Skip to main content
  • ASM
    • Antimicrobial Agents and Chemotherapy
    • Applied and Environmental Microbiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Eukaryotic Cell
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems
  • Log in
  • My alerts
  • My Cart

Main menu

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • COVID-19 Special Collection
    • Archive
    • Minireviews
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About AAC
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • AAC Podcast
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
  • ASM
    • Antimicrobial Agents and Chemotherapy
    • Applied and Environmental Microbiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Eukaryotic Cell
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems

User menu

  • Log in
  • My alerts
  • My Cart

Search

  • Advanced search
Antimicrobial Agents and Chemotherapy
publisher-logosite-logo

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • COVID-19 Special Collection
    • Archive
    • Minireviews
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About AAC
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • AAC Podcast
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
Mechanisms of Resistance

Immunodeficiency and Intermittent Dosing Promote Acquired Rifamycin Monoresistance in Murine Tuberculosis

Sang-Won Park, Rokeya Tasneen, Paul J. Converse, Eric L. Nuermberger
Sang-Won Park
aJohns Hopkins University School of Medicine, Baltimore, Maryland, USA
bSeoul National University College of Medicine and Boramae Medical Center, Seoul, Republic of Korea
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Sang-Won Park
Rokeya Tasneen
aJohns Hopkins University School of Medicine, Baltimore, Maryland, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul J. Converse
aJohns Hopkins University School of Medicine, Baltimore, Maryland, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eric L. Nuermberger
aJohns Hopkins University School of Medicine, Baltimore, Maryland, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1128/AAC.01502-17
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Article Figures & Data

Figures

  • Tables
  • FIG 1
    • Open in new tab
    • Download powerpoint
    FIG 1

    Lung log10 CFU counts before and after treatment with daily and intermittently dosed control (2RHZE/4RH) regimens in (A) BALB/c and (B) nude mice, omitting the results from mice in which resistance was selected. As explained in Table 5, group 3 received 5/7 treatments throughout. Groups 6 and 11 received 5/7 treatments for the first 2 weeks followed by twice-weekly therapy thereafter and differed only by the higher (group 6) or lower (group 11) dose of isoniazid (H). Drug doses were as follows unless otherwise noted: rifampin (R), 10 mg/kg; pyrazinamide (Z), 150 mg/kg; isoniazid (H), 10 mg/kg; ethambutol (E), 100 mg/kg. Asterisks (*) in Fig. 1B indicate the coexistence of CFU resistant to R or H at those points.

Tables

  • Figures
  • TABLE 1

    Lung CFU counts before and during treatmenta

    Treatment groupDrug regimenLog10 CFU count in mice sacrificed at:
    0–2 mo2–6 moMo 0.5Mo 1Mo 2bMo 4Mo 6
    BALB/c mice
        1Untreated
        2P 5/7P 5/7 5.07 ± 0.50Contaminated0.50 ± 1.00c0c
        3RHZE 5/7RH 5/76.36 ± 0.064.97 ± 0.242.90 ± 0.1400
        5PH50 1/7 00
        62wRHZE 5/7 + 6wRH25Z300E200 2/7RH25 2/7 5.12 ± 0.243.35 ± 0.070.89 ± 0.260
        8PH50 1/7 0.14 ± 0.310
        112wRH5ZE 5/7 + 6wRH12.5Z300E200 2/7RH12.5 2/76.36 ± 0.134.87 ± 0.132.700.34 ± 0.480
        13PH25 1/7 0.14 ± 0.310
    Nude mice
        1Untreated
        2P 5/7P 5/7 5.55 ± 0.246.706.52cND
        3RHZE 5/7RH 5/76.43 ± 0.375.95 ± 0.193.7700
        4P 1/7 4.82 ± 0.86c6.38
        5PH50 1/7 2.44 ± 0.320.08
        62wRHZE 5/7 + 6wRH25Z300E200 2/7RH25 2/7 6.15 ± 0.275.201.77 ± 0.580.16
        7P 1/7 6.63 ± 2.32c6.50c
        8PH50 1/7 2.09 ± 0.38c0c
        9P15H50 1/7 1.79 ± 0.30c0
        10P20H50 1/7 2.03 ± 0.42c0
        112wRH5ZE 5/7 + 6wRH12.5Z300E200 2/7RH12.5 2/76.74 ± 0.256.16 ± 0.434.102.28 ± 1.04c0.37c
        12P 1/7 6.82 ± 0.50c6.30c
        13PH25 1/7 2.09 ± 0.08c0.45c
        14P15H25 1/7 1.39 ± 0.422.51c
        15P20H25 1/7 0.74 ± 1.04c0
    • ↵a The log10 CFU counts at day 0 were 7.82 ± 0.22 for the BALB/c mice and 7.77 ± 0.18 for the nude mice. All members of group 1 of the BALB/c mice were dead before month 0.5; all members of group 1 of the nude mice were dead by day 9. Drug doses (in mg/kg) if not otherwise specified: rifampin (R), 10; rifapentine (P), 10; isoniazid (H), 10; pyrazinamide (Z), 150; ethambutol (E), 100. 2w, 2-week drug administration; 6w, 6-week drug administration; ND, not done due to death of all mice by month 4.

