Ketolides (Telithromycin, Cethromycin)

Updated February, 2008

George G. Zhanel, Ph.D.,,  Melinda M. Neuhauser, Pharm.D.

CLASS

               Ketolides are a new class of macrolides designed particularly to combat respiratory tract pathogens that have acquired resistance to macrolides. The main structural difference between the ketolides and the older macrolides is the lack of the L-cladinose sugar at position 3 of the erythronolide A ring and its replacement with a 3-keto functional group. Telithromycin and cethromycin (formerly ABT-773) have in vitro activity against many pathogens seen in community-acquired respiratory infections including penicillin and macrolide-resistant strains of Streptococcus pneumoniae (7, 26, 67). Presently, telithromycin has been approved for clinical use in the United States, Canada, several European and Latin American countries (108), while cethromycin is in Phase 3 development.

Chemical Structure

The ketolides are semi-synthetic derivatives of the 14-membered macrolide erythromycin A. They retain the macrolactone ring structure and the D-desosamine sugar attached at position 5 (3). However, a number of important structural changes have been made to improve on both the activity and the pharmacokinetics of earlier compounds. The defining characteristic of the ketolides is the removal of the neutral sugar, L-cladinose from the 3 position of the erythronolide ring, and the subsequent oxidation of the 3-hydroxyl to a 3-keto functional group (Figure 1). In addition the ketolides under development contain an 11, 12 cyclic carbamate linkage in place of the two hydroxyl groups of erythromycin A and an arylalkyl or an arylallyl chain linked to the molecule, imparting activity equal to or better than the newer macrolides (36).

Structure-Activity Relationship

The earliest macrolide antibiotics were found to quickly degrade in an acidic environment, and thus they had an erratic oral absorption and caused increased gastric irritation (200). One of the advantages of the ketolide molecules is an improved acid stability, which is due to the removal of the L-cladinose moiety (Figure 2). In addition, compounds with the 3-keto group do not trigger the expression of resistance to MLSB (macrolide lincosamide streptogramin B) antibiotics in strains with inducible erm determinants (24). This allows the ketolides to remain active against bacterial strains in which MLSB resistance would be induced by 14 and 15-membered macrolides such as azithromycin, clarithromycin and erythromycin (4, 166). One exception is the ketolide TE-802, which induces MLSB resistance, indicating that the 3-keto alone is not always sufficient to avoid induction and that the arylalkyl side chains probably play a role as well (202, 203). The side chain is of immense importance for the activity of the ketolides. Removal of L-cladinose from erythromycin A causes decreased ribosomal binding, but this can be more than adequately compensated for by the addition of the 11, 12-carbamate extension (55, 91).

The 11, 12-carbamate is present in both telithromycin and cethromycin (Figure 1). It has been shown that this structure improves activity in macrolides and greatly enhances the activity of ketolides (31). Having a 6-O-alkyl group and an 11, 12-carbamate structure also prevents 6-9 or 9-12 cyclization within the compound that would result in a hemi-ketal product commonly formed by erythromycin in acidic media (21).

Telithromycin and cethromycin (Figure 1) also contain heterocyclic aromatic rings spaced from the lactone ring structure via short alkyl or allyl linkages. These structures impart improved ribosomal binding and thereby increase the activity of the compounds against both macrolide-susceptible and resistant strains (91, 121). However, these two compounds differ in the nature of the linkages of the side chains to the lactone ring structure. Telithromycin has a butyl imidazolyl pyridinyl side chain attached to the carbamate nitrogen (Figure 1). The aromatic nature of the substituent facilitates an interaction with nucleotide A752 in domain II of the 23S rRNA in addition to the main interaction of the drugs in domain V (Figure 3). This results in tighter binding to ribosomes (91) and imparts some activity against methylated ribosomes in some species (35, 37, 196).

Cethromycin has an unsubstituted 11, 12-carbamate linkage, but contains a 3-quinolyl-propylene chain linked to the position 6 oxygen (Figure 1) (119). It was long thought that the 6-position could only accommodate a small substituent, (telithromycin has an O-methyl at the 6-position). However, cethromycin has excellent in vitro activity and it was found that the allyl linkage orients the aromatic group in such a way that it can interact in the same manner as the carbamate side chain in telithromycin. In solution it is believed that the aromatic group interacts with the hydrophobic face of the lactone ring; removal of the L-cladinose and addition of an aromatic ring system increase the hydrophobicity of the ketolides, thus improving their pharmacokinetics (21, 119, 146).

Other modifications have been attempted with the ketolide structure, and may show promise for the design of future chemical entities (Figure 2). Position 2 of the lactone ring has been found to require a tetrahedral bond structure to retain activity. This section of the molecule is found within a beta-keto ester functional moiety (positions 1 through 3), and it has been postulated that the 2-position may be subject to alkylation reactions. Thus, fluoro-ketolides have been synthesized to protect this position. Larger substituents, such as chlorine, bromine or methyl, decrease the activity of the compounds, whereas compounds with fluorine at this position retain their antimicrobial activity (31, 50). This in turn has allowed the synthesis of a number of 6-O-propargyl derivatives, but the in vitro activity of these compounds has not been determined (152). 2-Fluoro-ketolides have been found to have excellent activity and the structure is likely to be incorporated into future antimicrobial compounds (37, 39, 68, 77, 107).

Position 9 has also been used as a modification point, but most oxime and N-linked tricyclic structures were found to be less active than the corresponding 9-keto compounds and many were inactive against resistant strains (4). However, recent syntheses of 2-fluoro-6-oxime compounds have shown improved in vitro activities against both macrolide-susceptible and macrolide resistant respiratory pathogens (107). Position 10 has been shown to require a methyl substituent for activity, but position 13 can tolerate some structural variation (33). Aza-ketolide derivatives have also been synthesized, but as of yet none have shown activity (30).

