Ketolides in the treatment of respiratory infections

The ketolides are a new class of macrolides specifically designed to combat respiratory tract pathogens that have acquired resistance to macrolides. The ketolides are semi-synthetic derivatives of the 14-membered macrolide erythromycin A. There are currently two ketolides in the late stages of clinical development in the US (telithromycin [HMR-364, Kelek; Aventis] and ABT-773 [Abbot Laboratories]), as well as newer compounds in earlier stages of testing. Ketolides have a mechanism of action very similar to that of erythromycin A. They potently inhibit protein synthesis by interacting close to the peptidyl transferase site of the bacterial 50S ribosomal subunit. Ketolides bind to ribosomes with higher affinity than macrolides. The ketolides exhibit good activity against Gram-positive and some Gram-negative aerobes and have are active against macrolide-resistant Streptococcus species, including most mef A and erm B strains of Streptococcus pneumoniae. Ketolides have pharmacokinetics which allow once-daily dosing and extensive tissue distribution with very high uptake into respiratory tissues and fluids relative to serum. Evidence suggests the ketolides are primarily metabolised by the cytochrome P450 (CYP) enzyme system in the liver and that elimination is a combination of biliary, hepatic and urinary excretion. Clinical trial data are only available for telithromycin and have focused on respiratory tract infections (RTIs) including community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB), sinusitis and streptococcal pharyngitis. Bacteriological and clinical cure rates have been similar to comparators. Ketolides have similar safety profiles to the newer macrolides. In summary, early clinical trials support the clinical efficacy of the ketolides in common RTIs, including activity against macrolide-resistant pathogens.     

Ketolides in the treatment of respiratory infections

The ketolides are a new class of macrolides specifically designed to combat respiratory tract pathogens that have acquired resistance to macrolides. The ketolides are semi-synthetic derivatives of the 14-membered macrolide erythromycin A. There are currently two ketolides in the late stages of clinical development in the US (telithromycin [HMR-364^®, Kelek^®; Aventis] and ABT-773 [Abbot Laboratories]), as well as newer compounds in earlier stages of testing. Ketolides have a mechanism of action very similar to that of erythromycin A. They potently inhibit protein synthesis by interacting close to the peptidyl transferase site of the bacterial 50S ribosomal subunit. Ketolides bind to ribosomes with higher affinity than macrolides. The ketolides exhibit good activity against Gram-positive and some Gram-negative aerobes and have are active against macrolide-resistant Streptococcus species, including most mefA and ermB strains of Streptococcus pneumoniae. Ketolides have pharmacokinetics which allow once-daily dosing and extensive tissue distribution with very high uptake into respiratory tissues and fluids relative to serum. Evidence suggests the ketolides are primarily metabolised by the cytochrome P450 (CYP) enzyme system in the liver and that elimination is a combination of biliary, hepatic and urinary excretion. Clinical trial data are only available for telithromycin and have focused on respiratory tract infections (RTIs) including community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB), sinusitis and streptococcal pharyngitis. Bacteriological and clinical cure rates have been similar to comparators. Ketolides have similar safety profiles to the newer macrolides. In summary, early clinical trials support the clinical efficacy of the ketolides in common RTIs, including activity against macrolide-resistant pathogens.     

