Ketek is a ketolide, a new class of antibiotics structurally related to the macrolides. It has a bactericidal effect against the atypical pathogens Chlamydophila pneumoniae and Mycoplasma pneumoniae, and for that reason the researchers decided to study its potential role in acute asthma attacks, according to a report in the April 13 New England Journal of Medicine.
Ketek does not have FDA approval for asthma, but it was approved in April 2004 for community-acquired pneumonia, acute exacerbations of chronic bronchitis, and acute bacterial sinusitis in adults.
In the investigation, known as the TELICAST (Telithromycin, Chlamydophila, and Asthma) trial, 278 adults were enrolled within 24 hours of an acute exacerbation of asthma requiring short-term medical care. The patients were randomly assigned to 10 days of oral treatment with Ketek (800 mg daily) or placebo, in addition to usual care, reported Sebastian Johnston, M.D., Ph.D., of Imperial College London, and a multinational team of colleagues.
The two primary outcomes were split, Dr Johnston said. Asthma symptoms were significantly reduced among patients receiving Ketek compared with those given a placebo, whereas antibiotic therapy had no significant effect on the patients' morning measures of peak expiratory flow.
Mean (Â± SD) scores on a test of asthma symptoms (zero denoting no symptoms and six denoting severe symptoms) were 3.0Â±1.4 at baseline and 1.7Â±1.1 at the end of treatment for the Ketek group compared with 2.8Â±1.3 at baseline and 2.0Â±1.0 at the end of treatment for the placebo group.
The mean decrease in symptom scores during the treatment period was 1.3 for Ketek and 1.0 for placebo. This reduction was equal to a 40.4% reduction in symptoms for the Ketek group vs. a 26.5% reduction for the placebo group (mean difference, -13.9 percentage points; 95% CI -23.4 to -4.3 P=0.005), the researchers said.
Later analysis of the time until patients had a 50% reduction in symptoms found a significant three-day improvement for the Ketek group (five days versus eight days, P=0.03), according to the investigators.
Ketek treatment had no effect on the patients' own measurements of morning peak expiratory flow. However, a treatment benefit from baseline to the end of treatment was observed for four in-clinic assessments of pulmonary function: FEV1, peak expiratory flow (in clinic), FVC, and FEF25-75.
The rate of adverse effects was low and was similar to that of the placebo arm, with the exception of nausea, which was more common among the Ketek patients, the researchers reported.
Although most acute asthma attacks are associated with viral infections, the researchers found that altogether 61% of the patients had evidence of infection with two atypical pulmonary pathogens, specifically C. pneumoniae, M. pneumoniae, or both.
The role of these organisms in the pathogenesis of asthma remains controversial, Dr. Johnston said, adding that he believes the presence of these bacteria might increase the severity of asthma attacks. However, he added, interpretation of the study results with respect to these organisms is problematic, mainly because of the lack of accurate standardized laboratory tests to diagnose infection.
It was also impossible to compare the differences observed in this study with corticosteroid treatment, the investigators said. "Although a course of oral corticosteroids is standard treatment practice, it is remarkable that to our knowledge, there are no published studies comparing oral corticosteroids with placebo in the treatment of exacerbations of asthma," they wrote.
As for safety, a recent report highlighted three cases of severe liver injury among patients treated with Ketek, the researchers noted, adding that their study was too small to give reliable information about these rare adverse events.
However, they said, extensive safety data in the FDA's 2004 safety assessment came from controlled studies of more than 24,000 patients. The researchers said "the FDA is continuing to improve its understanding of the frequency of liver-related adverse events reported for approved antibiotics, including Ketek."
"If the significantly faster improvement in reduction of clinical symptoms with Ketek is confirmed by further study, it would be of clinical significance," Dr. Johnston said.
However, he said that although this study provides evidence of the role of treatment with a specific antibiotic, it does not provide clinical guidance. Additional studies are required to further define the patient populations most likely to benefit and to elucidate the mechanisms of action in these and in other related antibiotics, he concluded.
In an accompanying editorial, FrÃ©dÃ©ric Little, M.D., of the Boston University School of Medicine wrote that despite extensive pre-approval data in which hepatotoxic effects were no more common with Ketek than with several other oral antibiotics, this report should prompt clinicians to assess carefully the role of the drug for acute asthma.
"I agree with the TELICAST authors' statement that the results fall short of providing a basis for definitive clinical directive on the use of antibiotics in acute exacerbations of asthma," Dr. Little wrote.
Addressing the drug's role in atypical infections, Dr. Little wrote that Ketek is active against multi-drug-resistant isolates of Streptococcus pneumoniae, and this activity against atypical pathogens is of direct relevance to a central issue of the TELICAST study, namely the role of atypical infections. It was striking, he said, that nearly two-thirds of patients in the study met the criteria for infection, primarily on the basis of their antibody status.
However, he continued, the improvement in FEV1 during the treatment period in the Ketek group was the same whether the patients met the criteria for infection or not. The data clearly show a benefit that was not attributable solely to an antibiotic effect, he said, or at least to atypical pathogens. "It seems," he suggested, that a nonantibiotic effect was at play."
"The study's implications are provocative but not directive, he wrote. "It clearly establishes the foundation for additional direct examination of the therapeutic opportunity in asthma. It is time for further study, not for treatment."
- Reviewed by Robert Jasmer, MD Assistant Professor of Medicine, University of California, San Francisco
New England Journal of MedicineSource Reference: Sebastian L. Johnston, et al, "The Effect of Telithromycin in Acute Exacerbations of Asthma," New England Journal of Medicine 2006;354;15: 1589-1600.
New England Journal of MedicineSource Reference: FrÃ©dÃ©rick F. Little, "Treating Acute Asthma with Antibiotics-Not Quite Yet," New England Journal of Medicine 2006;354;15: 1632-1634.