Browsing by Author "Goldberg, Stefan."

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Evaluation of time to detection of mycobacterium tuberculosis in broth culture as a determinant for end points in treatment trials.
(American Society for Microbiology., 2010) Weiner, Marc.; Prihoda, Thomas J.; Burman, William.; Johnson, John L.; Goldberg, Stefan.; Padayatchi, Nesri.; Duran, Paula.; Engle, Melissa.; Muzanye, Grace.; Mugerwa, Roy D.; Sturm, Adriaan Willem.
Development of new treatments for tuberculosis is hampered by the lack of an accurate surrogate end point and the high degree of efficacy of current 6-month regimens. Sputum culture status after 2 months of therapy, a binary test, is widely used for phase IIB trials but has only moderate accuracy for predicting failure/relapse (12) and requires large sample sizes (4, 8). Changes in the number of colonies found in dilutions of sputum applied to solid medium is an end point that has been used to assess activities of single drugs and doses in phase IIA (early-bactericidal-activity) studies (10) and has also been suggested as an end point for phase IIB trials (15). Though promising, quantitative culture on solid medium involves prolonged sputum collections and intensive laboratory techniques and has been difficult to standardize at multiple sites. Time to detection in broth culture (TTD) is a potential end point that has a good correlation with quantitative culture on solid medium (11, 13). An initial small study had suggested a correlation between a shorter time to detection (an indication of higher numbers of viable bacilli) and poor treatment outcomes (9). In this study, TTD was evaluated as a marker of regimen potency. Preliminary results have been reported elsewhere (16).
Substitution of Moxifloxacin for Isoniazid during intensive phase treatment of Pulmonary Tuberculosis.
(American Thoracic Society., 2009) Dorman, Susan E.; Johnson, John L.; Goldberg, Stefan.; Muzanye, Grace.; Padayatchi, Nesri.; Bozeman, Lorna.; Heilig, Charles M.; Bernardo, John.; Choudhri, Shurjeel.; Grosset, Jacques H.; Guy, Elizabeth.; Guyadeen, Priya.; Leus, Maria Corazon.; Maltas, Gina.; Menzies, Dick.; Nuermberger, Eric L.; Villarino, Margarita.; Vernon, Andrew.; Chaisson, Richard E.
Rationale: Moxifloxacin has potent activity against Mycobacterium tuberculosis in vitro and in a mouse model of antituberculosis (TB) chemotherapy, but data regarding its activity in humans are limited. Objectives: Our objective was to compare the antimicrobial activity and safety of moxifloxacin versus isoniazid during the first 8 weeks of combination therapy for pulmonary TB. Methods: Adults with sputum smear–positive pulmonary TB were randomly assigned to receive either moxifloxacin 400 mg plus isoniazid placebo, or isoniazid 300 mg plus moxifloxacin placebo, administered 5 days/week for 8 weeks, in addition to rifampin, pyrazinamide, and ethambutol. All doses were directly observed. Sputum was collected for culture every 2 weeks. The primary outcome was negative sputum culture at completion of 8 weeks of treatment. Measurements and Main Results: Of 433 participants enrolled, 328 were eligible for the primary efficacy analysis. Of these, 35 (11%) were HIV positive, 248 (76%) had cavitation on baseline chest radiograph, and 213 (65%) were enrolled at African sites. Negative cultures at Week 8 were observed in 90/164 (54.9%) participants in the isoniazid arm, and 99/164 (60.4%) in the moxifloxacin arm (P=0.37). In multivariate analysis, cavitation and enrollment at an African site were associated with lower likelihood of Week-8 culture negativity. The proportion of participants who discontinued assigned treatment was 31/214 (14.5%) for the moxifloxacin group versus 22/205 (10.7%) for the isoniazid group (RR, 1.35; 95% CI, 0.81, 2.25).Conclusions: Substitution of moxifloxacin for isoniazid resulted in a small but statistically nonsignificant increase in Week-8 culture negativity.