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Early bactericidal activity of new drug regimens for tuberculosis

Early bactericidal
Diacon AH, Dawson R, von Groote-Bidlingmaier F, et al. 14 day isolation, are of little use to patients bactericidal activity of PA-824, bedaquiline, activity of new drug
pyrazinamide, and moxifl oxacin combinations:
a randomised trial. Lancet 2012; 380: 986–93.
regimens for
of the disease. Drug combinations 2 Udwadia ZF. MDR, XDR, TDR tuberculosis: ominous progression. Thorax 2012; tuberculosis
67: 286–88.
Udwadia ZF, Amale RA, Abjani KK, et al. Totally Andreas Diacon and colleagues acting on this need in their ground- (Sept 15, p 986)1 have undertaken breaking study.
Clin Infect Dis 2012; 54: 579–81.
Agarwal D, Udwadia ZF, Rodrigues C, et al. Increasing incidence of fl uoroquinolone treatment regimen for tuberculosis: moxifl resistant Mycobacterial tuberculosis in Mumbai, PA-824, bedaquiline, pyrazinamide, can cure MDR tuberculosis is a India. Int J Tuberc Lung Dis 2009; 13: 79–83.
and moxifl oxacin. How ever, sputum leap of faith at best. The types of sensitivity testing was done only strain encountered in many parts Andreas Diacon and colleagues1 for these four drugs. The sensitivity of the world are seldom resistant report equivalent 2-log reductions to isoniazid and rifampicin was not to just isoniazid and rifampicin. At in sputum colony-forming units known. Without including patients the Hinduja Hospital in Mumbai, (CFU) during 2 weeks of tuberculosis resistant to isoniazid and rifampicin, India, we have been treating MDR treatment with PA-824, moxifl oxacin, the eff ectiveness of the new regimen tuberculosis for the past two decades, and pyrazinamide versus isoniazid, in patients with multidrug-resistant and have witnessed fi rst hand rifampicin, pyrazinamide, and etham-(MDR) tuberculosis can only be the relentless amplifi cation of our butol. We question the signifi cance of guessed at. The pharmacokinetics patients’ resistance patterns from the fi nding.
and probability of pharmacodynamic MDR to extensively drug-resistant to target attainment (ratio of area totally drug-resistant tuberculosis.2,3 under the time curve to minimum The fl uoroquinolones are among the of well characterised tuberculosis inhibitory concentration) are likely most widely prescribed groups of drug combinations over 14 days to be altered in patients with MDR antibiotics in India, and around 50% (fi gure, right). One2 found equal 2-log tuberculosis.2 of all MDR tuberculosis strains we see reductions with the combination Thus, current clinical speculation are resistant even to moxifl oxacin.4 about the eff ectiveness of the new An analysis of our last 100 patients’ isoniazid alone. A second3 found the regimen on MDR tuberculosis seems drug susceptibility reports showed combination of isoniazid, rifampicin, to be overoptimistic and should that a third of these patients were streptomycin, and pyrazinamide to be based on the outcome data of a resistant to both pyrazinamide be at the threshold of superiority randomised clinical trial in patients and moxifl oxacin (in addition to over the combination of isoniazid, must be included in future clinical Diacon and colleagues’ triple-drug but only during days 2–28; equal trials of the new regimen to confi rm regimen to these patients with MDR 2-log reductions occurred at earlier its effi tuberculosis would be tantamount to timepoints. Isoniazid, rifampicin, We declare that we have no confl icts of interest.
monotherapy with PA-824, ensuring streptomycin, and pyrazinamide that resistance rapidly develops to yet given for 6 months cures tuberculosis with a relapse rate of 3%.4 By contrast, Great caution will need to be 22% of patients relapse if similarly
extreme forms of resistance almost and thiacetazone; 18 months of Department of Pulmonary Medicine, Government routinely encountered in some MDR treatment are required to reduce the Medical College and Hospital, 160030 Chandigarh, India hot spots. New regimens with three relapse rate to 3%.5 von Groote-Bidlingmaier F, et al. 14 day desperately need to cure them of to capture clinically important bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifl oxacin combinations: a randomised trial. Lancet I declare that I have no confl icts of interest.
2012; 380: 986–93.
