Giuseppe
Emeritus
[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]
In Vitro Synergy of Polymyxins and Carbapenems: Systematic Review and Meta Analysis
Oren Zusman a*, Tomer Avni a, Leonard Leibovici a, Amos Adler b, Lena Friberg c, Theodouli Stergiopoulou d, Yehuda Carmeli b and Mical Paul e
Author Affiliations: <SUP>a</SUP>Department of Medicine E, Rabin Medical Center, Petah-Tiqva, Israel <SUP>b</SUP>Division of Epidemiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel <SUP>c</SUP>Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden <SUP>d</SUP>Pediatric Service, Notre Dame des Bruy?res, CHU, Li?ge,, Belgium <SUP>e</SUP>Infectious Diseases Unit, Rambam Medical Center, Haifa, Israel
ABSTRACT
Objectives
To examine the evidence on in-vitro synergy of polymyxin-carbapenem combination therapy against Gram-negative bacteria (GNB)
Methods
Systematic review and meta-analysis. All studies examining in-vitro interactions of antibiotic combinations consisting of any carbapenem with colistin or polymyxin B against any GNB. A broad search was conducted with no language, date or publication status restrictions. Synergy rates, defined as fractional inhibitory concentration index ≤0.5 or >2log colony forming unit reduction, were pooled separately for time-kill, checkerboard, and E-test in a mixed-effects meta-analysis of rates. We examined whether synergy rate depended on testing method, type of antibiotic, bacteria and resistance to carbapenems. Pooled rates with 95% confidence intervals are shown.
Results
39 published studies and 15 conference proceeding were included, reporting on 246 different tests on 1054 bacterial isolates. In time-kill studies, combination therapy showed synergy rates of 77% (95% CI 64-87) for Acinetobacter baumannii, 44% (95% CI 30-59%) for Klebsiella pneumoniae and 50% (95% CI 30-69%) for Pseudomonas aeruginosa with low antagonism rates for all. Doripenem showed high synergy rates for all three bacteria. For A. baumannii, meropenem was more synergistic than imipenem, whereas for P. aeruginosa the opposite was true. Checkerboard and Etest studies generally reported lower synergy rates than time-kill. Use of combination therapy led to less resistance development in-vitro.
Conclusions
The combination of a carbapenem with a polymyxin against GNB, especially A. baumannii, is supported in-vitro by high synergy rates, with low antagonism and less resistance development. These findings should be examined in clinical studies.
FOOTNOTES
* Corresponding author. Tel: +972-3-937-7358; Fax: +972-3-9194665; E-mail: orenzu1@clalit.org.il
Copyright ? 2013, American Society for Microbiology. All Rights Reserved.
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In Vitro Synergy of Polymyxins and Carbapenems: Systematic Review and Meta Analysis
Oren Zusman a*, Tomer Avni a, Leonard Leibovici a, Amos Adler b, Lena Friberg c, Theodouli Stergiopoulou d, Yehuda Carmeli b and Mical Paul e
Author Affiliations: <SUP>a</SUP>Department of Medicine E, Rabin Medical Center, Petah-Tiqva, Israel <SUP>b</SUP>Division of Epidemiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel <SUP>c</SUP>Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden <SUP>d</SUP>Pediatric Service, Notre Dame des Bruy?res, CHU, Li?ge,, Belgium <SUP>e</SUP>Infectious Diseases Unit, Rambam Medical Center, Haifa, Israel
ABSTRACT
Objectives
To examine the evidence on in-vitro synergy of polymyxin-carbapenem combination therapy against Gram-negative bacteria (GNB)
Methods
Systematic review and meta-analysis. All studies examining in-vitro interactions of antibiotic combinations consisting of any carbapenem with colistin or polymyxin B against any GNB. A broad search was conducted with no language, date or publication status restrictions. Synergy rates, defined as fractional inhibitory concentration index ≤0.5 or >2log colony forming unit reduction, were pooled separately for time-kill, checkerboard, and E-test in a mixed-effects meta-analysis of rates. We examined whether synergy rate depended on testing method, type of antibiotic, bacteria and resistance to carbapenems. Pooled rates with 95% confidence intervals are shown.
Results
39 published studies and 15 conference proceeding were included, reporting on 246 different tests on 1054 bacterial isolates. In time-kill studies, combination therapy showed synergy rates of 77% (95% CI 64-87) for Acinetobacter baumannii, 44% (95% CI 30-59%) for Klebsiella pneumoniae and 50% (95% CI 30-69%) for Pseudomonas aeruginosa with low antagonism rates for all. Doripenem showed high synergy rates for all three bacteria. For A. baumannii, meropenem was more synergistic than imipenem, whereas for P. aeruginosa the opposite was true. Checkerboard and Etest studies generally reported lower synergy rates than time-kill. Use of combination therapy led to less resistance development in-vitro.
Conclusions
The combination of a carbapenem with a polymyxin against GNB, especially A. baumannii, is supported in-vitro by high synergy rates, with low antagonism and less resistance development. These findings should be examined in clinical studies.
FOOTNOTES
* Corresponding author. Tel: +972-3-937-7358; Fax: +972-3-9194665; E-mail: orenzu1@clalit.org.il
Copyright ? 2013, American Society for Microbiology. All Rights Reserved.
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