1. Antimicrob Agents Chemother. 2015 Jan;59(1):258-68. doi: 10.1128/AAC.04011-14.
Epub 2014 Oct 27.

Activities of Antibiotic Combinations against Resistant Strains of Pseudomonas
aeruginosa in a Model of Infected THP-1 Monocytes.

Buyck JM(1), Tulkens PM(1), Van Bambeke F(2).

Author information: 
(1)Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute,
Université catholique de Louvain, Brussels, Belgium. (2)Pharmacologie cellulaire 
et moléculaire, Louvain Drug Research Institute, Université catholique de
Louvain, Brussels, Belgium francoise.vanbambeke@uclouvain.be.

Antibiotic combinations are often used for treating Pseudomonas aeruginosa
infections but their efficacy toward intracellular bacteria has not been
investigated so far. We have studied combinations of representatives of the main 
antipseudomonal classes (ciprofloxacin, meropenem, tobramycin, and colistin)
against intracellular P. aeruginosa in a model of THP-1 monocytes in comparison
with bacteria growing in broth, using the reference strain PAO1 and two clinical 
isolates (resistant to ciprofloxacin and meropenem, respectively). Interaction
between drugs was assessed by checkerboard titration (extracellular model only), 
by kill curves, and by using the fractional maximal effect (FME) method, which
allows studying the effects of combinations when dose-effect relationships are
not linear. For drugs used alone, simple sigmoidal functions could be fitted to
all concentration-effect relationships (extracellular and intracellular
bacteria), with static concentrations close to (ciprofloxacin, colistin, and
meropenem) or slightly higher than (tobramycin) the MIC and with maximal efficacy
reaching the limit of detection in broth but only a 1 to 1.5 (colistin,
meropenem, and tobramycin) to 2 to 3 (ciprofloxacin) log10 CFU decrease
intracellularly. Extracellularly, all combinations proved additive by
checkerboard titration but synergistic using the FME method and more bactericidal
in kill curve assays. Intracellularly, all combinations proved additive only
based on both FME and kill curve assays. Thus, although combinations appeared to 
modestly improve antibiotic activity against intracellular P. aeruginosa, they do
not allow eradication of these persistent forms of infections. Combinations
including ciprofloxacin were the most active (even against the
ciprofloxacin-resistant strain), which is probably related to the fact this drug 
was the most effective alone intracellularly.

Copyright © 2015, American Society for Microbiology. All Rights Reserved.

PMID: 25348528  [PubMed - in process]