Double-Carbapenem Therapy for Carbapenemase-Producing Klebsiella pneumoniae

Bulik, Catharine C.; Nicolau, David P.

doi:10.1128/aac.01420-10

Cited by 184 publications

(147 citation statements)

References 11 publications

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“…Two examples are avibactam, 31 recently FDA approved, and RPX7009, currently in stage III clinical trials. 32 Modulation of carbapenem susceptibility in CRE strains through use of double carbapenem therapy or tigecycline-carbapenem combination has also been suggested in human case reports, 33,34 animal models, and/or in vitro studies. 35 However, it could be imagined that there are many other classes of compounds that might restore carbapenem efficacy through effects on antimicrobial transport, cell wall dynamics, or currently unknown mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Validation of a High-Throughput Screening Assay for Identification of Adjunctive and Directly Acting Antimicrobials Targeting Carbapenem-Resistant Enterobacteriaceae

Smith

Kirby

2016

ASSAY and Drug Development Technologies

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We describe development and validation of a high-throughput screen (HTS) for identifying small molecules that restore the efficacy of carbapenems (adjunctives) and/or directly inhibit growth of carbapenem-resistant Enterobacteriaceae (CRE). Our HTS assay is based on a screen-counterscreen approach using a representative multidrug-resistant CRE strain, Klebsiella pneumoniae BIDMC12A. Specifically, we tested the ability of small molecules to inhibit bacterial growth in the presence (screen) or absence (counterscreen) of meropenem, a representative carbapenem antibiotic. Primary screening of 11,698 known bioactive compounds identified 14 with adjunctive activity and 79 with direct antimicrobial effect. Secondary screening identified triclosan as a strongly synergistic meropenem adjunctive (fractional inhibitory concentration = 0.48) and confirmed azidothymidine (AZT) (minimal inhibitory concentration [MIC] = 4 lg mL ) as potent direct antimicrobials. Spectrum of activity of AZT and spectinomycin was tested against a collection of 103 representative Enterobacteriaceae strains (&50% CRE). AZT, a nucleoside analog used to treat human immunodeficiency virus, demonstrated an MIC 50 of 2 lg mL -1 . Spectinomycin, an antibiotic used to treat gonorrhea, had an MIC 50 of 32 lg mL -1 . Therefore, a significant percentage of CRE strains appeared relatively susceptible to these antimicrobials. These data identified AZT and spectinomycin as available agents warranting further study for potential treatment of multidrug-resistant CRE infection. Our results provide proof of principle and impetus for performing a largescale HTS for discovery of novel, small-molecule adjunctives and antibacterial agents directly targeting CRE.

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Section: Discussionmentioning

confidence: 99%

Validation of a High-Throughput Screening Assay for Identification of Adjunctive and Directly Acting Antimicrobials Targeting Carbapenem-Resistant Enterobacteriaceae

Smith

Kirby

2016

ASSAY and Drug Development Technologies

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“…В эксперимен-тальной работе in vitro и в опыте на мышах была показана эффективность подобной комбинации [26]. Теоретическое обоснование такой схемы лечения заключается в следующем: эртапенем легче, чем дори-пенем гидролизуется карбапенемазами энтеробак-терий.…”

Section: карбапенемыunclassified

Antibacterial Therapy of Septic Complications in Resistance of Pathogens to Carbapenems

Черненькая¹

2017

Neotložnaâ med. pomoŝʹ

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ГБУЗ «НИИ скорой помощи им. Н.В. Склифосовского Департамента здравоохранения г. Москвы», Москва, Российская Федерация Контактная информация: Татьяна Витальевна Черненькая, кандидат медицинских наук, заведующая научной лабораторией кли-нической микробиологии НИИ СП им. Н.В. Склифосовского ДЗ г. Москвы. Е-mail: chernenkayat@rambler.ru РЕЗЮМЕ В настоящее время устойчивость грамотрицательных бактерий к карбапенемам приобретает глобальные масштабы. В случае развития заболеваний, вызванных такими возбудителями, отме-чается неэффективность стандартных схем антибактериальной терапии. Следствие этого -зна-чительное увеличение длительности госпитализации, затрат на лечение и летальности. В обзоре литературы представлены возможности антибактериальной терапии для лечения инфекций, вы-званных резистентными к карбапенемам возбудителями. Ключевые слова:карбапенемы, резистентность, антибиотики, Acinetobacter spp., Pseudomonas aeruginosa, Klebsiella pneumonia.Chernenkaya грамотрицательных бактерий с помощью плазмид. А они в своем составе часто несут детерминанты устой-чивости к антибиотикам разных групп. Так очень быс-тро происходит одномоментная передача фенотипа множественной лекарственной устойчивости [12, 13]. Таким образом, резистентность к карбапенемам можно рассматривать как маркер множественной лекарственной устойчивости бактерий, и, следова-тельно, неэффективности стандартных схем антибак-териальной терапии. В связи с этим представляется актуальным обсуждение имеющихся терапевтических возможностей в лечении инфекций, вызванных резис-тентными к карбапенемам возбудителями. НОВЫЕ АНТИБИОТИКИ В 2009 г. Американское общество инфекционных болезней (Infectious Diseases Society of America -IDSA)анонсировало «инициативу 10х20», в рамках которой к 2020 г. предполагается разработать десять новых антибиотиков [14].В 2014 г. Управлением по надзору за качеством пищевых продуктов и медикаментов США (Food and Drug Administration U.S. -FDA) одобрены четыре антибиотика: далбаванцин (dalbavancin), тедизолид (tedizolid), оритаванцин (oritavancin) и цефтолозан/ тазобактам (ceftolozane/tazobactam) [15]. В 2015 г. был одобрен цефтазидим/авибактам (ceftazidime/avibactam) [16]. Первые три препарата обладают преимуществен-ной активностью против грамположительных возбу-дителей.Спектр активности цефтолозан/тазобактама включает грамотрицательные бактерии, в том числе БЛРС-продуцирующие энтеробактерии и Pseudomonas aeruginosa. Но препарат не ингибирует большинство сериновых карбапенемаз и металлобета-лактамаз, и, следовательно, в случае инфекций, вызванных устой-чивыми к карбапенемам возбудителями, он будет неэффективен [17].Цефтазидим/авибактам -первый цефалоспорин, обладающий активностью в отношении большинства карбапенемаз, за исключением металлобета-лактамаз [18]. В России он пока не зарегистрирован.Еще несколько препаратов с потенциальной актив-ностью против полирезистентных грамотрицательных бактерий в настоящее время находятся на 2-3-й стади-ях клинических испытаний. Но все они принадлежат к уже длительно применяемым классам антибиотиков:-Ами...