ANTIMICROBIAL ACTIVITY

Spectrum

The in vitro activities of the ketolides are presented in Tables 1 to 3. Clarithromycin and azithromycin are included in these tables for comparative purposes (5, 7, 12-15, 20, 23, 26, 29, 38, 46, 48, 52, 56, 58, 63, 65, 68, 70, 72, 76-78, 80, 89, 94-102, 114, 115, 118, 120, 122, 124-126, 128, 130, 131, 134-136, 138, 140, 145, 147, 148, 153, 158, 161, 167, 169, 171, 174-179, 185, 192, 194, 195, 201)(3, 89, 140, 145). The tables present the minimum concentration (µg/ml) of antibiotic required to inhibit growth of 50% of the tested isolates (MIC50) and 90% of the tested isolates (MIC90). The tables also show the range of MIC values of each organism reported in the literature and represent data on thousands of isolates. Data in the tables were not restricted as to growth or as to growth conditions or as to methodology of the study. The ketolides display good activity against the majority of Gram-positive aerobic bacteria (Table 1). Against the strains of S. pneumoniae reported in the references, the ketolides displayed excellent activity with MIC90 values ≤ 0.12 µg/mL.

The ketolides also retained activity against pneumococci with known erythromycin resistance mechanisms, although the MIC values tended to be a few dilutions higher than macrolide susceptible strains. Against Streptococcus pyogenes, the ketolides had activity against some erythromycin-resistant strains with good activity against isolates with the ermA genotype (Table 1). They showed a slight decrease in activity against strains with mefA/E efflux resistance, but with MIC90 values below proposed susceptible breakpoints. However, ketolides exhibited markedly decreased activity against strains displaying the ermB resistance genotype (75, 76, 140). The ketolides displayed activity against erythromycin susceptible Staphylococcus aureus; however, they lack activity against erythromycin resistant S. aureus or coagulase negative Staphylococcus spp. (3, 89, 140). The ketolides were more active against E. faecalis than the macrolides, but both the ketolides and macrolides exhibited poor activity against E. faecium. There was a wide interspecies variability in the susceptibility of Corynebacterium spp. to the macrolides and ketolides. Listeria monocytogenes showed susceptibility to all agents with MIC90 values ≤1 µg/mL (Table 1).

The activity of ketolides against clinically important Gram-negative aerobic bacteria is presented in Table 2. The majority of Gram-negative aerobes, including the Enterobacteriaciae and Pseudomonas aeruginosa, have proven to be intrinsically resistant to the macrolide class of antibiotics (1). This is also true of the ketolide antibiotics (140). However, ketolides and macrolides were active against a number of clinically important Gram-negative species. Ketolides display similar (or greater) activity against Haemophilus influenzae as azithromycin (Table 2). In addition, the ketolides displayed good activity against Moraxella catarrhalis, Neisseria species and Bordetella pertussis (MIC90 values ≤0.25 µg/mL). Limited data shows that ketolides have activity against macrolide susceptible Helicobacter pylori. However, it does not appear that macrolide resistant strains will be susceptible to the ketolide antibiotics (Table 2).

Ketolide activity against anaerobic bacteria is presented in Table 3. In general, ketolides had poor activity against Bacteroides species. However, they displayed good activity against Clostridium perfringens and limited activity against C. difficile. Other Clostridium species were variably inhibited, depending upon the organism and the antibiotic. Like macrolides, the ketolides exhibited poor activity against the Fusobacterium species. However, they showed good activity against Peptostreptococcus species (Table 3).

The ketolides showed in vitro activity against the clinically important intracellular and atypical pathogens Chlamydophila (Chlamydia) pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae and Ureaplasma urealyticum (18, 19, 61, 85, 140, 163, 172, 180, 197). The MIC90 values of telithromycin were ≤0.25 µg/mL for C. pneumoniae, ≤0.12 µg/mL for L. pneumophila, ≤0.001 µg/mL for M. pneumoniae and ≤0.03 µg/mL for U. urealyticum.

The ketolides display in vitro activity against organisms that could be used as agents for biological warfare (e.g., Bacillus anthracis, Yersinia pestis). The MIC90 values of cethromycin were 0.12 µg/mL for B. anthracis and 2 µg/mL for Y. pestis (92).

Pharmacodynamic

Effects Bactericidal Effects: Macrolides are generally considered bacteriostatic agents against most bacterial species, but have reported bactericidal activity against varying species (the nature of activity depends upon the antibiotic and a number of other factors) (200). Ketolides in general follow this pattern, displaying bacteriostatic activity against many species, but showing bactericidal activity at higher concentrations against some important pathogens. Telithromycin and cethromycin show bactericidal activity against S. pneumoniae. Importantly, these drugs are bactericidal against S. pneumoniae resistant to erythromycin A. (3, 23, 44, 48, 57, 84, 140, 144, 145, 147, 160). Telithromycin and cethromycin also demonstrate limited bactericidal activity against S. pyogenes, H. influenzae and M. catarrhalis by 24 hours depending upon the concentration of antibiotic (typically ≥4x the MIC value is required) and the size of the inoculum (3, 23, 44, 48, 57, 84, 140, 144, 145, 147, 160). However, at concentrations in the range of 2x to 10x the MIC, telithromycin and cethromycin are mainly bacteriostatic against S. aureus, Enterococcus spp., and Gram-positive bacilli (26, 27, 57, 69, 98, 120, 140, 145). In vitro pharmacodynamic models that simulates human unbound plasma concentrations of telithromycin has shown bacteriostatic activity against S. pneumoniae, H. influenzae, and S. aureus at the concentrations likely to be achieved in vivo (25).