Chigutsa E, Meredith S, Wiesner L, et al. Submissions should be
made via our electronic
pharmacodynamics of ofl oxacin in South 7–14 days’ duration show very similar submission system at
African patients with multidrug-resistant Hinduja Hospital and Research Center, Veer Savarkar results (fi gure, left).2,3,6,7 It seems tuberculosis. Antimicrob Agents Chemother
2012; 56: 3857–63.
instead to be an intrinsic limitation of thelancet/ Vol 381 January 12, 2013
which a patient’s Mycobacterium tuberculosis isolate is sensitive, and Figure: Published trials of quantitative sputum microbiology in patients with pulmonary tuberculosis
of 7–28 days’ duration
Left: Across-trial comparisons of similar treatments, showing similar results. Right: Within-trial comparisons of distinct treatments, showing similar results during fi rst 14 days. H=isoniazid; R=rifampicin, E=ethambutol; S=streptomycin, Z=pyrazinamide; T=thiacetazone. CFU=colony-forming units.
studies, in 2-month clinical trials, and in long-term clinical trials.2,3 The mouse Authors’ reply
such trials can inform the required We agree with Prasanta Mohapatra for constructing any new regimen duration of treatment is unsupported and colleagues and Zarir Udwadia to advance into clinical evaluation. by clinical data.
RSW is an employee and shareholder of Pfi zer. CN is moxifl oxacin-pyrazinamide regimen must then continue to be supported by must be shown in clinical trials that fi ndings in short-term, intermediate-include patients with multidrug- robert.wallis@pfi
Obviously, this regimen cannot be bactericidal activity of PA-824- Pfi zer, Groton, CT 06340, USA (RSW); and Sequella, appropriate for all such patients moxifl oxacin-pyrazinamide1 represents because their isolates can harbour the fi rst step in this systematic process. Diacon AH, Dawson R, von Groote-Bidlingmaier F, et al. 14 day resistance beyond that to isoniazid It remains an open, but extremely bactericidal activity of PA-824, bedaquiline, and rifampicin, including moxifl oxacin important, question as to exactly how pyrazinamide, and moxifl oxacin combinations: a randomised trial. Lancet 2012; 380: 986–93.
824-moxifl oxacin-pyrazinamide over the early phase of treatment (whether Wallis RS, Phillips M, Johnson JL, et al. Inhibition 8 weeks, which includes patients for 2 weeks or for 2 months) predict of INH-induced expression of M tuberculosis antigen 85 in sputum: a potential surrogate with MDR tuberculosis susceptible long-term outcomes; unfortunately to moxifl oxacin and pyrazinamide, there is no single biomarker or short- Antimicrob Agents Chemother 2001;
45: 1302–44.
is currently underway (ClinicalTrials.
Brindle R, Odhiambo J, Mitchison DA. Serial NCT01498419). evidence of the necessary treatment counts of Mycobacterium tuberculosis in sputum as surrogate markers of the sterilising activity of rifampicin and pyrazinamide in suggest that patients who receive that only after rigorous, methodical BMC Pulm Med 2001; 1: 2.
East and Central African-British Medical but neither isoniazid nor rifampicin, trial,1 our ongoing 2-month trial, and Research Council. Controlled clinical trial hitherto regarded as essential, will not of 4 short-course regimens of chemotherapy be therapeutically disadvantaged in we better understand the predictive (three 6-month and one 8-month) for pulmonary tuberculosis. Tubercle 1983; capability of short-term clinical studies. 64: 153–66.
Udwadia shares our enthusiasm We declare that we have no confl icts of interest.
East African-British Medical Research Councils. Results at 5 years of a controlled for constructing a combination of at *Andreas H Diacon, Peter R Donald, pulmonary tuberculosis. Am Rev Respir Dis that can be combined safely and to
1977; 116: 3–8.
which resistance would be unlikely Department of Biomedical Sciences, Faculty of Rustomjee R, Diacon AH, Allen J, et al. Early bactericidal activity and pharmacokinetics of Medicine and Health Sciences, Stellenbosch the diarylquinoline TMC 207 in pulmonary regimen would treat all forms of University, PO Box 19063, 7505 Tygerberg, South tuberculosis. Antimicrob Agents Chemother tuberculosis, thereby obviating the Africa (AHD); Department of Paediatrics and Child 2008; 52: 2831–35.
Health, Faculty of Medicine and Health Sciences, necessity for susceptibility testing for Diacon AH, Dawson R, Hanekom M, et al. Early Stellenbosch University, Cape Town, South Africa bactericidal activity and pharmacokinetics of drugs currently in use. Until such a (PRD); and Global Alliance for TB Drug patients. Antimicrob Agents Chemother 2010;
54: 3402–07. Vol 381 January 12, 2013



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