. 2019 Oct 10;54(4):1900982.

doi: 10.1183/13993003.00982-2019. Print 2019 Oct.

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance

Helen R Stagg^{1

2}, Graham H Bothamley^{3

4}, Jennifer A Davidson^{5

4}, Heinke Kunst^{6

4}, Maeve K Lalor^{7

5

4}, Marc C Lipman^{8

9

4}, Miranda G Loutet^{5

4}, Stefan Lozewicz^{10

4}, Tehreem Mohiyuddin^{5

4}, Aula Abbara^{11

4}, Eliza Alexander^{12

4}, Helen Booth^{13

4}, Dean D Creer^{14

4}, Ross J Harris^{15

4}, Onn Min Kon^{16

4}, Michael R Loebinger^{17

4}, Timothy D McHugh^{18

4}, Heather J Milburn^{19

4}, Paramita Palchaudhuri^{20

4}, Patrick P J Phillips^{21

4}, Erik Schmok^{3

4}, Lucy Taylor^{12

4}, Ibrahim Abubakar⁷; London INH-R TB study group

Collaborators, Affiliations

Collaborators

London INH-R TB study group:
Lucy V Baker, Jessica C Barrett, Helen Burgess, Catherine Cosgrove, Anne Dunleavy, Marie Francis, Urmi Gupta, Shahid Hamid, Brigitte M Haselden, Emma Holden, Vanessa Kahr, William Lynn, Felicity M Perrin, Ananna Rahman, Mohammad R Soobratty

Affiliations

¹ Institute for Global Health, University College London, London, UK helen.stagg@ed.ac.uk.
² Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
³ Respiratory Medicine, Homerton University Hospital, London, UK.
⁴ These authors contributed equally to this manuscript and are presented alphabetically.
⁵ Tuberculosis Unit, National Infection Service, Public Health England, London, UK.
⁶ Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁷ Institute for Global Health, University College London, London, UK.
⁸ Respiratory Medicine, Royal Free Hospital, London, UK.
⁹ UCL Respiratory, Division of Medicine, University College London.
¹⁰ Respiratory Medicine, North Middlesex University Hospital, London, UK.
¹¹ Infectious Diseases, London North West University Healthcare NHS Trust, London, UK.
¹² National Mycobacterial Reference Service South, Public Health England, London, UK.
¹³ Tuberculosis Service, University College London Hospitals/Whittington Health, London, UK.
¹⁴ Respiratory Medicine, Barnet General Hospital, Royal Free London NHS Foundation Trust, London, UK.
¹⁵ Statistics, Modelling and Economics Department, Public Health England, London, UK.
¹⁶ TB Service, Imperial College Healthcare, London, UK.
¹⁷ Respiratory Medicine, Chelsea and Westminster Hospital, London, UK.
¹⁸ Centre for Clinical Microbiology, University College London, London, UK.
¹⁹ Respiratory Medicine, Guy's and St Thomas' Hospital, London, UK.
²⁰ Respiratory Services, Queen Elizabeth Hospital, London, UK.
²¹ Dept of Medicine and Dept of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.

PMID: 31371444
PMCID: PMC6785706
DOI: 10.1183/13993003.00982-2019

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance

Helen R Stagg et al. Eur Respir J. 2019.

. 2019 Oct 10;54(4):1900982.

doi: 10.1183/13993003.00982-2019. Print 2019 Oct.

Authors

Collaborators

London INH-R TB study group:
Lucy V Baker, Jessica C Barrett, Helen Burgess, Catherine Cosgrove, Anne Dunleavy, Marie Francis, Urmi Gupta, Shahid Hamid, Brigitte M Haselden, Emma Holden, Vanessa Kahr, William Lynn, Felicity M Perrin, Ananna Rahman, Mohammad R Soobratty

Affiliations

¹ Institute for Global Health, University College London, London, UK helen.stagg@ed.ac.uk.
² Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
³ Respiratory Medicine, Homerton University Hospital, London, UK.
⁴ These authors contributed equally to this manuscript and are presented alphabetically.
⁵ Tuberculosis Unit, National Infection Service, Public Health England, London, UK.
⁶ Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁷ Institute for Global Health, University College London, London, UK.
⁸ Respiratory Medicine, Royal Free Hospital, London, UK.
⁹ UCL Respiratory, Division of Medicine, University College London.
¹⁰ Respiratory Medicine, North Middlesex University Hospital, London, UK.
¹¹ Infectious Diseases, London North West University Healthcare NHS Trust, London, UK.
¹² National Mycobacterial Reference Service South, Public Health England, London, UK.
¹³ Tuberculosis Service, University College London Hospitals/Whittington Health, London, UK.
¹⁴ Respiratory Medicine, Barnet General Hospital, Royal Free London NHS Foundation Trust, London, UK.
¹⁵ Statistics, Modelling and Economics Department, Public Health England, London, UK.
¹⁶ TB Service, Imperial College Healthcare, London, UK.
¹⁷ Respiratory Medicine, Chelsea and Westminster Hospital, London, UK.
¹⁸ Centre for Clinical Microbiology, University College London, London, UK.
¹⁹ Respiratory Medicine, Guy's and St Thomas' Hospital, London, UK.
²⁰ Respiratory Services, Queen Elizabeth Hospital, London, UK.
²¹ Dept of Medicine and Dept of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.