    • ↵b Due to fungal contamination, only a few plates were available for analysis at month 2.

    • ↵c CFU resistant to R or H coexisted at the indicated points between 2 and 6 months, but only CFU counts from mice without resistance are presented here.

  • TABLE 2

    Mortality of nude mice during the treatment perioda

    Treatment groupTreatment regimenNo. of mice showing mortality during the treatment period/total no. of mice
    0–2 mos2–6 mos0–2 mos2–6 mosb
    2P 5/7P 5/71/106/10 (6/6)
    3RHZE 5/7RH 5/73/150/10
    4P 1/71/10 (1/1)
    5PH50 1/70/10
    62wRHZE 5/7 + 6wRH25Z300E200 2/7RH25 2/72/100/10
    7P 1/71/10 (1/1)
    8PH50 1/70/10
    9P15H50 1/70/10
    10P20H50 1/70/10
    112wRH5ZE 5/7 + 6wRH12.5Z300E200 2/7RH12.5 2/73/154/10 (3/4)
    12P 1/73/10 (2/3)
    13PH25 1/71/10 (?)
    14P15H25 1/70/10
    15P20H25 1/71/10 (0/1)
    • ↵a Drug doses (in mg/kg) if not otherwise specified: rifampin (R), 10; rifapentine (P), 10; isoniazid (H), 10; pyrazinamide (Z), 150; ethambutol (E), 100. The mortality data include only mice dead from any cause before scheduled sacrifice or sacrificed earlier due to severe illness.

    • ↵b Numbers within parentheses indicate the proportions of dying mice harboring ≥1% resistant CFU. ?, not assessable.

  • TABLE 3

    Proportions of nude mice with selective amplification of resistance and emergence of resistance between month 2 and month 6

    Treatment groupDrug regimenNo. of mice with indicated result/total no. of mice
    Selective amplification onlyaResistanceb
    0–2 mos2–6 mosHRH or RHRH or R
    2P 5/7P 5/70/91/101/100/99/109/10
    3RHZE 5/7RH 5/70/100/100/100/100/100/10
    4P 1/70/100/100/100/101/101/10
    5PH50 1/70/100/100/100/100/100/10
    62wRHZE 5/7 + 6wRH25Z300E200 2/7RH25 2/70/100/100/100/100/100/10
    7P 1/70/101/101/101/106/106/10c
    8PH50 1/70/100/100/103/101/104/10
    9P15H50 1/70/100/100/102/100/102/10
    10P20H50 1/70/100/100/100/101/101/10
    112wRH5ZE 5/7 + 6wRH12.5Z300E200 2/7RH12.5 2/70/101/10d1/104/10d0/104/10
    12P 1/70/101/101/102/10d5/105/10d
    13PH25 1/70/100/100/101/101/102/10
    14P15H25 1/70/100/100/101/100/101/10
    15P20H25 1/70/100/100/101/101/102/10
    • Drug doses (in mg/kg) if not otherwise specified: rifampin (R,10); rifapentine (P, 10); isoniazid (H, 10); pyrazinamide (Z, 150); ethambutol (E, 100).

