Abstract
The spread of carbapenem-non-susceptible Klebsiella pneumoniae strains bearing different resistance determinants is a rising problem worldwide. Especially infections with KPC (Klebsiella pneumoniae carbapenemase) - producers are associated with high mortality rates due to limited treatment options. Recent clinical studies of KPC-blood stream infections revealed that colistin-based combination therapy with a carbapenem and/or tigecycline was associated with significantly decreased mortality rates when compared to colistin monotherapy. However, it remains unclear if these observations can be transferred to K. pneumoniae harboring other mechanisms of carbapenem resistance. A three-dimensional synergy analysis was performed to evaluate the benefits of a triple combination with meropenem, tigecycline and colistin against 20 K. pneumoniae isolates harboring different β-lactamases. To examine the mechanism behind the clinically observed synergistic effect, efflux properties and outer membrane porin (Omp) genes (ompK35 and ompK36) were also analyzed. Synergism was found for colistin-based double combinations for strains exhibiting high minimal inhibition concentrations against all of the three antibiotics. Adding a third antibiotic did not result in further increased synergistic effect in these strains. Antagonism did not occur. These results support the idea that colistin-based double combinations might be sufficient and the most effective combination partner for colistin should be chosen according to its MIC.
Highlights
The global spread of extended-spectrum β-lactamase (ESBL) producing enterobacteria has resulted in a worldwide increase in carbapenem consumption
The class KPC-carbapenemase is most frequently associated with K. pneumoniae and metallo-β-lactamases (MBLs) and the carbapenemase OXA-48 are regionally widespread in this species
Our in vitro results suggest that the best appropriate combination therapy to treat carbapenem resistant K. pneumoniae might be colistin / tigecycline
Summary
The global spread of extended-spectrum β-lactamase (ESBL) producing enterobacteria has resulted in a worldwide increase in carbapenem consumption. This selective pressure has fostered the emergence and spread of carbapenem hydrolyzing β-lactamase variants, like KPC, OXA-48, VIM or NDM in Gram-negative bacteria [1]. The first K. pneumoniae infection associated with KPC was reported in 2001 in the USA [2]. KPC-producing K. pneumoniae strains have spread across the north-eastern USA and southern European countries. The proportion of KPC in K. pneumoniae blood stream infections in southern European countries was recently reported with up to 49.8% (Greece) [3]
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