PMID: 31371444
PMCID: PMC6785706
DOI: 10.1183/13993003.00982-2019

Abstract

Introduction: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance.

Methods: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence).

Results: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42).

Conclusions: In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations.

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Conflict of interest statement

Conflict of interest: H.R. Stagg reports grants from National Institute for Health Research, UK (PDF-2014-07-008), during the conduct of the study; grants from Medical Research Council, UK (MC_PC_17101) and Korea Health Industry Development Institute, outside the submitted work. Conflict of interest: G.H. Bothamley has nothing to disclose. Conflict of interest: J.A. Davidson has nothing to disclose. Conflict of interest: H. Kunst has nothing to disclose. Conflict of interest: M.K. Lalor has nothing to disclose. Conflict of interest: M.C. Lipman has nothing to disclose. Conflict of interest: M.G. Loutet has nothing to disclose. Conflict of interest: S. Lozewicz has nothing to disclose. Conflict of interest: T. Mohiyuddin has nothing to disclose. Conflict of interest: A. Abbara has nothing to disclose. Conflict of interest: E. Alexander reports personal fees for advisory board work from Insmed, outside the submitted work. Conflict of interest: H. Booth has nothing to disclose. Conflict of interest: D.D. Creer has nothing to disclose. Conflict of interest: R.J. Harris has nothing to disclose. Conflict of interest: O.M. Kon has nothing to disclose. Conflict of interest: M.R. Loebinger has nothing to disclose. Conflict of interest: T.D. McHugh has nothing to disclose. Conflict of interest: H.J. Milburn has nothing to disclose. Conflict of interest: P. Palchaudhuri has nothing to disclose. Conflict of interest: P.P.J. Phillips has nothing to disclose. Conflict of interest: E. Schmok has nothing to disclose. Conflict of interest: L. Taylor has nothing to disclose. Conflict of interest: I. Abubakar reports grants from NIHR and MRC, outside the submitted work.

Figures

**FIGURE 1**
Flow chart of participants. Hr: isoniazid-resistant; TB: tuberculosis; PHE: Public Health England.

See this image and copyright information in PMC

Comment in

Is adding fluoroquinolones to regimens for treating isoniazid-resistant tuberculosis necessary?
Diel R, Schluger NW. Diel R, et al. Eur Respir J. 2019 Oct 10;54(4):1901494. doi: 10.1183/13993003.01494-2019. Print 2019 Oct. Eur Respir J. 2019. PMID: 31601721 No abstract available.

References

1. Stagg HR, Lipman MC, McHugh TD, et al. . Isoniazid-resistant tuberculosis: a cause for concern? Int J Tuberc Lung Dis 2017; 21: 129–139. - PMC - PubMed
1. World Health Organization (WHO). Global Tuberculosis Report 2018. Geneva, WHO; www.who.int/tb/publications/global_report/en/ Date last updated: September 2018. Date last accessed: April 2018.
1. Jenkins HE, Zignol M, Cohen T. Quantifying the burden and trends of isoniazid resistant tuberculosis, 1994–2009. PLoS One 2011; 6: e22927. - PMC - PubMed
1. Menzies D, Benedetti A, Paydar A, et al. . Effect of duration and intermittency of rifampin on tuberculosis treatment outcomes: a systematic review and meta-analysis. PLoS Med 2009; 6: e1000146. - PMC - PubMed
1. World Health Organization (WHO). WHO Treatment Guidelines For Isoniazid-Resistant Tuberculosis: Supplement to the WHO Treatment Guidelines for Drug-Resistant Tuberculosis. Geneva, WHO; www.who.int/tb/publications/2018/WHO_guidelines_isoniazid_resistant_TB/en/ Date last updated: July 2018. Date last accessed: July 2018. - PubMed

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Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance

Collaborators

Affiliations

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance

Authors

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Affiliations

Abstract

Conflict of interest statement

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