Telithromycin showed bactericidal activity against B. fragilis at 10x the MIC value (27, 28). Against other anaerobes telithromycin also showed some bactericidal activity after 24 hours at higher concentrations (≥4x the MIC), but was mainly bacteriostatic (43). Telithromycin and cethromycin were slowly bactericidal against C. pneumoniae and mainly bacteriostatic against L. pneumophila (10, 44, 85, 104).

Effects on Subinhibitory Concentrations: The development of in vitro resistance has been shown to be less frequent with telithromycin compared to clarithromycin, erythromycin, roxithromycin, clindamycin, and pristinamycin (47, 140). When exposing 5 macrolide-susceptible and 6 macrolide-resistant (3 mefE and 3 ermB strains) strains of S. pneumoniae to subinhibitory antimicrobial concentrations, a total of 54 mutants were isolated in the experiment. Only 3 mutants were resistant to telithromycin compared a range of 20 to 45 mutants were resistant to each of the other agents. The ability for cethromycin to select mutants was determined by growing organisms on agar plates with varying concentrations above the MICs (141). Cethromycin selected for resistant mutants in 8 of the 12 strains; however, this occurred at infrequent rates.

Postantibiotic Effects: Macrolides have been found to have extensive PAE values against the majority of important respiratory pathogens, allowing the extension of the dosing intervals. Recent work with the newer ketolides has demonstrated PAE values equal to or improved over macrolide comparators (28, 44, 48, 57, 139, 144, 160). Munckhof et al. conducted a number of PAE experiments at different antibiotic concentrations for telithromycin and determined a theoretical maximum PAE value against different isolates as exposure concentration of the antibiotic increased. The report calculated maximum PAE values of 3.7 hours for S. aureus, 8.9 hours for S. pyogenes and 9.7 hours for S. pneumoniae (macrolide-susceptible) with the drug telithromycin (133). PAE results for telithromycin against H. influenzae were also good, with values ≥6.7 hours at an exposure to 10x the MIC, and =1.3 hours against M. catarrhalis at 4x the MIC (48, 160). Telithromycin at 10x the MIC exhibit extensive PAE (=5 hours) and PASME (post antibiotic sub-MIC effect; =12 hours) values against H. pylori (84).

Cethromycin also displays extensive PAE values against a number of species. For S. pneumoniae, cethromycin gave PAE values at 10x the MIC of =1.7 hours (macrolide susceptible and macrolide-resistant), and values were greater than for comparator macrolides (44, 160). Against H. influenzae, cethromycin exhibited PAE values =4.9 hours, which is comparable to azithromycin, the macrolide with the longest PAE (48, 160). Against S. aureus, the PAE values obtained were =3.41 hours and against M. catarrhalis, the values were =3.8 hours (160). Cethromycin also gave PAE values of =2 hours against L. pneumophila

Effects on Host Immunity: Ketolides may have the ability to suppress the inflammatory response that causes significant morbidity and mortality during lower respiratory infections of S. pneumoniae. Ketolides have been shown to decrease levels of immune mediators and neutrophil recruitment due to live or heat killed S. pneumoniae in animal models and in vitro (59, 60, 103). PMN induced phospholipid mediators, such as platelet activating factor (PAF), have been shown to induce ciliary slowing and epithelial damage in the airways. Work by Feldman et al. has shown that telithromycin can antagonize the activity of bioactive phospholipids (66). The exact mechanism of these reactions remains to be elucidated, and additional work in vivo is needed to determine if this pharmacodynamic response in vitro can be translated into clinical efficacy during infection with S. pneumoniae and during other inflammatory conditions such as asthma.

Pharmacodynamic Correlates with Outcome: Ketolides have been found to display concentration dependent killing and that AUC (area under the curve)ketolide/MICpathogen is highly correlated with efficacy (6, 10, 42, 84, 112, 144, 188).

MECHANISM OF ACTION

Ketolides have a mechanism of action very similar to erythromycin A from which they have been derived. They inhibit bacterial protein synthesis by interacting close to the peptidyl transferase site of the 50S ribosomal subunit (21, 35, 37). It has been shown that the main sites of macrolide and ketolide interaction are within domains II and V of the 23S rRNA (Figure 3) (91, 196). Both macrolides and ketolides bind to the ribosome in a 1:1 ratio (21) indicating that domains II and V fold to lie in close proximity in the tertiary structure of the rRNA and thereby form a single drug binding pocket. This structure has recently been conclusively confirmed by the crystallographic models of the 50S subunit (11, 168, 198).

The main site of macrolide and ketolide interaction has been defined by chemical footprinting experiments (91, 196) and is located at nucleotides A2058 and A2059 in domain V (Figure 3). Although both macrolides and ketolides protect these bases from chemical modification, the ketolides display a higher affinity than macrolides for forming interactions with the ribosomes (21, 34). This increased affinity has been shown to be due to the additional interaction at A752 in domain II. This tighter interaction is mediated by the 11, 12-carbamate side chain (54, 91, 121).

Telithromycin protects position A752 in domain II from chemical modification, whereas erythromycin A enhances the reactivity of this position. This implies that ketolides with the 11/12 carbamate interact directly with the base of A752, whereas drugs without the carbamate probably interact in the vicinity of nucleotide A752, but without directly contacting its base (91, 196). Base substitutions at position A752 reduce the binding of ketolides, but not macrolides, reinforcing the notion that the adenine base at A752 is an important secondary contact site for the carbamate ketolides (143). This additional contact presumably enables the ketolides to retain activity against bacteria that have base modifications in domain V (20, 34, 54, 90, 143, 165).

