Next-generation fluoroquinolones may be effective against XDR-TB

Later-generation fluoroquinolones significantly improved outcomes in patients with extensively drug-resistant tuberculosis, according to results of a recent meta-analysis.

Despite the severity and prevalence of extensively drug-resistant tuberculosis (XDR-TB), it has only been examined in small, observational studies, according to researchers from several sites in Boston who conducted the analysis.

Results of 13 studies involving 560 patients were examined. All patients underwent at least 12 months of treatment after culture conversion. The percentage of patients who received later-generation fluoroquinolones ranged from 0% to 91.5%.

Overall, 43.7% of patients achieved a favorable outcome, defined as either cured or having completing the end of their treatment regimen. Specifically, nine studies followed WHO guidelines of at least five negative consecutive cultures during the past 12 months of treatment. Other studies required three negative cultures, one negative culture and treatment completion, or simply treatment completion.

The studies in which more patients received later-generation fluoroquinolones achieved significantly more favorable outcomes (P=.012). The researchers calculated that a cohort in which all patients received later-generation fluoroquinolones would have a 40% increase in favorable outcomes.

The success rate and the mortality rate, which was 20.8%, failed to compare favorably to such rates for multidrug-resistant TB. These findings further corroborate the higher lethality of XDR-TB as opposed to even MDR-TB, according to the researchers.

“When XDR-TB does occur, testing for resistance to later-generation fluoroquinolones, systematic report of treatment interventions and outcomes, treating with a later-generation fluoroqinonlone, and pooling of smaller cohorts are needed to strengthen the evidence base for treatment of this virulent form of the disease,” the researchers wrote.

PERSPECTIVE

The favorable outcome in the study by Jacobson and colleagues (43.7%, 95% CI, 32.8%-54.5%) is much less than the approximately 60% obtained in some other systematic reviews and meta-analyses carried out in MDR-TB patients. However, like in previous studies, Jacobson and colleagues showed that the rate of favorable outcomes varied thoroughly among the different studies, with some of them where this rate is higher than 60%. Interestingly, random effects meta-analysis and meta-regression showed that studies in which a higher proportion of patients received a later-generation fluoroquinolones reported a higher proportion of favorable treatment outcomes (P<.012). With each 10% increase in the proportion of patients receiving a later-generation fluoroquinolone, a 4% increase in the proportion of those with favorable outcomes was observed. Then, for those studies in which at least 50% of patients received a later-generation fluoroquinolone, the weighted proportion of favorable outcomes was 59.3%; on the contrary, in those studies in which less than 50% of the patients received a later-generation fluoroquinolone, the weighted proportion of favorable outcomes was only 30.6%.

From this and other information in the study, we can conclude:

As it was supposed, the prognosis of the XDR-TB patients is unfavorable, much worse than that of the MDR-TB patients. However, the good outcome treatment achieved in some of the articles analyzed in the meta-analysis gives the evidence that, with good support, the outcome can be improved.
This study gives good evidence that later-generation fluoroquinolones must be used systematically in the treatment of XDR-TB. In this way, not only moxifloxacin should be considered, but also high-dose levofloxacin.
We should begin using the laboratory drug susceptibility test on later-generation fluoroquinolones to better determine in which patients these drugs could work.
This is new evidence that the current definition of XDR-TB should be revised to include the resistance to all the first line drugs, all the second line injectable drugs and all fluoroquinolones. With this pattern of resistance the prognosis is clearly worse than in MDR-TB patients.
More evidence is necessary to analyze better the role of linezolid and surgery in the treatment of the XDR-TB patients.

Jose A. Caminero, MD
Pneumology Department, General Hospital of Gran Canaria MDR-TB Unit Coordinator. International Union against Tuberculosis and Lung Disease

Jacobson KR. Clin Infect Dis. 2010;51:6-14.