Clinical efficacy of ketolides in the treatment of respiratory tract infections

Ralf René Reinert*

Institute of Medical Microbiology, National Reference Centre for Streptococci, Pauwelsstrasse 30, 52074 Aachen, Germany


    Abstract
 Top
 Abstract
 Introduction
 Mechanism of action and...
 Pharmacokinetics and...
 Overview of clinical trials...
 AECB
 Pharyngitis
 Acute sinusitis
 Telithromycin post-marketing...
 The role of ketolides...
 References
 
Ketolides are a new class of semi-synthetic agents derived from erythromycin A designed to overcome erythromycin A resistance in Streptococcus pneumoniae. Telithromycin (HMR 3647) is the first member of this new class to be approved for clinical use. Cethromycin (ABT-773) has been developed up to Phase III, but its further development seems questionable at the moment. Other ketolides are only in the first stages of preclinical development and may not be available within the foreseeable future. Ketolide compounds inhibit bacterial protein synthesis by interacting with the peptidyl transferase site of the 50S ribosomal subunit, and interact closely with domains II at A752 and V at A2058 and A2059 of the 23S rRNA. These compounds also inhibit the formation of the 50S subunit of the ribosome. Ketolides show good activity against the Gram-positive bacteria responsible for respiratory tract infections including penicillin G- and erythromycin A-resistant S. pneumoniae. The 15 clinical trials with telithromycin published to date include four randomized, double-blind comparative trials and three open-label studies in community-acquired pneumonia, three randomized double-blind trials in acute exacerbation of chronic bronchitis, two randomized double-blind trials in pharyngitis, and two double-blind comparative trials and one open-label trial in acute maxillary sinusitis. Clinical response rates were favourable in all clinical trials, with eradication rates in patients with pneumococcal bacteraemia and penicillin G- and erythromycin A-resistant pneumococcal infections at least as high as those of comparators. As resistance to macrolides continues to emerge, the availability of other ketolides besides telithromycin and a development programme for the application of ketolides in children would appear to be warranted to obtain a new class of antibiotics that may one day replace macrolides.

Keywords: respiratory tract infections, telithromycin, ABT-773, HMR 3647


    Introduction
 Top
 Abstract
 Introduction
 Mechanism of action and...
 Pharmacokinetics and...
 Overview of clinical trials...
 AECB
 Pharyngitis
 Acute sinusitis
 Telithromycin post-marketing...
 The role of ketolides...
 References
 
Ketolides are a new class of semi-synthetic agents derived from erythromycin A. These compounds were originally designed to overcome erythromycin A resistance in Streptococcus pneumoniae. Approved indications for telithromycin in Europe are mild and moderate respiratory tract infections, including those caused by resistant S. pneumoniae.

Ketolides are characterized by the lack of the L-cladinose sugar at position 3 of the erythronolide A moiety, which is replaced by a keto group.1 Telithromycin (HMR 3647) is the first member of this new class to be approved for clinical use.2,3

Cethromycin (ABT-773) has been developed up to Phase III, but its further development seems questionable at the moment.413 Both compounds belong to the subgroup of carbamate ketolides. The 11,12-carbamate is known to improve in vitro activity of ketolides and to influence pharmacokinetics and pharmacodynamics (for review see Bryskier1).

Telithromycin and cethromycin differ in the lack of a substituent on the C11, C12 carbamate residue for cethromycin and a butyl imidazolyl pyridinyl chain for telithromycin. Telithromycin possesses a 6-OCH3 group, preventing internal ketalization with the 3-keto function, and cethromycin a 6-O-quinolinyl propylene chain.1 Other compounds of this subgroup are TE-810 (tricyclic compound) and HMR 3004 (carbazate residue).1416

Oral telithromycin has been available for clinical use in Germany since 2001, and subsequently in other European countries such as France and Spain (Table 1). The medical need for development of alternatives to currently available antibacterials has been stressed in many recent reviews,1,3,4,10,17 and arises primarily from the fact that existing therapeutic options are very limited for the treatment of respiratory tract infections in areas where antibiotic-resistant S. pneumoniae are widespread or in patients with ß-lactam intolerance.


