Ketolides (Telithromycin, Cethromycin)

George G. Zhanel, Ph.D.

Professor

Department of Medical Microbiology

Faculty of Medicine, University of Manitoba

Coordinator-Antibiotic Resistance Program

Department of Medicine

Health Sciences Center

MS673-Microbiology, Health Sciences Centre

820 Sherbrook Street

Winnipeg, Manitoba

Canada R3A 1R9

Ph: 204 787-4902

Fax: 204 787-4699

Email: ggzhanel@pcs.mb.ca

Melinda M. Neuhauser, Pharm.D.

Clinical Pharmacy Specialist, Infectious Diseases

National Institute of Health

BLDG#10 Room 1N-257 MSC-1196

10 Center Drive

Bethesda, MD 20892-1196

Email: mneuhauser@cc.nih.gov

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, 28, 69). Presently, telithromycin has been approved for clinical use in the United States, Canada, several European and Latin American countries (107), 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 (4). 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 (40).

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 (198). 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 MLS_B (macrolide lincosamide streptogramin B) antibiotics in strains with inducible erm determinants (26). This allows the ketolides to remain active against bacterial strains in which MLS_B resistance would be induced by 14 and 15-membered macrolides such as azithromycin, clarithromycin and erythromycin (4, 164). One exception is the ketolide TE-802, which induces MLS_B 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 (200, 201). 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 (57, 92).

               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 (39). 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 (92, 120). 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 (92) and imparts some activity against methylated ribosomes in some species (38, 40, 194).

               Cethromycin has an unsubstituted 11, 12-carbamate linkage, but contains a 3-quinolyl-propylene chain linked to the position 6 oxygen (Figure 1) (117). 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, 117, 145).

               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 (34, 52). 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 (151). 2-Fluoro-ketolides have been found to have excellent activity and the structure is likely to be incorporated into future antimicrobial compounds (40, 42, 69, 79, 106).

               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 (106). Position 10 has been shown to require a methyl substituent for activity, but position 13 can tolerate some structural variation (36). Aza-ketolide derivatives have also been synthesized, but as of yet none have shown activity (32).

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, 24, 28, 31, 41, 47, 49, 50, 54, 58, 61, 66, 67, 70, 72, 74, 77, 80, 82, 90, 94-102, 112, 113, 116, 118, 121, 123-125, 127, 129, 130, 133-135, 137, 139, 144, 146, 147, 152, 157, 160, 165, 167, 169, 172-177, 183, 190, 192, 193, 199). 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 (77, 78, 139). The ketolides displayed activity against erythromycin susceptible Staphylococcus aureus; however, they lack activity against erythromycin resistant S. aureus or coagulase negative Staphylococcus spp. (3, 90, 139, 144). 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 (139). 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, 64, 86, 162, 170, 178, 195). 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.

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) (198). Ketolides in general follow this pattern, displaying bacteriostatic activity against many species, but showing bactericidal activity at higher concentrations against some important pathogens. Telithromycin, HMR-3004, cethromycin, HMR-3562 and HMR-3787 show bactericidal activity against S. pneumoniae. Importantly, these drugs are bactericidal against S. pneumoniae resistant to erythromycin A. (3, 49, 143, 144, 147, 159). Telithromycin, HMR-3004 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, 24, 29, 45, 49, 60, 85, 139, 143, 144, 146, 159). However, at concentrations in the range of 2x to 10x the MIC, telithromycin, HMR-3004 and cethromycin are mainly bacteriostatic against S. aureus, Enterococcus spp., and Gram-positive bacilli (29, 30, 60, 71, 98, 118, 139, 144). 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 (27).