In addition to inhibiting protein synthesis the ketolides also demonstrate a significant inhibitory effect on the formation of 50S ribosomal subunits (35, 37). When tested against S. aureus cells, the IC50 (inhibitory concentration) of formation of the 50S subunit was found to be roughly equivalent to that of the IC50 of the inhibition of translation (35). At higher concentrations, the 11, 12-carbamate ketolides inhibit protein synthesis to such an extent that the formation of the 30S ribosomal subunit was also impaired (37). These results show ketolides to be very potent inhibitors of protein synthesis in vivo.

MECHANISM OF RESISTANCE

Macrolide resistance in several key pathogens is well documented globally, and it can occur via a number of mechanisms (93). The most common resistance mechanisms in Gram-positive cocci are mediated by mef - encoded efflux or erm encoded methylation of 23S ribosomal RNA. According to the nomenclature proposed by Roberts et al. efflux resistance in S. pneumoniae and S. pyogenes is encoded by mefA, while ribosomal methylation is encoded by ermB in S. pneumoniae, and ermB and ermA in S. pyogenes (162). In addition to the more common mechanisms, macrolide resistance has also included mutations in the ribosomal proteins or RNA (31, 183, 189). Extremely rare mechanisms that are as yet undetected in streptococci, include direct inactivation of erythromycin by esterases, phosphorylases or glycosidases (31, 191).

One of the driving forces behind the development of the ketolides was the search for agents to overcome these various resistance mechanisms. It has been shown that ketolides remain active against bacterial strains expressing efflux resistance (54, 121, 183). While MIC values increase for strains with efflux-mediated resistance, this resistance is less effective against ketolides either because of their high intrinsic activity and/or tight ribosomal binding or because they are poor substrates for efflux pumps (113). Point mutations in domain V affect ketolide binding, but macrolides are affected to a much greater extent (54, 121, 183).

In clinical strains of S. pneumoniae, mutations of A2058/9  G, and A2062  C, confer resistance to 14,15 and 16-membered macrolides, lincosamides and streptogramins (MLSB), but do not affect telithromycin activity (51, 182). Mutations in the L4 ribosomal protein have been shown to affect ketolide binding. An insertion of 6 amino acid residues in L4 confers ketolide resistance, whereas single amino acid substitutions and smaller deletions or insertions in the same region of L4 confer macrolide resistance without giving cross-resistance to ketolides (182, 183).

Expression of an erm resistance determinant in bacteria leads to the production of a methyltransferase enzyme that modifies the key nucleotide, A2058, in the MLSB antibiotic binding site and thereby confers resistance to these drugs. Expression of erm may be constitutive or inducible. Ketolides offer a significant advantage over macrolides in strains that have inducible erm genes. It has been found that the L-cladinose moiety contributes to the strong induction effect of the macrolide antibiotics, leading to expression of the MLSB phenotype (24), whereas cethromycin and telithromycin both lack the capability to induce erm expression, giving them clinical activity against strains inducibly resistant to macrolides (35, 123, 203). Interestingly, ketolides remain potent agents against most S. pneumoniae strains regardless of their erythromycin susceptibility; even retaining activity against isolates constitutively expressing the ermB gene (48, 76, 165, 201). This however is not necessarily the case with other streptococci such as S. pyogenes (100). It has been shown that ketolides still have some affinity for the methylated ribosome; however, it is lower than in wild type unmethylated cells (48). It seems that the activity of ketolides against MLSB resistant strains depends upon the proportion of ribosomes that erm -gene product has managed to methylate.

In vitro and in vivo experiments have shown that exposure of streptococci to ketolides is less likely to result in resistance than upon exposure to macrolides (3, 47, 62, 69). These selection experiments typically resulted in only slight increases in MIC values, and they occurred at mutational frequencies lower than those obtained for macrolides under the same conditions (47). Telithromycin affected the susceptibility of the normal flora of the oropharynx and the bowel less than did clarithromycin, although its in vivo use did select for some resistant Bacteroides isolates (62). Therefore, it appears that it may be more difficult to select for ketolide resistance in the clinical setting.

A potential for the development of clinical resistance could occur via mutations in domain II of the 23S rRNA in strains that already express a modified domain V (48, 76, 201). In areas with documented macrolide resistance, the use of ketolides may put pressure on bacterial species to select for strains with constitutive erm expression. This could create ketolide resistance in species like S. aureus or S. pyogenes (20, 76, 90). However, it appears that ketolides will retain activity against the majority of S. pneumoniae strains, making them useful in the treatment of respiratory tract infections (48, 75, 201).

PHARMACOKINETICS

The pharmacokinetic parameters of telithromycin and cethromycin after oral dosing are displayed in Table 4 (9, 22, 62, 116, 137, 151, 155-157).

Absorption

The bioavailability of telithromycin is approximately 60%, and absorption appears to be rapid, reaching Cmax (maximum concentration in serum) in approximately 1 hour (109, 137, 151). Cethromycin appears to have dose dependent absorption with Tmax (time to maximum concentration in serum) increasing from 0.9 hours to 5.1 hours with increasing dosage (Table 4). The Cmax values of telithromycin and cethromycin are also variable, differ slightly and form linearity with increasing dose (21, 162). The plasma Cmax value for telithromycin after a single 800 mg dose was found to range from 1.90-2.27 µg/mL (162). Results for cethromycin have only been reported for healthy volunteers, but plasma Cmax values range from 0.14 to 1.19 µg/mL from a single oral dose within the range of 100 to 1200 mg once daily (Table 4). The values achieved for both telithromycin and cethromycin in the plasma are above the MIC values reported for the most common respiratory tract pathogens with the potential exception of H. influenzae (Tables 1 – 4). Additionally, food does not appear to have a significant effect on either the Cmax values or the times to peak absorption for both telithromycin and cethromycin (157, 200).

