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2008 The Union
A randomised controlled trial of
2 Petty T I, Mitchell R S. Successful treatment of advanced high-dose isoniazid adjuvant therapy for
i soniazid- and streptomycin-resistant pulmonary tuberculosis multidrug-resistant tuberculosis
with ethionamide, pyrazinamide, and isoniazid. Am Rev Respir Dis 1962; 86: 503–512.
The fi ndings by Katiyar et al. in a recent issue of the 3 Moulding T S. Should isoniazid be used in retreatment of tuber- Journal that the adjuvant use of high-dose isoniazid culosis despite acquired isoniazid resistance? Am Rev Respir Dis 1981: 123: 262–264. (INH) signifi cantly improves results when retreating 4 Canetti G, Kreis B, Thibier R, Gay P, Le Lirzin M. Current data on multidrug-resistant tuberculosis (MDR-TB) is a wel- primary resistance in pulmonary tuberculosis in adults in France. come fi nding.1 An earlier non-randomized trial by 2nd survey of the Centre d’Etudes sur la Resistance Primaire: Petty et. al. found similar superior results when high- 1965–1966. Rev Tuberc Pneumol (Paris) 1967; 31: 433–474. dose isoniazid (INH) was added to a retreatment regi- 5 Morlock G P, Metchock B, Sikes D, Crawford J T, Cooksey R C. EthA, inhA, and katG loci of ethionamide-resistant clinical My- men of ethionamide (ETH) and pyrazinamide (PZA).2 cobacterium tuberculosis isolates. Antimicrob Agents Chemother In a discussion of this issue, I presented a line of rea- soning that the superior results found by Petty et al. may have been specifi c for an ETH-containing regi- men, as it is known that strains with INH resistance have an unusual pattern of cross-resistance with ETH.3 We thank Dr Moulding for his insightful comments on Low-grade INH-resistant organisms are often resis- the implications of our work.1 He raises an extremely tant to ETH, and high-grade INH resistance organ- pertinent question regarding the possibility of cross- isms are more susceptible to ETH.4 Therefore, adding resistance of isoniazid (INH) resistant strains with high-dose INH kills the low-grade INH-resistant or- prothionamide (PTH). All the subjects in our study ganisms, leaving only high-grade INH-resistant organ- received a standardized course of second-line anti- isms that are more susceptible to ETH, resulting in tuberculosis treatment that included PTH, and we do better clinical results.3 Less compelling evidence was not have laboratory data on the PTH resistance pro- presented showing that there is a similar process of fi le of these patients. The clinical protocol of our trial cross-resistance between INH and PZA.3 Katiyar et did not permit us to compare INH-resistant MDR-TB al. added high-dose INH to regimens containing pro- patients who did or did not receive PTH. Therefore, it thionamide, kanamycin, levofl oxacin, cycloserine and will not be possible to directly answer the question PAS.1 Prothionamide and ETH are very similar in raised from our study data. While generalizing the re- structure, but it is unknown to me if they have the sults of our trial one should therefore bear in mind that same patterns of cross-resistance with INH. the effectiveness of high-dose INH adjuvant therapy The issue is important, because clinicians need to was observed in the context of a PTH-containing regi- know whether or not to add high-dose INH to all re- men for second-line treatment. Generalization to other treatment regimens or only to retreatment regimens regimens will need more laboratory and clinical work.
containing specifi c drugs. A recent article by Morlock Regarding reference 28 being misquoted, we would et al., which described the genetic mechanism for the like to clarify that the four references included to- INH-ETH cross-resistance patterns, may prove to be gether in our article were categorized as ‘other experi- one line of investigation that could help answer this ences’. We certainly could have been more explicit, but what we wanted to convey was that INH has value in Note: Reference #28 in the article by Kariyar et al. both preventing and treating MDR-TB. We again to one of my publications is apparently an error, since thank Dr Moulding for these very helpful comments.
it addresses an entirely different issue.
Division of Respiratory and Critical Care *Department of Tuberculosis & Ganesh Shankar Vidyarthi Memorial 1 Katiyar S K, Bihari S, Prakash S, Mamtani M, Kulkarni H. A † Lata Medical Research Foundation randomised controlled trial of high-dose isoniazid adjuvant ther-apy for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis e-mail:


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