Review of macrolides and ketolides: focus on respiratory tract infections

The first macrolide, erythromycin A, demonstrated broad-spectrum antimicrobial activity and was used primarily for respiratory and skin and soft tissue infections. Newer 14-, 15- and 16-membered ring macrolides such as clarithromycin and the azalide, azithromycin, have been developed to address the limitations of erythromycin. The main structural component of the macrolides is a large lactone ring that varies in size from 12 to 16 atoms. A new group of 14-membered macrolides known as the ketolides have recently been developed which have a 3-keto in place of the L-cladinose moiety. Macrolides reversibly bind to the 23S rRNA and thus, inhibit protein synthesis by blocking elongation. The ketolides have also been reported to bind to 23S rRNA and their mechanism of action is similar to that of macrolides. Macrolide resistance mechanisms include target site alteration, alteration in antibiotic transport and modification of the antibiotic. The macrolides and ketolides exhibit good activity against gram-positive aerobes and some gram-negative aerobes. Ketolides have excellent activity versus macrolide-resistant Streptococcus spp. Including mefA and ermB producing Streptococcus pneumoniae. The newer macrolides, such as azithromycin and clarithromycin, and the ketolides exhibit greater activity against Haemophilus influenzae than erythromycin. The bioavailability of macrolides ranges from 25 to 85%, with corresponding serum concentrations ranging from 0.4 to 12 mg/L and area under the concentration-time curves from 3 to 115 mg/L x h. Half-lives range from short for erythromycin to medium for clarithromycin, roxithromycin and ketolides, to very long for dirithromycin and azithromycin. All of these agents display large volumes of distribution with excellent uptake into respiratory tissues and fluids relative to serum. The majority of the agents are hepatically metabolised and excretion in the urine is limited, with the exception of clarithromycin. Clinical trials involving the macrolides are available for various respiratory infections. In general, macrolides are the preferred treatment for community-acquired pneumonia and alternative treatment for other respiratory infections. These agents are frequently used in patients with penicillin allergies. The macrolides are well-tolerated agents. Macrolides are divided into 3 groups for likely occurrence of drug-drug interactions: group 1 (e.g. erythromycin) are frequently involved, group 2 (e.g. clarithromycin, roxithromycin) are less commonly involved, whereas drug interactions have not been described for group 3 (e.g. azithromycin, dirithromycin). Few pharmacoeconomic studies involving macrolides are presently available. The ketolides are being developed in an attempt to address the increasingly prevalent problems of macrolide-resistant and multiresistant organisms.     

Ketolides: an emerging treatment for macrolide-resistant respiratory infections,focusing on S. pneumoniae

Resistance to antibiotics in community acquired respiratory infections is increasing worldwide. Resistance to the macrolides can be class-specific, as in efflux or ribosomal mutations, or, in the case of erythromycin ribosomal methylase (erm)-mediated resistance, may generate cross-resistance to other related classes. The ketolides are a new subclass of macrolides specifically designed to combat macrolide-resistant respiratory pathogens. X-ray crystallography indicates that ketolides bind to a secondary region in domain II of the 23S rRNA subunit, resulting in an improved structure–activity relationship. Telithromycin and cethromycin (formerly ABT-773) are the two most clinically advanced ketolides, exhibiting greater activity towards both typical and atypical respiratory pathogens. As a subclass of macrolides, ketolides demonstrate potent activity against most macrolide-resistant streptococci, including ermB- and macrolide efflux (mef)A-positive Streptococcus pneumoniae. Their pharmacokinetics display a long half-life as well as extensive tissue distribution and uptake into respiratory tissues and fluids, allowing for once-daily dosing. Clinical trials focusing on respiratory infections indicate bacteriological and clinical cure rates similar to comparators, even in patients infected with macrolide-resistant strains.     

Ketolides: an emerging treatment for macrolide-resistant respiratory infections, focusing on S. pneumoniae

Resistance to antibiotics in community acquired respiratory infections is increasing worldwide. Resistance to the macrolides can be class-specific, as in efflux or ribosomal mutations, or, in the case of erythromycin ribosomal methylase (erm)-mediated resistance, may generate cross-resistance to other related classes. The ketolides are a new subclass of macrolides specifically designed to combat macrolide-resistant respiratory pathogens. X-ray crystallography indicates that ketolides bind to a secondary region in domain II of the 23S rRNA subunit, resulting in an improved structure-activity relationship. Telithromycin and cethromycin (formerly ABT-773) are the two most clinically advanced ketolides, exhibiting greater activity towards both typical and atypical respiratory pathogens. As a subclass of macrolides, ketolides demonstrate potent activity against most macrolide-resistant streptococci, including ermB- and macrolide efflux (mef)A-positive Streptococcus pneumoniae. Their pharmacokinetics display a long half-life as well as extensive tissue distribution and uptake into respiratory tissues and fluids, allowing for once-daily dosing. Clinical trials focusing on respiratory infections indicate bacteriological and clinical cure rates similar to comparators, even in patients infected with macrolide-resistant strains.     

Ketolides: the future of the macrolides?

