Role of inorganic phosphate concentrations in in vitro activity of fosfomycin
Copyright © 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved..
OBJECTIVES: The objective of this study was to evaluate the in vitro activity of fosfomycin under different physiological concentrations of inorganic phosphate (Pi).
gfpmut2 or PuhpT::gfpmut2 promoter fusions in standard Mueller-Hinton Broth (MHB), supplemented with Pi (13 or 42 mM) ± glucose-6-phosphate. Fosfomycin activity was quantified, estimating fosfomycin EC50 under different Pi concentrations (1, 13 and 42 mM + glucose-6-phosphate) and in time-kill assays using fosfomycin concentrations of 307 (maximum plasma concentration (Cmax)), 1053 and 4415 mg/L (urine Cmax range), using MHB with 28 mM Pi (mean urine Pi concentration) + 25 mg/L glucose-6-phosphate.
RESULTS: All the strains showed decreased susceptibility to fosfomycin linked to increased Pi concentrations: 1-4 log2 dilution differences from 1 to 13 mM, and 1-8 log2 dilution differences at 42 mM Pi. Changes in phosphate concentration did not affect the expression of fosfomycin transporters. By increasing Pi concentrations higher fosfomycin EC50 bacterial viability was observed, except against ΔglpT-uhpT. The increase in Pi reduced the bactericidal effect of fosfomycin.
DISCUSSION: Pi variations in physiological fluids may reduce fosfomycin activity against E. coli. Elevated Pi concentrations in urine may explain oral fosfomycin failure in non-wild-type but fosfomycin-susceptible E. coli strains.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:28 |
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| Enthalten in: |
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases - 28(2022), 2 vom: 20. Feb., Seite 302.e1-302.e4 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ortiz-Padilla, Miriam [VerfasserIn] |
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| Links: |
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| Themen: |
2N81MY12TE |
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| Anmerkungen: |
Date Completed 31.01.2022 Date Revised 31.01.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.cmi.2021.09.037 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM331753529 |
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| 041 | |a eng | ||
| 100 | 1 | |a Ortiz-Padilla, Miriam |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Role of inorganic phosphate concentrations in in vitro activity of fosfomycin |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Completed 31.01.2022 | ||
| 500 | |a Date Revised 31.01.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved. | ||
| 520 | |a OBJECTIVES: The objective of this study was to evaluate the in vitro activity of fosfomycin under different physiological concentrations of inorganic phosphate (Pi) | ||
| 520 | |a METHODS: The wild-type BW25113 strain, four isogenic mutants (ΔglpT, ΔuhpT, ΔglpT-uhpT, and ΔphoB) and six clinical isolates of Escherichia coli with different fosfomycin susceptibilities were used. EUCAST breakpoints were used. Susceptibility was evaluated by agar dilution using standard Mueller-Hinton agar (Pi concentration of 1 mM similar to human plasma concentration) and supplemented with Pi (13 and 42 mM, minimum and maximum urinary Pi concentrations) and/or glucose-6-phosphate (25 mg/L). Fosfomycin transporter promoter activity was assayed using PglpT::gfpmut2 or PuhpT::gfpmut2 promoter fusions in standard Mueller-Hinton Broth (MHB), supplemented with Pi (13 or 42 mM) ± glucose-6-phosphate. Fosfomycin activity was quantified, estimating fosfomycin EC50 under different Pi concentrations (1, 13 and 42 mM + glucose-6-phosphate) and in time-kill assays using fosfomycin concentrations of 307 (maximum plasma concentration (Cmax)), 1053 and 4415 mg/L (urine Cmax range), using MHB with 28 mM Pi (mean urine Pi concentration) + 25 mg/L glucose-6-phosphate | ||
| 520 | |a RESULTS: All the strains showed decreased susceptibility to fosfomycin linked to increased Pi concentrations: 1-4 log2 dilution differences from 1 to 13 mM, and 1-8 log2 dilution differences at 42 mM Pi. Changes in phosphate concentration did not affect the expression of fosfomycin transporters. By increasing Pi concentrations higher fosfomycin EC50 bacterial viability was observed, except against ΔglpT-uhpT. The increase in Pi reduced the bactericidal effect of fosfomycin | ||
| 520 | |a DISCUSSION: Pi variations in physiological fluids may reduce fosfomycin activity against E. coli. Elevated Pi concentrations in urine may explain oral fosfomycin failure in non-wild-type but fosfomycin-susceptible E. coli strains | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Escherichia coli | |
| 650 | 4 | |a Fosfomycin | |
| 650 | 4 | |a Fosfomycin activity | |
| 650 | 4 | |a Fosfomycin transporters | |
| 650 | 4 | |a Inorganic phosphate | |
| 650 | 4 | |a Resistance | |
| 650 | 7 | |a Anti-Bacterial Agents |2 NLM | |
| 650 | 7 | |a Phosphates |2 NLM | |
| 650 | 7 | |a Fosfomycin |2 NLM | |
| 650 | 7 | |a 2N81MY12TE |2 NLM | |
| 700 | 1 | |a Portillo-Calderón, Inés |e verfasserin |4 aut | |
| 700 | 1 | |a Maldonado, Natalia |e verfasserin |4 aut | |
| 700 | 1 | |a Rodríguez-Martínez, José |e verfasserin |4 aut | |
| 700 | 1 | |a de Gregorio-Iaria, Belén |e verfasserin |4 aut | |
| 700 | 1 | |a Merino-Bohórquez, Vicente |e verfasserin |4 aut | |
| 700 | 1 | |a Rodríguez-Baño, Jesús |e verfasserin |4 aut | |
| 700 | 1 | |a Pascual, Álvaro |e verfasserin |4 aut | |
| 700 | 1 | |a Docobo-Pérez, Fernando |e verfasserin |4 aut | |
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