Distribution

The ketolide antibiotics have an improved lipophilic character over their macrolide precursors due to the removal of the L-cladinose sugar (21). Macrolides have been shown to exhibit extensive penetration into tissues and fluids outside the blood plasma resulting in an increased volume of distribution and possibly increased activity against organisms localized to these extra-plasma sites (186, 187). Ketolides have also demonstrated excellent penetration into sites other than the plasma. A number of experiments have been performed in vitro showing that ketolides have excellent uptake into macrophages and polymorphonuclear (PMN) cells (1, 62, 74, 105, 106, 111, 127, 129, 132, 149, 181, 190). The kinetics of accumulation depends upon the agent tested. Telithromycin has a slow accumulation that is more similar to azithromycin (171) and the efflux from the PMNs was slow, suggesting that the drug may be ionically trapped within granules due to differences in pH (186, 187).

In addition, telithromycin is extensively concentrated in other tissues and fluids as shown in Table 5 (1, 62, 74, 105, 106, 111, 127, 129, 132, 149, 181, 190). The ratios reported for telithromycin are greater than 1 (Table 5), suggesting that activity may not correlate with serum drug concentrations. Telithromycin may remain active at sites of infection when the concentration in serum is below the MIC of the infecting organism.

Routes of Elimination

Metabolism and Excretion: Approximately 70% of a telithromycin dose is metabolized (33% presystemic and 37% systemic) (109). Evidence suggests the ketolides are primarily metabolised by the cytochrome 450 (CYP) enzyme system in the liver. The main pathway of metabolism involves hydrolysis of the aryl group from the side chain leaving a hydroxyl group that may be further oxidized to a carboxylic acid. The predominant metabolite excreted is the hydroxyl-containing compound. Four metabolites of telithromycin have been identified in humans: an alcohol, an acid, an N-desmethyl-desosamine and an N-oxide pyridine derivative (137, 181). Absorbed telithromycin, which represents 57% of administered drug, is eliminated via various pathways with 7% excreted unchanged in faeces, 13% excreted unchanged in urine and 37% metabolized by the liver (109).

Studies of cethromycin metabolism in vivo in humans have not been reported; however, preliminary animal data and in vitro human hepatocyte experiments show well-characterized metabolism. It appears that the most common metabolic pathway of cethromycin involves demethylation of the D-desosamine sugar moiety (either singly or doubly) with or without hydroxylation of the C10 methyl group (83).

Pharmacokinetic Parameters

Telithromycin has a biphasic half-life with an overall terminal half-life of approximately 9.5 hours (137). From a single dose of 800 mg, this terminal half-life is 7.2 hours in a healthy male population (Table 4). This allows for once daily dosing for telithromycin at the established dose of 800 mg, with only slight accumulation of the drug at steady state (137). The half-life of cethromycin ranges from 3.6 – 6.7 hours (Table 4) following a single oral dose in healthy adult males (156). A preliminary multiple dose study indicate that cethromycin administered 150 mg twice daily for 5 days produce mean AUC24 and Cmin values that are approximately 2-fold and 7-fold greater than cethromycin 150mg once daily, respectively (86). Another multiple dose study has shown that cethromycin 300mg orally once daily resulted in an approximately 3-fold increase in Cmax and AUC compared with cethromycin 150mg orally once daily (41).

CNS/CSF Disposition

No data available on the penetration of the ketolides into the CNS/CSF.

Effects of Disease States

No dosage adjustment is required with telithromycin in patients with mild to moderate renal impairment. In the presence of severe renal impairment with or without co-existing hepatic impairment, dose reduction is recommended in the package insert (110). No dosage adjustment is necessary in patients with mild, moderate or severe hepatic impairment, unless renal function is severely impaired (109). No change in the dose is required based on other factors like age, gender, smoking status or infection severity. While it was found that these patient groups could affect telithromycin elimination pharmacokinetics in a minor way, none were clinically significant (155). Data for cethromycin elimination in humans are not yet available.

DOSAGE

For community acquired-pneumonia, the dose of telithromycin is 800mg orally once a day, which is supplied as two 400mg capsules (110). The recommended duration of therapy is 7 – 10 days. Telithromycin may be taken with or without food (22). This agent is not available in the parenteral and liquid dosage formulations. The manufacturer recommends dose reduction to 600mg (2 tablets of 300mg) once daily in patients with severe renal impairment (CLcr <30mL/min) including end-stage renal disease patients undergoing dialysis. A further dose reduction to 400mg once daily is recommended in patients with severe renal impairment in conjunction with hepatic dysfunction (110). If possible, telithromycin should be avoided in pregnancy (pregnancy category C) and breastfeeding (108).

Before prescribing telithromycin, one should closely review the contraindications, warnings and precautions reported in the most recently updated package insert (110). Telithromycin is contraindicated in patients with myasthenia gravis, history of hepatitis and/or jaundice with telithromycin or macrolide, co-administration of telithromycin with cisapride or pimozide, and history of hypersensitivity to telithromycin or macrolide. Serious adverse events associated with telithromycin that are described in the warnings include hepatotoxicity, QTc prolongation, visual disturbances, loss of consciousness, and pseudomembranous colitis (Refer to Adverse Effects and Monitoring Requirements). Due to the telithromycin’s potential to prolong the QTc interval, the manufacturer recommends that telithromycin should not be administered in the following conditions: 1) congenital abnormalities associated with QTc prolongation 2) co-administration of telithromycin with Class 1A (e.g. quinidine or procainamide) or Class III (e.g. dofetilide) antiarrhythmic agents 3) hypokalemia, hypomagnesemia, bradycardia or other conditions that may predispose a patient in having an arrhythmia.

