1. Clin Microbiol Infect. 2019 Aug 9:S1198-743X(19)30420-3. doi: 
10.1016/j.cmi.2019.07.028. Online ahead of print.

Influence of pH on the activity of finafloxacin against extracellular and 
intracellular Burkholderia thailandensis, Yersinia pseudotuberculosis and 
Francisella philomiragia and on its cellular pharmacokinetics in THP-1 
monocytes.

Chalhoub H(1), Harding SV(2), Tulkens PM(1), Van Bambeke F(3).

Author information:
(1)Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, 
Université catholique de Louvain (UCLouvain), Brussels, Belgium.
(2)CBR Division, Defence Science and Technology Laboratory, Porton Down, 
Salisbury, UK.
(3)Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, 
Université catholique de Louvain (UCLouvain), Brussels, Belgium. Electronic 
address: francoise.vanbambeke@uclouvain.be.

OBJECTIVES: Burkholderia pseudomallei, Yersinia pestis and Francisella 
tularensis are facultative intracellular bacteria causing life-threatening 
infections. We have (a) compared the activity of finafloxacin (a fluoroquinolone 
in development showing improved activity at acidic pH) with that of 
ciprofloxacin, levofloxacin and imipenem against the extracellular and 
intracellular (THP-1 monocytes) forms of infection by attenuated surrogates of 
these species (B. thailandensis, Y. pseudotuberculosis, F. philomiragia) and (b) 
assessed finafloxacin cellular pharmacokinetics (accumulation, distribution, 
efflux).
METHODS: Bacteria in broth or in infected monocytes were exposed to antibiotics 
at pH 7.4 or 5.5 for 24 hr. Maximal relative efficacies (Emax) and static 
concentrations (Cs) were calculated using the Hill equation 
(concentration-response curves). Finafloxacin pharmacokinetics in cells at pH 
7.4 or 5.5 was investigated using 14C-labelled drug.
RESULTS: Extracellularly, all drugs sterilized the cultures, with finafloxacin 
being two to six times more potent at acidic pH. Intracellularly, Emax reached 
the limit of detection (4-5 log10 cfu decrease) for finafloxacin against all 
species, but only against B. thailandensis and F. philomiragia for ciprofloxacin 
and levofloxacin, while imipenem caused less than 2 log10 cfu decrease for all 
species. At acid pH, Cs shifted to two to five times lower values for 
finafloxacin and to one to four times higher values for the other drugs. 
Finafloxacin accumulated in THP-1 cells by approximately fivefold at pH 7.4 but 
up to 20-fold at pH 5.5, and distributed in the cytosol.
CONCLUSIONS: Fluoroquinolones have proven to be effective in reducing the 
intracellular reservoirs of B. thailandensis, Y. pseudotuberculosis and 
F. philomiragia, with finafloxacin demonstrating an additional advantage in 
acidic environments.

Copyright © 2019 European Society of Clinical Microbiology and Infectious 
Diseases. All rights reserved.

DOI: 10.1016/j.cmi.2019.07.028
PMID: 31404671