HLA-DR alleles, it would have been interesting to see data from other combinations with DRB1*0301 rather than only. DRB1*0101. It is not clear whether ...
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HLA-DR alleles, it would have been interesting to see data from other combinations with DRB1*0301 rather than only DRB1*0101. It is not clear whether peptide-binding algorithms were not available for DRB1 alleles in other combinations, or if they were rare in the particular population of Caucasians from which the allele frequency data was derived. In the Swedish sarcoidosis patients, several other alleles are certainly combined with DRB1*0301 with a frequency similar to that of DRB1*0101. Regarding the clinical importance of having one or two copies of a certain DRB1 allele, we looked into this in our sarcoidosis patient database containing greater than 700 entries. Despite the large number of patients, there were too few who were homozygous for DR3 or homozygous for DR15 to draw any definite conclusions, but it did not seem to matter for the clinical disease course whether patients had one or two copies of DR3 (associated with good prognosis) or one or two copies of DR15 (poor prognosis). In patients with one copy of each (i.e., who were DR3pos/DR15pos), the beneficial effect of DR3 seemed dominant, and the patients tended to recover spontaneously. One reason that the superior epitope-binding capacity of DRB1*0301 may be further enhanced is that carriers of that allele almost always also express DRB3*0101, encoding a structurally similar HLA-DR molecule able to present identical antigenic peptides (4). Finally, it should be remembered that HLA-DR associations with disease may also be caused by close genetic linkage with other HLA genes (such as DQ2 in the case of DR3), or with non-HLA genes that are part of the MHC complex. Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
JAN WAHLSTRO¨M ANDERS EKLUND JOHAN GRUNEWALD Karolinska Institutet and Karolinska University Hospital Stockholm, Sweden References 1. Grunewald J, Eklund A. Lo¨fgren’s syndrome: human leukocyte antigen strongly influences the disease course. Am J Respir Crit Care Med 2009;179:307–312. 2. Saltini C, Pallante M, Puxeddu E, Contini S, Voorter CE, Drent M, Amicosante M. M. avium binding to HLA-DR expressed alleles in silico: a model of phenotypic susceptibility to sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2008;25:100–116. 3. Chen ES, Wahlstrom J, Song Z, Willett MH, Wiken M, Yung RC, West EE, McDyer JF, Zhang Y, Eklund A, et al. T cell responses to mycobacterial catalase-peroxidase profile a pathogenic antigen in systemic sarcoidosis. J Immunol 2008;181:8784–8796. 4. Nagvekar N, Corlett L, Jacobson LW, Matsuo H, Chalkley R, Driscoll PC, Deshpande S, Spack EG, Willcox N. Scanning a DRB3*0101 (DR52a)-restricted epitope cross-presented by DR3: overlapping natural and artificial determinants in the human acetylcholine receptor. J Immunol 1999;162:4079–4087.
Should Moxifloxacin Be Substituted for Isoniazid as a First-Line Antituberculosis Drug? To the Editor:
Dr. Dorman and colleagues, in their article, report on using moxifloxacin, a fluoroquinolone, in a clinical trial as a first-line drug against tuberculosis (TB) (1). Up to now, the fluoroquinolones have been used as second-line antitubercular drugs. Resistance to any fluoroquinolone is an essential criterion of extensively drug-resistant TB (XDR-TB). Moxifloxacin is an
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important drug in treating XDR TB (2, 3). Should this fluoroquinolone be used as a first-line anti-TB drug and replace other bactericidal first-line antitubercular drugs? The latest Cochrane meta-analysis has opposed the use of moxifloxacin, even as a first-line drug substitute (4). All tuberculosis drugs have the ability to produce a lag period except quinolones. Thus, the quinolones should not be used for intermittent therapy and should not be administered for 5 days/week as was done in this study (1). High-level phenotypic resistance to fluoroquinolones has been demonstrated among Mycobacterium tuberculosis clinical isolates, which appears to be predominantly due to gyrA mutations, and these isolates exhibited cross-resistance to all six clinically used fluoroquinolones (5). In addition to cross-resistance to all the fluoroquinolones, the problem of resistance is further complicated by the broad indications of this class of antimicrobials in lower-respiratory, gastrointestinal, genitourinary, and other infections. Such use partially contributes to emerging resistance to fluoroquinolones. The global threat of extensively drug-resistant TB has revealed weaknesses in TB control and also has highlighted the lack of new tools for TB control (2, 6). At present, no better drugs are in the pipelines, and we are left with few bacteriostatic antitubercular drugs. Losing the fluoroquinolones means losing a potent and minimally toxic option for second-line drug therapy. Their use should be restricted to the treatment of confirmed multidrug-resistant tuberculosis (MDR-TB) cases, particularly in tuberculosis endemic areas. Different strategies are needed for tackling drug-resistant infection. We should not create a situation that can increase XDR-TB in years to come. Conflict of Interest Statement: The author has no financial relationship with a commercial entity that has an interest in the subject of this manuscript.
