Drugs of the 21st century: telithromycin (HMR 3647)—the first ketolide

Grit Ackermann* and Arne C. Rodloff

Institute for Medical Microbiology and Epidemiology of Infectious Diseases, University of Leipzig, Liebigstrasse 24, 04103 Leipzig, Germany


    Abstract
 Top
 Abstract
 Introduction
 Chemistry and structure-activity...
 Mechanism of action
 Antibacterial activity
 Resistance
 Animal studies and clinical...
 Pharmacodynamic characteristics...
 Pharmacokinetic characteristics...
 Metabolism and drug interaction
 Ecological profile, adverse...
 Additional information
 Other ketolides
 References
 
Telithromycin (HMR 3647) is the first ketolide introduced into clinical practice. Ketolides are semisynthetic derivates of erythromycin A that carry novel biological properties on the erythronolide A ring. This new class of antimicrobials was designed to overcome current resistance mechanisms against erythromycin A within Gram-positive cocci. Ketolides do not induce macrolide–lincosamide–streptogramin B (MLSB) resistance and are active against erythromycin resistance methylase gene (erm)-carrying Gram-positive cocci. This review summarizes published data on telithromycin and intends to define the challenge that a new antimicrobial brings to medical practice.

Keywords: new antimicrobials, telithromycin, resistance


    Introduction
 Top
 Abstract
 Introduction
 Chemistry and structure-activity...
 Mechanism of action
 Antibacterial activity
 Resistance
 Animal studies and clinical...
 Pharmacodynamic characteristics...
 Pharmacokinetic characteristics...
 Metabolism and drug interaction
 Ecological profile, adverse...
 Additional information
 Other ketolides
 References
 
The emergence of antibiotic-resistant bacterial strains is driving the search for new antimicrobial agents and will hopefully lead to the widespread application of new antibiotics in the future. Within the last 3 years, a number of new agents, such as the newer fluoroquinolones and the oxazolidinones, reached the market. They show significantly improved activity against bacteria that have acquired resistance or show limited susceptibility to older agents.1,2

Penicillin resistance in pneumococci has already reached alarming levels worldwide.3,4 Additionally, the lack of activity against atypical pathogens limits the usage of penicillins in lower respiratory tract infection. Also the resistance and cross-resistance of macrolides, which initially offered a good activity against a wide spectrum of respiratory pathogens, is increasing among agents of the class.5,6

Macrolides were introduced to the field of anti-infectives, beginning with erythromycin A, in the early 1950s.7 Advantages over existing drugs were their value in patients with ß-lactam intolerance and activity against penicillin-resistant pathogens. Drawbacks were rapidly evolving resistance, instability of the drug in acid environment, poor absorbance by the oral route and gastrointestinal side-effects.8 New substances ideally have activity against key pathogens and overcome resistance problems. A new or extended mechanism of action is needed to fulfil these requirements.

Telithromycin (HMR 3647) is the first antibiotic belonging to a new class of 14-membered ring macrolides, named ketolides, to reach clinical use. This new addition to the macrolide–lincosamide–streptogramin B (MLSB) group was developed specifically for the treatment of community-acquired respiratory tract infections. Telithromycin was developed at Aventis (Romainville, France) and reached the market (Germany and Spain) as Ketek late in 2001.

This review will define the therapeutic uses of this advance. The data provided here are intended to help in the selection of the appropriate antibiotic therapy aimed at preserving potency of this new agent.


    Chemistry and structure–activity relationship
 Top
 Abstract
 Introduction
 Chemistry and structure-activity...
 Mechanism of action
 Antibacterial activity
 Resistance
 Animal studies and clinical...
 Pharmacodynamic characteristics...
 Pharmacokinetic characteristics...
 Metabolism and drug interaction
 Ecological profile, adverse...
 Additional information
 Other ketolides
 References
 