               Telithromycin and HMR-3004 showed bactericidal activity against B. fragilis at 10x the MIC value (29, 30). Against other anaerobes telithromycin also showed some bactericidal activity after 24 hours at higher concentrations (≥4x the MIC), but was mainly bacteriostatic (44). Telithromycin, HMR-3004 and cethromycin were slowly bactericidal against C. pneumoniae and mainly bacteriostatic against L. pneumophila (10, 59, 86, 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 (48). 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 (140). 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 (30, 45, 49, 60, 138, 143, 159). Munckhof et al. conducted a number of PAE experiments at different antibiotic concentrations for telithromycin and HMR-3004 and concluded that these ketolides would have 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 and a range of 3.1 to 4.9 hours with HMR-3004 (132). 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 (60, 143). Telithromycin and HMR-3004 at 10x the MIC exhibit extensive PAE (5 hours) and PASME (post antibiotic sub-MIC effect; 12 hours) values against H. pylori (85).

               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 (49, 159). Against H. influenzae, cethromycin exhibited PAE values 4.9 hours, which is comparable to azithromycin, the macrolide with the longest PAE (45, 159). Against S. aureus, the PAE values obtained were 3.41 hours and against M. catarrhalis, the values were 3.8 hours (159). Cethromycin also gave PAE values of 2 hours against L. pneumophila (59).

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 (62, 63, 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 both HMR-3004 and telithromycin can antagonize the activity of bioactive phospholipids (68). 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/MIC_pathogen is highly correlated with efficacy (6, 10, 43, 85, 110, 143, 186).

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 (38, 40). 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) (92, 194). 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, 166, 196).

               The main site of macrolide and ketolide interaction has been defined by chemical footprinting experiments (92, 194) 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, 37). 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 (56, 92, 120).

               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 (92, 194). 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 (142). This additional contact presumably enables the ketolides to retain activity against bacteria that have base modifications in domain V (20, 37, 56, 91, 142, 164).

               In addition to inhibiting protein synthesis the ketolides also demonstrate a significant inhibitory effect on the formation of 50S ribosomal subunits (38, 40). 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 (40). 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 (38). 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 (33, 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 (161). In addition to the more common mechanisms, macrolide resistance has also included mutations in the ribosomal proteins or RNA (33, 181, 187). Extremely rare mechanisms that are as yet undetected in streptococci, include direct inactivation of erythromycin by esterases, phosphorylases or glycosidases (33, 189).

               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 (20, 37, 78, 91). 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 (111). Point mutations in domain V affect ketolide binding, but macrolides are affected to a much greater extent (56, 120, 181). 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 (MLS_B), but do not affect telithromycin activity (53, 180). 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 (180, 181).

               Expression of an erm resistance determinant in bacteria leads to the production of a methyltransferase enzyme that modifies the key nucleotide, A2058, in the MLS_B 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 MLS_B phenotype (26), whereas cethromycin and telithromycin both lack the capability to induce erm expression, giving them clinical activity against strains inducibly resistant to macrolides (38, 122, 201). 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 (49, 77, 164, 199). 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 (37). It seems that the activity of ketolides against MLS_B 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, 48, 65, 71). 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 (48). 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 (65). 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 (142). 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, 78, 91). 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 (49, 77, 199).

PHARMACOKINETICS

               The pharmacokinetic parameters of telithromycin and cethromycin after oral dosing are displayed in Table 4 (9, 23, 65, 114, 136, 150, 154-156).

Absorption

               The bioavailability of telithromycin is approximately 60%, and absorption appears to be rapid, reaching C_max (maximum concentration in serum) in approximately 1 hour (108, 136, 150). Cethromycin appears to have dose dependent absorption with T_max (time to maximum concentration in serum) increasing from 0.9 hours to 5.1 hours with increasing dosage (Table 4). The C_max values of telithromycin and cethromycin are also variable, differ slightly and form linearity with increasing dose (136, 155). The plasma C_max value for telithromycin after a single 800 mg dose was found to range from 1.90-2.27 µg/mL (136). Results for cethromycin have only been reported for healthy volunteers, but plasma C_max 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 C_max values or the times to peak absorption for both telithromycin and cethromycin (23, 156).

