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Multidrug-Resistant Escherichia coli and Klebsiella pneumoniae: Treatment, Selection and International Spread
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
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 [en]
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: urn:nbn:se:uu:diva-182897ISBN: 978-91-554-8537-5 (print)OAI: oai:DiVA.org:uu-182897DiVA: diva2:563708
Public defence
2012-12-15, Gustavianum, Auditorium minus, Akademigatan 3, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2012-11-23 Created: 2012-10-18 Last updated: 2015-09-30Bibliographically approved
List of papers
1. Foreign Travel Is a Major Risk Factor for Colonization with Escherichia coli Producing CTX-M-Type Extended-Spectrum beta-Lactamases: a Prospective Study with Swedish Volunteers
Open this publication in new window or tab >>Foreign Travel Is a Major Risk Factor for Colonization with Escherichia coli Producing CTX-M-Type Extended-Spectrum beta-Lactamases: a Prospective Study with Swedish Volunteers
2010 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 54, no 9, 3564-3568 p.Article in journal (Refereed) Published
Abstract [en]

Foreign travel has been suggested to be a risk factor for the acquisition of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. To our knowledge, this has not previously been demonstrated in a prospective study. Healthy volunteers traveling outside Northern Europe were enrolled. Rectal swabs and data on potential travel-associated risk factors were collected before and after traveling. A total of 105 volunteers were enrolled. Four of them did not complete the study, and one participant carried ESBL-producing Escherichia coli before travel. Twenty-four of 100 participants with negative pretravel samples were colonized with ESBL-producing Escherichia coli after the trip. All strains produced CTX-M enzymes, mostly CTX-M-15, and some coproduced TEM or SHV enzymes. Coresistance to several antibiotic subclasses was common. Travel to India was associated with the highest risk for the acquisition of ESBLs (88%; n = 7). Gastroenteritis during the trip was an additional risk factor (P = 0.003). Five of 21 volunteers who completed the follow-up after 6 months had persistent colonization with ESBLs. This is the first prospective study demonstrating that international travel is a major risk factor for colonization with ESBL-producing Enterobacteriaceae. Considering the high acquisition rate of 24%, it is obvious that global efforts are needed to meet the emergence and spread of CTX-M enzymes and other antimicrobial resistances.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-135414 (URN)10.1128/AAC.00220-10 (DOI)000281005900005 ()
Available from: 2010-12-07 Created: 2010-12-06 Last updated: 2017-12-11Bibliographically approved
2. Radical reduction of cephalosporin use at a tertiary hospital after educational antibiotic intervention during an outbreak of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae
Open this publication in new window or tab >>Radical reduction of cephalosporin use at a tertiary hospital after educational antibiotic intervention during an outbreak of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae
Show others...
2011 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 66, no 5, 1161-1167 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: During an outbreak of extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae at our hospital, we performed an educational antibiotic intervention aimed at reducing prescriptions of second- and third-generation cephalosporins and preventing increased use of fluoroquinolones and carbapenems. In this report, we describe the implementation strategy used and evaluate the intervention effect according to Cochrane recommendations. Methods: New recommendations for empirical intravenous antibiotic treatment were communicated to prescribers throughout the hospital by infectious diseases physicians working with Strama (the Swedish strategic programme against antibiotic resistance). No restrictive measures were used. The intervention effect was analysed with interrupted time series (ITS) regression analysis of local and national monthly antibiotic sales data. Results: A radical immediate and sustained reduction was demonstrated for the cephalosporins targeted in the intervention, whereas consumption of piperacillin/tazobactam and penicillin G increased substantially. Fluoroquinolone and carbapenem use was essentially unchanged. The ESBL outbreak subsided and no increased resistance to piperacillin/tazobactam was detected in K. pneumoniae, Escherichia coli or Pseudomonas aeruginosa blood isolates during the 2.5 year follow-up. Conclusions: Our study clearly demonstrates that an educational intervention can have an immediate and profound effect on antibiotic prescription patterns at a large tertiary hospital. ITS regression analysis of local and national antibiotic sales data was valuable to readily assess the immediate and sustained effects of the intervention.

Keyword
interrupted time series, ESBLs, piperacillin/tazobactam
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-152851 (URN)10.1093/jac/dkr053 (DOI)000289584000031 ()
Available from: 2011-05-02 Created: 2011-05-02 Last updated: 2017-12-11Bibliographically approved
3. Frequent emergence of porin-deficient subpopulations with reduced carbapenem susceptibility in ESBL-producing Escherichia coli during exposure to ertapenem in an in vitro pharmacokinetic model
Open this publication in new window or tab >>Frequent emergence of porin-deficient subpopulations with reduced carbapenem susceptibility in ESBL-producing Escherichia coli during exposure to ertapenem in an in vitro pharmacokinetic model
Show others...
2013 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 68, no 6, 1319-1326 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES:

Ertapenem resistance is increasing in Enterobacteriaceae. The production of extended-spectrum β-lactamases (ESBLs) and reduced expression of outer membrane porins are major mechanisms of resistance in ertapenem-resistant Klebsiella pneumoniae. Less is known of ertapenem resistance in Escherichia coli. The aim of this study was to explore the impact of ESBL production in E. coli on the antibacterial activity of ertapenem.

METHODS:

Two E. coli strains, with and without ESBL production, were exposed to ertapenem in vitro for 48 h at concentrations simulating human pharmacokinetics with conventional and higher dosages.

RESULTS:

Isolates with non-susceptibility to ertapenem (MICs 0.75-1.5 mg/L) were detected after five of nine time-kill experiments with the ESBL-producing strain. All of these isolates had ompR mutations, which reduce the expression of outer membrane porins OmpF and OmpC. Higher dosage did not prevent selection of porin-deficient subpopulations. No mutants were detected after experiments with the non-ESBL-producing strain. Compared with other experiments, experiments with ompR mutants detected in endpoint samples showed significantly less bacterial killing after the second dose of ertapenem. Impaired antibacterial activity against E. coli with ESBL production and ompR mutation was also demonstrated in time-kill experiments with static antibiotic concentrations.

CONCLUSIONS:

The combination of ESBL production and porin loss in E. coli can result in reduced susceptibility to ertapenem. Porin-deficient subpopulations frequently emerged in ESBL-producing E. coli during exposure to ertapenem at concentrations simulating human pharmacokinetics. Inappropriate use of ertapenem should be avoided to minimize the risk of selection of ESBL-producing bacteria with reduced susceptibility to carbapenems.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-197878 (URN)10.1093/jac/dkt044 (DOI)000319468900016 ()23478794 (PubMedID)
Available from: 2013-04-05 Created: 2013-04-05 Last updated: 2017-12-06Bibliographically approved
4. Evaluation of Double- and Triple-Antibiotic Combinations for VIM- and NDM-Producing Klebsiella pneumoniae by In Vitro Time-Kill Experiment
Open this publication in new window or tab >>Evaluation of Double- and Triple-Antibiotic Combinations for VIM- and NDM-Producing Klebsiella pneumoniae by In Vitro Time-Kill Experiment
Show others...
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.

National Category
Infectious Medicine Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-183597 (URN)10.1128/AAC.00741-13 (DOI)000332175100061 ()
Available from: 2012-10-31 Created: 2012-10-30 Last updated: 2017-12-07Bibliographically approved

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