    • ↵a Selective amplification defined by 0.01 < H < 1% or 0.001 < R < 1% of resistance on H (0.2 μg/ml) or R (1.0 μg/ml).

    • ↵b Resistance defined by resistant CFU comprising ≥1% of total CFU.

    • ↵c One isolate was multidrug resistant (MDR) which was resistant to both H (0.2 μg/ml) and R (1.0 μg/ml).

    • ↵d One isolate had heterogenous strains which were resistant to either H (0.2 μg/ml) or R (1.0 μg/ml) but not both.

  • TABLE 4

    MIC and mutational analysis of isolates harboring >1% resistancea

    Treatment group and regimenDuration of treatment (wks)Resistant CFUb (%)MIC (μg/ml)katG mutationrpoB mutation
    HRHRNucleotideAmino acidNucleotideAmino acid
    BALB/c mice
        G2, P 5/716097 >16 1592 C→TS531L
    24077 >16 1576 C→TH526Y
    Nude
        G2, P 5/74<0.012 >16 1577 A→GH526R
    13<0.01100 >16 1576 C→TH526Y
    13<0.012 2–4 1598 T→CL533P
    130100 >16 1576 C→TH526Y
    13<0.0120 >16 1577 A→GH526R
    1606 >16 1565 C→TS522L
        G7, (2 + 6)wRHZE + 4P 1/716<0.013 >16 1592 C→GS531W
    160.060.25>16c>16c1513 T→CW505R1592 C→TS531L
    24<0.016 >16 1576 C→TH526Y
        G8, (2 + 6)wRHZE + 4PH50 1/716330>16 765 G→CM255I
    161000>16 691 A insFrame shift
    240100 >16 1592 C→TS531L
        G9, (2 + 6)wRHZE + 4P15H50 1/7161000>16 902 AG delFrame shift
    16750>16 WT
        G11, (2 + 6)wRH5ZE + 4RH12.5 2/7191000.0014>16 853 G insFrame shift
        G13, (2 + 6)wRH5ZE + 4PH25 1/7160100 >16 1592 C→TS531L
        G14, (2 + 6)wRH5ZE + 4P15H25 1/716160>16 1856 T→GL619R
    241000>16 1643 G→AG548D
        G15, (2 + 6)wRH5ZE + 4P20H25 1/716300>16 WT
    160100 >16 1592 C→TS531L
    • ↵a Drug doses (in mg/kg) if not otherwise specified: rifampin (R), 10; rifapentine (P), 10; isoniazid (H), 10; pyrazinamide (Z), 150; ethambutol (E), 100. (2 + 6)w, combination of 2-week plus 6-week drug administration; G, group; ins, insertion; del, deletion; WT, wild type.

    • ↵b Resistance defined by growth on H (0.2 μg/ml) or R (1 μg/ml).

    • ↵c MIC measured only with resistant isolates on H (0.2 μg/ml) or R (1 μg/ml).

