Modelling of ciprofloxacin killing enhanced by hyperbaric oxygen treatment in Pseudomonas aeruginosa PAO1 biofilms

PLoS One. 2018 Jun 14;13(6):e0198909. doi: 10.1371/journal.pone.0198909. eCollection 2018.

Abstract

Outline: In chronic lung infections by Pseudomonas aeruginosa (PA) the bacteria thrive in biofilm structures protected from the immune system of the host and from antibiotic treatment. Increasing evidence suggests that the susceptibility of the bacteria to antibiotic treatment can be significantly enhanced by hyperbaric oxygen treatment. The aim of this study is to simulate the effect of ciprofloxacin treatment in a PAO1 biofilm model with aggregates in agarose when combined with hyperbaric oxygen treatment. This is achieved in a reaction-diffusion model that describes the combined effect of ciprofloxacin diffusion, oxygen diffusion and depletion, bacterial growth and killing, and adaptation of the bacteria to ciprofloxacin. In the model, the oxygen diffusion and depletion use a set of parameters derived from experimental results presented in this work. The part of the model describing ciprofloxacin killing uses parameter values from the literature in combination with our estimates (Jacobs, et al., 2016; Grillon, et al., 2016). Micro-respirometry experiments were conducted to determine the oxygen consumption in the P. aeruginosa strain PAO1. The parameters were validated against existing data from an HBOT experiment by Kolpen et al. (2017). The complete oxygen model comprises a reaction-diffusion equation describing the oxygen consumption by using a Michaelis-Menten reaction term. The oxygen model performed well in predicting oxygen concentrations in both time and depth into the biofilm. At 2.8 bar pure oxygen pressure, HBOT increases the penetration depth of oxygen into the biofilm almost by a of factor 4 in agreement with the scaling that follows from the stationary balance between the consumption term and diffusion term.

Conclusion: In the full reaction-diffusion model we see that hyperbaric oxygen treatment significantly increases the killing by ciprofloxacin in a PAO1 biofilm in alignment with the experimental results from Kolpen et al. (Kolpen, et al., 2017; Kolpen, et al. 2016). The enhanced killing, in turn, lowers the oxygen consumption in the outer layers of the biofilm, and leads to even deeper penetration of oxygen into the biofilm.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Biofilms / drug effects*
  • Ciprofloxacin / pharmacology*
  • Drug Synergism
  • Microbial Viability / drug effects*
  • Models, Biological*
  • Oxygen / metabolism
  • Oxygen / pharmacology*
  • Oxygen Consumption / drug effects
  • Pseudomonas aeruginosa / drug effects*
  • Pseudomonas aeruginosa / metabolism
  • Pseudomonas aeruginosa / physiology*

Substances

  • Anti-Bacterial Agents
  • Ciprofloxacin
  • Oxygen

Grants and funding

This work was supported by grants from University of Copenhagen, Center for Antimicrobial Research, UC-CARE, http://uc-care.ku.dk, Award Number: 50061804231-F16 | Recipient: Mette Kolpen; Danish Council for Independent Research, Technology and Production Sciences, FTP, http://dff.ufm.dk, Award Number: DFF–4184-00515 | Recipient: Peter Østrup Jensen; and Cystic Fibrosis Foundation, USA, http://www.cff.org, Award Number: HOIBY05A0 | Recipient: Niels Høiby. The funders played no role in experimental design, data analysis and interpretation, nor the decision to submit the work for publication.