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 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.     

The ketolides: a critical review

Ketolides are a new class of macrolides designed particularly to combat respiratory tract pathogens that have acquired resistance to macrolides. The ketolides are semi-synthetic derivatives of the 14-membered macrolide erythromycin A, and retain the erythromycin macrolactone ring structure as well as the D-desosamine sugar attached at position 5. The defining characteristic of the ketolides is the removal of the neutral sugar, L-cladinose from the 3 position of the ring and the subsequent oxidation of the 3-hydroxyl to a 3-keto functional group. The ketolides presently under development additionally contain an 11, 12 cyclic carbamate linkage in place of the two hydroxyl groups of erythromycin A and an arylalkyl or an arylallyl chain, imparting in vitro activity equal to or better than the newer macrolides. Telithromycin is the first member of this new class to be approved for clinical use, while ABT-773 is presently in phase III of development. Ketolides have a mechanism of action very similar to erythromycin A from which they have been derived. 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 aerobes and some Gram-negative aerobes, and have excellent activity against drug-resistant Streptococcus pneumoniae, including macrolide-resistant (mefA and ermB strains of S. pneumoniae). Ketolides such as telithromycin display excellent pharmacokinetics allowing once daily dose administration and extensive tissue distribution relative to serum. Evidence suggests the ketolides are primarily metabolised in the liver and that elimination is by a combination of biliary, hepatic and urinary excretion. Pharmacodynamically, ketolides display an element of concentration dependent killing unlike macrolides which are considered time dependent killers. Clinical trial data are only available for telithromycin and have focused on respiratory infections including community-acquired pneumonia, acute exacerbations of chronic bronchitis, sinusitis and streptococcal pharyngitis. Bacteriological and clinical cure rates have been similar to comparators. Limited data suggest very good eradication of macrolide-resistant and penicillin-resistant S. pneumoniae. As a class, the macrolides are well tolerated and can be used safely. Limited clinical trial data suggest that ketolides have similar safety profiles to the newer macrolides. Telithromycin interacts with the cytochrome P450 enzyme system (specifically CYP 3A4) in a reversible fashion and limited clinically significant drug interactions occur. In summary, clinical trials support the clinical efficacy of the ketolides in upper and lower respiratory tract infections caused by typical and atypical pathogens including strains resistant to penicillins and macrolides. Considerations such as local epidemiology, patterns of resistance and ketolide adverse effects, drug interactions and cost relative to existing agents will define the role of these agents. The addition of the ketolides in the era of antibacterial resistance provides clinicians with more options in the treatment of respiratory infections.     

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.     

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.     

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.     

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.     

The macrolide-bacterium interaction and its biological basis

Erythromycin, the first antibacterial macrolide introduced into the clinical setting over 50 years ago, was used extensively not only for the treatment of respiratory tract infections in both adults and children, but also for bone and soft tissue infections, and specific sexually transmitted diseases. Macrolide antibiotics have undergone a dramatic chemical evolution over the past 50 years, culminating in the improved 14- and 16-membered macrolides, acylides and new ketolides. In all cases, improvements in antibacterial activity involved changes in the interplay between the chemical structure of the macrolide and the components of the bacterial cell that dictate ultimate antibacterial activity and efficacy. Target site modification by methylation of ribosomal RNA, the so-called Macrolide-Streptogramin-Lincosamide, (MLS0 resistance and active efflux are the two most common forms of resistance present in the clinic today; however, other resistance mechanisms are known. The first macrolide that bound to MLS-resistant ribosomes was reported in 1989, demonstrating that appropriate structural changes could regain access to the modified ribosome-binding site. In addition, macrolide analogs with reduced affinity for the active efflux pump were identified in 1990, demonstrating that features of pump recognition could be separated from ribosome binding site recognition. Progressive medicinal chemistry led to the synthesis and development of the more recent ketolide class, which combines attributes of both prototypes into one molecule, i.e. non-recognition by the efflux pump and regaining some access to the modified ribosome binding site. Ketolide also lack of induction of erm methylase as do 16-member macrolides.     

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.     

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.     

Synthesis and in vitro antimicrobial activity of 3-keto 16-membered macrolides derived from tylosin

Several series of 14-membered ketolides derived from erythromycin exhibit useful antimicrobial activity against macrolide-resistant bacteria. To determine if 16-membered ketolides may possess analogous activity, 3-keto derivatives of 5-O-mycaminosyl-23-O-acetyltylonolide and desmycosin were synthesized by protection of susceptible functional groups, oxidation of the 3-hydroxyl group under modified Moffatt-Pfitzner conditions, and subsequent deprotection. The resulting 3-keto products unexpectedly adopted the 2,3-trans enol rather than the 3-keto tautomer. The trans configuration of the 2,3-double bond in the macrolide chain is most likely the result of hydrogen bond stabilization between the enol hydroxyl and lactone carbonyl, which places these two groups in a cis relationship. This preference for the enol tautomer in 16-membered macrolides is not seen with 14-membered ketolides. The in vitro antimicrobial activity of the enol derivatives was greatly reduced compared to their unoxidized parent compounds, but the reduced antimicrobial activity of the enol derivatives paralleled results from corresponding 2,3-anhydro derivatives of 16-membered macrolides, which also have 2,3-trans stereochemistry. These results are in contrast to those from 14-membered-ring macrolides in which 3-keto and 2,3-anhydro derivatives exhibit greater activity than 3-hydroxy compounds.     

