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Experimental Therapeutics

Ciprofloxacin Pharmacokinetics/Pharmacodynamics against Susceptible and Low-Level Resistant Escherichia coli Isolates in an Experimental Ascending Urinary Tract Infection Model in Mice

Lotte Jakobsen, Carina Vingsbro Lundberg, Niels Frimodt-Møller
Lotte Jakobsen
aBacteria, Parasites & Fungi, Statens Serum Institut, Copenhagen, Denmark
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Carina Vingsbro Lundberg
aBacteria, Parasites & Fungi, Statens Serum Institut, Copenhagen, Denmark
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Niels Frimodt-Møller
aBacteria, Parasites & Fungi, Statens Serum Institut, Copenhagen, Denmark
bDepartment of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark
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  • ORCID record for Niels Frimodt-Møller
DOI: 10.1128/AAC.01804-20
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ABSTRACT

The mouse ascending urinary tract infection model was used to study the pharmacokinetic/pharmacodynamic (PKPD) relationships of the effect of ciprofloxacin in subcutaneous treatment for 3 days with varying doses and dosing intervals against a susceptible Escherichia coli strain (MIC, 0.032 mg/liter). Further, a humanized dose of ciprofloxacin was administered for 3 days against three E. coli strains with low-level resistance, i.e., MICs of 0.06, 0.25, and 1 mg/liter, respectively. Against the susceptible isolate, ciprofloxacin was highly effective in clearing the urine with daily doses from 10 mg/kg, but the dosing regimen had to be divided into at least two doses for optimal effect. Ciprofloxacin could not clear the urine or kidneys for the low-level-resistant strains. PKPD correlations with all strains combined showed that for the AUC24/MIC there was a slightly higher correlation with effect in urine and kidneys (R2, 0.71 and 0.69, respectively) than the %T>MIC (R2, 0.41 and 0.61, respectively). Equal correlations for the two PKPD indices were found for reduction of colony counts (CFU) in the bladder tissue, but not even the highest dose of 28 mg/kg × 6 could clear the bladder tissue. In conclusion, ciprofloxacin is highly effective in clearing the urine and kidney tissue for fully susceptible E. coli, while even low-level resistance in E. coli obscures this effect. While the effect of ciprofloxacin is mostly AUC/MIC driven against E. coli infection in the urinary tract, the effect in urine depends on the presence of ciprofloxacin in the urine during most of a 24-h period.

FOOTNOTES

    • Received 21 August 2020.
    • Returned for modification 26 September 2020.
    • Accepted 19 October 2020.
    • Accepted manuscript posted online 26 October 2020.
  • Supplemental material is available online only.

  • Copyright © 2020 American Society for Microbiology.

All Rights Reserved.

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Ciprofloxacin Pharmacokinetics/Pharmacodynamics against Susceptible and Low-Level Resistant Escherichia coli Isolates in an Experimental Ascending Urinary Tract Infection Model in Mice
Lotte Jakobsen, Carina Vingsbro Lundberg, Niels Frimodt-Møller
Antimicrobial Agents and Chemotherapy Dec 2020, 65 (1) e01804-20; DOI: 10.1128/AAC.01804-20

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Ciprofloxacin Pharmacokinetics/Pharmacodynamics against Susceptible and Low-Level Resistant Escherichia coli Isolates in an Experimental Ascending Urinary Tract Infection Model in Mice
Lotte Jakobsen, Carina Vingsbro Lundberg, Niels Frimodt-Møller
Antimicrobial Agents and Chemotherapy Dec 2020, 65 (1) e01804-20; DOI: 10.1128/AAC.01804-20
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KEYWORDS

urinary tract infection
E. coli
ciprofloxacin
PKPD
ciprofloxacin resistance
Escherichia coli
experimental mouse model

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