The manufacturer also recommends that patients receiving telithromycin should limit activities such as driving due to the potential risk of visual disturbances and syncope; total avoidance of such activities is recommended if the patient experiences one of these adverse events. The manufacturer also created a medication guide that provides an overview of telithromycin with particular emphasis on adverse events (110). The dispensing pharmacist should provide a medication guide for every patient that receives a prescription of telithromycin. In addition, the pharmacist should communicate the major topics discussed in the medication guide such as potential adverse events and drug-drug interactions and encourage the patient to review the medication guide as well.

ADVERSE EFFECTS

In Phase III clinical trials, most adverse events in patients receiving telithromycin 800mg once daily for up to 10 days were mild to moderate in intensity. Overall rates of discontinuations due to treatment-related adverse events were similar between telithromycin- and comparator-treated patients (4.3% vs 4.4%, respectively). The most common adverse effects associated with telithromycin were gastro-intestinal (GI) such as diarrhea (10.8%), nausea (7.9%) and vomiting (2.9%). Elevation in liver function tests (AST and ALT) have been reported in patients being treated with telithromycin. In patients receiving 800 mg once daily, elevations in liver enzymes occurred in <1.0 % in patients with normal baseline enzyme levels being treated for respiratory infections other than CAP, and in <2.0% of CAP patients with normal baseline levels. The incidence of elevated hepatic enzymes levels was higher in patients with abnormal baseline enzyme levels (109). Overall, however, the elevation in liver enzymes was similar to comparator agents (109).

Serious adverse effects associated with telithromycin include hepatotoxicity, exacerbations of myasthenia gravis, QTc prolongation, visual disturbance, and loss of consciousness. Post-marketing surveillance has revealed that telithromycin is associated with potentially life-threatening hepatotoxicity (40, 82, 166); this has led to significant modifications in the prescribing information for telithromycin. In June 2006 (approximately 2 years after FDA approval of telithromycin for the three indications), telithromycin had been associated with 35 cases of hepatotoxicity (23/35 with acute severe liver injury and 12/35 with acute liver failure) (166). Four of the patients with acute liver failure died. The number of hepatotoxic effects increased to a total of 53 cases by December 2006 (166). The manufacturer reports that cases of hepatotoxicity have ranged from fulminant hepatitis, hepatic necrosis, and hepatic failure (110).

Clay and colleagues published the first case reports of severe hepatotoxicity in patients receiving telithromycin (40). All three patients were previously healthy adults that developed severe hepatotoxicity following telithromycin therapy. These patients were not receiving other prescription medications; however, two patients had a history of alcohol consumption. Only one patient had a favorable outcome with resolution of signs and symptoms of hepatotoxicity. In comparison, one of two patients with history of alcohol consumption died while the other underwent an orthotopic liver transplantation (40). The investigators report that both of the livers had significant necrosis (40).

Exacerbations of myasthenia gravis associated with telithromycin were recognized before the agent was approved by the FDA through safety monitoring in Europe. Post-marketing surveillance in the United States has further documented fatal and life-threatening respiratory failure in telithromycin-treated patients with myasthenia gravis. The package insert has been revised to indicate that telithromycin is contraindicated in this patient population (110). Similarly, it was previously recognized that telithromycin has the potential to lengthen the QTc interval in certain patients. Post-marketing surveillance has reported cases of torsades de pointes (110).

Due to the potential for visual disturbances and loss of consciousness, patients performing certain activities such as driving need to exercise additional caution. In Phase III studies, visual disturbances (e.g. blurred vision, difficulty focusing, diplopia) occurred in 1.1% of telithromycin-treated compared to 0.28% of comparators-treated patients (110). A higher incidence was noted in female ≤40 years who received telithromycin (14/683, 2.1%) versus comparators (0/534, 0.0%); the difference was less pronounced in females > 40 years old (7/703, 1.0% vs 2/574, 0.35%, respectively). The inability to properly accommodate appears to be the proposed mechanism of the visual disturbances; this typically results in mild or moderate visual adverse events although severe cases have also been reported. Furthermore, post-marketing surveillance has revealed that telithromycin can be associated with temporary loss of consciousness.

With respect to cethromycin, at the time of this writing, the Phase II/III trial for community-acquired pneumonia has only been published in abstract form (64). In the phase II/III trial that evaluated cethromycin 150mg orally once daily compared to 150mg twice daily for 10 days, the incidence of drug-related adverse events was 23% for the once daily and 25% for the twice daily regimen. Serious adverse events occurred 3.9% and 5.3%, respectively. The most frequently reported drug related adverse event was gastrointestinal related (11% and 10%, respectively) (64).

MONITORING REQUIREMENTS

Due to the reports of acute hepatic failure and severe liver injury associated with telithromycin, physicians should closely monitor signs and symptoms of hepatitis in patients receiving telithromycin (110). If clinical hepatitis is suspected, telithromycin should be immediately discontinued as fatal cases have been reported. Patients with telithromycin or macrolide induced hepatitis and/or jaundice should never be re-challenged with telithromycin. In addition, physicians and pharmacists should educate patients receiving telithromycin to monitor for signs of liver damage (e.g., fatigue, loss of appetite, yellowing of skin and/or eyes, stomach pain dark-colored urine and pale bowel movements). Patients should also be monitored and educated about other potential serious adverse events such as QTc prolongation, visual disturbance, and loss of consciousness.

