Ketolide antibiotics
Ketolide antibiotics are semisynthetic derivatives of erythromycin A and belong to the macrolide class, primarily functioning as inhibitors of bacterial protein synthesis. Their mechanism involves tightly binding to specific sites on the 50S ribosomal subunit, enhancing their effectiveness against bacteria compared to traditional macrolides. This increased binding affinity makes ketolides a potential solution to the growing problem of antibiotic resistance, especially in treating respiratory tract infections caused by both susceptible and resistant strains of gram-positive and certain gram-negative bacteria.
The most well-known ketolide is telithromycin, which is approved for treating mild-to-moderate community-acquired pneumonia. However, it carries a significant black-box warning against use in patients with myasthenia gravis due to the risk of severe respiratory complications. As antibiotic resistance continues to rise, ketolides offer a promising alternative for managing infections that do not respond to conventional treatment, although judicious use is advised to mitigate further resistance development. Overall, ketolides represent an important advancement in the fight against resistant bacterial infections.
Ketolide antibiotics
Definition
Ketolide antibiotics are semisynthetic derivates of erythromycin A and members of the macrolide class of antibiotics. Broadly, ketolides are inhibitors of bacterial protein synthesis.
Mechanism of Action
The inhibition of bacterial protein synthesis by ketolides is produced though reversible binding close to the peptidyl transferase site of the 50S ribosomal subunit, specifically the II and V domains of the 23S rRNA (ribosomal ribonucleic acid). The binding affinity is reported to be ten to one hundred times greater than that seen with erythromycin. One of the most notable chemical structural changes between macrolides and ketolides is the absence of an L-cladinose from the 3 position of the erythonolide ring, which functionally is important in increasing the compound’s acid stability. Additionally, in its place, a keto-functional group is formed. Like macrolides, ketolides exhibit bacteriostatic activity, although bactericidal activity has been achieved at higher levels. Ketolides that are being investigated, including cethromycin (ABT-773), utilize various other chemical modifications.
Susceptible and Nonsusceptible Organisms
Ketolides were introduced as an alternative to macrolides in the treatment of respiratory tract infections. The increasing use of macrolides (including azithromycin, erythromycin, and clarithromycin) and the subsequent resistance to macrolide antibiotics, coupled with increasing resistance to other antibiotics such as beta-lactams, has highlighted the need for new antibiotics to treat these resistant strains.
Common bacteria responsible for respiratory infections against which ketolides are active include nonresistant and resistant gram-positive aerobic bacteria (Streptococcus pneumoniae, S. pyogenes, Viridans group streptococci, Staphylococcus aureus, and coagulase-negative staphylococci). Gram-negative bacteria against which ketolides are active include Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumoniae, Mycoplasma pneumoniae, Neisseria species, Bordetella pertussis, and Ureaplasma urealyticum. Organisms against which ketolides are not active include Pseudomonas aeruginosa, Enterobacteriacae, and Clostridium difficile.
Clinical Significance
The only ketolide approved by the U.S. Food and Drug Administration is telithromycin (Ketek). Telithromycin is approved for the treatment of mild-to-moderate community acquired pneumonia caused by susceptible strains of S. pneumoniae (including resistant strains), H. influenzae, C. pneumoniae, M. catarrhalis, and M. pneumoniae. Telithromycin carries a black-box warning that it should not be used in persons with myasthenia gravis because of reports of fatal and life-threatening respiratory failure. To slow the growth of resistant microorganisms, ketolides should be reserved for persons in whom susceptible strains are known or presumed. Other ketolide medications are in developemnt.
Impact
In an era of increasing antibiotic use and increasing patterns of resistance, antibiotics with the ability to target microorganisms that are resistant to older antibiotics are critical. Respiratory tract infections are a time and health burden on both patients and the medical system. Antibiotics such as ketolides provide an additional tool for practitioners to combat resistant bacteria.
Bibliography
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