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“…80 Others have found that various combinations of rifampin, β−lactams, aminoglycosides, quinolones, colistin/polymyxin B, fosfomycin or other agents are synergistic in vitro, or in animal models, against MDR Pseudomonas or Acinetobacter spp. 2,31,81,82 Many authors argue that rifampin should be considered for addition to other active antibiotics in the treatment of uncontrolled infection due to MDR bacteria, 31,55,78,83-85 though there is little evidence of why rifampicin should improve outcome and no randomized trials to show that it does improve these outcomes.…”

Section: Combination Therapy In Infections Due To Resistant Gram-negamentioning

confidence: 99%

Targeted therapy against multi-resistant bacteria in leukemic and hematopoietic stem cell transplant recipients: guidelines of the 4th European Conference on Infections in Leukemia (ECIL-4, 2011)

et al. 2013

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The detection of multi-resistant bacterial pathogens, particularly those to carbapenemases, in leukemic and stem cell transplant patients forces the use of old or non-conventional agents as the only remaining treatment options. These include colistin/polymyxin B, tigecycline, fosfomycin and various anti-gram-positive agents. Data on the use of these agents in leukemic patients are scanty, with only linezolid subjected to formal trials. The Expert Group of the 4 th European Conference on Infections in Leukemia has developed guidelines for their use in these patient populations. Targeted therapy should be based on (i) in vitro susceptibility data, (ii) knowledge of the best treatment option against the particular species or phenotype of bacteria, (iii) pharmacokinetic/pharmacodynamic data, and (iv) careful assessment of the risk-benefit balance. For infections due to resistant Gram-negative bacteria, these agents should be preferably used in combination with other agents that remain active in vitro, because of suboptimal efficacy (e.g., tigecycline) and the risk of emergent resistance (e.g., fosfomycin). The paucity of new antibacterial drugs in the near future should lead us to limit the use of these drugs to situations where no alternative exists. ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o n 2 0 1 3organizing committee and experts were solicited to form the working group. The group reviewed the published English-language literature and prepared proposals on treatment options for infections due to resistant bacteria. Papers for review were sought using PubMed with the terms "linezolid", "daptomycin", "quinupristin/ dalfopristin", "colistin or polymyxin", "tigecycline", "fosfomycin", "telavancin", "ceftaroline" AND "stem cell transplantation or bone marrow transplant or leukemia or hematological malignancy or cancer". References cited in the articles identified were also considered. In respect of 'Duration of therapy', the main search terms used were "antibiotic therapy"; "stem cell transplantation or bone marrow transplantation or hematological malignancy or cancer"; "febrile neutropenia" and "duration therapy", "discontinuation antibiotics" and "microbiologically documented infection". Definitions of resistanceA bacterial isolate was considered non-susceptible if it was categorized resistant, intermediate or non-susceptible when using clinical breakpoints of the European Committee on Antimicrobial Susceptibility Testing (EUCAST), Clinical and Laboratory Standards Institute (CLSI) or the US Food and Drug Administration (FDA). Definitions of 'MDR' vary among authors and usually presume resistance to at least two antibiotics used in empiric therapy (3 rd 4 th -generation cephalosporins, carbapenems or piperacillin/tazobactam) or resistance to at least three of the following antibiotic classes: antipseudomonal penicillins, cephalosporins, carbapenems, aminoglycosides and fluoroquinolones. [11][12][13][14][15] According to the recent definition of the European Centre for Disease Prevention and Control...

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Double-Carbapenem Therapy for Carbapenemase-Producing Klebsiella pneumoniae

Cited by 184 publications

References 11 publications

Validation of a High-Throughput Screening Assay for Identification of Adjunctive and Directly Acting Antimicrobials Targeting Carbapenem-Resistant Enterobacteriaceae

Validation of a High-Throughput Screening Assay for Identification of Adjunctive and Directly Acting Antimicrobials Targeting Carbapenem-Resistant Enterobacteriaceae

Antibacterial Therapy of Septic Complications in Resistance of Pathogens to Carbapenems

Targeted therapy against multi-resistant bacteria in leukemic and hematopoietic stem cell transplant recipients: guidelines of the 4th European Conference on Infections in Leukemia (ECIL-4, 2011)

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