Ketolides are semisynthetic derivatives of erythromycin A. They represent a new chemical entity characterized by the replacement of L-cladinose fixed on the erythronolide A ring with a 3-keto function (Figure 1). The 3-hydroxyl residue left after removing the neutral sugar L-cladinose was oxidized to a 3-keto group. Hence, the class name is derived from the 3-keto-group (keto) and the lactone ring (olide). The L-cladinose sugar was long thought to be essential for the antimicrobial activity of the 14-membered ring macrolides, since its removal from clarithromycin, azithromycin and roxithromycin leads to loss of antimicrobial activity. However, with the ketolides, modifications at other positions of the macrolactone ring compensate the loss of cladinose (C3, C6, C11/12).9 Telithromycin is differentiated from other known ketolides by the introduction of a large aromatic N-substituted carbamate extension at position C11–C12. This ring also has an imidazo-pyridyl group attachment. Telithromycin possesses a 6-OCH3 group (like clarithromycin), avoiding internal hemiketalization with the 3-keto function and giving the ketolide molecule excellent acid stability.10,11



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Figure 1. Chemical structure of telithromycin; (a) the methoxy-group at C6 improves acid stability and prevents internal hemiketalization; (b) 3-keto-function avoids MLSB resistance induction and improves ribosome binding; (c) C11/12 carbamate side-chain increases affinity for the ribosomes and improves interaction with MLSB-resistant ribosomes.

 
Like erythromycin, roxithromycin, clarithromycin and azithromycin, the ketolides belong to the MLSB group of antimicrobials.


    Mechanism of action
 Top
 Abstract
 Introduction
 Chemistry and structure-activity...
 Mechanism of action
 Antibacterial activity
 Resistance
 Animal studies and clinical...
 Pharmacodynamic characteristics...
 Pharmacokinetic characteristics...
 Metabolism and drug interaction
 Ecological profile, adverse...
 Additional information
 Other ketolides
 References
 
MLSB antimicrobials target the bacterial ribosomes, which consist of two subunits, 30S and 50S. The two subunits are made of ribosomal RNA (rRNA) and numerous protein (r-protein) components. The 30S ribosomal subunit interacts with the messenger RNA (mRNA) and translates in conjunction with transfer RNAs (tRNAs) the genetic code on the mRNA. The large subunit (50S) provides the catalytic centre (peptidyl transferase centre) where a peptide bond is formed between the amino acid and the peptide chain previously synthesized. The growing peptide passes through a peptide exit channel within the 50S subunit to emerge on the back of the ribosome.9

Ketolides inhibit the synthesis of new proteins by preventing the bacterial ribosome from translating its mRNA. This process is blocked in two different ways.

(1) The peptidyl transferase centre in the 50S subunit is the site of interaction of MLSB antibiotics and of chloramphenicol and puromycin. The structure of the 50S subunit has recently been resolved by visualizing molecular details at atomic resolution using X-ray crystallography. The peptidyl transferase centre appears to be constructed entirely from elements of 23S rRNA, which is composed of six domains. This indicates that peptide bonds are catalysed by rRNA and that the catalytic centre is formed mainly from structures in domain V of the 23S rRNA. MLSB drugs, such as chloramphenicol and puromycin, bind to closely related sites on the 50S ribosomal subunit and interact with an internal loop structure within domain V of bacterial 23S rRNA in the upper portion of the peptide exit channel close to the peptidyl transferase centre (Figure 2).9,1216 Macrolides and ketolides bind to the same region of 23S rRNA. Because of the C11/12 carbamate arm in ketolide antimicrobials, the strength of interaction is different from those of macrolides. The drugs bind to the ribosome and interact with specific nucleotides in the rRNA, preventing these nucleotides from reacting with chemical reagents. Erythromycin and telithromycin interact with domains II and V of the 23S rRNA (Figure 2). In particular, erythromycin and its ketolide derivates protect in the same manner the residues A2058, A2059 and G2505 in the central loop of domain V from chemical modification. They enhance the accessibility of the neighbouring adenine at 2062.9,16 The drug-binding sites in hairpin 35 of domain II and the peptidyl transferase loop of domain V of the 23S rRNA are folded close to each other, forming a binding pocket for macrolides and other drug types.9,11 The alkyl–aryl extension at C11–C12 in the ketolide lactone ring produces the dominant effect in protecting position A752 in hairpin 35 of domain II. The cladinose moiety influences this position by expressing a less strong binding. The binding affinity for telithromycin evaluated as dissociation constants is ~10-fold stronger than that for erythromycin.16 Hairpin 35 and the peptidyl transferase loop act as a single drug-binding site on the ribosome, binding one ketolide molecule.9,16 The distance between the nucleotides involved in drug binding is probably spanned by the C11/12 carbamate compounds, whereas erythromycin and clarithromycin might not be capable of making direct contact with the base of A752.9



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Figure 2. Secondary structure models of the peptidyl transferase centre in domain V of 23S rRNA (a) and hairpin 35 in domain II (b). Positions of macrolide interactions and of mutations that confer macrolide resistance are indicated and nucleotides are circled, respectively. Ery, erythromycin; Cbm, carbomycin; Tyl, tylosin; Tel, telithromycin (figure from reference 13). Reproduced with permission from the American Society for Microbiology.

