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Antimicrob Agents Chemother. 2019 Apr 25;63(5). pii: e00112-19. doi: 10.1128/AAC.00112-19. Print 2019 May.

Apotransferrin in Combination with Ciprofloxacin Slows Bacterial Replication, Prevents Resistance Amplification, and Increases Antimicrobial Regimen Effect.

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Institute for Clinical Pharmacodynamics, Schenectady, New York, USA.
University of Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, New York, USA.
Department of Medicine, Keck School of Medicine at the University of Southern California, Los Angeles, California, USA.
Department of Molecular Microbiology and Immunology, Keck School of Medicine at the University of Southern California, Los Angeles, California, USA.
Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
Departments of Pharmacology, Molecular Biology and Microbiology, Biochemistry, and Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio, USA.
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA.
Department of Medicine, Keck School of Medicine at the University of Southern California, Los Angeles, California, USA


There has been renewed interest in combining traditional small-molecule antimicrobial agents with nontraditional therapies to potentiate antimicrobial effects. Apotransferrin, which decreases iron availability to microbes, is one such approach. We conducted a 48-h one-compartment in vitro infection model to explore the impact of apotransferrin on the bactericidal activity of ciprofloxacin. The challenge panel included four Klebsiella pneumoniae isolates with ciprofloxacin MIC values ranging from 0.08 to 32 mg/liter. Each challenge isolate was subjected to an ineffective ciprofloxacin monotherapy exposure (free-drug area under the concentration-time curve over 24 h divided by the MIC [AUC/MIC ratio] ranging from 0.19 to 96.6) with and without apotransferrin. As expected, the no-treatment and apotransferrin control arms showed unaltered prototypical logarithmic bacterial growth. We identified relationships between exposure and change in bacterial density for ciprofloxacin alone (R 2 = 0.64) and ciprofloxacin in combination with apotransferrin (R 2 = 0.84). Addition of apotransferrin to ciprofloxacin enabled a remarkable reduction in bacterial density across a wide range of ciprofloxacin exposures. For instance, at a ciprofloxacin AUC/MIC ratio of 20, ciprofloxacin monotherapy resulted in nearly 2 log10 CFU increase in bacterial density, while the combination of apotransferrin and ciprofloxacin resulted in 2 log10 CFU reduction in bacterial density. Furthermore, addition of apotransferrin significantly reduced the emergence of ciprofloxacin-resistant subpopulations compared to monotherapy. These data demonstrate that decreasing the rate of bacterial replication with apotransferrin in combination with antimicrobial therapy represents an opportunity to increase the magnitude of the bactericidal effect and to suppress the growth rate of drug-resistant subpopulations.


Klebsiella ; antibiotic resistance; ciprofloxacin; fluoroquinolone; transferrin

[Available on 2019-10-25]

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