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Table 1. Overview of the status of licensing and availability of telithromycin by January 2004
 

    Mechanism of action and antibacterial activity
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 Abstract
 Introduction
 Mechanism of action and...
 Pharmacokinetics and...
 Overview of clinical trials...
 AECB
 Pharyngitis
 Acute sinusitis
 Telithromycin post-marketing...
 The role of ketolides...
 References
 
Ketolides possess at least a dual mode of action. First, these antibiotics inhibit bacterial protein synthesis by interacting with the peptidyl transferase site of the 50S ribosomal subunit. Protein synthesis is inhibited due to the blockade of the nascent peptidyl exit tunnel of the ribosome.

Ketolides interact closely with domains II and V of the 23S rRNA. A2058 and A2059 are the primary targets within domain V nucleotides. In comparison with the 14- and 15-membered ring macrolides, telithromycin has a greater affinity for interactions with ribosomes because of an additional interaction at A752 in domain II. Cethromycin also interacts with domains II and III.4,18 The interaction of telithromycin is mediated by the C11, C12 cyclic carbamate. In addition, other interactions between ketolides and ribosomal structures have been identified (for a review see Poehlsgaard & Douthwaite19).

Secondly, in Gram-positives these compounds act as inhibitors of 50S subunit formation, and their inhibitory effect on particle synthesis is equivalent to their effect on translation.20

In Haemophilus influenzae, pulse–chase labelling assays conducted to examine the effect of ketolides on subunit formation showed no specific effect of the compounds on 50S subunit assembly. Therefore, H. influenzae seems to have only one significant target for these antibiotics, and this may explain at least in part why these drugs are not more effective than macrolides in preventing the growth of this microorganism.21,22

Ketolides show good activity against Gram-positive bacteria responsible for respiratory tract infections2334 (see the recent review by Ackermann & Rodloff35).

In brief, telithromycin and cethromycin are more active than 14-, 15- and 16-membered ring macrolides against S. pneumoniae, with MIC50 values of <=0.008–0.03 mg/L. One of the most significant features of ketolides is that they retain high activity against erythromycin A-resistant S. pneumoniae isolates. Against S. pneumoniae harbouring the efflux type of resistance [mef(E)-positive strains], some, but not all, strains show slightly elevated MICs of up to 1 mg/L. Resistance to telithromycin in S. pneumoniae is extremely rare. Data from the worldwide PROTEKT study (in 2002; n = 6320) found >=99.7% of all strains susceptible to telithromycin with an MIC <= 1 mg/L. Only 16 strains were telithromycin-intermediate or -resistant (www.protekt.org).32,36

Resistance of Streptococcus pyogenes to telithromycin is also low in most countries. In Greece, however, resistance rates of >10% (combined rates of telithromycin-intermediate and -resistant strains) have been reported.37

The level of erythromycin A resistance in S. pyogenes and S. pneumoniae is increasing worldwide, but varies widely between countries. In S. pyogenes, rates of ~30% and above have been reported from Italy, Spain, Portugal and Greece. In S. pneumoniae the erythromycin A resistance rate is highest in Asia (>80%) and France (>60%), but is also >30% in some other European countries, including Belgium, Italy, Spain and Hungary (www.protekt.org; Table 2).


