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Pharmacology

Ex Vivo Urinary Bactericidal Activity and Urinary Pharmacodynamics of Fosfomycin after Two Repeated Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Subjects

E. Wenzler, K. M. Meyer, S. C. Bleasdale, M. Sikka, R. E. Mendes, K. L. Bunnell, M. Finnemeyer, S. L. Rosenkranz, L. H. Danziger, K. A. Rodvold
E. Wenzler
aCollege of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA
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K. M. Meyer
aCollege of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA
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S. C. Bleasdale
bCollege of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
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M. Sikka
bCollege of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
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R. E. Mendes
cJMI Laboratories, North Liberty, Iowa, USA
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K. L. Bunnell
aCollege of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA
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M. Finnemeyer
dHarvard TH Chan School of Public Health, Boston, Massachusetts, USA
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S. L. Rosenkranz
dHarvard TH Chan School of Public Health, Boston, Massachusetts, USA
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L. H. Danziger
aCollege of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA
bCollege of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
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K. A. Rodvold
aCollege of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA
bCollege of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
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DOI: 10.1128/AAC.02102-19
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    FIG 1

    Mean log10 CFU/ml versus time profile for each isolate against fosfomycin-laden urine collected from subjects during the QOD dosing regimen on day 1 (A) and day 5 (B) and during the QD dosing regimen on day 1 (C) and day 5 (D). Curves represent average concentrations for triplicate experiments. The y axis is in the log scale.

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    FIG 2

    Mean log10 CFU/ml versus time profile for each isolate against fosfomycin-laden urine collected from subjects during the QOD dosing regimen on day 5 without G6P (A) and with 25 mg/liter G6P (B) and during the QD dosing regimen on day 5 without G6P (C) and with 25 mg/liter G6P (D). Curves represent average concentrations for triplicate experiments. The y axis is in the log scale.

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  • TABLE 1

    Genotypic and phenotypic susceptibilities obtained against isolates included in the study

    TABLE 1
    • ↵a According to CLSI M100-S29 (16). NA, CLSI breakpoints not available; S, susceptible; I, intermediate; R, resistant.

    • ↵b Reference broth microdilution method includes 25 mg/liter G6P. MIC results obtained in the absence of G6P were interpreted for comparison purposes only.

    • ↵c The following genes and respective alterations were observed in isolate UIC45 compared with wild-type ATCC 25922: uhpB (P84S, S374T, Q441H, G459D, Q463H, H482T), uhpC (T72P, A177S, S417A, A435T), and cyaA (S222G, A349E, S356K, G359E, E362D, D837E, T840A).

    • ↵d The transport system regulator UhpABC was not detected.

    • ↵e The following genes and respective alterations were observed in the ATCC 700603 compared with wild-type ATCC 43816: uhpA (T3I, A25T, T41A, E64A, I87V, S183N), uhpC (E55D, A185T, C192G, M236L, S237T, A240E, V415A, T438A), uhpT (V434I), glpT (G196A, K234E, E237Q, I260V, V337I, P344A, I429V), ptsI (S241N), and murA (S148N, T206S, S210T).

  • TABLE 2

    Median reciprocal fosfomycin UBT and AUBT24 for all 18 subjects against the first 5 isolates tested

    TABLE 2
  • TABLE 3

    Median reciprocal fosfomycin UBT and AUBT24 for 5 representative subjects against all 8 isolates tested on study day 5 with and without 25 mg/liter G6P

    TABLE 3

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      Supplemental Table S1

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Ex Vivo Urinary Bactericidal Activity and Urinary Pharmacodynamics of Fosfomycin after Two Repeated Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Subjects
E. Wenzler, K. M. Meyer, S. C. Bleasdale, M. Sikka, R. E. Mendes, K. L. Bunnell, M. Finnemeyer, S. L. Rosenkranz, L. H. Danziger, K. A. Rodvold for the Antibacterial Resistance Leadership Group
Antimicrobial Agents and Chemotherapy Jan 2020, 64 (2) e02102-19; DOI: 10.1128/AAC.02102-19

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Ex Vivo Urinary Bactericidal Activity and Urinary Pharmacodynamics of Fosfomycin after Two Repeated Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Subjects
E. Wenzler, K. M. Meyer, S. C. Bleasdale, M. Sikka, R. E. Mendes, K. L. Bunnell, M. Finnemeyer, S. L. Rosenkranz, L. H. Danziger, K. A. Rodvold for the Antibacterial Resistance Leadership Group
Antimicrobial Agents and Chemotherapy Jan 2020, 64 (2) e02102-19; DOI: 10.1128/AAC.02102-19
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KEYWORDS

fosfomycin
urinary bactericidal titers
pharmacodynamics
urine
urinary tract infection

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