A critical evaluation of co-administered agents should be conducted for patients receiving telithromycin. The co-administration of telithromycin with certain agents that are metabolized through the cytochrome P-450 system may be contraindicated (e.g. cisapride, ergot alkaloid derivatives, pimozide, astemizole, terfenadine, quinidine, procainamide, or dofetilide) or should be cautiously administered (e.g. digoxin) (Refer to Drug Interactions).

DRUG INTERACTIONS

As derivatives of the macrolide class of antimicrobials, ketolides may interact with concomitant medications in a similar manner. Clinically significant interactions between macrolides and other drugs have been summarized in a previous review (200). The majority of these interactions involve pronounced inhibition by the macrolides of cytochrome (CYP) 3A4 enzymes resulting in the impairment of drug metabolism of the certain co-administered medications. Telithromycin interacts with these enzymes reversibly and is a competitive inhibitor of some enzyme subgroups (CYP3A4 and CYP2D6) (109). This has also been observed in vivo, where telithromycin has shown some indication of clinically significant interactions with agents metabolized by the cytochrome P450 system. Similar to the macrolides, telithromycin is contraindicated with concomitant administration of many agents including cisapride, ergot alkaloid derivatives, pimozide, astemizole, and terfenadine (200). It should also be avoided in patients receiving Class 1A (e.g., quinidine, procainamide) or Class III (e.g., dofetilide) antiarrhythmic agents. Telithromycin administration should be avoided with inducers of the CYP3A4 such as rifampin, phenytoin, carbamazepine, St. John’s wort. Caution should be exercised with co-administration of drugs that are metabolized through cytochrome P450 system and possess a narrow therapeutic window such as cyclosporine, tacrolimus, sirolimus, and hexobarbital.

Telithromycin

CYP3A4 Inhibitors

Ketoconazole

In a healthy volunteer study, the coadministration of ketoconazole, a potent inhibitor of the CYP3A4, increased telithromycin’s Cmax by 52% and AUC by 95% (109). These findings indicate a dose reduction may be necessary with this combination. Another study evaluated the effect of ketoconazole administered with telithromycin in elderly subjects (age = 60 years old) with mild (CLcr 50-80mL/min) or moderate (30-49mL/min) renal insufficiency (108). A further increase in both Cmax and AUC were noted in the elderly subjects with mild to moderate renal insufficiency compared to healthy volunteers receiving the combination. Additional dose reductions may be necessary with telithromycin administered with ketoconazole in patients with renal insufficiency.

Itraconazole

Similar to ketoconazole, the coadministration of itraconazole with telithromycin resulted in an inhibition of telithromycin's metabolism; however, this effect was less than seen with ketoconazole (109).

Grapefruit Juice

Grapefruit juice did not affect the pharmacokinetics of telithromycin when administered together (109).

CYP3A4 Inducer

The co-administration of rifampicin, a known inducer of CYP3A4, and telithromycin resulted in a decreased Cmax and AUC of telithromycin by 5- and 7-fold, respectively. Concomitant administration of telithromycin and rifampicin is contraindicated (108).

CYP3A4 Substrates

Cisapride: Coadministration of telithromycin and cisapride resulted in a 1.9X increase in Cmax and a 2.6X increase in AUC of cisapride (109). Due to the increased potential for QT interval irregularities and ventricular arrhythmias, concomitant administration of cisapride with ketolides is contraindicated (109, 200).

Midazolam: The AUC of midazolam was increased 2-fold for the oral and 6-fold for the intravenous formulations with the coadministration of telithromycin (109). Dosage adjustments will be necessary for benzodiazepines that are metabolized through the CYP3A4 such as midazolam or triazolam to avoid prolonged sedation or other toxicities.

Simvastatin: Telithromycin has been shown to significantly affect the metabolism of simvastatin leading to significant increase in Cmax (5.3x) and AUC (8.9x) (109). Hepatitis has been documented when simvastatin has interacted with another drug known to increase simvastatin levels (106). Levels are increased in a manner similar to that observed previously for macrolide antibiotics. Rhabdomyolysis has been observed when macrolides were concomitantly administered, although this has not been observed with telithromycin to date (109, 200). The package insert recommends avoiding the concomitant administration of telithromycin with HMG CoA reductase inhibitors that are metabolized by CYP3A4 such as simvastatin, atorvastatin, lorvastatin. Thus, the HMG CoA reductase inhibitor should be suspended during the course of telithromycin therapy.

CYP2D6 Substrates

Metoprolol: The co-administration of metoprolol, a known CYP2D6 substrate, and telithromycin resulted in an increased Cmax and AUC of metoprolol by approximately 40% (108). Telithromycin should be used cautiously in patients receiving metoprolol for heart failure (110).

Paroxetine: The administration of paroxetine, a substrate of the CYP2D6, with telithromycin did not alter the pharmacokinetics of paroxetine (109).

Other Drugs

Digoxin: Telithromycin also caused a moderate increase in digoxin levels (1.2x Cmin and 1.4x AUC); however, the mechanism of this interaction was not presented (109). Due to the low therapeutic index of digoxin, monitoring side effects and/or serum levels is warranted with co-administration.

Oral Contraceptives: The coadministration of telithromycin and oral contraceptives was clinically insignificant (109).

