What is a ketolide and how does it work?
Ketek, with the active ingredient telithromycin, is the first and only ketolide antibiotic to have been approved for use in the United States. Ketolides are a subclass of macrolide antibiotics, but feature a key chemical modification that distinguishes them. Specifically, ketolides are structurally altered semisynthetic derivatives of the macrolide erythromycin A.
The fundamental mechanism of action for ketolides involves inhibiting bacterial protein synthesis. This is achieved by binding to the 50S ribosomal subunit of bacteria, an essential cellular component for protein production. The precise location of this binding is at two different domains of the 23S ribosomal RNA, domains II and V. This dual binding enhances the drug's activity and affinity for the ribosome compared to traditional macrolides, making it effective against some macrolide-resistant bacteria. This was a major driver for the development of ketolides in an era of increasing antibiotic resistance.
Ketolide vs. Macrolide: A comparison
While closely related, ketolides differ from macrolides both structurally and functionally. The core structure of macrolides is a large lactone ring, typically with one or more sugar moieties attached. Ketolides, on the other hand, replace a sugar group on the lactone ring with a 3-keto functional group. This modification provides several key advantages that were intended to improve upon the traditional macrolide class:
- Enhanced Activity: Ketolides have a higher binding affinity to the bacterial 50S ribosomal subunit, giving them more potent inhibitory effects.
- Overcoming Resistance: By binding to two sites on the ribosome instead of one, ketolides can overcome resistance mechanisms developed by some bacteria against older macrolides.
- Acid Stability: The structural change at the 3-position also increases the molecule's stability in an acidic environment, like the stomach.
Comparison Table: Ketolide vs. Macrolide
| Feature | Ketolide (Telithromycin) | Macrolide (e.g., Erythromycin) |
|---|---|---|
| Structural Basis | Semisynthetic erythromycin derivative with a 3-keto group | Natural or semisynthetic 14- or 16-membered lactone ring |
| Ribosomal Binding | Binds strongly to two domains (II & V) of the 50S subunit | Binds primarily to one domain (V) of the 50S subunit |
| Affinity | Significantly higher binding affinity | Lower binding affinity relative to ketolides |
| Bacterial Resistance | Designed to be active against macrolide-resistant strains | Resistance, especially in S. pneumoniae, is a growing issue |
| Clinical Efficacy | Historically used for respiratory tract infections | Wide range of uses, but resistance limits use for some infections |
| Safety Profile | Significant safety concerns, including liver and nerve toxicity | Generally well-tolerated, but can cause gastrointestinal side effects |
Why was Ketek withdrawn from the U.S. market?
Despite the initial promise of a new antibiotic class, Ketek's journey in the U.S. market was fraught with controversy and ultimately ended with its withdrawal. The primary reasons for this were significant safety issues that emerged after its approval by the U.S. Food and Drug Administration (FDA) in 2004.
- Severe Hepatotoxicity: Reports of serious liver injury, including acute liver failure and deaths, began to surface. An article in Annals of Internal Medicine in 2006 highlighted severe hepatotoxicity cases linked to telithromycin use.
- Myasthenia Gravis Exacerbation: A severe and potentially fatal risk was the exacerbation of myasthenia gravis, a neuromuscular disease. This led to a black box warning, the FDA's strongest safety warning, advising against its use in patients with this condition.
- Visual Disturbances and Fainting: Patients also reported visual issues, such as blurred or double vision and difficulty focusing, along with episodes of syncope (fainting).
- Clinical Trial Fraud: Adding to the drug's issues, a key clinical trial used for its approval was found to be tainted by research misconduct and fraud, further eroding confidence in its safety data.
In response to these issues, the FDA removed the indications for acute bacterial sinusitis and acute exacerbations of chronic bronchitis in 2007. Eventually, the manufacturer, Sanofi-Aventis, stopped active sales in the U.S..
Conclusion
Ketek (telithromycin) is a ketolide antibiotic, a class of drugs derived from macrolides that were developed to combat antibiotic resistance. Its distinguishing feature was its enhanced ribosomal binding and structural modification to increase acid stability and overcome macrolide resistance mechanisms. However, the story of Ketek serves as a cautionary tale in drug development and regulation. Despite its innovative mechanism, the drug's association with severe adverse effects, particularly liver failure and myasthenia gravis exacerbation, and the discovery of fraud in its clinical trials, led to its withdrawal from the U.S. market. The case of Ketek highlights the critical importance of rigorous post-market surveillance and transparency in the drug approval process. Today, clinicians rely on alternative, safer antibiotic options for treating respiratory infections. For more on the regulatory actions surrounding this drug, see the FDA's official page.