 
(2) The numerous r-protein components of rRNAs are required to create the two subunits of newly formatted ribosomes. Some 34 r-proteins and two rRNA molecules (5S and 23S) form a functionally active 50S subunit. Macrolides and ketolides interact with partially assembled 50S subunit precursors to block this process, leading to nucleolytic degradation of the unassembled precursor particles. In cells treated with erythromycin, a 50S precursor particle accumulates. Erythromycin is bound by this particle that contains 23S and 5S rRNAs but only 18 of the 34 large subunit r-proteins. Cellular ribonucleases degrade the unassembled 50S subunit particle.9


    Antibacterial activity
 Top
 Abstract
 Introduction
 Chemistry and structure-activity...
 Mechanism of action
 Antibacterial activity
 Resistance
 Animal studies and clinical...
 Pharmacodynamic characteristics...
 Pharmacokinetic characteristics...
 Metabolism and drug interaction
 Ecological profile, adverse...
 Additional information
 Other ketolides
 References
 
The microbiological profile of telithromycin is characterized by high in vitro activity against many common and atypical/intracellular respiratory pathogens, including MLSB-resistant strains as shown in Table 1. Telithromycin has improved in vitro activity against Gram-positive aerobes compared with macrolides and azalides. High activity of telithromycin against atypical respiratory pathogens (Bordetella spp., Legionella spp., Chlamydia pneumoniae, Mycoplasma pneumoniae) was demonstrated.24,27,28,30 Its potency against key community-acquired Gram-negative respiratory pathogens such as Moraxella catarrhalis and Haemophilus influenzae appeared similar to that of azithromycin.32,33 Telithromycin was found to be active against several Gram-positive and -negative anaerobic bacteria such as Clostridium spp., Peptostreptococcus spp. and Bacteroides spp.36


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Table 1.  Susceptibility of bacterial species to telithromycin, erythromycin, azithromycin and clarithromycin, MBCs for selected species; if not stated MICs are MIC50/90
 
Telithromycin is inactive against Enterobacteriaceae, non-fermentative Gram-negative bacilli, Acinetobacter baumanii and constitutively MLSB-resistant Staphylococcus aureus.

In a study from Spain, telithromycin displayed significant in vitro activity against Streptococcus pneumoniae isolates regardless of the presence of different macrolide resistance determinants [erm(B), mef(A)].20 Telithromycin is two to five times more active than clarithromycin against Gram-positive cocci susceptible to erythromycin A. Telithromycin is bactericidal against S. pneumoniae.37

Depending on the type of resistance mechanism, S. aureus isolates display MICs of 0.06–0.25 mg/L (strains harbouring an inducible MLSB phenotype) or >16 mg/L (constitutive phenotype). Similar results were obtained with coagulase-negative staphylococci.17 As shown with macrolides, telithromycin lacks activity against methicillin-resistant strains of S. aureus (MRSA). A high percentage of MRSA strains harbour genes conferring resistance to different antimicrobials, i.e. MLSB and fluoroquinolones.

Telithromycin was the most active agent (MIC50/90 0.06/ 4.0 mg/L) against Enterococcus faecalis compared with erythromycin A, azithromycin, clarithromycin, roxithromycin, clindamycin or quinupristin–dalfopristin. However, MICs between 1.0 and 4.0 mg/L were measured for E. faecalis strains resistant to both erythromycin A and clindamycin.23 Vancomycin-resistant enterococci showed reduced susceptibility to telithromycin.17,23

In vitro pharmacodynamic studies of telithromycin against extracellular or intracellular Helicobacter pylori showed promising results. The ketolide exhibited a pronounced concentration-dependent killing, a significant post-antibiotic effect (PAE) and a reduction of intracellular H. pylori.35

