American Journal of Respiratory and Critical Care Medicine

To the Editor:

We read with interest the article by Dooley and colleagues, which showed that high-dose isoniazid (10–15 mg/kg) had early bactericidal activity for Mycobacterium tuberculosis (MTB) strains with inhA mutations similar to that observed with normal-dose isoniazid (5 mg/kg) for susceptible strains (1). The authors concluded that high-dose isoniazid represents a useful addition to second-line tuberculosis (TB) treatment regimens for patients with rifampicin-resistant TB and isolated inhA mutations.

We believe that high-dose isoniazid may also play an important role in first-line TB treatment. At present, the World Health Organization recommends adding a second-line TB drug (levofloxacin) to three first-line drugs (rifampicin, ethambutol, and pyrazinamide) in patients with TB resistant to isoniazid without concurrent rifampicin resistance. Isoniazid would not be included in this levofloxacin-strengthened first-line regimen (2). This recommendation has several major implications.

To implement this recommendation, rifampicin and isoniazid susceptibility testing should be performed, particularly in previously treated patients, who are at risk of initial resistance. Before prescribing levofloxacin for patients with rifampicin-susceptible/isoniazid-resistant TB, additional fluoroquinolone susceptibility testing is recommended (2). Access to rifampicin susceptibility testing has increased substantially, but access to isoniazid and fluoroquinolone susceptibility testing is still poor in most high-TB-burden countries, where samples still have to be transported to referral laboratories. Although novel diagnostic tools, such as Xpert MTB/XDR, are on the horizon, their widespread implementation will still take years. This will cause treatment delays of several months and result in losses to follow-up between the time of TB diagnosis and treatment initiation. In addition, not all rifampicin resistance is detected by frequently used rapid tests, such as Xpert MTB/RIF and GenoType MTBDRplus. rpoB mutations outside the 81-bp rifampicin resistance determining region are not covered by these commercial assays. Another, not unusual cause of missed rifampicin resistance is heteroresistance resulting from a mixed population of both susceptible and resistant TB bacilli (3). If patients with resistance to isoniazid and missed rifampicin resistance were treated with the World Health Organization levofloxacin-strengthened first-line regimen, resistance to fluoroquinolone would emerge rapidly. Because the efficacy of second-line TB treatment relies on a fluoroquinolone as a core drug, treatment options would be dramatically reduced. Finally, as shown by Dooley and colleagues, as well as by previous studies (4), high-dose isoniazid may overcome mutations that confer resistance to isoniazid and render normal doses ineffective (4). Excluding isoniazid, which has the highest early bactericidal activity of all first-line drugs, increases the risk of acquiring rifampicin resistance, as mutant bacilli may survive the early phase of TB treatment.

Moreover, Boeree and colleagues showed that high-dose rifampicin (35 mg/kg) was safe and reduced time to culture conversion when compared with normal-dose rifampicin (10 mg/kg) (5). Although isoniazid is used for its bactericidal activity against actively replicating bacilli, rifampicin has both a bactericidal effect against rapidly replicating bacilli and a sterilizing effect against dormant bacilli. Both types of action are needed to ensure a relapse-free cure (6).

Globally, about 11.6% of patients with recurrent TB have rifampicin-susceptible/isoniazid-resistant TB. Studies should compare high-dose first-line regimens with normal-dose regimens in terms of safety, treatment success, and acquired rifampicin resistance in patients with rifampicin-susceptible/isoniazid-resistant TB. If it is shown to be safe and efficacious, high-dose first-line treatment could be used in all patients with recurrent rifampicin-susceptible TB, regardless of initial isoniazid resistance, thus avoiding delays in retreatment. Such an improved use of first-line anti-TB drugs would have major advantages. No additional susceptibility testing beyond rifampicin testing would be required and there would be no delay between a diagnosis of rifampicin-susceptible recurrent TB and initiation of treatment. If first-line treatment could rely on first-line drugs only, second-line treatment options would be maximally safeguarded.

1. Dooley KE, Miyahara S, von Groote-Bidlingmaier F, Sun X, Hafner R, Rosenkranz SL, et al.; A5312 Study Team. Early bactericidal activity of different isoniazid doses for drug resistant TB (INHindsight): a randomized open-label clinical trial. Am J Respir Crit Care Med [online ahead of print] 16 Jan 2020; DOI:
2. World Health Organization. WHO treatment guidelines for isoniazid-resistant tuberculosis: supplement to the WHO treatment guidelines for drug-resistant tuberculosis WHO/CDS/TB/2018; 2018 [accessed 2020 Jan 29]. Available from:
3. Van Deun A, Aung KJM, Bola V, Lebeke R, Hossain MA, de Rijk WB, et al. Rifampin drug resistance tests for tuberculosis: challenging the gold standard. J Clin Microbiol 2013;51:26332640.
4. Katiyar SK, Bihari S, Prakash S, Mamtani M, Kulkarni H. A randomised controlled trial of high-dose isoniazid adjuvant therapy for multidrug-resistant tuberculosis [letter]. Int J Tuberc Lung Dis 2008;12:139145.
5. Boeree MJ, Heinrich N, Aarnoutse R, Diacon AH, Dawson R, Rehal S, et al.; PanACEA consortium. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial. Lancet Infect Dis 2017;17:3949.
6. Van Deun A, Decroo T, Piubello A, de Jong BC, Lynen L, Rieder HL. Principles for constructing a tuberculosis treatment regimen: the role and definition of core and companion drugs. Int J Tuberc Lung Dis 2018;22:239245.
*Corresponding author (e-mail: ).

Author Contributions: T.D. wrote the first draft. B.C.d.J., A.P., M.B.S., L.L., and A.V.D. critically reviewed the subsequent versions. All authors approved the final version.

Originally Published in Press as DOI: 10.1164/rccm.202001-0201LE on March 4, 2020

Author disclosures are available with the text of this letter at


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American Journal of Respiratory and Critical Care Medicine

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