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Table 2. Overview of erythromycin A resistance in S. pyogenes and S. pneumoniae as provided by the PROTEKTa study, 2002
 
Hsueh et al.38 recently reported on telithromycin MICs ranging from 1 to 2 mg/L for 15% of isolates, and telithromycin MICs of 4 mg/L in 1% of strains among 936 clinical isolates of S. pneumoniae isolated from 2000 to 2001 in different parts of Taiwan, a country where macrolide resistance is observed in >90% of strains but where ketolides are not licensed or used to date. Of note, these investigators determined MICs using the agar dilution method, with incubation in 5–6% CO2. The presence of CO2 has been demonstrated to increase telithromycin MIC by one to six dilution steps, which should to be considered when testing telithromycin activity in vitro.39

One common feature of these telithromycin non-susceptible strains was that they all showed the constitutive MLSB type of macrolide resistance. Streptococcal strains with constitutive MLSB resistance show variable MICs to ketolides, but are intermediate or resistant to erythromycin A. The degree of resistance is determined by how effectively the rRNA is methylated. Monomethylation has been shown to confer high resistance to lincosamides, intermediate resistance to the macrolides, clarithromycin and erythromycin, and low resistance to streptogramin B, while only mildly affecting susceptibility to ketolides. In contrast, in dimethylated isolates, high-level resistance to all MLSB antibiotics and ketolide drugs is observed.40

Within the past few years some new resistance mechanisms of S. pneumoniae against macrolides have been described, including mutations of 23S rRNA17,4147 and alterations in the ribosomal protein L442,43,45,4749 and L22.43,49,50 Ketolides usually retain activity against such strains,43 although some isolates may show slightly elevated MICs. Strains with mutations in L22 may have MICs of 1 mg/L.51

Ketolides also show good activity against clinical S. pyogenes isolates including erythromycin A-resistant strains harbouring the erm(A) or mef(A) (efflux) genotype. Some, but not all, erm(B)-positive S. pyogenes strains may be telithromycin-resistant with MICs of up to 64 mg/L.52,53 The MICs suggest that the in vitro activity of cethromycin against streptococcal isolates may be slightly higher than that of telithromycin, but the clinical relevance of this observation remains to be determined.

Ketolides are also active against other respiratory pathogens, such as Bordetella spp., Legionella spp., Chlamydophila pneumoniae and Mycoplasma pneumoniae.23,5458

In one study of the in vitro activities of ketolides against genetically characterized isolates of H. influenzae (n = 250) and Moraxella catarrhalis (n = 500),55 cethromycin (H. influenzae: MIC range 0.03–8 mg/L, MIC90 4 mg/L; M. catarrhalis: MIC range 0.015–0.25 mg/L, MIC90 0.12 mg/L) and telithromycin (H. influenzae: MIC range 0.06–8 mg/L; MIC90 4 mg/L; M. catarrhalis: MIC range 0.015– 0.25 mg/L, MIC90 0.12 mg/L) showed similar activity to that of azithromycin (H. influenzae: MIC range 0.03–8 mg/L, MIC90 2 mg/L; M. catarrhalis: MIC range 0.015–0.12 mg/L, MIC90 0.06 mg/L), confirming findings of other investigators.5962

Ketolides show good activity against Staphylococcus aureus. Both telithromycin and cethromycin lack activity against constitutive erythromycin A-resistant S. aureus, but retain good activities against S. aureus with inducible erythromycin A resistance (cethromycin MIC90 0.06 mg/L; telithromycin MIC90 0.5 mg/L).1,14,24,31,63

Furthermore, ketolides show a low potential to select for resistance and cross-resistance both in vitro and in vivo.17

Like the macrolides, the ketolides telithromycin and cethromycin show bacteriostatic activity against many bacterial species with the important exception of S. pneumoniae, including erythromycin A-resistant strains. Bactericidal activity against S. pneumoniae has also been confirmed in animal models.6466 In addition, both compounds demonstrate limited bactericidal activity against H. influenzae and M. catarrhalis.58,60,6773

Telithromycin has also been shown to have a long-lasting post-antibiotic effect of 0.4–2.7 h in S. pyogenes, 0.3–2.4 h in S. aureus and 0.5–3.8 h in S. pneumoniae.74