Warfarin: In a healthy volunteer study, the coadministration of warfarin and telithromycin did not result in clinically significant interaction (170). However, post-marketing surveillance has reported elevated PT/INR; therefore, close monitoring of PT/INR should occur during concomitant administration of telithromycin with warfarin.

Theophylline: Telithromycin administered with theophylline resulted in a 16% increase of Cmax and AUC for theophylline (109). No empiric dosage adjustments are necessary with this combination due to the modest increase in theophylline concentrations.

Ranitidine and Antacids: Absorption of telithromycin was unaffected by agents affecting gastric pH in the stomach, such as antacids or the H2 receptor blocker ranitidine (117).

Cethromycin

Limited data are available on drug interactions with the other ketolides.

Ranitidine or Sucralfate: In a healthy volunteer study, subjects were evaluated for the effect of administering ranitidine or sucralfate one hour prior to cethromycin (154). The Cmax and AUC of cethromycin were reduced by 25.7% and 15.8%, respectively, with prior ranitidine administration. No differences in pharmacokinetic parameters of cethromycin were noted with prior sucralfate administration.

Theophylline: Similar to telithromycin, co-administration of cethromycin with theophylline did not result in clinically significant interaction (17).

CLINICAL INDICATIONS

The FDA originally approved telithromycin in April 2004 for three indications (i.e., community-acquired pneumonia, acute exacerbations of chronic bronchitis, and acute bacterial sinusitis). However, in February 2007, the FDA removed the indications for acute exacerbations of chronic bronchitis and acute bacterial sinusitis as the potential risks do not outweigh the potential benefits for these infections. Currently, the only FDA approved indication for telithromycin is the treatment of community-acquired pneumonia (mild to moderate severity) due to S. pneumoniae (including multi-drug resistant isolates), H. influenzae, M. catarrhalis, C. pneumoniae, or M. pneumoniae in adults (≥ 18 years older). Due to the potential risk of life-threatening hepatotoxicity, telithromycin should only be utilized in situations when the potential benefits outweigh the potential risks for the treatment of community-acquired pneumonia. Telithromycin should only be considered when safer, first-line agents (e.g., -lactams, macrolides, doxycycline, fluoroquinolones) (16) and second-line agents (e.g., clindamycin, linezolid, trimethoprim-sulfamethoxazole) can not be administered due to factors such as tolerance, co-morbidities, and susceptibility.

Comparative clinical trials of telithromycin have shown similar efficacy to the macrolides or beta-lactams for a variety of upper and lower respiratory track infections (8, 32, 71, 87, 88, 108, 142, 159, 164, 184, 199). These clinical trials have been previously summarized in a review (200). Despite similar efficacy, clinicians should avoid off-label usage of telithromycin for treatment of infections such as pharyngitis due to FDA labeling and safety concerns.

Cethromycin is currently in Phase 3 development for community-acquired pneumonia. It recently was granted Orphan Drug Designation for prophylaxis of inhalational anthrax by the FDA.

Community-Acquired Pneumonia

Telithromycin has demonstrated similar efficacy rates to comparative agents (amoxicillin, clarithromycin and trovafloxacin) for the treatment of mild-moderate community-acquired pneumonia for 7 – 10 days. Per-protocol (PP) clinical cure rates ranged from 88.3% to 94.6% in six clinical trials of telithromycin, in which half of the studies were randomized, double-blind comparative trials (87, 88, 108). Reduced PP clinical cure rate of 84.2% and 86.2% were noted in patients that isolated penicillin resistant (defined as MIC > 2 µg/mL) and erythromycin resistant (defined as MIC >1µg/mL) organisms, respectively. A further reduction in PP clinical cure rates to 72.7% was seen when isolates were resistant to both penicillin and erythromycin 4. Telithromycin has shown excellent clinical cure rates for patients isolated with atypical organisms (based upon serologic diagnosis): 94.1% (32/34) for C. pneumoniae, 96.8% (30/31) for M. pneumoniae, and 100.0% (12/12) for L. pneumophilia 181,182. Telithromycin also has shown considerable success (clinical cure in 40/44 patients or 90.9%) in treating S. pneumoniae bacteremia associated with respiratory tract infections (71).

Efficacy data are available for two cethromycin regimens studied in a double-blind, parallel-group, multi-center phase II/III trial (64). Clinical cure rates for intent-to-treat population were similar for cethromycin 150mg orally once daily compared to 150mg twice daily for 10 days (83% vs 81%, 95% CI -5.2, 8.3). Bacteriological cure rates were also similar between two dosage regimens (83% vs 82%, 95% CI -7.2, 9.9) (64). The pivotal, Phase III clinical trials for treatment of community-acquired pneumonia are currently on-going.

TABLES AND FIGURES

Table 1. In vitro Activity of Ketolides and Comparator Macrolides Against Aerobic Gram-Positive Bacteria

Table 2. In vitro Activity of Ketolides and Comparator Macrolides Against Aerobic Gram-Negative Bacteria

Table 3. In vitro Activity of Ketolides and Comparator Macrolides Against Anaerobic Bacteria

Table 4. Pharmacokinetic Properties of Telithromycin and Cethromycin

Table 5. Tissue Distribution of Telithromycin

Table 6. Adverse Effects Reported for Telithromycin

Figure 1. Chemical Structure of Telithromycin and Cethromycin.

Figure 2. Structure Activity Relationship of the Ketolide Antibiotics.

Figure 3. A: Schematic representation of the bacterial 23S rRNA secondary structure. Boxed are (B) hairpin 35 of domain II, and (C) the central loop of domain V of the rRNA. The encircled nucleotides A752, A2058, A2059 and G2505 (E. coli numbering) constitute the binding site for macrolide and ketolide antibiotics 

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