The prevalence of antibiotic resistance in bacterial pathogens associated with community-acquired respiratory tract infections is increasing. Ketolides, semi-synthetic derivatives of erythromycin, overcome the macrolide resistance mechanisms found in Streptococcus pneumoniae and Streptococcus pyogenes, two key pathogens. They also have improved potency and longer post-antibiotic effects, while maintaining the antibacterial spectrum of the macrolide class. The new ketolides cethromycin (ABT-773) and telithromycin have overall antibacterial properties that suggest they will be clinically useful new antibiotics and are undergoing clinical development and regulatory review.     

Recent developments on ketolides and macrolides

Recent semi-synthetic studies of erythromycin A culminated in the discovery of two ketolide drug candidates, HMR-3647 and ABT-773, for the treatment of community-acquired bacterial infections caused by both macrolide- and beta-lactam-susceptible and -resistant S. pneumoniae, gram negative bacteria, and intracellular atypical pathogens. The discovery of ketolides has rekindled interest in macrolides, and recent efforts have also led to a novel class of 4'-carbamates with activity against macrolide-resistant organisms. This review is an account of recent developments on ketolides and macrolides in terms of both chemistry and antibacterial activity.     

Ketolides: pharmacological profile and rational positioning in the treatment of respiratory tract infections

Ketolides differ from macrolides by removal of the 3-O-cladinose (replaced by a keto group), a 11,12- or 6,11-cyclic moiety and a heteroaryl-alkyl side chain attached to the macrocyclic ring through a suitable linker. These modifications allow for anchoring at two distinct binding sites in the 23S rRNA (increasing activity against erythromycin-susceptible strains and maintaining activity towards Streptococcus pneumoniae resistant to erythromycin A by ribosomal methylation), and make ketolides less prone to induce methylase expression and less susceptible to efflux in S. pneumoniae. Combined with an advantageous pharmacokinetic profile (good oral bioavailability and penetration in the respiratory tract tissues and fluids; prolonged half-life allowing for once-a-day administration), these antimicrobial properties make ketolides an attractive alternative for the treatment of severe respiratory tract infections such as pneumonia in areas with significant resistance to conventional macrolides. For telithromycin (the only registered ketolide so far), pharmacodynamic considerations suggest optimal efficacy for isolates with minimum inhibitory concentration values < or = 0.25 mg/l (pharmacodynamic/pharmacokinetic breakpoint), calling for continuous and careful surveys of bacterial susceptibility. Postmarketing surveillance studies have evidenced rare, but severe, side effects (hepatotoxicity, respiratory failure in patients with myasthenia gravis, visual disturbance and QTc prolongation in combination with other drugs). On these bases, telithromycin indications have been recently restricted by the US FDA to community-acquired pneumonia, and caution in patients at risk has been advocated by the European authorities. Should these side effects be class related, they may hinder the development of other ketolides such as cethromycin (in Phase III, but on hold in the US) or EDP-420 (Phase II).     

Telithromycin: a brief review of a new ketolide antibiotic

Telithromycin (Ketek, Aventis) is a semisynthetic antibacterial agent belonging to a class of drugs called ketolides, which are a variation on the existing class of antibiotics known as macrolides (e.g., erythromycin), whose structure includes a 14-molecule ring. The FDA approved telithromycin for use as a treatment for upper respiratory tract infections in April of 2004. Its primary use is to treat community-acquired pneumonia and sinusitis. Telithromycin fulfills a role that has arisen due to the rise of microbial resistance to existing macrolides and appears to be effective against macrolide-resistant Streptococcus pneumoniae. The defining differentiating characteristic of the ketolides as opposed to other macrolides is the removal of the neutral sugar, L-cladinose from the 3 position of the macrolide ring and the subsequent oxidation of the 3-hydroxyl to a 3-keto functional group. Telithromycin seems to be an effective antibiotic in the treatment of a variety of skin infections, although double-blind trials have not proven this and currently no indication for treatment of skin infection is being sought from the FDA. Telithromycin also has excellent penetration into the female genial tract and could be useful for treating infections in this area.     