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 (198). 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, 75, 126, 148, 184, 185). The kinetics of accumulation depend upon the agent tested, with HMR-3004 showing a rapid uptake initially followed by a slower accumulation over a further 3 hours, which is very similar to monobasic macrolides such as erythromycin A (184). Telithromycin on the other hand has a slower accumulation that is more similar to azithromycin (185). In both cases efflux from the PMNs was slow, suggesting that the drugs may be ionically trapped within granules due to differences in pH (184, 185).

               In addition, telithromycin is extensively concentrated in other tissues and fluids as shown in Table 5 (1, 65, 76, 105, 109, 126, 128, 131, 148, 179, 188). 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) (108). 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 (136, 179). 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 (108, 179).

               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 (84).

Pharmacokinetic Parameters

               Telithromycin has a biphasic half-life with an overall terminal half-life of approximately 9.5 hours (136). 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 (136). The half-life of cethromycin ranges from 3.6 – 6.7 hours (Table 4) following a single oral dose in healthy adult males (155). A preliminary multiple dose study indicate that cethromycin administered 150 mg twice daily for 5 days produce mean AUC₂₄ and C_min values that are approximately 2-fold and 7-fold greater than cethromycin 150mg once daily, respectively (87).

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 may be necessary (107). No dosage adjustment is necessary in patients with mild, moderate or severe hepatic impairment, unless renal function is severely impaired (108). 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 (154). Data for cethromycin elimination in humans are not yet available.

DOSAGE

               In the clinical trials, the dosage of telithromycin was 800mg orally once a day, which was supplied as two 400mg capsules. The duration of therapy used in clinical trials varied for type of infection: 7 -10 days for community acquired pneumonia (with the exception of one trial that had therapy duration of 5 days), 5 – 10 days for acute sinusitis, and 5 days for AECB and pharyngitis. Telithromycin may be taken with or without food (23). This agent is not available in the parenteral and liquid dosage formulations. No dosage adjustment is required in patients with mild (CLcr 50 – 80 mL/min) to moderate renal impairment (Clcr 30 – 49 mL/min). In the presence of severe renal impairment (Clcr < 30mL/min), pharmacokinetics studies suggest that the dose of telithromycin should be reduced (107, 108); However, specific guidelines are not available with regard to dose reduction in this setting. No dosage adjustment is necessary in patients with mild, moderate or severe hepatic impairment, unless renal function is severely impaired (108). Telithromycin should be avoided in pregnancy and breastfeeding woman (107).

ADVERSE EFFECTS

               As a class, the macrolide antibiotics are a safe and well-tolerated group of therapeutic agents (198). With respect to the newer ketolides, early clinical trials suggests telithromycin and cethromycin have similar safety profiles to the newer macrolides (clarithromycin and azithromycin) (65, 107, 108, 136).

               Clinical trials to date have demonstrated that most adverse events in patients receiving telithromycin 800mg once daily for up to 10 days are mild to moderate in intensity and treatment-related discontinuation because of treatment-related adverse events is uncommon (4.4%) (107). In 8 comparator-controlled studies, the incidence and profile of adverse events were similar for telithromycin and comparators (108). The most common adverse effects associated with telithromycin (n=2045) in 8 randomized, double-blind comparator-controlled Phase 3 studies were gastro-intestinal (GI) such as diarrhea (13.3%), nausea (8.1%) and vomiting (2.8%) (171). The majority of cases of diarrhea were mild (69%) or moderate (25%) in severity and resulting treatment discontinuation (0.9% of all telithromycin-treated patients) were similar to pooled comparators (0.8%) and lower than amoxicillin/clavulanate (2.4%) (108). The incidence of more serious side effects of telithromycin was reported to be similar to that of the pooled comparators in trials for CAP, AECB, sinusitis and pharyngitis (Table 6) (108).

               The tolerability profile of telithromycin versus comparator antibiotics in clinical trials has been summarized by Sharma et al (Table 6) (171). The total treatment related GI effects were higher for the telithromycin arms than for the pooled comparators at 26.1% versus 15.9% respectively. However, most were of mild to moderate severity and rates of discontinuation were similar between all antibiotics. Total discontinuations of treatment due to adverse effects were 4.8% for telithromycin versus 4.4% for the comparator antibiotics (171).