Telithromycin displayed good in vitro activity against intracellular pathogens, such as Rickettsia spp. and Bartonella spp. At concentrations of 0.25–8 mg/L, telithromycin was ineffective against Ehrlichia chaffensis.31


    Resistance
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 Abstract
 Introduction
 Chemistry and structure-activity...
 Mechanism of action
 Antibacterial activity
 Resistance
 Animal studies and clinical...
 Pharmacodynamic characteristics...
 Pharmacokinetic characteristics...
 Metabolism and drug interaction
 Ecological profile, adverse...
 Additional information
 Other ketolides
 References
 
Three main mechanisms of resistance account for acquired resistance to MLSB antimicrobials: (i) target site modification, (ii) reduced intracellular accumulation due to decreased influx or increased efflux of the drug and (iii) production of inactivating enzymes.

Target site modification

Target site modification occurs as a mutation on 23S rRNA or on ribosomal proteins, or is due to mono- or dimethylation of 23S rRNA at positions A2058 and A2059. Methylation is usually governed by the acquisition of erm genes. erm genes encode methyltransferases that N6-dimethylate specific adenine residues within a conserved region of the rRNA. Ribosomal methylation confers cross-resistance to MLSB antibiotics because the binding sites of these drugs overlap. The methylation leads to a conformational change in the ribosome, resulting in decreased affinity for all MLSB antibiotics. Numerous erm genes have been described for different clinically important bacterial species.13,38,39 Methylation or substitution of A2058 alters the major contact site for the drugs. Binding of clarithromycin and erythromycin to Escherichia coli ribosomes is reduced over 10 000-fold by the 23S rRNA A2058G mutation. Binding of telithromycin is reduced by the A2058G mutation, but this mechanism is clearly less efficacious than for other MLSB drugs.

G2057 and C2611 form a base pair that closes the central loop in domain V being at the periphery of the binding site (Figure 2). Mutations in both nucleotides (2057A, 2611U) confer erythromycin, but not MLSB, resistance.40 Ketolides with a C11/12 carbamate remain active against most strains that are resistant to erythromycin due to changes in the drug-binding site. These agents are anchored more tightly to domain II of the rRNA and this makes up for the effect of the 2058G mutation in domain V.40 The improved domain II interaction enables telithromycin to maintain a precarious, but crucial, foothold in domain V of MLSB-resistant ribosomes.13 However, a single point mutation (U754A) in hairpin 35 domain II of 23S rRNA was found to confer resistance to lower concentrations of telithromycin. The U754A mutation in the stem of hairpin 35 is suggested to change the overall conformation of the hairpin loop, making it less favourable for interaction with the antibiotic.41 The degree of resistance to MLSB and ketolide antibiotics is determined by how effectively the rRNA is methylated. For instance, streptococcal species dimethylate their rRNA with different efficiencies. Monomethylation only mildly affects the antimicrobial activity of telithromycin.42

Repeated in vitro exposure of pneumococci to telithromycin selected for pneumococcal mutants with increased MICs. Resistance was less often selected with telithromycin than with macrolides, clindamycin or pristinamycin.43 Four high-level ketolide-resistant streptococci (two S. pneumoniae and two Streptococcus pyogenes) isolated from clinical patients have been characterized. All four were found to harbour versions of erm(B), one of them in combination with an L4 mutation.44 Recently, a transition of U to C at position 2609 of the 23S rRNA was described to confer resistance to ketolide antibiotics while leaving cells sensitive to other types of macrolides or even with slightly increased sensitivity to erythromycin. A possible direct interaction of ketolides with position 2609 in 23S rRNA was postulated.45

Expression of MLSB resistance can be constitutive (the methylating enzyme is produced continuously) or inducible (the presence of an inducing antibiotic is required for production of the enzyme), being, respectively, the iMLSB or cMLSB phenotypes. In staphylococci 14- (erythromycin, clarithromycin, roxithromycin) and 15- (azithromycin) membered ring macrolides are inducers, whereas 16- (josamycin) membered ring macrolides and lincosamides are not. Streptococci show cross-resistance between MLSB antibiotics, which are efficient inducers.39 Ketolides are unable to induce MLSB resistance in streptococci. They remain active against erythromycin A-inducible resistant bacteria. The replacement of the L-cladinose group of macrolides with a keto group was suggested to be linked to the lack of inducibility of MLSB resistance phenotype in ketolides.46 However, telithromycin was able to select for constitutive erm(A) mutants in staphylococci, in which the erm(A) translational activator was found to be altered. The inducible expression of erm(A) could be turned into constitutive expression by selection with telithromycin overnight. Thus, ketolides should be avoided in the treatment of infections with staphylococci showing inducible resistance to MLSB antibiotics.47

