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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

Exemplary isoboles of the double combinations of the antibiotics.A-C: Isoboles of strain NRZ 00246 (OXA-48 producer) exhibiting synergistic effects. D-F: Isoboles of strain RKI 318/11 (KPC producer) yielding no synergism. FIC = fractional inhibitory concentration.
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pone.0126479.g003: Exemplary isoboles of the double combinations of the antibiotics.A-C: Isoboles of strain NRZ 00246 (OXA-48 producer) exhibiting synergistic effects. D-F: Isoboles of strain RKI 318/11 (KPC producer) yielding no synergism. FIC = fractional inhibitory concentration.

Mentions: Synergism of all three colistin-based combinations (MEM / CST, TGC / CST and MEM / TGC / CST) was found in 5 isolates (Fig 3A–3C). For one additional isolate, only MEM / CST and for another one TGC / CST and MEM / TGC / CST synergies were found. A clearly visible reduction of the FICIMEM/TGC/CST compared to FICITGC/CST could not be observed for the isolates with synergism (Table 1) indicating that the addition of meropenem to the tigecycline / colistin combination or tigecycline to the meropenem / colistin combination did not increase the antimicrobial efficacy. No significant correlation of the MICMEM to the FICIMEM/CST or FICIMEM/TGC/CST could be determined. However, all isolates with FICIMEM/CST < 0.8 exhibited MICMEM of ≥ 8 mg/L and carried various β-lactamase variants (KPC, OXA-48 or CTX-M-15) indicating that there is also no causal relationship between the β-lactamase type and synergism with colistin. The MICs for colistin showed some weak correlation with FICITGC/CST (ρ = -0.52, P = 0.017) and FICIMEM/TGC/CST (ρ = -0.61, P = 0.003). Isolates with synergism generally showed increased MICCST values (MICCST > 8 mg/L). Similar correlations were found between increased resistance to tigecycline (MICTGC) and the FICIMEM/TGC (ρ = -0.70, P <0.001), FICITGC/CST (ρ = -0.70, P < 0.001) and FICIMEM/TGC/CST (ρ = -0.73, P < 0.001). All isolates with synergism exhibited MICTGC ≥ 2 mg/L. A correlation between the efflux properties and the FICI values could not be shown. For detailed results see S3 Table.


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)

Exemplary isoboles of the double combinations of the antibiotics.A-C: Isoboles of strain NRZ 00246 (OXA-48 producer) exhibiting synergistic effects. D-F: Isoboles of strain RKI 318/11 (KPC producer) yielding no synergism. FIC = fractional inhibitory concentration.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0126479.g003: Exemplary isoboles of the double combinations of the antibiotics.A-C: Isoboles of strain NRZ 00246 (OXA-48 producer) exhibiting synergistic effects. D-F: Isoboles of strain RKI 318/11 (KPC producer) yielding no synergism. FIC = fractional inhibitory concentration.
Mentions: Synergism of all three colistin-based combinations (MEM / CST, TGC / CST and MEM / TGC / CST) was found in 5 isolates (Fig 3A–3C). For one additional isolate, only MEM / CST and for another one TGC / CST and MEM / TGC / CST synergies were found. A clearly visible reduction of the FICIMEM/TGC/CST compared to FICITGC/CST could not be observed for the isolates with synergism (Table 1) indicating that the addition of meropenem to the tigecycline / colistin combination or tigecycline to the meropenem / colistin combination did not increase the antimicrobial efficacy. No significant correlation of the MICMEM to the FICIMEM/CST or FICIMEM/TGC/CST could be determined. However, all isolates with FICIMEM/CST < 0.8 exhibited MICMEM of ≥ 8 mg/L and carried various β-lactamase variants (KPC, OXA-48 or CTX-M-15) indicating that there is also no causal relationship between the β-lactamase type and synergism with colistin. The MICs for colistin showed some weak correlation with FICITGC/CST (ρ = -0.52, P = 0.017) and FICIMEM/TGC/CST (ρ = -0.61, P = 0.003). Isolates with synergism generally showed increased MICCST values (MICCST > 8 mg/L). Similar correlations were found between increased resistance to tigecycline (MICTGC) and the FICIMEM/TGC (ρ = -0.70, P <0.001), FICITGC/CST (ρ = -0.70, P < 0.001) and FICIMEM/TGC/CST (ρ = -0.73, P < 0.001). All isolates with synergism exhibited MICTGC ≥ 2 mg/L. A correlation between the efflux properties and the FICI values could not be shown. For detailed results see S3 Table.

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