INT J TUBERC LUNG DIS 18(1):1–2 © 2014 The Union http://dx.doi.org/10.5588/ijtld.13.0739

EDITORIAL

Fluoroquinolone resistance in Mycobacterium tuberculosis. What have we learnt? FLUOROQUINOLONES play a pivotal role in regimens used in the treatment of multidrug-resistant tuberculosis, defined as bacillary resistance to at least isoniazid and rifampicin. Additional resistance to this class of agents has greatly hampered its therapeutic efficacy.1 Today, several mechanisms have been identified in the development of fluoroquinolone-resistant tuberculosis. The most important of these is the suboptimal treatment of multidrug-resistant tuberculosis patients with fluoroquinolone-based regimens, due to inadequate physician prescription and/or patient adherence in some countries or geographical settings.2,3 Programmatic management of drug-resistant tuberculosis to ensure good patient outcome cannot be overemphasised. An additional mechanism at play is the ‘exuberant’ use of this class of agents in the treatment of community-acquired bacterial infections, in particular respiratory infections. A systematic review and meta-analysis has yielded a pooled odds ratio of 2.7 for developing fluoroquinolone resistance in Mycobacterium tuberculosis.4 However, it has been suggested that short periods of administration of fluoroquinolones (for 5–7 days) are still justified in treating selected patients with pneumonia in clinical settings with a low likelihood of tuberculosis.5 In countries or geographical regions with a high prevalence of tuberculosis, the benefit versus risk for the case must be very carefully weighed. Members of the fluoroquinolone family that have good patient tolerability, even when administered at high doses, would appear to be therapeutically advantageous. On the other hand, the recurrent use of fluoroquinolones, even for a short duration, engenders a higher risk of fluoroquinoloneresistant tuberculosis.6 It appears that the cumulative dose of the fluoroquinolone(s) received over a period of time might be critical in determining the risk of resistance in M. tuberculosis. Ascertainment of the categorical role of fluoroquinolones in the treatment of drug-susceptible tuberculosis, especially in terms of shortening the duration of treatment, still awaits the results of the analyses of sizeable Phase III trials such as the REMox and Oflotub trials.7 The risk of development of fluoroquinolone resistance in M. tuberculosis strains of patients who fail treatment or relapse will also hopefully be unravelled by these studies. A recent trial that attempted to address the efficacy of fluoroquinolones (moxifloxacin or gatifloxacin at 400 mg) given thrice weekly as first-line treatment for tuberculosis was terminated prematurely due to the significantly worse patient outcome with these regimens compared to the

standard short-course regimen.8 Such drug scheduling might also be associated with a risk of creating fluoroquinolone-resistant tuberculosis similar to the effects of intermittent rifampicin administration at conventional doses.9 Finally, the health authorities in all countries should be mindful to ensure the quality of the fluoroquinolones that are marketed, as substandard formulations would definitely contribute to the development of fluoroquinolone-resistant tuberculosis.10 Unless zealous, multi-pronged efforts are directed at curtailing the development of acquired bacillary resistance to fluoroquinolones, transmission of fluoroquinolone-resistant tuberculosis in the community will fuel the burden of such disease and will pose a continued challenge to global tuberculosis control.11 Wing-Wai Yew* Christoph Lange† *Stanley Ho Centre for Emerging Infectious Diseases The Chinese University of Hong Kong Hong Kong, China † Research Center Borstel Center for Medicine and Biosciences Borstel, Germany e-mail: [email protected] References 1 Yew W W, Chan C K, Chau C H, et al. Outcomes of patients with multidrug-resistant pulmonary tuberculosis treated with ofloxacin/levofloxacin-containing regimens. Chest 2000; 117: 744–751. 2 Huang T S, Kunin C M, Shin-Jung Lee S, Chen Y S, Tu H Z, Liu Y C. Trends in fluoroquinolone resistance of Mycobacterium tuberculosis complex in a Taiwanese medical centre: 1995–2003. J Antimicrob Chemother 2005; 56: 1058–1062. 3 Park I-N, Hong S-B, Oh Y-M, et al. Impact of short-term exposure to fluoroquinolones on ofloxacin resistance in HIV-negative patients with tuberculosis. Int J Tuberc Lung Dis 2007; 11: 319–324. 4 Chen T C, Lu P L, Lin C Y, Lin W R, Chen Y H. Fluoroquinolones are associated with delayed treatment and resistance in tuberculosis: a systematic review and meta-analysis. Int J Infect Dis 2011; 15: e211–e216. 5 Shen G H, Tsao T C, Kao S J, et al. Does empirical treatment of community-acquired pneumonia with fluoroquinolones delay tuberculosis treatment and result in fluoroquinolone resistance in Mycobacterium tuberculosis? Controversies and solutions. Int J Antimicrob Agents 2012; 39: 201–205. 6 Long R, Chong H, Hoeppner V, et al. Empirical treatment of community-acquired pneumonia and the development of fluoroquinolone-resistant tuberculosis. Clin Infect Dis 2009; 48: 1354–1360. 7 Yew W-W, Nuermberger E. High-dose fluoroquinolones in

[A version in French of this article is available from the Editorial Office in Paris and from the Union website www.theunion.org]

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short-course regimens for treatment of MDR-TB: the way forward? Int J Tuberc Lung Dis 2013; 17: 853–854. Jawahar M S, Banurekha V V, Paramasivan C N, et al. Randomized clinical trial of thrice-weekly 4-month moxifloxacin or gatifloxacin containing regimens in the treatment of new sputum positive pulmonary tuberculosis patients. PLOS ONE 2013; 8: e67030. Chang K C, Leung C C, Grosset J, Yew W W. Treatment of tuberculosis and optimal dosing schedules. Thorax 2011; 66: 997–1007. Bate R, Jensen P, Hess K, Mooney L, Milligan J. Substandard and falsified anti-tuberculosis drugs: a preliminary field analysis. Int J Tuberc Lung Dis 2013; 17: 308–311. Chang K C, Yew W W. Management of difficult multidrugresistant tuberculosis and extensively drug-resistant tuberculosis: update 2012. Respirology 2013; 18: 8–21.

Fluoroquinolone resistance in Mycobacterium tuberculosis. What have we learnt?

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