A novel mouse model of chronic suppurative otitis media and its use in preclinical antibiotic evaluation

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Abstract

A novel mouse model of chronic ear infections is used to investigate antibiotic failure in humans.

Abstract

Chronic suppurative otitis media (CSOM) is a neglected pediatric disease affecting 330 million worldwide for which no new drugs have been introduced for over a decade. We developed a mouse model with utility in preclinical drug evaluation and antimicrobial discovery. Our model used immune-competent mice, tympanic membrane perforation and inoculation with luminescent Pseudomonas aeruginosa that enabled bacterial abundance tracking in real-time for 100 days. The resulting chronic infection exhibited hallmark features of clinical CSOM, including inhibition of tympanic membrane healing and purulent ear discharge. We evaluated the standard care fluoroquinolone ofloxacin and demonstrated that this therapy resulted in a temporary reduction of bacterial burden. These data are consistent with the clinical problem of persistent infection in CSOM and the need for therapeutic outcome measures that assess eradication post-therapeutic endpoint. We conclude that this novel mouse model of CSOM has value in investigating new potential therapies.

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Most cited references 31

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Persister cells and tolerance to antimicrobials.

Iris Keren, Niilo Kaldalu, Amy L Spoering … (2004)

Bacterial populations produce persister cells that neither grow nor die in the presence of microbicidal antibiotics. Persisters are largely responsible for high levels of biofilm tolerance to antimicrobials, but virtually nothing was known about their biology. Tolerance of Escherichia coli to ampicillin and ofloxacin was tested at different growth stages to gain insight into the nature of persisters. The number of persisters did not change in lag or early exponential phase, and increased dramatically in mid-exponential phase. Similar dynamics were observed with Pseudomonas aeruginosa (ofloxacin) and Staphylococcus aureus (ciprofloxacin and penicillin). This shows that production of persisters depends on growth stage. Maintaining a culture of E. coli at early exponential phase by reinoculation eliminated persisters. This suggests that persisters are not at a particular stage in the cell cycle, neither are they defective cells nor cells created in response to antibiotics. Our data indicate that persisters are specialized survivor cells.

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Bacterial biofilm development as a multicellular adaptation: antibiotic resistance and new therapeutic strategies.

César de la Fuente-Núñez, Fany Reffuveille, Lucia Fernandez … (2013)

Bacteria have evolved the ability to form multicellular, surface-adherent communities called biofilms that allow survival in hostile environments. In clinical settings, bacteria are exposed to various sources of stress, including antibiotics, nutrient limitation, anaerobiosis, heat shock, etc., which in turn trigger adaptive responses in bacterial cells. The combination of this and other defense mechanisms results in the formation of highly (adaptively) resistant multicellular structures that are recalcitrant to host immune clearance mechanisms and very difficult to eradicate with the currently available antimicrobial agents, which are generally developed for the eradication of free-swimming (planktonic) bacteria. However, novel strategies that specifically target the biofilm mode of growth have been recently described, thus providing the basis for future anti-biofilm therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

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Biofilms and planktonic cells of Pseudomonas aeruginosa have similar resistance to killing by antimicrobials.

A Spoering, K. Lewis (2001)

Biofilms are considered to be highly resistant to antimicrobial agents. Strictly speaking, this is not the case-biofilms do not grow in the presence of antimicrobials any better than do planktonic cells. Biofilms are indeed highly resistant to killing by bactericidal antimicrobials, compared to logarithmic-phase planktonic cells, and therefore exhibit tolerance. It is assumed that biofilms are also significantly more tolerant than stationary-phase planktonic cells. A detailed comparative examination of tolerance of biofilms versus stationary- and logarithmic-phase planktonic cells with four different antimicrobial agents was performed in this study. Carbenicillin appeared to be completely ineffective against both stationary-phase cells and biofilms. Killing by this beta-lactam antibiotic depends on rapid growth, and this result confirms the notion of slow-growing biofilms resembling the stationary state. Ofloxacin is a fluoroquinolone antibiotic that kills nongrowing cells, and biofilms and stationary-phase cells were comparably tolerant to this antibiotic. The majority of cells in both populations were eradicated at low levels of ofloxacin, leaving a fraction of essentially invulnerable persisters. The bulk of the population in both biofilm and stationary-phase cultures was tolerant to tobramycin. At very high tobramycin concentrations, a fraction of persister cells became apparent in stationary-phase culture. Stationary-phase cells were more tolerant to the biocide peracetic acid than were biofilms. In general, stationary-phase cells were somewhat more tolerant than biofilms in all of the cases examined. We concluded that, at least for Pseudomonas aeruginosa, one of the model organisms for biofilm studies, the notion that biofilms have greater resistance than do planktonic cells is unwarranted. We further suggest that tolerance to antibiotics in stationary-phase or biofilm cultures is largely dependent on the presence of persister cells.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): SciAdv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: August 2020

Publication date (Electronic): 14 August 2020

Volume: 6

Issue: 33

Electronic Location Identifier: eabc1828

Affiliations

[1 ]Department of Otolaryngology, Head and Neck Surgery, Stanford University, Stanford, CA, USA.

[2 ]Department of Otolaryngology, Head and Neck Surgery, Tehran University of Medical Sciences, Tehran, Iran.

[3 ]Department of Medicine, Infectious Diseases, Stanford University, Stanford, CA, USA.

[4 ]Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.

[5 ]Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.

Author notes

[*]

These authors contributed equally to this work.

[† ]Corresponding author. Email: petersantamaria@ 123456stanford.edu

Author information

Kelly M. Khomtchouk http://orcid.org/0000-0001-6241-8558

Solange M. Massa http://orcid.org/0000-0001-9931-906X

Jolien M. Sweere http://orcid.org/0000-0002-9602-8117

Daniel Pletzer http://orcid.org/0000-0001-5750-7505

Robert E. Hancock http://orcid.org/0000-0001-5989-8503

Paul L. Bollyky http://orcid.org/0000-0003-2499-9448

Peter L. Santa Maria http://orcid.org/0000-0002-3428-3497

Article

Publisher ID: abc1828

DOI: 10.1126/sciadv.abc1828

PMC ID: 7428333

PubMed ID: 32851190

SO-VID: cb818bc2-dbad-4c4d-a0a3-99994c171beb

Copyright © Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

History

Date received : 10 April 2020

Date accepted : 02 July 2020

Funding

Funded by: doi http://dx.doi.org/10.13039/100005492, Stanford University;

Funded by: doi http://dx.doi.org/10.13039/100012893, Division of Loan Repayment;

Funded by: doi http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;

Award ID: FDN-154287

Funded by: doi http://dx.doi.org/10.13039/501100000245, Michael Smith Foundation for Health Research;

Funded by: doi http://dx.doi.org/10.13039/501100000703, Action on Hearing Loss;

Funded by: doi http://dx.doi.org/10.13039/501100001804, Canada Research Chairs;

Funded by: UBC Killam Professorship;

Funded by: Stanford Nano Shared Facilities;

Award ID: ECCS-1542152

Funded by: Stanford SPARK;

Funded by: Stanford Maternal and Child Health Research Institute;

Funded by: Bill and Susan Oberndorf Foundation;

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Copyeditor Kyle Solis

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A novel mouse model of chronic suppurative otitis media and its use in preclinical antibiotic evaluation

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Most cited references 31

Persister cells and tolerance to antimicrobials.

Bacterial biofilm development as a multicellular adaptation: antibiotic resistance and new therapeutic strategies.

Biofilms and planktonic cells of Pseudomonas aeruginosa have similar resistance to killing by antimicrobials.

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