  • TABLE 5

    Experimental schemea

    Treatment groupDrug regimenBoth strains or nude mice only?bNo. of mice sacrificed/total no. of miceTotal
    0–2 mos2–6 mosMo 0.5Mo 1Mo 2Mo 4Mo 6
    1Untreated +/+ 5/10 5/10
    2P 5/7P 5/7+/+ 5/55/55/55/520/20
    3RHZE 5/7RH 5/7+/+5/55/55/55/55/525/25
    4P 1/70/+ 0/50/50/10
    5PH50 1/7+/+ 5/55/510/10
    62wRHZE 5/7 + 6wRH25Z300E200 2/7RH25 2/7+/+ 5/55/55/55/520/20
    7P 1/70/+ 0/50/50/10
    8PH50 1/7+/+ 5/55/510/10
    9P15H50 1/70/+ 0/50/50/10
    10P20H50 1/70/+ 0/50/50/10
    112wRH5ZE 5/7 + 6wRH12.5Z300E200 2/7RH12.5 2/7+/+5/55/55/55/55/525/25
    12P 1/70/+ 0/50/50/10
    13PH25 1/7+/+ 5/55/510/10
    14P15H25 1/70/+ 0/50/50/10
    15P20H25 1/70/+ 0/50/50/10
    Total 125/200c15/2020/2020/2035/7035/70125/200
    • ↵a Drug doses (in mg/kg) if not otherwise specified: rifampin (R), 10; rifapentine (P), 10; isoniazid (H), 10; pyrazinamide (Z), 150; ethambutol (E), 100.

    • ↵b +/+, arm included both BALB/c and nude mice; 0/+, arm included nude mice only.

    • ↵c Four BALB/c mice sacrificed on day −17 and 6 nude mice sacrificed on day 0 were not included.

PreviousNext
Back to top
Download PDF
Citation Tools
Immunodeficiency and Intermittent Dosing Promote Acquired Rifamycin Monoresistance in Murine Tuberculosis
Sang-Won Park, Rokeya Tasneen, Paul J. Converse, Eric L. Nuermberger
Antimicrobial Agents and Chemotherapy Oct 2017, 61 (11) e01502-17; DOI: 10.1128/AAC.01502-17

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Print

Alerts
Sign In to Email Alerts with your Email Address
Email

Thank you for sharing this Antimicrobial Agents and Chemotherapy article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Immunodeficiency and Intermittent Dosing Promote Acquired Rifamycin Monoresistance in Murine Tuberculosis
(Your Name) has forwarded a page to you from Antimicrobial Agents and Chemotherapy
(Your Name) thought you would be interested in this article in Antimicrobial Agents and Chemotherapy.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Immunodeficiency and Intermittent Dosing Promote Acquired Rifamycin Monoresistance in Murine Tuberculosis
Sang-Won Park, Rokeya Tasneen, Paul J. Converse, Eric L. Nuermberger
Antimicrobial Agents and Chemotherapy Oct 2017, 61 (11) e01502-17; DOI: 10.1128/AAC.01502-17
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Top
  • Article
    • ABSTRACT
    • INTRODUCTION
    • RESULTS
    • DISCUSSION
    • MATERIALS AND METHODS
    • ACKNOWLEDGMENTS
    • FOOTNOTES
    • REFERENCES
  • Figures & Data
  • Info & Metrics
  • PDF

KEYWORDS

antitubercular agents
Drug Resistance, Bacterial
rifamycins
tuberculosis
acquired rifamycin resistance
nude mouse
tuberculosis
intermittent therapy
immunodeficiency

Related Articles

Cited By...

About

  • About AAC
  • Editor in Chief
  • Editorial Board
  • Policies
  • For Reviewers
  • For the Media
  • For Librarians
  • For Advertisers
  • Alerts
  • AAC Podcast
  • RSS
  • FAQ
  • Permissions
  • Journal Announcements

Authors

  • ASM Author Center
  • Submit a Manuscript
  • Article Types
  • Ethics
  • Contact Us

Follow #AACJournal

@ASMicrobiology

       

ASM Journals

ASM journals are the most prominent publications in the field, delivering up-to-date and authoritative coverage of both basic and clinical microbiology.

About ASM | Contact Us | Press Room

 

ASM is a member of

Scientific Society Publisher Alliance

 

American Society for Microbiology
1752 N St. NW
Washington, DC 20036
Phone: (202) 737-3600

Copyright © 2021 American Society for Microbiology | Privacy Policy | Website feedback

Print ISSN: 0066-4804; Online ISSN: 1098-6596