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Assessment of early combination effects of colistin and meropenem against Pseudomonas aeruginosa and Acinetobacter baumannii in dynamic time-kill experiments

Tängdén, Thomas; Karvanen, Matti; Friberg, Lena E.; Odenholt, Inga LU and Cars, Otto (2017) In Infectious Diseases 49(7). p.521-527
Abstract

Background: In view of the paucity of clinical evidence, in vitro studies are needed to find antibiotic combinations effective against multidrug-resistant Gram-negative bacteria. Interpretation of in vitro effects is usually based on bacterial growth after 24 h in time-kill and checkerboard experiments. However, the clinical relevance of the effects observed in vitro is not established. In this study we explored alternative output parameters to assess the activities of colistin and meropenem against Pseudomonas aeruginosa and Acinetobacter baumannii. Methods: Four strains each of P. aeruginosa and A. baumannii were exposed to colistin and meropenem, alone and in combination, in 8 h dynamic time-kill experiments. Initial (1 h), maximum... (More)

Background: In view of the paucity of clinical evidence, in vitro studies are needed to find antibiotic combinations effective against multidrug-resistant Gram-negative bacteria. Interpretation of in vitro effects is usually based on bacterial growth after 24 h in time-kill and checkerboard experiments. However, the clinical relevance of the effects observed in vitro is not established. In this study we explored alternative output parameters to assess the activities of colistin and meropenem against Pseudomonas aeruginosa and Acinetobacter baumannii. Methods: Four strains each of P. aeruginosa and A. baumannii were exposed to colistin and meropenem, alone and in combination, in 8 h dynamic time-kill experiments. Initial (1 h), maximum and 8 h bacterial reductions and the area under the bacterial time-kill curve were evaluated. Checkerboards, interpreted based on fractional inhibitory concentration indices after 24 h, were performed for comparison. Results: In the time-kill experiments, the combination resulted in enhanced 1 h, maximum and 8 h bacterial reductions against 2, 3 and 5 of 8 strains, respectively, as compared to the single drugs. A statistically significant reduction in the area under the time-kill curve was observed for three strains. In contrast, the checkerboards did not identify synergy for any of the strains. Conclusions: Combination effects were frequently found with colistin and meropenem against P. aeruginosa and A. baumannii in time-kill experiments but were not detected with the checkerboard method. We propose that the early dynamics of bacterial killing and growth, which may be of great clinical importance, should be considered in future in vitro combination studies.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
checkerboards, Gram-negative bacteria, synergy, time-kill experiments
in
Infectious Diseases
volume
49
issue
7
pages
7 pages
publisher
Informa Healthcare
external identifiers
  • scopus:85014533570
  • wos:000399555100006
ISSN
2374-4235
DOI
10.1080/23744235.2017.1296183
language
English
LU publication?
yes
id
68e6a8ac-096a-48e7-bc26-add925d04215
date added to LUP
2017-03-17 14:42:24
date last changed
2018-01-07 11:56:15
@article{68e6a8ac-096a-48e7-bc26-add925d04215,
  abstract     = {<p>Background: In view of the paucity of clinical evidence, in vitro studies are needed to find antibiotic combinations effective against multidrug-resistant Gram-negative bacteria. Interpretation of in vitro effects is usually based on bacterial growth after 24 h in time-kill and checkerboard experiments. However, the clinical relevance of the effects observed in vitro is not established. In this study we explored alternative output parameters to assess the activities of colistin and meropenem against Pseudomonas aeruginosa and Acinetobacter baumannii. Methods: Four strains each of P. aeruginosa and A. baumannii were exposed to colistin and meropenem, alone and in combination, in 8 h dynamic time-kill experiments. Initial (1 h), maximum and 8 h bacterial reductions and the area under the bacterial time-kill curve were evaluated. Checkerboards, interpreted based on fractional inhibitory concentration indices after 24 h, were performed for comparison. Results: In the time-kill experiments, the combination resulted in enhanced 1 h, maximum and 8 h bacterial reductions against 2, 3 and 5 of 8 strains, respectively, as compared to the single drugs. A statistically significant reduction in the area under the time-kill curve was observed for three strains. In contrast, the checkerboards did not identify synergy for any of the strains. Conclusions: Combination effects were frequently found with colistin and meropenem against P. aeruginosa and A. baumannii in time-kill experiments but were not detected with the checkerboard method. We propose that the early dynamics of bacterial killing and growth, which may be of great clinical importance, should be considered in future in vitro combination studies.</p>},
  author       = {Tängdén, Thomas and Karvanen, Matti and Friberg, Lena E. and Odenholt, Inga and Cars, Otto},
  issn         = {2374-4235},
  keyword      = {checkerboards,Gram-negative bacteria,synergy,time-kill experiments},
  language     = {eng},
  month        = {03},
  number       = {7},
  pages        = {521--527},
  publisher    = {Informa Healthcare},
  series       = {Infectious Diseases},
  title        = {Assessment of early combination effects of colistin and meropenem against Pseudomonas aeruginosa and Acinetobacter baumannii in dynamic time-kill experiments},
  url          = {http://dx.doi.org/10.1080/23744235.2017.1296183},
  volume       = {49},
  year         = {2017},
}