Epidemiological aspects of antibiotic resistance in respiratory pathogens

Respiratory infections are the most frequent reason for primary health care consultation. The main causes of respiratory tract infections in children are viruses and the most common types are upper respiratory tract infections: common cold, pharyngitis, otitis media and sinusitis. Pneumonia is much more serious. As well as viruses, bacteria are often involved in respiratory tract infections. Three bacterial species are most commonly isolated: Streptococcus pneumoniae, non-encapsulated Haemophilus influenzae and Moraxella (Branhamella) catarrhalis. The most common bacterial cause of pharyngitis is Streptococcus pyogenes. Bacteria isolated from community-acquired infection usually are sensitive to the majority of suitable drugs, but during the past two decades, significant antibiotic resistance has emerged. Resistance to penicillins has spread among H. influenzae and S. pneumoniae. The mechanism of penicillin resistance in H. influenzae is mainly by production of β-lactamases TEM-1 and ROB-1, whereas in S. pneumoniae resistance is an effect of the changes in penicillin binding proteins. Among respiratory pathogens, resistance to tetracyclines, macrolides, trimethoprim–sulphamethoxazole and fluoroquinolones has also appeared. Several mechanisms depending on changes in target, active efflux and modifying enzymes are involved.     

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.     

International guidelines for the treatment of community-acquired pneumonia in adults: the role of macrolides

The significance of community-acquired pneumonia (CAP) has led to the publication of guidelines from numerous international organisations. Because the macrolide class of antimicrobials is active against most of the key pathogens associated with CAP, agents from this class are commonly included in recommendations from these guidelines. However, there are differences among the various guidelines concerning the positioning of the macrolides for empirical therapy. An important factor concerning the use of macrolides for CAP is the emergence of resistance of Streptococcus pneumoniae over the past decade. The rate of S. pneumoniae resistance to macrolides ranges from 4 to 70% of strains in worldwide surveillance studies. The most common mechanisms of resistance include methylation of a ribosomal target encoded by the erm gene and efflux of the macrolides by a cell membrane protein transporter, encoded by the mef gene. S. pneumoniae strains with the mef gene are resistant at a lower level (with minimum inhibitory concentration [MIC] values generally 1-16 microg/ml) than erm resistant strains; and it is possible that such strains may be inhibited if sufficiently high levels of macrolide can be obtained at the infected site. Currently mef-associated resistance predominates in North America, whereas erm predominates in Europe. Until recently, reports of failure of treatment of CAP with macrolides has been rare, particularly for patients with low-risk for drug-resistant strains. However, since 2000, several patients treated with an oral macrolide who have subsequently required admission to the hospital for macrolide-resistant S. pneumoniae (MRSP) bacteraemia have been reported in the literature. Major issues, which are fundamental to the use of the macrolides as recommended in the various guidelines, include the importance of providing therapy for 'atypical' pathogens and the clinical significance of MRSP. Presently, the macrolides are more prominently recommended in the North American guidelines than in other parts of the world. The difference in the emphasis placed on the importance of the atypical pathogens as well as the expression of MRSP in North America compared with Europe partly explains this variance.     

PROTEKT 1999-2000: a multicentre study of the antibiotic susceptibility of respiratory tract pathogens in Hong Kong, Japan and South Korea

A multicentre surveillance study performed in the Far East during 1999-2000 investigated the in vitro activity of >20 antibacterials against common respiratory pathogens. In Hong Kong, Japan, and South Korea, 57.1, 44.5 and 71.5% Streptococcus pneumoniae were penicillin-resistant and 71.4, 77.9 and 87.6% were erythromycin-resistant, respectively. Overall, >90% of penicillin-resistant strains were also macrolide-resistant. All strains were susceptible to telithromycin. Fluoroquinolone-resistant isolates in Japan (1.3%), Hong Kong (14.3%) and South Korea (2.9%) were mostly co-resistant to penicillin, macrolides and tetracycline. Beta-lactamase production by Haemophilus influenzae isolates was 8.5% in Japan, 17.1% in Hong Kong and 64.7% in strains from South Korea. A single (0.27%) BLNAR isolate was obtained in Japan. There was no fluoroquinolone resistance. Moraxella catarrhalis was inhibited by telithromycin at 相似文献   

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。     

Telithromycin: an oral ketolide for respiratory infections

The ketolides represent a new subclass of antibiotics among the macrolide-lincosamide-streptogramin group. Telithromycin, the first ketolide to be awarded approvable status for clinical use, demonstrates in vitro activity against community-acquired respiratory pathogens including penicillin- and erythromycin-resistant Streptococcus pneumoniae. An extended half-life permits once-daily oral administration. Telithromycin is a substrate for cytochrome P450 (CYP) 3A4 and also inhibits drugs metabolized by CYP3A4. A relatively high frequency of mild-to-moderate gastrointestinal adverse effects has been reported. Similar clinical and microbiologic efficacy has been demonstrated with oral dosing in comparative clinical trials for community-acquired pneumonia, acute sinusitis, acute exacerbations of chronic bronchitis, and pharyngitis. Although limited data on penicillin-resistant S. pneumoniae and erythromycin-resistant Streptococcus pyogenes are available from clinical trials, this drug appears promising for respiratory infections caused by these pathogens.     

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.