               At least ten postmarketing cases of hepatic adverse events associated with telithromycin use have been reported. Severity of reactions ranged from serious to fatal (2 patients died) and involved cholestatic hepatitis, abnormal aminotransferase levels, increased bilirubin levels, and hepatocellular damage were seen. Two patients died. Duration of telithromycin use ranged from 1 to 30 days, and patient ages ranged from 35 to 85 years. Only 2 cases were described with telithromycin in the absence of other agents; both involved increased aminotransferase levels and required hospitalization, but neither resulted in death (42a).

               More serious treatment related but less common side effects (0.3%) observed with telithromycin in clinical trials include allergic reactions, liver injury, pseudomembranous colitis, erythema multiforme, blurred vision, gastroenteritis and severe vomiting (107, 171). These occurrences are comparable to other antibiotic agents currently used in treating respiratory infections (108). No incidences of ototoxicity were reported. There were no treatment-related deaths due to telithromycin in any of the trials (108). Laboratory results have also been analyzed in telithromycin clinical trials. 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 (108). Overall, however, the elevation in liver enzymes were similar to comparator agents (108).

               Telithromycin showed no significant effect on the QT interval at therapeutic dose, with a QT interval after 2 hours equivalent to clarithromycin and to placebo (51, 108). Results showed no significant change in QT interval when telithromycin was dose ranged from 800 mg to 2400 mg per day. Studies measuring cardiovascular (CV) adverse effects also included a small population of high-risk subjects with underlying CV disease (108).

               With respect to cethromycin, at the time of this writing, clinical trials have not been published, however, preliminary human pharmacokinetic data suggests that adverse effects associated with cethromycin are dose-related, and involve symptoms similar to those described for telithromycin (155, 156). No significant adverse effects or changes in laboratory values were recorded for cethromycin in these pharmacokinetic studies (155, 156).

MONITORING REQUIREMENTS

               Similar to the macrolides, routine therapeutic monitoring of serum concentrations is not necessary with the ketolides. However, 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, and terfenadine) or should be cautiously administered (e.g. digoxin) (Refer to Drug Interactions). Although extremely rare, monitoring of liver function may be indicated because of reports of fulminant hepatitis.

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 (198). 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) (108). 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 (198). Telithromycin administration should be avoided with inducers of the CYP3A4 such as rifampicin, phenytoin, carbamazepine, St. John’s wort. Only preliminary studies have been conducted with telithromycin (see below), and it is probable that the full range of drug interactions remains to be expanded upon introduction into clinical practice.

Telithromycin

CYP3A4 Inhibitors

Ketoconazole

               In a healthy volunteer study, the coadministration of ketoconazole, a potent inhibitor of the CYP3A4, increased telithromycin’s C_max by 52% and AUC by 95% (108). 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 (107). A further increase in both C_max 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 (108).

Grapefruit Juice

               Grapefruit juice did not affect the pharmacokinetics of telithromycin when administered together (108).

CYP3A4 Inducer

               The co-administration of rifampicin, a known inducer of CYP3A4, and telithromycin resulted in a decreased C_max and AUC of telithromycin by 5- and 7-fold, respectively. Concomitant administration of telithromycin and rifampicin is contraindicated (107).

CYP3A4 Substrates

Cisapride: Coadministration of telithromycin and cisapride resulted in a 1.9X increase in C_max and a 2.6X increase in AUC of cisapride (108). Due to the increased potential for QT interval irregularities and ventricular arrhythmias, concomitant administration of cisapride with ketolides is contraindicated (108, 198).