C-9 Alkenylidine bridged macrolides: WO2008061189

Ketolides, which represent the third generation of erythromycin A derivatives, were developed as a result of the need for new and potent antibacterial agents. This class of compounds has a significantly improved pharmacokinetic profile and, above all, shows activity against macrolide-resistant strains. When compared with other macrolides, ketolide structural differences are characterized by the removal of the 3-O-cladinose moiety and by a heteroaryl-alkyl side chain attached to the macrocycle by a flexible linker. The bridged bicyclic ketolides (BBK) are one of the three classes of ketolide; the present application from Enanta Pharmaceuticals, Inc. discloses a series of novel C-9 alkenylidine bridged macrolides belonging to BBK. These compounds are 3,6- and 6,11-bicyclolides, which have the alkenylidine second anchor portion attached to C-9 of the molecule.     

Molecular analytical evaluation of macrolide- and ketolide-resistant Streptococcus pneumoniae--mechanism of action of telithromycin and resistance to it

PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) is a worldwide epidemiologic survey for investigating drug susceptibility against major bacterial pathogens in respiratory tract infections, and that is also designed to identify the action mechanism of telithromycin (TEL), a ketolide antibacterial agent, on the resistant Streptococcus pneumoniae and the resistance mechanism for TEL on the TEL-resistant S. pneumoniae strain, in addition to determine macrolide/ketolide resistant S. pneumoniae activities of TEL using molecular analysis. TEL exerted the antibacterial action on the macrolide-resistant S. pneumoniae regardless maintaining the macrolide-resistant mechanism and exhibited the potent antibacterial activity against all of ermB gene-positive strains, mefA gene-positive strains and ribosome variants. This result was considered to reflect the fact that TEL did not induce resistance to ermB and had extremely low ability to select resistant strain by mutation. These actions of TEL were considered to be derived from its novel chemical structure and might be characteristics of ketolides not possessed by macrolides. In the survey of PROTEKT in 1999 to 2002, among 13,864 strains of S. pneumoniae isolated worldwide, ketolide-resistant strain (TEL MIC > or = 4 microg/ml) was observed in 10 strains (0.07%). MIC of these 10 strains was 4 or 8 microg/mL and all of these strains were ermB-positive strains. Based on this fact, potential involvement of adenine demethylase (ermB gene product) was considered in the background of development of ketolide-resistant S. pneumoniae.     

第三代大环内酯类抗生素的结构改造及合成方法

酮内酯类抗生素是具有大环内酯结构的红霉素衍生物。大量耐药病原菌的迅速出现使红霉素类半合成抗生素临床应用出现了挑战,也促使了针对耐药菌的第三代酮内酯类药物的研发并取得了丰硕的研究成果,其代表药物为泰利霉素和喹红霉素。本文综述了近年来对酮内酯类抗生素C-6位、C-5位糖环、三环类、C-11,12位及C-12位等处结构修饰方面的新进展,重点介绍了第三代酮内酯半合成抗生素合成的方法研究。     

Clinical impact of antibiotic resistance in respiratory tract infections

Streptococcus pneumoniae is the most common causative pathogen of community-acquired respiratory tract infections. In vitro evidence indicates that S. pneumoniae is increasingly resistant to commonly prescribed antimicrobial agents including the macrolides. The clinical relevance of resistance, however, has not been clearly established. This article reviews the risk factors influencing selection of resistant pneumococci, discusses endpoints used to assess the impact of resistance on clinical outcome, and proposes strategies to minimise the impact of resistance. Evidence demonstrating treatment failures due to macrolide-resistant S. pneumoniae is also reviewed. Increasing rates of resistance among S. pneumoniae present numerous clinical challenges, and require carefully selected treatment strategies to preserve antibacterial efficacy. Antibiotics with a low propensity for stimulating resistance should be chosen wherever possible.     