    Pharmacokinetics and pharmacodynamics
 Top
 Abstract
 Introduction
 Mechanism of action and...
 Pharmacokinetics and...
 Overview of clinical trials...
 AECB
 Pharyngitis
 Acute sinusitis
 Telithromycin post-marketing...
 The role of ketolides...
 References
 
The pharmacokinetic and pharmacodynamic properties of the ketolides have recently been extensively reviewed by Zhanel et al.3

In brief, the bioavailability of telithromycin is ~57%. The drug is rapidly absorbed, reaching a Cmax of 1.9 mg/L within 1 h.75,76 Absorption of cethromycin is dose dependent, with Cmax ranging between 0.14 and 1.17 mg/L for doses of 100 and 1200 mg, respectively.77 Like macrolides, ketolides penetrate extensively into tissues and fluids outside the blood plasma,78 which may increase their activity against organisms localized at these sides.

Telithromycin accumulates in the bronchial mucosa and the epithelial lining fluid. Mean concentrations (12 h) of telithromycin measured in plasma, bronchial mucosa and epithelial lining fluid following multiple oral doses were 0.23 mg/L, 1.41 mg/kg and 3.27 mg/L, respectively.79

Ketolides also accumulate in macrophages and granulocytes, as shown by numerous in vitro studies.8083 Data on the distribution of cethromycin in humans is limited to date. However, preliminary data show that cethromycin achieves high intracellular concentrations within human polymorphonuclear leucocytes.6,84

Ketolides are primarily metabolized by the cytochrome P-450 enzyme system in the liver. The half-life of telithromycin (800 mg once daily) is 7.2 h, allowing once daily dose administration.75 The half-life of cethromycin ranges from 3.6 to 6.7 h after single oral doses of 100 and 1200 mg, respectively, in healthy adult males,3 with results from Phase I healthy subject studies (dose-escalation study ranging from 100 to 1200 mg in fasting human subjects) supporting the need for twice daily dosing for this drug.


    Overview of clinical trials with the ketolides
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 Abstract
 Introduction
 Mechanism of action and...
 Pharmacokinetics and...
 Overview of clinical trials...
 AECB
 Pharyngitis
 Acute sinusitis
 Telithromycin post-marketing...
 The role of ketolides...
 References
 
The efficacy and safety of oral telithromycin has been evaluated in controlled clinical trials in patients with community-acquired pneumonia (CAP),85 acute exacerbation of chronic bronchitis (AECB), tonsillopharyngitis and acute sinusitis (Table 3).3,86


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Table 3. Overview of telithromycin clinical trials performed
 
Cethromycin was found to have a satisfactory safety profile in initial human studies, permitting further clinical development. However, no clinical studies of cethromycin have been published to date.3,87

Four randomized, double-blind comparative trials and four open-label studies of telithromycin have been performed in patients with CAP.8895

Telithromycin was administered orally at a dose of 800 mg once daily for 5 or 7–10 days, and compared with amoxicillin, clarithromycin, cefuroxime and trovafloxacin. Clinical response rates (per protocol) ranged from 88.3 to 94.6%, with bacteriological response rates ranging between 80.0 and 92.9%. Pooled analysis of data from eight clinical trials in patients with CAP showed high clinical cure rates in patients infected with S. pneumoniae (94%), H. influenzae (90%), M. catarrhalis (88%), and other pathogens such as M. pneumoniae (97%), C. pneumoniae (94%) and Legionella pneumophila (100%) (Table 4).96


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Table 4. Clinical trials on telithromycin in CAP: clinical cure according to pathogen (pooled data)
 
