Fluoroquinolone resistance worsens outcomes in MDR-TB

Nearly 10% of MDR-TB strains are extensively drug resistant (XDR), i.e., resistant to both fluoroquinolones and second-line injectable drugs, the researchers say.

For the new study, Dr. Dick Menzies from the Montreal Chest Institute and members of the Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB conducted a patient-level data analysis to explore the treatment outcomes for 6,724 MDR-TB patients.

The researchers stratified patients according to whether their infecting strains had additional resistance to either fluoroquinolones or second-line injectable drugs or both.

Most patients (70%) had been previously treated for TB, and 11% were infected with HIV, according to an October 25 online paper in the European Respiratory Journal.

Nearly two-thirds of patients (62%) were treated successfully. In 7% of cases, treatment failed or the patient relapsed. In 9%, patients died, and 17% were lost to follow-up.

Treatment success rates declined as drug resistance patterns advanced, the authors note.

After adjustment for clinical characteristics and clustering by centers, success rates were significantly lower in all three groups with additional resistance (MDR plus fluoroquinolone resistance, MDR plus second-line injectable drug resistance, and XDR-TB) than in patients with MDR-TB susceptible to either group of drugs.

XDR-TB patients who received six or more drugs likely to be effective in the intensive phase and MDR-TB "only" patients who received four drugs had higher likelihoods of treatment success than patients receiving fewer drugs.

In the continuation phase, receipt of four drugs by XDR-TB patients and three drugs by MDR-TB patients without fluoroquinolone resistance was associated with the highest odds of treatment success.

For patients without additional fluoroquinolone resistance, an intensive phase lasting 6.6 to 9.0 months (with a total duration of treatment between 20.1 and 25.0 months) brought the highest odds of treatment success.

"Current treatment guidelines for MDR-TB recommend the use of pyrazinamide along with at least four second-line TB medications likely to be effective given in vitro susceptibility results and prior history," the researchers note. "A typical regimen can be created using a fluoroquinolone, a second-line aminoglycoside or capreomycin, ethionamide/prothionamide, and cycloserine/terizidone or p-aminosalicylic acid (PAS)."

Based on their results, they add, XDR-TB patients should receive a regimen of similar duration but including more drugs.

Still, they acknowledge the limitations of an observational study, noting, "Randomized controlled trials are needed to optimize treatment regimens, including ancillary measures such as surgery."

Dr. Menzies did not respond to a request for comments.

Dr. Dennis Falzon from the World Health Organization, Geneva, Switzerland, who was not involved in the study, told Reuters Health by email, "I think it is important that we underline with this article firstly the importance of preventing the emergence of drug-resistance in TB patients. With the development of multidrug resistance in particular the likelihood of a patient having a successful outcome, even after many months of treatment with a pretty toxic cocktail of drugs, is reduced very much in comparison to the patient with non-resistant TB."

"Secondly, when patients with MDR develop further resistance to second-line injectables and fluoroquinolones, the most important drugs in a second line regimen, their chances of success are reduced further and risk of death increases," Dr. Falzon said.

Very important, he said, is "better access of TB patients in resource-constrained settings to laboratories which can perform drug susceptibility testing reliably in order to detect resistance promptly."

In addition, "New drugs which can be delivered in effective regimens are urgently needed to improve the outcomes of patients with the forms of drug resistance described in this study."

"The World Health Assembly in 2009 urged countries to provide for universal access to care for drug-resistant TB by 2015," Dr. Falzon added. "In 2011, out of more than 600,000 prevalent MDR-TB cases that the World Health Organization estimated to occur at any one time in the world, only about 60,000 cases were reported to have been enrolled on treatment by the countries."

He provided links to sites with more details: http://bit.ly/RFDCso (a Powerpoint deck), http://bit.ly/RFDCso and http://bit.ly/RFDCso

As for the authors of the report, they warn: "The addition of second-line drugs from the existent armamentarium of TB medications will only make a very modest difference once fluoroquinolones and second-line injectable agents are no longer an option."

SOURCE: http://bit.ly/TurHtJ

Eur Respir J 2012.

Source: Medscape Today