Efflux pumps

Efflux pumps for erythromycin A have been described for several Gram-positive cocci. The efflux-mediated resistance pattern, known as M phenotype, is encoded by different genes: mef(A) or mef(E) in streptococci, and msr(A) and msr(B) in staphylococci.37,48,49

The phenotype of macrolide resistance in S. pyogenes is differentiated by the so-called double- or triple-disc assay.22 The conventional double-disc assay uses erythromycin and clindamycin to identify strains expressing the M phenotype, which is characterized by susceptibility to lincosamides, even after induction, and 16-membered macrolides. This resistance pattern has also been observed in S. pneumoniae.4850 Adding josamycin to the assay makes it possible to differentiate three subtypes of inducible resistant S. pyogenes strains (iMLS subtype A: highly resistant to josamycin; subtypes B and C: susceptible to josamycin, high-level and low-level resistance, respectively, after induction). Genotypic investigations showed that all M isolates had only the efflux gene [mef(A), also found in a variable proportion of strains of the other phenotypes]. erm(B) was detected in all cMLS and iMLS-A isolates, and erm(TR) in all iMLS-B and iMLS-C isolates. Neither methylase gene was found in isolates of other groups.22 Telithromycin retained good activity against streptococci harbouring mef genes. The ketolide acts as an inducer of msr genes in staphylococci, but is not a good substrate for Msr pumps.37

Production of antibiotic inactivating enzymes

Degradation due to hydrolysis of the macrolide lactone ring by an esterase and modification due to macrolide phosphorylation and lincosamide nucleotidylation appear to play a minor role in MLSB resistance. Only a few strains have been reported to harbour corresponding genes and to produce inactivating enzymes.51,52

Mutations in ribosomal proteins

A new resistance mechanism was detected in S. pneumoniae strains. Proteins L4 and L22 of the 50S ribosomal subunit are in contact with the nucleotides A2058 and A752 of the peptidyl transferase region. Mutations in the ribosomal protein L4 were found to be responsible for macrolide resistance in S. pneumoniae due to altering the conformation of the drug-binding site.53

However, the whole matter of phenotypic and genotypic diversity in macrolide resistance still seems to be far from being completely analysed.


    Animal studies and clinical trials
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 Abstract
 Introduction
 Chemistry and structure-activity...
 Mechanism of action
 Antibacterial activity
 Resistance
 Animal studies and clinical...
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 Pharmacokinetic characteristics...
 Metabolism and drug interaction
 Ecological profile, adverse...
 Additional information
 Other ketolides
 References
 
The results of several animal studies and clinical trials are presented in Tables 2 and 3.


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Table 2.  Activity of telithromycin in animal models
 

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Table 3.  Efficacy of telithromycin in the treatment of human infections
 
Telithromycin has been investigated for a variety of localized and systemic infections. Using animal models, the possibilities as well as limitations of the compound were shown (Table 2). Good activity was reported for telithromycin in pneumonia, thigh and systemic infection. The results were better than or comparable to substances such as erythromycin, azithromycin and clarithromycin.54,57,61,65 Interestingly, telithromycin was found to reduce the lipid accumulation in the aortic root of mice with a chronic C. pneumoniae infection.62 The ketolide was active in septicaemia induced by pathogens resistant to erythromycin A, showed high therapeutic activity against H. influenzae and was also active in thigh muscle infection by S. aureus.54 Telithromycin was slightly more effective at eradicating the infectious organisms in the liver and spleen than erythromycin in a mouse infection model of systemic listeriosis. In the brain of intracerebrally infected mice, eradication of the listeria was delayed (clearance began after day 7 of infection).55 In Bacteroides fragilis-induced intra-abdominal abscesses in mice, the ketolide was as effective as clindamycin and more effective than metronidazole.56 Telithromycin was active in Legionella pneumophila-infected guinea pigs.27 In contrast to its poor in vitro activity, telithromycin showed significant activity in the treatment of Mycobacterium avium infection in mice; 100 and 200 mg/kg per day of telithromycin showed bacteriostatic effects, but 400 mg/kg per day of telithromycin was bactericidal. Moreover, the frequency of the emergence of resistance was low, despite long courses of therapy.79 Low doses of telithromycin used in combination with ineffective doses of atoquavone, clindamycin or sulphadiazine were highly effective in the treatment of toxoplasmosis in mice.58