Midazolam: The AUC of midazolam was increased 2-fold for the oral and 6-fold for the intravenous formulations with the coadministration of telithromycin (108). 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 C_max (5.3x) and AUC (8.9x) (108). Hepatitis has been documented when simvastatin has interacted with another drug known to increase simvastatin levels (105a). 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 (108, 198). Caution should be used with the concomitant administration of telithromycin with HMG CoA reductase inhibitors that are metabolized by CYP3A4 such as simvastatin, atorvastatin, lorvastatin (108). Dosage adjustments of the HMG CoA reductase inhibitor may be necessary or switching to agents that are not metabolized by CYP3A4 such as pravastatin.

CYP2D6 Substrates

Metoprolol: The co-administration of metoprolol, a known CYP2D6 substrate, and telithromycin resulted in an increased C_max and AUC of metoprolol by approximately 40%. No empiric dosage adjustment of metoprolol appears to be necessary. Patients should be monitored for signs and symptoms of elevated metoprolol concentrations (e.g. hypotension) (107).

Paroxetine: The administration of paroxetine, a substrate of the CYP2D6, with telithromycin did not alter the pharmacokinetics of paroxetine (108).

Other Drugs

Digoxin: Telithromycin also caused a moderate increase in digoxin levels (1.2x C_min and 1.4x AUC); however, the mechanism of this interaction was not presented (108). Due to the low therapeutic index of digoxin, caution is warranted with co-administration.

Oral Contraceptives: The coadministration of telithromycin and oral contraceptives was clinically insignificant (108).

Warfarin: In a healthy volunteer study, the coadministration of warfarin and telithromycin did not result in clinically significant interaction (168).

Theophylline: Telithromycin administered with theophylline resulted in a 16% increase of Cmax and AUC for theophylline (108). 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 (115).

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 (153). The C_max 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

               With the prevalence of antibiotic resistance among respiratory tract pathogens increasing over the past decade, the ketolides represent a new class of antimicrobials that overcomes resistance mechanisms that render macrolide antibiotics ineffective. The ketolides have a broad spectrum of activity against community-acquired respiratory organisms including penicillin and/or macrolide resistant S. pneumoniae (55, 93). Telithromycin is approved for clinical use in the United States, Canada and several European countries. Cethromycin is currently in Phase 3 development. 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, 35, 88, 89, 107, 141, 158, 163, 182, 197).

               In the following sections, a brief summary of clinical trials that consist of adult populations in the majority of cases, with adolescents included in the pharyngitis trials will be discussed. The trials included analysis of both the intent-to-treat population (mITT = modified intent-to-treat; any patient enrolled in the study that received at least one dose of antibiotic), as well as the per-protocol population (PP = the number of patients who did not have any major protocol violations as predefined in the protocol). Clinical cure was defined as improvement in signs and symptoms or a return to pre-infection state without the need for additional antimicrobials and assessed 10-14 days after the end of treatment. Additionally, trials evaluated bacterial eradication when a causative pathogen could be identified.

Community-Acquired Pneumonia

               Macrolides are commonly used for the treatment of mild to moderate treatment of community-acquired pneumonia (16). With increasing resistance of penicillin and macrolide to S. pneumoniae, ketolides may represent a suitable alternative for outpatient treatment of mild to moderate community-acquired pneumonia, particularly in those instances in which a resistant pathogen is isolated or highly suspected. 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 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 (88, 89, 107). Reduced PP clinical cure rate of 84.2% and 86.2% were noted in patients that isolated penicillin resistant (defined as MIC 2 g/mL) and erythromycin resistant (defined as MIC1g/mL) organisms, respectively (107). A further reduction in PP clinical cure rates to 72.7% was seen when isolates were resistant to both penicillin and erythromycin (107). 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 (89, 107). Telithromycin also shown considerable success (clinical cure in 40/44 patients or 90.9%) in treating S. pneumoniae bacteraemia associated with respiratory tract infections (73).

