cited by 14 publications

References 23 publications

Polymyxin Combinations Combat Escherichia coli Harboring mcr-1 and bla NDM-5 : Preparation for a Postantibiotic Era

Polymyxin Combinations Combat Escherichia coli Harboring mcr-1 and bla NDM-5 : Preparation for a Postantibiotic Era

Review of the international consensus guidelines for the optimal use of the polymyxins

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Product

Resources

About

Polymyxin Combinations Combat Escherichia coli Harboring mcr-1 and bla _NDM-5 : Preparation for a Postantibiotic Era

Polymyxin Combinations Combat Escherichia coli Harboring mcr-1 and bla _NDM-5 : Preparation for a Postantibiotic Era