PRASANTA RAGHAB MOHAPATRA Government Medical College and Hospital Chandigarh Chandigarh, India References 1. Dorman SE, Johnson JL, Goldberg S, Muzanye G, Padayatchi N, Bozeman L, Heilig CM, Bernardo J, Choudhri S, Grosset JH, et al. Substitution of moxifloxacin for isoniazid during intensive phase treatment of pulmonary tuberculosis. Am J Respir Crit Care Med 2009;180: 273–280. 2. Aggarwal D, Mohapatra PR, Janmeja AK. Treatment of extensively drug-resistant tuberculosis. Lancet 2009;373:26–27. 3. Mitnick CD, Shin SS, Seung KJ, Rich ML, Atwood SS, Furin JJ, Fitzmaurice GM, Alacantara Viru FA, Appleton SC, Bayona JN, et al. Comprehensive treatment of extensively drug resistant tuberculosis. N Engl J Med 2008;359:563–574. 4. Ziganshina LE, Squire SB. Fluoroquinolones for treating tuberculosis. Cochrane Database Syst Rev 2008 (1):CD004795. 5. Cheng AF, Yew WW, Chan EW, Chin ML, Hui MM, Chan RC. Multiplex PCR amplimer conformation analysis for rapid detection of gyrA mutations in fluoroquinolone resistant Mycobacterium tuberculosis clinical isolates. Antimicrob Agents Chemother 2004;48:596–601. 6. Raviglione MC, Smith IM. XDR tuberculosis—implications for global public health. N Engl J Med 2007;356:656–659.
From the Authors:
Dr. Mohapatra raises an important point about the potential for emergence of resistance to moxifloxacin and other fluoroquinolones, which currently play a critical role in treatment of drug-resistant tuberculosis (TB). Experience has shown that the introduction of new drugs sooner or later results in the emergence of disease caused by bacilli resistant to the new drugs—unfortunately usually sooner in weak TB-control programs.
Correspondence
The long duration of current short-course regimens is a major obstacle to better TB control worldwide. Our phase 2 trial evaluated the antimicrobial activity of moxifloxacin to examine whether it might be useful in new regimens to shorten the duration of treatment (1). Controlled clinical trials, like our study, are essential to test new drugs and regimens and develop the necessary evidence base to support moving ahead with phase 3 trials to improve TB treatment strategies. To date, studies have shown that moxifloxacin and gatifloxacin are active in the treatment of TB, but it is not known whether the use of fluoroquinolones will permit treatment shortening. Controlled trials examining this are underway. Until these studies are completed, it would be premature to incorporate fluoroquinolones into routine first-line treatment at the TB program level. Should regimens using fluoroquinolones such as moxifloxacin be proved effective in shortening therapy in phase 3 clinical trials, then this situation will indeed challenge the TB community, including national TB programs and the World Health Organization, to develop revised treatment guidelines that balance the many factors involved. In the treatment of infectious diseases, major questions revolve around whether to use the most active drugs and regimens first, or to reserve them for use if initial treatment fails. Arguments similar to Mohapatra’s were made when rifampin was first introduced—it was suggested that rifampin be reserved for treatment of patients with unsuccessful results after initial treatment with less active regimens. Subsequent research demonstrated that using rifampin during initial therapy for TB significantly improved outcomes and reduced default and treatment failure. Whether this will be the case for moxifloxacin or other fluoroquinolones is
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not yet known. We also recognize that there are important differences in TB and HIV epidemiology between the era of rifampin introduction and our own. In the meantime, the strengthening of TB programs—including optimization of adherence, improved diagnosis of TB and drug resistance, and prompt initiation of effective multidrug therapy—remains essential for decreasing the emergence of acquired drug resistance. Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
SUSAN E. DORMAN Johns Hopkins University Baltimore, Maryland JOHN L. JOHNSON Case Western Reserve University and University Hospitals Case Medical Center Cleveland, Ohio RICHARD E. CHAISSON Johns Hopkins University Baltimore, Maryland
Reference 1. Dorman SE, Johnson JL, Goldberg S, Muzanye G, Padayatchi N, Bozeman L, Heilig CM, Bernardo J, Choudhri S, Grosset JH, et al. Substitution of moxifloxacin for isoniazid during intensive phase treatment of pulmonary tuberculosis. Am J Respir Crit Care Med 2009;180:273– 280.
