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Influence of Ph on the Activity of Finafloxacin Against Extracellular Clinical Microbiology and Infection 26 (2020) 1254.e1e1254.e8 Contents lists available at ScienceDirect Clinical Microbiology and Infection journal homepage: www.clinicalmicrobiologyandinfection.com Original article 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 * H. Chalhoub 1, S.V. Harding 2, P.M. Tulkens 1, F. Van Bambeke 1, 1) Pharmacologie cellulaire et moleculaire, Louvain Drug Research Institute, Universite catholique de Louvain (UCLouvain), Brussels, Belgium 2) CBR Division, Defence Science and Technology Laboratory, Porton Down, Salisbury, UK article info abstract Article history: Objectives: Burkholderia pseudomallei, Yersinia pestis and Francisella tularensis are facultative intracellular Received 25 May 2019 bacteria causing life-threatening infections. We have (a) compared the activity of finafloxacin (a fluo- Received in revised form roquinolone in development showing improved activity at acidic pH) with that of ciprofloxacin, levo- 11 July 2019 floxacin and imipenem against the extracellular and intracellular (THP-1 monocytes) forms of infection Accepted 25 July 2019 by attenuated surrogates of these species (B. thailandensis, Y. pseudotuberculosis, F. philomiragia) and (b) Available online 9 August 2019 assessed finafloxacin cellular pharmacokinetics (accumulation, distribution, efflux). Editor: W. Couet 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 Keywords: (concentrationeresponse curves). Finafloxacin pharmacokinetics in cells at pH 7.4 or 5.5 was investigated Burkholderia thailandensis using 14C-labelled drug. Finafloxacin Results: Extracellularly, all drugs sterilized the cultures, with finafloxacin being two to six times more Fluoroquinolones potent at acidic pH. Intracellularly, Emax reached the limit of detection (4e5 log10 cfu decrease) for Francisella philomiragia finafloxacin against all species, but only against B. thailandensis and F. philomiragia for ciprofloxacin and Imipenem levofloxacin, while imipenem caused less than 2 log cfu decrease for all species. At acid pH, C shifted to Intracellular infection 10 s fi fi fl Yersinia pseudotuberculosis two to ve times lower values for na oxacin 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. H. Chalhoub, Clin Microbiol Infect 2020;26:1254.e1e1254.e8 © 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved. Introduction tularaemia, and fluoroquinolones as alternatives for the last two diseases [1]. All three pathogens are facultative intracellular or- Burkholderia pseudomallei, Yersinia pestis and Francisella tular- ganisms, thriving in the cytosol [3], the phagolysosomes [4] or in ensis are potential biothreat agents [1,2] causing lethal infections both [5]. Validated in vitro pharmacodynamic models [6] have (melioidosis, plague and tularaemia) and requiring potent, rapidly demonstrated that b-lactams and aminoglycosides fail to eradicate effective antibiotics. First-line therapies include ceftazidime or intracellular bacteria, irrespective of their subcellular localization carbapenems for melioidosis [2], aminoglycosides for plague and [6e8]. Fluoroquinolones display better intracellular efficacy [7e10] but have not been evaluated in pharmacodynamic models against these biothreat agents. Here, we compare three fluo- roquinolones (finafloxacin, ciprofloxacin and levofloxacin) with * Corresponding author. F. Van Bambeke, Avenue Mounier 73, B1.73.05, 1200 Bruxelles, Belgium. imipenem for activity in human THP-1 monocytes [10] infected E-mail address: [email protected] (F. Van Bambeke). by Burkholderia thailandensis, Yersinia pseudotuberculosis and https://doi.org/10.1016/j.cmi.2019.07.028 1198-743X/© 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved. H. Chalhoub et al. / Clinical Microbiology and Infection 26 (2020) 1254.e1e1254.e8 1254.e2 Francisella philomiragia, which are appropriate surrogates for the pH 7.4 or 5.5, following which the cells were collected and their corresponding biothreat agents with regards to their intracellular integrity, protein content and cfu counts measured as described fate [11e13]. Finafloxacin has been shown to have enhanced ac- above. tivity at mild acidic pH [14,15], which could confer an advantage when considering bacteria sojourning in phagolysosomes and other acidic microenvironments [16]. We also studied the cellular Finafloxacin pharmacokinetics