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Clinical Therapeutics

Pharmacodynamic Evaluation of Fosfomycin against Escherichia coli and Klebsiella spp. from Urinary Tract Infections and the Influence of pH on Fosfomycin Activities

Nayara Helisandra Fedrigo, Josmar Mazucheli, James Albiero, Danielle Rosani Shinohara, Fernanda Gomes Lodi, Ana Cristina dos Santos Machado, Sherwin K. B. Sy, Maria Cristina Bronharo Tognim
Nayara Helisandra Fedrigo
aDepartamento de Ciências Básicas da Saúde, Universidade Estadual de Maringá, Maringá, PR, Brazil
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Josmar Mazucheli
bPrograma de Pós-Graduação em Bioestatística, Departamento de Estatística, Universidade Estadual de Maringá, Maringá, PR, Brazil
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James Albiero
aDepartamento de Ciências Básicas da Saúde, Universidade Estadual de Maringá, Maringá, PR, Brazil
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Danielle Rosani Shinohara
aDepartamento de Ciências Básicas da Saúde, Universidade Estadual de Maringá, Maringá, PR, Brazil
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Fernanda Gomes Lodi
aDepartamento de Ciências Básicas da Saúde, Universidade Estadual de Maringá, Maringá, PR, Brazil
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Ana Cristina dos Santos Machado
aDepartamento de Ciências Básicas da Saúde, Universidade Estadual de Maringá, Maringá, PR, Brazil
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Sherwin K. B. Sy
bPrograma de Pós-Graduação em Bioestatística, Departamento de Estatística, Universidade Estadual de Maringá, Maringá, PR, Brazil
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  • ORCID record for Sherwin K. B. Sy
Maria Cristina Bronharo Tognim
aDepartamento de Ciências Básicas da Saúde, Universidade Estadual de Maringá, Maringá, PR, Brazil
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DOI: 10.1128/AAC.02498-16
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  • FIG 1
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    FIG 1

    Survival-type antimicrobial susceptibility curves for Escherichia coli isolates (n = 158) and Klebsiella isolates (n = 87) from patients with urinary tract infections stratified on the basis of pHs of 6.0 (solid line) and 7.0 (dotted line).

  • FIG 2
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    FIG 2

    Fosfomycin MIC frequency in 158 Escherichia coli and 87 Klebsiella clinical isolates at pH 6.0 and 7.0 and probability of target attainment of an AUC/MIC of 23 against E. coli (right) and Klebsiella spp. (left) in serum (top) and urine (bottom) matrices for a fosfomycin dosing regimen consisting of a single dose of 3,000 mg in 10,000 virtual patients. PTA, probability of target attainment; AUC, area under the concentration-time curve.

  • FIG 3
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    FIG 3

    Molecular structure of fosfomycin and pKa values derived from the Chemicalize database (https://chemicalize.com/#/calculation ).

  • FIG 4
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    FIG 4

    Relationship between the microspecies distribution percentage for fosfomycin and pH adapted from the Chemicalize database (https://chemicalize.com/#/calculation ).

Tables

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  • TABLE 1

    In vitro susceptibilities to fosfomycin of E. coli and Klebsiella spp. clinical isolates from patients with UTIs at pH 6.0 and 7.0a

    MicroorganismNo. of strainspH of testNo. of isolates with the following MIC (μg/ml):MIC (mg/liter)% of isolates
    CLSIEUCAST
    0.250.51248163264128256512>51250%90%RangeSIRSR
    Escherichia coli 1587.0−−361541961031−−14161 to >5129811973
    6.0−963521213521−−−1280.5 to >51299 1982
    Klebsiella spp.b877.0−−−−−−22−23212217256>51216 to >51252669595
    6.0−−−−−236152619791285128 to >5123030401387
    • ↵a −, no isolate; S, susceptible; I, intermediate susceptibility; R, resistant; CLSI, Clinical and Laboratory Standards Institute interpretative criteria (susceptible, MIC of ≤64 μg/ml; intermediate, MIC of 128 μg/ml; resistant, MIC of ≥256 μg/ml; EUCAST, European Committee on Antimicrobial Susceptibility Testing interpretative criteria (susceptible, MIC of ≤32 μg/ml; resistant, MIC of ≥32 μg/ml).

    • ↵b The species isolated included Klebsiella pneumoniae (n = 81) and K. oxytoca (n = 6).

  • TABLE 2

    CFR at AUC/MIC of 23 for a single 3,000-mg oral dose of fosfomycin against a collection of clinical isolates by bacterial type

    Bacterial type% of isolates
    pH 6pH 7
    SerumUrineSerumUrine
    E. coli 93.5998599
    Klebsiella spp.2.7550.628
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Pharmacodynamic Evaluation of Fosfomycin against Escherichia coli and Klebsiella spp. from Urinary Tract Infections and the Influence of pH on Fosfomycin Activities
Nayara Helisandra Fedrigo, Josmar Mazucheli, James Albiero, Danielle Rosani Shinohara, Fernanda Gomes Lodi, Ana Cristina dos Santos Machado, Sherwin K. B. Sy, Maria Cristina Bronharo Tognim
Antimicrobial Agents and Chemotherapy Jul 2017, 61 (8) e02498-16; DOI: 10.1128/AAC.02498-16

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Pharmacodynamic Evaluation of Fosfomycin against Escherichia coli and Klebsiella spp. from Urinary Tract Infections and the Influence of pH on Fosfomycin Activities
Nayara Helisandra Fedrigo, Josmar Mazucheli, James Albiero, Danielle Rosani Shinohara, Fernanda Gomes Lodi, Ana Cristina dos Santos Machado, Sherwin K. B. Sy, Maria Cristina Bronharo Tognim
Antimicrobial Agents and Chemotherapy Jul 2017, 61 (8) e02498-16; DOI: 10.1128/AAC.02498-16
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KEYWORDS

Anti-Bacterial Agents
Escherichia coli
Escherichia coli Infections
fosfomycin
Klebsiella
Klebsiella Infections
urinary tract infections
Enterobacteriaceae
fosfomycin
Monte Carlo simulation
acidic pH
pharmacodynamics
urinary tract infection

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