Acute Exacerbations of Chronic Bronchitis

               Telithromycin has been evaluated for the treatment of acute exacerbations of chronic bronchitis (AECB) in three separate randomized, double-blind trials (8, 107, 197). A 5-day course of telithromycin 800mg once daily was compared to a 10-day course of amoxicillin/clavulanic acid (500 mg/125 mg) three times daily (8), cefuroxime axetil 500 mg twice daily (197), or clarithromycin 500mg po twice daily (107). Per-protocol clinical cure rates ranged from 85.8% to 86.4% for telithromycin compared to 82.1% to 89.2% for the comparators (107). In patients with causative pathogens isolated, bacteriological success rates were seen in both telithromycin and comparator groups (77.0% vs. 77.9%), which represents combined data for two of the clinical studies (107).

Pharyngitis

               Penicillin remains the drug of choice for the treatment of Group A streptococcal pharyngitis, while macrolides are commonly used as an alternative in penicillin allergic individuals (25). With increasing macrolide resistant S. pyogenes being reported worldwide (22, 46), ketolides may have a role future in the treatment of macrolide-resistant S. pyogenes in the penicillin allergic patient. Telithromycin has been evaluated in the treatment of pharyngitis in two randomized, double-blind clinical trials (141, 158). In both trials, a 5-day telithromycin course was compared to a 10-day treatment regimen of either penicillin V 500 mg three times daily (141) or clarithromycin 250 mg twice daily (158). In both trials, satisfactory outcomes were achieved in both arms, with 84.3% - 91.3% bacteriological eradication in the PP population of the telithromycin group and 88.1% - 89.1% bacteriological eradication in the comparator groups (141, 158). In the mITT populations, clinical cure was achieved in 79.7 - 83.2% and 79.3 – 83.1%, respectively. Eradication of S. pyogenes was greater than 85% for the telithromycin and comparators (141, 158).

Acute Sinusitis

               Telithromycin has been evaluated for the treatment of acute sinusitis in three randomized, double-blind clinical trials (35, 107, 163, 182). In the first trial by Roos et al. telithromycin 800 mg once daily was compared in a 5-day course versus a 10-day course. Both courses were found to have satisfactory outcomes and were equivalent in efficacy, with 91.1% cure in the 5-day group PP population versus 91.0% cure in the 10-day PP population (163). Bacteriological outcomes were also similar for both treatments (92.9% for the 5 day course and 89.9% for the 10 day course) and covered all of the most common causative agents effectively. In the second trial by Tellier et al., telithromycin 800 mg for 5 days was compared to telithromycin 800 mg for 10 days and to amoxicillin/clavulanic acid 500 mg/125 mg three times daily for 10 days (182). Results in the PP population were lower than in the trial by Roos et al., but were equivalent for all three treatment modalities (75.3% for telithromycin 5 day, 72.9% for telithromycin 10 day and 74.5% for amoxicillin/clavulanate 10 day) (108, 182). Satisfactory bacteriological outcomes were equivalent for the two telithromycin groups, and were slightly higher than the amoxicillin/clavulanate group (85.7% for the 5 and 10 day treatments, and 75.0% for the amoxicillin/clavulanate group). In the third study by Buchanan et al. telithromycin 800mg once daily for 5 days was compared to cefuroxime axetil 250mg twice daily for 10 days. Clinical cure in the PP population were equivalent (85.2% versus 82.0%, respectively). Bacteriological outcomes were similar for both treatments (84.0% and 79.6%, respectively) (35).

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 [Adapted from (108, 171)].

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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58. Dubois J, St -Pierre C. In vitro activity of ABT-773 versus macrolides and quinolones against resistant respiratory tract pathogens. Diagn Microbiol Infect Dis 2001;40:35-40. [PubMed]

59. Dubois J, St-Pierre C. Abstract 02.33. Intracellular activity and post-antibiotic effect of ABT-773 against Legionella. In: 5th International Conference on the Macrolides, Azalides, Streptogramins, Ketolides and Oxazolidinones. Seville, Spain: 2000. [PubMed]

