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Three Dimensional Checkerboard Synergy Analysis of Colistin, Meropenem, Tigecycline against Multidrug-Resistant Clinical Klebsiella pneumonia Isolates.

Stein C, Makarewicz O, Bohnert JA, Pfeifer Y, Kesselmeier M, Hagel S, Pletz MW - PLoS ONE (2015)

Bottom Line: 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.Adding a third antibiotic did not result in further increased synergistic effect in these strains.Antagonism did not occur.

View Article: PubMed Central - PubMed

Affiliation: Center for Infectious Diseases and Infection Control, Jena University Hospital, Erlanger Allee 101, D-07747, Jena, Germany.

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.

No MeSH data available.


Related in: MedlinePlus

Sequence alignment of ompK36 genes.The sequence of ompK36 of K. pneumoniae strain JM45 (accession number CP006656) was used as reference. The boxes marked the most relevant changes within the ompk36 sequences. Alterations are described above the boxes and the positions of the corresponding amino acid residues are indicated below the boxes.
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pone.0126479.g002: Sequence alignment of ompK36 genes.The sequence of ompK36 of K. pneumoniae strain JM45 (accession number CP006656) was used as reference. The boxes marked the most relevant changes within the ompk36 sequences. Alterations are described above the boxes and the positions of the corresponding amino acid residues are indicated below the boxes.

Mentions: Sequence analyses revealed that all strains exhibited mutations in the ompK genes. Three strains lost OmpK35 and three other strains lost OmpK36 due to nonsense mutations in the respective genes. One strain exhibited only a modified OmpK36. One strain lost both porins whereas 10 strains lost the OmpK35 but harbored modified OmpK36 (Fig 2).


Three Dimensional Checkerboard Synergy Analysis of Colistin, Meropenem, Tigecycline against Multidrug-Resistant Clinical Klebsiella pneumonia Isolates.

Stein C, Makarewicz O, Bohnert JA, Pfeifer Y, Kesselmeier M, Hagel S, Pletz MW - PLoS ONE (2015)

Sequence alignment of ompK36 genes.The sequence of ompK36 of K. pneumoniae strain JM45 (accession number CP006656) was used as reference. The boxes marked the most relevant changes within the ompk36 sequences. Alterations are described above the boxes and the positions of the corresponding amino acid residues are indicated below the boxes.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4465894&req=5

pone.0126479.g002: Sequence alignment of ompK36 genes.The sequence of ompK36 of K. pneumoniae strain JM45 (accession number CP006656) was used as reference. The boxes marked the most relevant changes within the ompk36 sequences. Alterations are described above the boxes and the positions of the corresponding amino acid residues are indicated below the boxes.
Mentions: Sequence analyses revealed that all strains exhibited mutations in the ompK genes. Three strains lost OmpK35 and three other strains lost OmpK36 due to nonsense mutations in the respective genes. One strain exhibited only a modified OmpK36. One strain lost both porins whereas 10 strains lost the OmpK35 but harbored modified OmpK36 (Fig 2).

Bottom Line: 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.Adding a third antibiotic did not result in further increased synergistic effect in these strains.Antagonism did not occur.

View Article: PubMed Central - PubMed

Affiliation: Center for Infectious Diseases and Infection Control, Jena University Hospital, Erlanger Allee 101, D-07747, Jena, Germany.

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.

No MeSH data available.


Related in: MedlinePlus