Multidrug-resistant Streptococcus pneumoniae infections: current and future therapeutic options

Antibacterial resistance in Streptococcus pneumoniae is increasing worldwide, affecting principally beta-lactams and macrolides (prevalence ranging between approximately 1% and 90% depending on the geographical area). Fluoroquinolone resistance has also started to emerge in countries with high level of antibacterial resistance and consumption. Of more concern, 40% of pneumococci display multi-drug resistant phenotypes, again with highly variable prevalence among countries. Infections caused by resistant pneumococci can still be treated using first-line antibacterials (beta-lactams), provided the dosage is optimised to cover less susceptible strains. Macrolides can no longer be used as monotherapy, but are combined with beta-lactams to cover intracellular bacteria. Ketolides could be an alternative, but toxicity issues have recently restricted the use of telithromycin in the US. The so-called respiratory fluoroquinolones offer the advantages of easy administration and a spectrum covering extracellular and intracellular pathogens. However, their broad spectrum raises questions regarding the global risk of resistance selection and their safety profile is far from optimal for wide use in the community. For multi-drug resistant pneumococci, ketolides and fluoroquinolones could be considered. A large number of drugs with activity against these multi-drug resistant strains (cephalosporins, carbapenems, glycopeptides, lipopeptides, ketolides, lincosamides, oxazolidinones, glycylcyclines, quinolones, deformylase inhibitors) are currently in development. Most of them are only new derivatives in existing classes, with improved intrinsic activity or lower susceptibility to resistance mechanisms. Except for the new fluoroquinolones, these agents are also primarily targeted towards methicillin-resistant Staphylococcus aureus infections; therefore, demonstration of their clinical efficacy in the management of pneumococcal infections is still awaited.     

Macrolide resistance from the ribosome perspective

Macrolides are important antibiotics used in treatment of respiratory tract infections in humans. Although some of these compounds have been in use for 50 years, it has not been until the last few years that their mechanism of action and the nature of ribosomal-based resistance could be more fully understood. With the advent of robust crystals of ribosomal 50S subunits, and structural resolution of macrolides and ketolides complexed to either Haloarcula marismortui or Deinococcus radiodurans 50S, the ability to dissect the binding modes and understand resistance at the level of the ribosome became possible. This review article compares the binding features of 14-, 15-, and 16-membered macrolides to that of ketolides telithromycin and ABT-773 as revealed at the atomistic level. Attempts to understand how modifications to 23S rRNA and/or mutations in ribosomal proteins L4 and L22 that have been found to confer resistance in Streptococcus pneumoniae, Streptococcus pyogenes, and Haemophilus influenzae are told from the perspective of the ribosome.     

Evaluation of the degree of susceptibility of Streptococcus pyogenes erythromycin-resistant strains to rokitamycin (a 16-membered macrolide) using the Epsilometer test

Routine hospital screening of the resistance of Streptococcus pyogenes to macrolides is usually done using the erythromycin, clarithromycin or azithromycin disk diffusion technique. When a strain is found to be resistant to one of these macrolides, it is generally assumed to be resistant to the whole class. However this approach gives only partial qualitative information because S. pyogenes strains with inducible and M phenotype resistance are still susceptible to 16-membered ring macrolides such as rokitamycin. Seventy-four erythromycin-resistant (22 inducible and 52 M phenotype) strains of S. pyogenes were tested for their susceptibility to rokitamycin and clindamycin (control) by means of the agar disk diffusion test and the results were compared with those obtained using the Epsilometer test, a quantitative technique for measuring bacterial susceptibility and minimal inhibitory concentrations (MIC). Epsilometer testing of erythromycin in comparison with rokitamycin is useful for measuring the real degree of susceptibility of macrolide-resistant strains quickly and simply. This is important because strains with the same disk diffusion diameter do not necessarily have the same MIC, but a scattered distribution of susceptibility.     

The emerging new generation of antibiotic: ketolides

The bacterial ribosome is a target for a variety of drug classes including macrolides. Macrolide antibiotics are primarily used for the treatment of respiratory tract infections. One of the most important features of the macrolide class is the excellent safety profile allowing the drug to be used broadly across all age groups. The emergence of macrolide resistance, especially in S. pneumoniae, threatens the long-term usefulness of macrolide antibiotics. The newly developed ketolide class, including telithromycin and ABT-773, evolved from the macrolide class and displays significant improvements over macrolides while maintaining safety profiles similar to macrolides. The key improvement in antimicrobial spectrum is the in vitro potency against macrolide resistant pathogens, especially S. pneumoniae. This review outlines the key improvements of ketolides over macrolides in terms of in vitro microbiology, as well as the pharmacokinetic and pharmacodynamic profiles and updates the current understanding of drug-ribosome interactions. The application of cutting-edge technology such as ribosome structure-based rational drug design and genetic engineering are also briefly discussed.     

