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The nonantibiotic macrolide em703 improves survival in a model of quinolone-treated pseudomonas aeruginosa airway infection

Kasetty, Gopinath LU ; Bhongir, Ravi K.V. LU ; Papareddy, Praveen LU ; Herwald, Heiko LU and Egesten, Arne LU (2017) In Antimicrobial Agents and Chemotherapy 61(9).
Abstract

Macrolide antibiotics are used as anti-inflammatory agents, e.g., for prevention of exacerbations in chronic obstructive pulmonary disease and cystic fibrosis. Several studies have shown improved outcomes after the addition of macrolides to -lactam antibiotics for treatment of severe community-acquired pneumonia. However, a beneficial effect of macrolides in treating Gram-negative bacterial airway infections, e.g., those caused by Pseudomonas aeruginosa, remains to be shown. Macrolide antibiotics have significant side effects, in particular, motility-stimulating activity in the gastrointestinal tract and promotion of bacterial resistance. In this study, EM703, a modified macrolide lacking antibiotic and motility-stimulating activities... (More)

Macrolide antibiotics are used as anti-inflammatory agents, e.g., for prevention of exacerbations in chronic obstructive pulmonary disease and cystic fibrosis. Several studies have shown improved outcomes after the addition of macrolides to -lactam antibiotics for treatment of severe community-acquired pneumonia. However, a beneficial effect of macrolides in treating Gram-negative bacterial airway infections, e.g., those caused by Pseudomonas aeruginosa, remains to be shown. Macrolide antibiotics have significant side effects, in particular, motility-stimulating activity in the gastrointestinal tract and promotion of bacterial resistance. In this study, EM703, a modified macrolide lacking antibiotic and motility-stimulating activities but with retained anti-inflammatory properties, was used as an adjunct treatment for experimental P. aeruginosa lung infection, in combination with a conventional antibiotic. Airway infections in BALB/cJRj mice were induced by nasal instillation of P. aeruginosa; this was followed by treatment with the quinolone levofloxacin in the absence or presence of EM703. Survival, inflammatory responses, and cellular influx to the airways were monitored. Both pretreatment and simultaneous administration of EM703 dramatically improved survival in levofloxacin-treated mice with P. aeruginosa airway infections. In addition, EM703 reduced the levels of proinflammatory cytokines, increased the numbers of leukocytes in bronchoalveolar lavage fluid, and reduced the numbers of neutrophils present in lung tissue. In summary, the findings of this study show that the immunomodulatory properties of the modified macrolide EM703 can be important when treating Gram-negative pneumonia, as exemplified by P. aeruginosa infection in this study.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Anti-inflammatory, EM703, Host defense, macrolide, Pseudomonas aeruginosa
in
Antimicrobial Agents and Chemotherapy
volume
61
issue
9
publisher
American Society for Microbiology
external identifiers
  • scopus:85028354305
  • wos:000408309000092
ISSN
0066-4804
DOI
10.1128/AAC.02761-16
language
English
LU publication?
yes
id
3304151a-dbd5-49a7-973a-b797ad1d7ed4
date added to LUP
2017-10-04 10:15:56
date last changed
2018-01-16 13:20:34
@article{3304151a-dbd5-49a7-973a-b797ad1d7ed4,
  abstract     = {<p>Macrolide antibiotics are used as anti-inflammatory agents, e.g., for prevention of exacerbations in chronic obstructive pulmonary disease and cystic fibrosis. Several studies have shown improved outcomes after the addition of macrolides to -lactam antibiotics for treatment of severe community-acquired pneumonia. However, a beneficial effect of macrolides in treating Gram-negative bacterial airway infections, e.g., those caused by Pseudomonas aeruginosa, remains to be shown. Macrolide antibiotics have significant side effects, in particular, motility-stimulating activity in the gastrointestinal tract and promotion of bacterial resistance. In this study, EM703, a modified macrolide lacking antibiotic and motility-stimulating activities but with retained anti-inflammatory properties, was used as an adjunct treatment for experimental P. aeruginosa lung infection, in combination with a conventional antibiotic. Airway infections in BALB/cJRj mice were induced by nasal instillation of P. aeruginosa; this was followed by treatment with the quinolone levofloxacin in the absence or presence of EM703. Survival, inflammatory responses, and cellular influx to the airways were monitored. Both pretreatment and simultaneous administration of EM703 dramatically improved survival in levofloxacin-treated mice with P. aeruginosa airway infections. In addition, EM703 reduced the levels of proinflammatory cytokines, increased the numbers of leukocytes in bronchoalveolar lavage fluid, and reduced the numbers of neutrophils present in lung tissue. In summary, the findings of this study show that the immunomodulatory properties of the modified macrolide EM703 can be important when treating Gram-negative pneumonia, as exemplified by P. aeruginosa infection in this study.</p>},
  articleno    = {e02761-16},
  author       = {Kasetty, Gopinath and Bhongir, Ravi K.V. and Papareddy, Praveen and Herwald, Heiko and Egesten, Arne},
  issn         = {0066-4804},
  keyword      = {Anti-inflammatory,EM703,Host defense,macrolide,Pseudomonas aeruginosa},
  language     = {eng},
  month        = {09},
  number       = {9},
  publisher    = {American Society for Microbiology},
  series       = {Antimicrobial Agents and Chemotherapy},
  title        = {The nonantibiotic macrolide em703 improves survival in a model of quinolone-treated pseudomonas aeruginosa airway infection},
  url          = {http://dx.doi.org/10.1128/AAC.02761-16},
  volume       = {61},
  year         = {2017},
}