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Evaluation of Double- and Triple-Antibiotic Combinations for VIM- and NDM-Producing Klebsiella pneumoniae by In Vitro Time-Kill Experiment
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
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2014 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, no 3, 1757-1762 p.Article in journal (Refereed) Published
Abstract [en]

Combination therapy is recommended for infections with carbapenemase-producing Klebsiella pneumoniae. However, limited data exist on which antibiotic combinations are the most effective. The aim of this study was to find effective antibiotic combinations against metallo-beta-lactamase-producing K. pneumoniae (MBL-KP). Two VIM- and two NDM-producing K. pneumoniae strains, all susceptible to colistin, were exposed to antibiotics at clinically relevant static concentrations during 24-h time-kill experiments. Double- and triple-antibiotic combinations of aztreonam, ciprofloxacin, colistin, daptomycin, fosfomycin, meropenem, rifampin, telavancin, tigecycline, and vancomycin were used. Synergy was defined as a >= 2 log(10) decrease in CFU/ml between the combination and its most active drug after 24 h, and bactericidal effect was defined as a >= 3 log(10) decrease in CFU/ml after 24 h compared with the starting inoculum. Synergistic or bactericidal activity was demonstrated for aztreonam, fosfomycin, meropenem, and rifampin in double-antibiotic combinations with colistin and also for aztreonam, fosfomycin, and rifampin in triple-antibiotic combinations with meropenem and colistin. Overall, the combination of rifampin-meropenem-colistin was the most effective regimen, demonstrating synergistic and bactericidal effects against all four strains. Meropenem-colistin, meropenem-fosfomycin, and tigecycline-colistin combinations were not bactericidal against the strains used. The findings of this and other studies indicate that there is great potential of antibiotic combinations against carbapenemase-producing K. pneumoniae. However, our results deviate to some extent from those of previous studies, which might be because most studies to date have included KPC-producing rather than MBL-producing strains. More studies addressing MBL-KP are needed.

Place, publisher, year, edition, pages
2014. Vol. 58, no 3, 1757-1762 p.
National Category
Infectious Medicine Microbiology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-183597DOI: 10.1128/AAC.00741-13ISI: 000332175100061OAI: oai:DiVA.org:uu-183597DiVA: diva2:563707
Available from: 2012-10-31 Created: 2012-10-30 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Multidrug-Resistant Escherichia coli and Klebsiella pneumoniae: Treatment, Selection and International Spread
Open this publication in new window or tab >>Multidrug-Resistant Escherichia coli and Klebsiella pneumoniae: Treatment, Selection and International Spread
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The prevalence of Escherichia coli and Klebsiella pneumoniae producing extended-spectrum beta-lactamases (ESBLs) and carbapenemases is increasing worldwide. Therapeutic options for infections with these bacteria are limited not only by the production of ESBLs and carbapenemases, which confer resistance to cephalosporins and carbapenems, but also by frequent co-resistance to other antibiotics. The overall aim of this thesis was to obtain a better understanding of multidrug-resistant E. coli and K. pneumoniae in relation to epidemiology, selection and susceptibility to antibiotic therapy.

In a prospective study ESBL-producing E. coli was found to spread easily through international travel. Twenty-four of 100 Swedes travelling outside Northern Europe acquired ESBL-producing E. coli in the intestinal flora. The risk was highest for travelers visiting India and those suffering from gastroenteritis during travel.

To minimize selection of ESBL-producing K. pneumoniae during a hospital outbreak with these bacteria, an educational antibiotic intervention was performed at Uppsala University Hospital in 2006. The primary aim of the intervention was to reduce the consumption of parenteral cephalosporins. An immediate and radical reduction of cephalosporins was demonstrated with interrupted time series analysis. The outbreak declined during 2007 and no increased resistance to replacement antibiotics was detected.

The impact of ESBL production on the antibacterial activity of ertapenem was studied in time-kill experiments. It was shown that porin-deficient subpopulations with reduced susceptibility to ertapenem frequently emerged in ESBL-producing E. coli during exposure to ertapenem at concentrations simulating human pharmacokinetics.

Further, the antibacterial effects of antibiotic combinations against four strains of K. pneumoniae producing carbapenemases of the metallo-beta-lactamase type were studied in time-kill experiments. Double and triple combinations of aztreonam, fosfomycin, meropenem, rifampin and colistin at clinically relevant static concentrations were effective despite that the bacteria were frequently resistant to the individual drugs. These results indicate that there is a largely unexplored potential of antibiotic combination therapy for multidrug-resistant K. pneumoniae.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 71 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 840
Keyword
Escherichia coli, Klebsiella pneumoniae, extended-spectrum beta-lactamases, carbapenemases, metallo-beta-lactamases, synergy, antibiotic interventions
National Category
Infectious Medicine Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-182897 (URN)978-91-554-8537-5 (ISBN)
Public defence
2012-12-15, Gustavianum, Auditorium minus, Akademigatan 3, Uppsala, 09:00 (Swedish)
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Available from: 2012-11-23 Created: 2012-10-18 Last updated: 2015-09-30Bibliographically approved

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Tängdén, ThomasHickman, Rachel A.Lagerbäck, PernillaCars, Otto

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