Four international, multicentre clinical trials reported an overall success rate of 90% in terms of microbiological outcome (eradication or presumed eradication) and a clinical success rate of 92%. Telithromycin proved to be as efficacious as fluoroquinolones and macrolides in the treatment of community-acquired pneumonia (CAP). In addition its efficacy is retained in CAP caused by penicillin- or erythromycin-resistant pneumococci.8083 Clinical trials presented at ICAAC 2001 reported differing rates for pathogen eradication and clinical cure (Table 3). The infections studied were respiratory tract infections, such as acute maxillary sinusitis, acute exacerbation of chronic bronchitis and CAP. S. pneumoniae, H. influenzae, S. pyogenes and atypical respiratory pathogens were identified as causative pathogens. The clinical efficacy of telithromycin was compared with that of cefuroxime, co-amoxiclav, clarithromycin and penicillin. Telithromycin has demonstrated equal or better clinical efficacy than commonly used drugs for the treatment of community-acquired respiratory tract infections. No significant differences in clinical cure rates and pathogen eradication were seen between the groups treated for 5 or 10 days with 800 mg of telithromycin.

Further information can be obtained from excellent summaries published by Shain & Amsden,84 and Johnson.85


    Pharmacodynamic characteristics (Table 4)
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 Abstract
 Introduction
 Chemistry and structure-activity...
 Mechanism of action
 Antibacterial activity
 Resistance
 Animal studies and clinical...
 Pharmacodynamic characteristics...
 Pharmacokinetic characteristics...
 Metabolism and drug interaction
 Ecological profile, adverse...
 Additional information
 Other ketolides
 References
 
Boswell et al.90 demonstrated concentration- and inoculum-dependent bacteriostatic activity for telithromycin and respiratory pathogens, enterococci and B. fragilis. Ketolides express concentration-dependent killing, including pneumococci resistant to erythromycin. Bactericidal activity was only seen at higher concentration but not with all strains studied. Telithromycin exhibited a significant PAE ranging from 1.2 to 8.2 h at 10 x MIC. In vitro experiments showed a bactericidal activity against S. pneumoniae at or above the MIC and a 99% reduction in viability within 12–24 h at 2 x MIC.33 These results could be confirmed in vivo using a mouse septicaemia model.91 A PAE up to several hours at 2 x and 4 x MIC against both erythromycin-susceptible and -resistant strains of S. pneumoniae and S. aureus, and both ß-lactamase-negative and -positive strains of H. influenzae and M. catarrhalis, was demonstrated.33,89 Comparing PAEs for erythromycin A-susceptible and -resistant strains of streptococci A, much longer PAEs against erythromycin A-susceptible strains have been reported. These differences were not seen with staphylococci.92


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Table 4.  Pharmacodynamic and pharmacokinetic profile8689
 

    Pharmacokinetic characteristics (Table 4)
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 Abstract
 Introduction
 Chemistry and structure-activity...
 Mechanism of action
 Antibacterial activity
 Resistance
 Animal studies and clinical...
 Pharmacodynamic characteristics...
 Pharmacokinetic characteristics...
 Metabolism and drug interaction
 Ecological profile, adverse...
 Additional information
 Other ketolides
 References
 
Ketolides are highly stable in acidic media. The C11–C12 carbamate substituent is responsible for improved activity in comparison with erythromycin A. Differences in the side chains fixed to the C11–C12 carbamate residues characterize numerous carbamate ketolides such as HMR 3004, ABT 773 and telithromycin.93,94 In addition, the C11–C12 fixed side chain defines in vitro activities, pharmacodynamics, intracellular uptake, accumulation and efflux, and tolerance.95