Of note, clinical cure rates for penicillin G- and erythromycin A-resistant S. pneumoniae isolates were also high, ranging between 84 and 100% (Table 5). In an analysis by Fogarty et al.,97 data from 3935 patients who had participated in one Japanese Phase II study and in 11 Phase III studies in CAP, AECB or acute sinusitis were pooled. Telithromycin showed a high level of clinical efficacy against S. pneumoniae, with clinical cure rates of 92.8% for all isolates, 91.7% for those with reduced susceptibility to penicillin G and 86.0% for those with reduced susceptibility to erythromycin A. Bacterial eradication rates were consistent with the clinical outcomes. High rates of clinical cure and bacterial eradication were also observed for infections caused by isolates demonstrating high-level resistance to erythromycin A [clinical cure rate 100% (13/13)].97,98


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Table 5. Clinical trials of telithromycin in CAP: clinical cure for penicillin G- and erythromycin A-resistant S. pneumoniae isolates (pooled dataa)
 
In all studies performed with telithromycin in CAP, 82 cases of pneumococcal bacteraemia were documented, and patients treated with telithromycin showed a cure rate of 90%. Cure rates of 71% (five of seven) and 80% (eight of 10) were documented in penicillin G- and erythromycin A-resistant S. pneumoniae bacteraemia, respectively, although these data should be interpreted with caution owing to the relatively low number of available patients (Table 6).99


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Table 6. Clinical trials of telithromycin in CAP: clinical cure rates for 82 patients with pneumococcal bacteraemia (pooled data99)
 

    AECB
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 Abstract
 Introduction
 Mechanism of action and...
 Pharmacokinetics and...
 Overview of clinical trials...
 AECB
 Pharyngitis
 Acute sinusitis
 Telithromycin post-marketing...
 The role of ketolides...
 References
 
Three clinical trials have been performed in patients with AECB. Telithromycin (800 mg/once daily) was given for 5 days and compared with co-amoxiclav (three times daily, 10 days),100 cefuroxime axetil (twice daily, 10 days)101 or clarithromycin (twice daily, 10 days).102 The clinical cure rate for telithromycin was 85.8–86.4% in all studies, and 82.1–89.2% for comparators (Table 3). Bacteriological cure rates ranged between 69.2 and 81.9% for telithromycin and between 70 and 82.9% for comparators. Analysis of AECB patients with increased risk factors showed cure rates with telithromycin of 85% in the elderly (>=65 years), 83% in patients with at least two morbidity risk factors and 79% in patients with FEV1/FVC <60% (Table 7).103


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Table 7. Clinical trials of telithromycin in AECB: clinical cure by risk factors for morbidity (pooled dataa)
 

    Pharyngitis
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 Abstract
 Introduction
 Mechanism of action and...
 Pharmacokinetics and...
 Overview of clinical trials...
 AECB
 Pharyngitis
 Acute sinusitis
 Telithromycin post-marketing...
 The role of ketolides...
 References
 
Two randomized, double-blind clinical trials of telithromycin (800 mg, once daily, 5 days) in the treatment of patients with pharyngitis have been performed, one by Norrby et al.104 and one by Quinn et al.105 In those studies, penicillin V (500 mg, three times daily, 10 days) and clarithromycin (250 mg, twice daily, 10 days) were the comparators (Table 3). In both studies, both treatment regimens were effective and showed a bacteriological eradication rate ranging from 84.3 to 91.3% for telithromycin and from 88.1 to 89.1% for comparators. Telithromycin also showed satisfactory clinical success rates in patients with erythromycin A-resistant S. pyogenes infections, although further clinical evaluation is required, especially for infections caused by erm(B)-positive, erythromycin A-resistant strains.