60. Dubois J, St-Pierre C. Abstract 1242. Post-antibiotic effect (PAE) and bactericidal activity of HMR 3647 and other antimicrobial agents against respiratory pathogens. In: 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, USA: 1999. [PubMed]

61. Dubois J, St-Pierre C. Abstract 2152. In vitro study of the minimal inhibitory concentrations (MIC) of telithromycin (HMR 3647), macrolides and quinolones against Haemophilus, Streptococcus, Staphylococcus and Moraxella strains obtained from upper and lower respiratory tract infections and from maxillary sinus aspiration. In: 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Canada: 2000. [PubMed]

62. Duong M, Simard M, Bergeron Y, Bergeron MG. Kinetic study of the inflammatory response in Streptococcus pneumoniae experimental pneumonia treated with the ketolide HMR 3004. Antimicrob Agents Chemother 2001;45:252-62. [PubMed]

63. Duong M, Simard M, Bergeron Y, Ouellet N, Cote-Richer M, Bergeron MG. Immunomodulating effects of HMR 3004 on pulmonary inflammation caused by heat-killed Streptococcus pneumoniae in mice. Antimicrob Agents Chemother 1998;42:3309-12. [PubMed]

64. Edelstein PH, Edelstein MA. In vitro activity of the ketolide HMR 3647 (RU 6647) for Legionella spp., its pharmacokinetics in guinea pigs, and use of the drug to treat guinea pigs with Legionella pneumophila pneumonia. Antimicrob Agents Chemother 1999;43:90-5. [PubMed]

65. Edlund C, Alvan G, Barkholt L, Vacheron F, Nord CE. Pharmacokinetics and comparative effects of telithromycin (HMR 3647) and clarithromycin on the oropharyngeal and intestinal microflora. J Antimicrob Chemother 2000;46:741-9. [PubMed]

66. Ednie LM, Jacobs MR, Appelbaum PC. Comparative antianaerobic activities of the ketolides HMR 3647 (RU 66647) and HMR 3004 (RU 64004). Antimicrob Agents Chemother 1997;41:2019-22. [PubMed]

67. Engler KH, Warner M, George RC. In vitro activity of ketolides HMR 3004 and HMR 3647 and seven other antimicrobial agents against Corynebacterium diphtheriae. J Antimicrob Chemother 2001;47:27-31. [PubMed]

68. Feldman C, Anderson R, Theron A, Mokgobu I, Cole PJ, Wilson R. The effects of ketolides on bioactive phospholipid-induced injury to human respiratory epithelium in vitro. Eur Respir J 1999;13:1022-8. [PubMed]

69. Felmingham D, Robbins MJ, Methias I, Bryskier A. Abstract 2154. In vitro activity of two ketolides, HMR 3562 and HMR 3787 against clinical bacterial isolates. In: 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, USA: 1999. [PubMed]

70. Felmingham D, Tesfaslasie YK, Robbins MJ, Bryskier A. Abstract 02.23. The in vitro activity of telithromycin (HMR 3647) against 817 isolates of Streptococcus pneumoniae collected from 27 centres throughout Great Britain and Ireland during the 1997 - 1998 cold season. In: 5th International Conference on the Macrolides, Azalides, Streptogramins, Ketolides and Oxazolidinones. Seville, Spain: 2000. [PubMed]

71. Fernandez-Roblas R, Calvo R, Esteban J, Bryskier A, Soriano F. The bactericidal activities of HMR 3004, HMR 3647 and erythromycin against gram-positive bacilli and development of resistance. J Antimicrob Chemother 1999;43:285-9. [PubMed]

72. Finegold SM, Summanen P, Molitoris D, Vaisanen ML, Wexler HM. Abstract 02.30. In vitro activity of ABT -773 against anaerobic bacteria isolated from bowel flora. In: 5th International Conference on the Macrolides, Azalides, Streptogramins, Ketolides and Oxazolidinones. Seville, Spain: 2000. [PubMed]