Namour et al.87 evaluated the single- and multiple-dose pharmacokinetics and dose proportionality of telithromycin given once daily over the dose range of 400–1600 mg/day in healthy human subjects. Absorbance after oral administration was rapid, reaching Cmax within 1 h of dosing. Food intake did not affect absorption. Steady-state plasma concentrations were reached within 2–3 days of multiple dosing, regardless of the dose. Total plasma protein binding was ~70% with an absolute bioavailability of telithromycin of 57%. A moderate accumulation was observed after 7 days of dosing. The authors explained this phenomenon by a slight decrease in non-renal clearance with multiple dosing. They concluded that a once-daily 800 mg oral dose of telithromycin maintains an effective concentration in plasma for the treatment of respiratory tract infections involving key respiratory pathogens.87 Studies of pharmacokinetics of telithromycin in special populations (elderly, impaired renal or hepatic function) did not indicate an alteration of dosing for those patients.

Intracellular accumulation of telithromycin was characterized by an intracellular/extracellular ratio ranging from 27 ± 8.1 (5 min) to 348 ± 27.1 (180 min). It was detected mainly in the granule fraction of polymorphonuclear neutrophils (PMNs).96 Telithromycin reached intracellular concentrations 130 and 71 times higher than extracellular concentrations in human neutrophils and human peritoneal macrophages. The uptake was rapid and non-saturable. The slow efflux from human phagocytic cells suggested that these cells could act as transport vehicles for the antibiotic to the site of infection. However, the intracellular activity of telithromycin against S. aureus did not correlate with the concentrations obtained. The intracellular survival rate of S. aureus in PMNs was not reduced at 3 h.97 The concentration of telithromycin in alveolar macrophages exceeded that in plasma up to 146 times 8 h after dosing. The drug was retained in alveolar macrophages 24 h after dosing (still quantifiable after 48 h).88 Good penetration of telithromycin into respiratory tissues was reported after administration of multiple oral doses of 800 mg. Mean MIC90s for common respiratory pathogens S. pneumoniae, M. catarrhalis and M. pneumoniae (0.12, 0.03 and 0.001 mg/L) were exceeded for 24 h by concentrations of telithromycin in bronchial mucosa and epithelial lining fluid.98 Similar to macrolides and azalides, telithromycin uptake into extracellular tissue appears to be enhanced by inflammation.84

Testing S. pneumoniae and H. influenzae, AUC/MIC ratios for telithromycin were favourable in comparison with azithromycin. In animal models, the Cmax/MIC ratio of telithromycin was far higher than those achieved with macrolide antimicrobials.94 Supported by the pharmacodynamic data, once-daily dose regimens of telithromycin were suggested.


    Metabolism and drug interaction
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 Abstract
 Introduction
 Chemistry and structure-activity...
 Mechanism of action
 Antibacterial activity
 Resistance
 Animal studies and clinical...
 Pharmacodynamic characteristics...
 Pharmacokinetic characteristics...
 Metabolism and drug interaction
 Ecological profile, adverse...
 Additional information
 Other ketolides
 References
 
Telithromycin undergoes hepatic metabolization and is eliminated primarily through the faeces (~80%).86 RU 76363, an alcohol resulting from hydrolysis of the aryl rings of the carbamate side chain of telithromycin, is the major hepatic metabolite, and is 4- to 16-fold less active than telithromycin in vitro. Its AUC represents ~10–12% that of telithromycin.87 Excretion of telithromycin is almost complete in urine after 24 h and in faeces after 72 h.86

Telithromycin is an inhibitor of CYP3A4 and in vitro of CYP2D6. Telithromycin should not be used in combination with drugs such as simvastatin, midazolam and cisaprid. Plasma concentrations of cyclosporin, tacrolimus and sirolimus need to be monitored during telithromycin therapy. An increase in QTc interval (<500 ms) in special patients has been described.84 The increase in the AUC of telithromycin due to therapy with itraconazole and ketoconazole does not indicate a dose adjustment. AUCs of theophylline, digoxin and levonorgestrel are increased in the presence of telithromycin.37,99


    Ecological profile, adverse effects and clinical use
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 Abstract
 Introduction
 Chemistry and structure-activity...
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 Animal studies and clinical...
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 Metabolism and drug interaction
 Ecological profile, adverse...
 Additional information
 Other ketolides
 References
 