    Acute sinusitis
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 Abstract
 Introduction
 Mechanism of action and...
 Pharmacokinetics and...
 Overview of clinical trials...
 AECB
 Pharyngitis
 Acute sinusitis
 Telithromycin post-marketing...
 The role of ketolides...
 References
 
Three randomized trials using telithromycin in the treatment of acute sinusitis have been presented. Telithromycin once daily for 5 days was found to be as effective as the same dosage for 10 days.106 Consequently, two other studies compared the telithromycin 5 day regimen with co-amoxiclav 500 mg/125 mg three times daily for 10 days and cefuroxime axetil 250 mg twice daily for 10 days. In both studies, clinical cure rates and bacteriological outcomes were similar for telithromycin and the comparators.107,108


    Telithromycin post-marketing observational survey in Germany
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 Abstract
 Introduction
 Mechanism of action and...
 Pharmacokinetics and...
 Overview of clinical trials...
 AECB
 Pharyngitis
 Acute sinusitis
 Telithromycin post-marketing...
 The role of ketolides...
 References
 
An observation study of the effectiveness and tolerability of telithromycin in standard clinical practice for the treatment of CAP, AECB, acute sinusitis and tonsillopharyngitis in standard clinical practice was initiated in Germany in October 2001.109

An interim evaluation performed in July 2002 based on data from >24 000 patients showed a high level of satisfaction with telithromycin therapy, particularly with respect to rapid symptom relief and resumption of normal activities. Of note, a low incidence of mild or moderate adverse events was demonstrated (541 of 24 356 patients, 2.2%), involving the gastrointestinal tract (1.5%), the central nervous system (0.5%) and the skin (0.2%). Eye disorders, such as blurred vision, were reported in 0.2% of patients, which may require further clinical observation.

A total of 99 serious adverse events were reported in 48 patients (0.2%), with gastrointestinal and eye disorders being most frequent. Recently, cases of potentially life-threatening exacerbations of myasthenia gravis have been reported in patients treated with telithromycin.110 Similar cases have been reported with many other therapeutic agents. In anti-infectives, such cases have been reported for macrolides111,112 and for fluoroquinolones.113 Consequently, telithromycin is not recommended for use in patients with myasthenia gravis unless no other therapeutic options are available.


    The role of ketolides in the treatment of respiratory tract infections
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 Abstract
 Introduction
 Mechanism of action and...
 Pharmacokinetics and...
 Overview of clinical trials...
 AECB
 Pharyngitis
 Acute sinusitis
 Telithromycin post-marketing...
 The role of ketolides...
 References
 
The rapid emergence of macrolide resistance, especially in the southern Europe32,114,115 (Table 2), has limited therapeutic options for the treatment of respiratory tract infections. The emergence of pneumococcal isolates with penicillin G MICs of 2–4 mg/L32,114,115 and the increasing number of penicillin/ß-lactam allergic patients further highlights the need for the development of novel antibacterial agents for use in this setting.116 For mild and moderate respiratory tract infections, ketolides provide full coverage against the most common causative organisms, including atypical pathogens. Furthermore, ketolides have a low potential to select for resistance and cross-resistance, both in vitro and in vivo, making them an attractive option for the empirical treatment of respiratory tract infections.17 Recent reports of the emergence of telithromycin resistance in Taiwan, a region where ketolides have not been used to date, are cause of some concern.38 While such reports clearly merit further attention, it should be noted that these data were derived using the agar dilution test in CO2 atmosphere, which is known to have methodological limitations for the determination of telithromycin susceptibility in S. pneumoniae.27

Even in countries such as Germany, where resistance of respiratory tract pathogens does not play a major role, ketolides such as telithromycin may be of clinical utility due to their favourable pharmacokinetic profile, which allows once daily dosing and very high tissue levels. Preliminary post-marketing data from Germany support the findings of earlier clinical studies, showing telithromycin to have a good safety profile with a low rate of adverse events and treatment discontinuation. However, some adverse events, primarily blurred vision and the exacerbation of myasthenia gravis, would appear to merit further, careful observation.

Consequently, professional bodies and medical societies have already addressed the issue of ketolide use for the treatment of respiratory tract infections. In its recent recommendations the IDSA stated that telithromycin may have a role as an alternative to macrolides in the treatment of patients with CAP. However, at the time when the recommendations were made, the compound was not yet FDA approved.117 In Germany, the Paul-Ehrlich Society for Chemotherapy has recommended the use of ketolides as an alternative treatment option for CAP, acute and chronic sinusitis, tonsillitis, and AECB.118 Other societies have also addressed the use of telithromycin in the treatment of respiratory tract infections (for reviews see File119 and File & Tan120).