The wobbly status of ketolides: where do we stand?

Ketolides are erythromycin A derivatives with a keto group replacing the cladinose sugar and an aryl-alkyl group attached to the lactone macrocycle. The aryl-alkyl extension broadens its antibacterial spectrum to include all pathogens responsible for community-acquired pneumonia (CAP): Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis as well as atypical pathogens (Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila). Ketolides have extensive tissue distribution, favorable pharmacokinetics (oral, once-a-day) and useful anti-inflammatory/immunomodulatory properties. Hence, they were considered attractive additions to established oral antibacterials (quinolones, β-lactams, second-generation macrolides) for mild-to-moderate CAP. The first ketolide to be approved, Sanofi-Aventis’ telithromycin (RU 66647, HMR 3647, Ketek®), had tainted clinical development, controversial FDA approval and subsequent restrictions due to rare, irreversible hepatotoxicity that included deaths. Three additional ketolides progressed to non-inferiority clinical trials vis-à-vis clarithromycin for CAP. Abbott’s cethromycin (ABT-773), acquired by Polymedix and subsequently by Advanced Life Sciences, completed Phase III trials, but its New Drug Application was denied by the FDA in 2009. Enanta’s modithromycin (EDP-420), originally codeveloped with Shionogi (S-013420) and subsequently by Shionogi alone, is currently in Phase II in Japan. Optimer’s solithromycin (OP-1068), acquired by Cempra (CEM-101), is currently in Phase III. Until this hepatotoxicity issue is resolved, ketolides are unlikely to replace established antibacterials for CAP, or lipoglycopeptides and oxazolidinones for gram-positive infections.     

Telithromycin: the first ketolide for the treatment of respiratory infections.

PURPOSE: The pharmacology, mechanisms of resistance, in vitro activity, clinical efficacy, pharmacokinetics, indications, adverse effects, dosage and administration, and place in therapy of telithromycin in the treatment of respiratory infections are reviewed. SUMMARY: Telithromycin is the first ketolide to be approved in the United States for use against common respiratory pathogens. The unique structure of telithromycin allows for enhanced binding to bacterial ribosomal RNA, thereby blocking protein synthesis. Its spectrum of activity includes pathogens implicated in common respiratory infections (Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumonia, and Chlamydia pneumoniae) and multidrug-resistant isolates of pneumococcus. Clinical efficacy has been documented in several multicenter, comparative trials for the treatment of community-acquired pneumonia, acute exacerbation of chronic bronchitis, acute maxillary sinusitis, and pharyngitis tonsillitis. Although studies have demonstrated that the clinical efficacy of telithromycin is comparable to macrolides, telithromycin is unique in that it provides activity against penicillin- and macrolide-resistant respiratory pathogens. The recommended dosage of telithromycin is 800 mg p.o. once daily. The most common adverse events resulting from telithromycin use include diarrhea, nausea, headache, dizziness, vomiting, loose stools, dysgeusia, and dyspepsia. The drug's adverse-event profile is comparable to that of similar agents. Telithromycin is a strong inhibitor of cytochrome P-450 isoenzyme 3A4; therefore, it can affect the efficacy and toxicity profile of medications that are metabolized by this isoenzyme. CONCLUSION: Telithromycin is a reasonable addition to the current treatment options for upper-respiratory-tract infections. Its use should be restricted to infections caused by penicillin- and macrolide-resistant pathogens.     

大环内酯类药物抗性基因及新药研究进展

大环内酯类抗生素在广泛使用的过程中,细菌的耐药现象（特别是在G＋菌中）日益严重,随着对细菌耐药机制及编码基因研究的深入,人们改造出新的4－氨基甲酸酯大环内酯和酮酯（大环内酯的3－酮衍生物）类抗生素,它对已发现的大环内酯耐药菌有较强的活性,此外,大环内酯其余的许多非抗菌活性,如抑制细胞因子的生成,抗癌,抗寄生虫等活性,在最近也陆贯有所报道。