in THP-1 cells pharmacokinetics of finafloxacin. We used a published protocol [18] with media buffered at pH Materials and methods values ranging from 5.5 to 7.4 and 14C-labelled finafloxacin (mixed with unlabelled drug to achieve the desired total concentration). Antibiotics For influx studies, cells were incubated with finafloxacin at 37C, pelleted by centrifugation, washed in cold PBS, pelleted again (at Levofloxacin and imipenem were procured as TAVANIC® and 4C) and resuspended in distilled water. They were sonicated and TIENAM®, respectively. Finafloxacin HCl (potency, 84.19%) was used for radioactivity determination (by scintillation counting) and from MerLion Pharmaceuticals GmbH (Berlin, Germany), cipro- protein assay. For efflux studies, cells were first incubated with floxacin (potency, 98%) from Sigma-Aldrich (St Louis, MO, USA) and finafloxacin for 2 hr, pelleted by centrifugation, washed in ice-cold gentamicin sulphate (potency, 60.7%) from VWR, Radnor, PA. 14C- PBS, pelleted again at 4C, resuspended and then incubated at 37C labelled finafloxacin (specific activity 57 mCi/mmol) was produced in drug-free media (adjusted to the same pH as when studying by Pharmeron UK Ltd, Cardiff, UK. influx). They were finally collected and used as for the accumula- tion studies. Drug accumulation (apparent cellular to extracellular Bacteria and culture media concentration ratio) was calculated using a conversion factor of 5 mL of cell volume per mg of cell protein [7]. B. thailandensis ATCC 700388, Y. pseudotuberculosis ATCC 29833 and F. philomiragia ATCC 25015 were from the American Type Culture Collection (Manassas, VA, USA). B. thailandensis and F. philomiragia were grown on Schaedler agar (Sigma-Aldrich), and Finafloxacin subcellular distribution in uninfected and infected THP- Y. pseudotuberculosis on trypticase soy or MuellereHinton agar (BD 1 cells Life Sciences, Franklin Lakes, NJ, USA). MuellereHinton cation- adjusted broth (CA-MHB; BD Life Sciences) was used for the three Uninfected THP-1 cells were incubated with 14C-labelled fina- species. Cell culture media and sera were from Gibco/ThermoFisher floxacin for 30 min, washed and resuspended in ice-cold 0.25 M Scientific (Waltham, MA, USA). sucrose e 3 mM Na EDTA e 3 mM imidazole (pH 7.4). For infected cells, monocytes were first allowed to phagocytize bacteria (as MIC determination described above), washed, returned to fresh medium for 2 hr (to allow for complete bacteria internalization), and incubated for MICs were determined by broth microdilution in CA-MHB at pH 30 min with 14C-labelled finafloxacin at a sub-MIC concentration. 7.4 or adjusted to pH 6.5 or 5.5 by addition of HCl. After washing, they were resuspended in sucrose- eEDTAeimidazole for fractionation. The homogenization method, Extracellular antibiotic activity centrifugation conditions (to yield three fractions (N, nuclei and unbroken cells; MLP, mitochondria, lysosomes, membranes and Concentrationekill curves were determined after 24 hr of in- other organelles; and S, supernate (cytosol))), and assay techniques cubation in CA-MHB adjusted to pH 7.4 or 5.5 using a starting (radioactivity, protein, activity of marker enzymes (cytochrome c- inoculum of 106 cfu/mL (see Fig. S1) and antibiotic concentrations oxidase (mitochondria), N-acetyl-b-hexosaminidase (lysosomes), ranging from 0.003 to 100 Â MIC. Serially diluted aliquots were lactate dehydrogenase (cytosol)) were previously described [19]. plated on agar containing 0.4% activated charcoal to adsorb residual antibiotic. Finafloxacin accumulation in bacteria Intracellular models of infection Bacterial suspensions (109 cfu/mL) were incubated with 14C- We adapted the protocol developed for P. aeruginosa and THP-1 labelled finafloxacin (1.4 mg/L; 0.2 mCi/L (required for accurate monocytes [10] (see Fig. S2 for details and model validation). Bac- radioactivity detection)), collected by centrifugation (4000 rpm; teria (opsonized with human serum) were added to monocytes to 7 min) at 4C and washed three times with cold PBS. Aliquots were obtain suitable bacteria/cell ratios, and incubated at 37Cin5%CO 2 taken for cfu counts and radioactivity measurement (after lysis by to allow for phagocytosis. Cells were pelleted by centrifugation, two cycles of freezing/thawing (e80C to room temperature). To washed and incubated for 1 hr with gentamicin at high concen- mitigate artefacts caused by drug
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