Telithromycin is not currently licensed for use in children. In the European Union, telithromycin is approved for the treatment of mild and moderate CAP and AECB in patients aged >=18 years, or as an alternative in acute sinusitis and tonsillitis/pharyngitis when ß-lactam antibiotics are not appropriate. Telithromycin may also be used for the treatment of tonsillitis/pharyngitis in patients aged 12–18 years under the same conditions (www.emea.eu.int). As the armamentarium for the treatment of respiratory tract infections in children is limited in some parts of the world, clinical evaluation of telithromycin in the paediatric population is clearly warranted. Ease of administration (e.g. once daily treatment, short course of therapy and acceptable taste) is a major requirement for a new antibacterial for the treatment of respiratory tract infections in children to achieve high compliance.

It may be speculated that this new class of antibiotics may replace macrolides not only partially, especially in parts of the world where macrolide resistance rates of >60% of S. pneumoniae are being increasingly reported. To provide a new class of antibiotics, the availability of other ketolides besides telithromycin may be helpful. At the moment, however, it seems that the clinical development of cethromycin appears to have slowed down. Other ketolides, including the 2-fluoroketolides HMR 3787121 and HMR 3562,122 and other ketolides such as TE-810, HMR 3004 and HMR 3832,123 are only in the first stages of preclinical development. EP-13159 is a novel 2-fluoroketolide antibiotic that appears able to overcome macrolide-resistant S. aureus with the MLSB-resistance phenotype and is active against vancomycin-resistant enterococci and methicillin-resistant S. aureus, in addition to having good overall MICs against resistant respiratory tract pathogens.124

As telithromycin and cethromycin, although highly active against a broad range of Gram-positive bacteria, are relatively less active against H. influenzae, new compounds have been developed with enhanced antibacterial properties against H. influenzae. Modifications of 5-O-mycaminosyl tylonolide at the 23-O position provide novel compounds that show MIC ranges of 0.5–2 mg/L against H. influenzae.125 JNJ-17156581 and JNJ-17156815 are 2-fluoro-6-O-3-(biheteroaryl)-2-propenyl ketolides prepared synthetically from 15-methylerythromycin A, produced in genetically modified strains. MICs of JNJ-17156581 and JNJ-17156815 were equivalent to values eight times lower than those of telithromycin against H. influenzae, as well as macrolide-susceptible and -resistant Gram-positive cocci.126 However, these compounds are only in the early stages of development, and are unlikely be available within the foreseeable future.

In conclusion, the ketolide telithromycin has demonstrated high clinical and bacteriological efficacy in the treatment of CAP, AECB, acute sinusitis and pharyngitis. High efficacy was also maintained in those patient groups considered to be at high risk of complications and those with infections caused by penicillin G- or erythromycin A-resistant S. pneumoniae. The favourable tolerability profile and convenient short once daily-dosing regimen of telithromycin indicate it to be an attractive new antibacterial for the empirical treatment of community-acquired respiratory tract infections. To obtain a new class of antibiotics that may one day replace macrolides, as resistance to macrolides continues to emerge, the availability of other ketolides besides telithromycin, a development programme for the application of ketolides in children, and the availability of a parenteral formulation would appear to be warranted.


    Footnotes
 
* Tel: +49-241-80-89-787; Fax: +49-241-80-82-483; E-mail: reinert{at}rwth-aachen.de Back


    References
 Top
 Abstract
 Introduction
 Mechanism of action and...
 Pharmacokinetics and...
 Overview of clinical trials...
 AECB
 Pharyngitis
 Acute sinusitis
 Telithromycin post-marketing...
 The role of ketolides...
 References
 
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