1. Patients with pulmonary tuberculosis receiving a shortened, 4-month treatment regimen with gatifloxacin were more likely to experience an unfavourable outcome at 24 months than patients receiving the standard 6-month regimen.
2. Patients in the experimental group were less likely to have treatment failure but were more likely to have a recurrence of tuberculosis than those receiving standard therapy,
Evidence Rating Level: 1 (Excellent)
Study Rundown: Although the incidence and mortality rates of tuberculosis peaked a decade ago, the disease remains a public health challenge. Millions of individuals are still affected each year and the incidence of multi-drug resistant tuberculosis (MDR-TB) is rising, as a result of failure to complete treatment course or inappropriate use of drug therapies. The standard treatment of tuberculosis requires 6 months of multiple antimicrobial medications. Fluoroquinolones have shown promise in shortening the duration of treatment and have been investigated in attempts to improve treatment adherence.
This phase 3 trial randomized patients to a 4-month treatment regimen with the fluoroquinolone, gatifloxacin, or the standard 6-month regimen using ethambutol during the initial phase of management. The study was unable to show noninferiority of a 4-month regimen with gatifloxacin compared to the standard 6-month regimen. It is possible that drug levels were insufficient to demonstrate the true effect of the experimental regimen since a standard dose of gatifloxacin was given without adjustment according to body weight. Overall, the use of a composite outcome that included outcomes of varying severity made the findings difficult to interpret. Although promising in phase 2 trials, shortened fluoroquinolone-containing treatment regimens have failed to show noninferiority compared to the standard regimen thus far.
Click to read the study in NEJM
Click to read an accompanying editorial in NEJM
Relevant Reading: Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis
In-Depth [randomized controlled trial]: This phase 3, open-label, randomized controlled trial included 1836 patients with smear-positive, rifampin-sensitive pulmonary tuberculosis in 5 countries in sub-Saharan Africa. Patients were randomized to a standard 6-month regimen including a 2-month intensive treatment phase with ethambutol, or the experimental 4-month regimen substituting 400 mg gatifloxacin per day for ethambutol during the intensive phase and continued for the duration of treatment. The primary outcome was a composite of treatment failure, recurrence, death, or study dropout, measured at 24 months after the end of treatment.
Modified intention-to-treat analysis of the primary outcome in 1356 patients showed a risk difference of 3.5 percentage points (experimental group minus control group; 95% CI, -0.7 to 7.7). The per-protocol analysis demonstrated an adjusted difference of 5.5 percentage points (experimental group minus control group; 95% CI, 1.6 to 9.4). Treatment failure occurred more frequently in the control group compared to the experimental group (2.4% vs. 1.7%); however, more patients in the experimental group had a recurrence of tuberculosis (14.6% vs. 7.1%).
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