The impact of telithromycin on the oropharyngeal flora was studied, i.e. in comparison with clarithromycin. Both compounds were associated with the selection of resistant intestinal and oropharyngeal strains. High concentrations were measured for both antibiotics in saliva and faeces. The concentration of telithromycin exceeded that of clarithromycin.100 Telithromycin selected resistant B. fragilis strains in the human intestinal microflora. E. coli and enterococci were reduced whereas overgrowth of staphylococci was observed.101 The impact of telithromycin compared with co-amoxiclav on the intestinal (stool yeasts increased in both groups), skin (flora remained stable) and oropharyngeal microflora (emergence of resistant streptococci more frequent in the co-amoxiclav group) of healthy volunteers was investigated, showing that telithromycin did not lead to Clostridium difficile colonization.102

Summarizing the data evaluated in four multicentre clinical trials, diarrhoea was the most common adverse event occurring in patients treated with 800 mg once daily (in 13.7% of patients). The incidence of other adverse reaction was as follows: nausea 8.7%, headache 6.7%, dizziness 3.5%, vomiting 3.1%.8083

More clinical data and the surveillance of bacterial susceptibility will define the place of telithromycin in the management of CAP.


    Additional information
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 Abstract
 Introduction
 Chemistry and structure-activity...
 Mechanism of action
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 Metabolism and drug interaction
 Ecological profile, adverse...
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 Other ketolides
 References
 
Breakpoints for telithromycin are still under consideration. Suggested MICs for susceptibility and resistance according to the marketing company (Aventis) are <=0.5 and >2 mg/L, respectively.99

Methodological factors in susceptibility tests influence the outcome of strains expressing different resistance patterns. The presence of 5–6% CO2 had a remarkable effect on the MICs for eryR strains of S. pneumoniae. Adding 5–6% CO2 resulted in 1–6 two-fold increased dilutions of MICs.21

In total, 4175 Gram-positive strains were used to evaluate interpretive criteria and quality control parameters for telithromycin disc diffusion susceptibility tests using 15 µg telithromycin discs. For staphylococci, the following tentative disc criteria were proposed: <=19 mm for resistant, 20–22 for intermediate, >=23 for susceptible. Testing S. pneumoniae and other streptococci incubation with 5–7% CO2 is recommended by this group as well. Interpretive zone size criteria are <=16 for resistant, 17–19 for intermediate and >=20 for susceptible.103

Aventis (formerly Hoechst-Marion-Roussell) provides a website where actual data on susceptibility of bacterial pathogens isolated from patients with community-acquired respiratory tract infections from >20 countries on five continents can be obtained (PROTEKT: Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin; www.protekt.org).3,5 Epidemiological data including the activity of telithromycin against those pathogens are reported.


    Other ketolides
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 Abstract
 Introduction
 Chemistry and structure-activity...
 Mechanism of action
 Antibacterial activity
 Resistance
 Animal studies and clinical...
 Pharmacodynamic characteristics...
 Pharmacokinetic characteristics...
 Metabolism and drug interaction
 Ecological profile, adverse...
 Additional information
 Other ketolides
 References
 
Several new ketolides developed by different companies are under investigation. Champney & Tober94 studied structure–activity relations for six ketolides in S. aureus cells. These antibiotics are all 3-keto, 6-methoxy, 11,12-carbamate macrolactone molecules. Their chemical structures differ in the type of aromatic ring substituent and in the presence or absence of a 2-fluoro group. ABT 773 is a 6-O-substituted ketolide exhibiting higher in vitro activity than telithromycin. Their results indicated that ABT 773 and HMR 3004 might optimally be used as antimicrobial agents against S. aureus. As a result of their aromatic ring structure they showed a tight ribosome association.94 HMR 3004 showed substantially shorter PAEs than telithromycin against streptococci (3.2–4.4 h).92 HMR 3787 is a new fluoroketolide that was tested with pneumococci and S. pyogenes. HMR 3787 had lower MICs for erm(B) strains than telithromycin.104


    Footnotes
 
* Corresponding author. Tel: +49-341-971-5200; Fax: +49-341-971-5209; E-mail: ackermg{at}medizin.uni-leipzig.de Back


    References
 Top
 Abstract
 Introduction
 Chemistry and structure-activity...
 Mechanism of action
 Antibacterial activity
 Resistance
 Animal studies and clinical...
 Pharmacodynamic characteristics...
 Pharmacokinetic characteristics...
 Metabolism and drug interaction
 Ecological profile, adverse...
 Additional information
 Other ketolides
 References
 
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