In vivo demonstration of Pseudomonas aeruginosa biofilms as independent pharmacological microcompartments
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In vivo demonstration of Pseudomonas aeruginosa biofilms as independent pharmacological microcompartments. / Christophersen, Lars; Schwartz, Franziska Angelika; Lerche, Christian Johann; Svanekjær, Trine; Kragh, Kasper Nørskov; Laulund, Anne Sofie; Thomsen, Kim; Henneberg, Kaj Åge; Sams, Thomas; Høiby, Niels; Moser, Claus.
In: Journal of Cystic Fibrosis, Vol. 19, No. 6, 2020, p. 996-1003.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - In vivo demonstration of Pseudomonas aeruginosa biofilms as independent pharmacological microcompartments
AU - Christophersen, Lars
AU - Schwartz, Franziska Angelika
AU - Lerche, Christian Johann
AU - Svanekjær, Trine
AU - Kragh, Kasper Nørskov
AU - Laulund, Anne Sofie
AU - Thomsen, Kim
AU - Henneberg, Kaj Åge
AU - Sams, Thomas
AU - Høiby, Niels
AU - Moser, Claus
PY - 2020
Y1 - 2020
N2 - Background: Pseudomonas aeruginosa is difficult to eradicate from the lungs of cystic fibrosis (CF) patients due to biofilm formation. Organs and blood are independent pharmacokinetic (PK) compartments. Previously, we showed in vitro biofilms behave as independent compartments impacting the pharmacodynamics. The present study investigated this phenomenon in vivo. Methods: Seaweed alginate beads with P. aeruginosa resembling biofilms, either freshly produced (D0) or incubated for 5 days (D5) were installed s.c in BALB/c mice. Mice (n = 64) received tobramycin 40 mg/kg s.c. and were sacrificed at 0.5, 3, 6, 8, 16 or 24 h after treatment. Untreated controls (n = 14) were sacrificed, correspondingly. Tobramycin concentrations were determined in serum, muscle tissue, lung tissue and beads. Quantitative bacteriology was determined. Results: The tobramycin peak concentrations in serum was 58.3 (±9.2) mg/L, in lungs 7.1 mg/L (±2.3), muscle tissue 2.8 mg/L (±0.5) all after 0.5 h and in D0 beads 19.8 mg/L (±3.5) and in D5 beads 24.8 mg/L (±4.1) (both 3 h). A 1-log killing of P. aeruginosa in beads was obtained at 8h, after which the bacterial level remained stable at 16 h and even increased in D0 beads at 24 h. Using the established diffusion retardation model the free tobramycin concentration inside the beads showed a delayed buildup of 3 h but remained lower than the MIC throughout the 24 h. Conclusions: The present in vivo study based on tobramycin exposure supports that biofilms behave as independent pharmacological microcompartments. The study indicates, reducing the biofilm matrix would increase free tobramycin concentrations and improve therapeutic effects.
AB - Background: Pseudomonas aeruginosa is difficult to eradicate from the lungs of cystic fibrosis (CF) patients due to biofilm formation. Organs and blood are independent pharmacokinetic (PK) compartments. Previously, we showed in vitro biofilms behave as independent compartments impacting the pharmacodynamics. The present study investigated this phenomenon in vivo. Methods: Seaweed alginate beads with P. aeruginosa resembling biofilms, either freshly produced (D0) or incubated for 5 days (D5) were installed s.c in BALB/c mice. Mice (n = 64) received tobramycin 40 mg/kg s.c. and were sacrificed at 0.5, 3, 6, 8, 16 or 24 h after treatment. Untreated controls (n = 14) were sacrificed, correspondingly. Tobramycin concentrations were determined in serum, muscle tissue, lung tissue and beads. Quantitative bacteriology was determined. Results: The tobramycin peak concentrations in serum was 58.3 (±9.2) mg/L, in lungs 7.1 mg/L (±2.3), muscle tissue 2.8 mg/L (±0.5) all after 0.5 h and in D0 beads 19.8 mg/L (±3.5) and in D5 beads 24.8 mg/L (±4.1) (both 3 h). A 1-log killing of P. aeruginosa in beads was obtained at 8h, after which the bacterial level remained stable at 16 h and even increased in D0 beads at 24 h. Using the established diffusion retardation model the free tobramycin concentration inside the beads showed a delayed buildup of 3 h but remained lower than the MIC throughout the 24 h. Conclusions: The present in vivo study based on tobramycin exposure supports that biofilms behave as independent pharmacological microcompartments. The study indicates, reducing the biofilm matrix would increase free tobramycin concentrations and improve therapeutic effects.
KW - Alginate beads
KW - Biofilm model
KW - Chronic infection
KW - Independent pharmacological compartment
KW - Pharmacodynamics
KW - Pharmacokinetics
U2 - 10.1016/j.jcf.2020.01.009
DO - 10.1016/j.jcf.2020.01.009
M3 - Journal article
C2 - 32067957
AN - SCOPUS:85079364182
VL - 19
SP - 996
EP - 1003
JO - Journal of Cystic Fibrosis
JF - Journal of Cystic Fibrosis
SN - 1569-1993
IS - 6
ER -
ID: 236724671