73. Fogarty CM, Kohno S, Buchanan P, Aubier M, Baz M. Community-acquired respiratory tract infections caused by resistant pneumococci: clinical and bacteriological efficacy of the ketolide telithromycin. J Antimicrob Chemother 2003;51:947-55. [PubMed]

74. Fujikawa T, Miyazaki S, Matsumoto T, Ohno A, Furuya N, Ishii Y, Tateda K, Yamaguchi K. Abstract 2166. In vitro activities of ABT-773, a new ketolide, against major respiratory pathogens. In: 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Canada: 2000. [PubMed]

75. Garcia I, Pascual A, Ballesta S, del Castillo C, Perea EJ. Accumulation and activity of cethromycin (ABT-773) within human polymorphonuclear leucocytes. J Antimicrob Chemother 2003;52:24-8. [PubMed]

76. Gia HP, Roeder V, Namour F, Sultan E, Lenfant B. Abstract 09.27. Telithromycin (HMR 3647) achieves high and sustained concentrations in white blood cells in man. In: 5th International Conference on the Macrolides, Azalides, Streptogramins, Ketolides and Oxazolidinones. Seville, Spain: 2000. [PubMed]

77. Giovanetti E, Montanari MP, Marchetti F, Varaldo PE. In vitro activity of ketolides telithromycin and HMR 3004 against italian isolates of Streptococcus pyogenes and Streptococcus pneumoniae with different erythromycin susceptibility. J Antimicrob Chemother 2000;46:905-8. [PubMed]

78. Giovanetti E, Montanari MP, Mingoia M, Varaldo PE. Phenotypes and genotypes of erythromycin-resistant Streptococcus pyogenes strains in Italy and heterogeneity of inducibly resistant strains. Antimicrob Agents Chemother 1999;43:1935-40. [PubMed]

79. Girard D, Mathieu HW, Finegan SM. Abstract 1816. In vivo antibacterial activity of CP-654,743, a new C2-fluoro ketolide, against macrolide resistant pneumococci and Haemophilus influenzae. In: 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Canada: 2000. [PubMed]

80. Goldstein EJ, Citron DM, Hunt Gerardo S, Hudspeth M, Merriam CV. Activities of HMR 3004 (RU 64004) and HMR 3647 (RU 66647) compared to those of erythromycin, azithromycin, clarithromycin, roxithromycin, and eight other antimicrobial agents against unusual aerobic and anaerobic human and animal bite pathogens isolated from skin and soft tissue infections in humans. Antimicrob Agents Chemother 1998;42:1127-32. [PubMed]

81. Goldstein EJ, Citron DM, Merriam CV, Warren Y, Tyrrell K. Activities of telithromycin (HMR 3647, RU 66647) compared to those of erythromycin, azithromycin, clarithromycin, roxithromycin, and other antimicrobial agents against unusual anaerobes. Antimicrob Agents Chemother 1999;43:2801-5. [PubMed]

82. Goldstein EJ, Citron DM, Merriam CV, Warren Y, Tyrrell K. Comparative in vitro activities of ABT-773 against aerobic and anaerobic pathogens isolated from skin and soft-tissue animal and human bite wound infections. Antimicrob Agents Chemother 2000;44:2525-9. [PubMed]

83. Goldstein EJ, Conrads G, Citron DM, Merriam CV, Warren Y, Tyrrell K. In vitro activities of ABT-773, a new ketolide, against aerobic and anaerobic pathogens isolated from antral sinus puncture specimens from patients with sinusitis. Antimicrob Agents Chemother 2001;45:2363-7. [PubMed]

84. Guan Z, Jayanti V, Johnson M, Nequist G, Reisch T, Anderson L, Everitt E, Roberts E, Schmidt J, Rotert G, Surber B, Thomas S, Rodriquez C, Lee R, Kumar G, Roberts S, Lin J. Abstract 09.32. In vitro and in vivo metabolism of [14C] ABT-773. In: 5th International Conference on the Macrolides, Azalides, Streptogramins, Ketolides and Oxazolidinones. Seville, Spain: 2000. [PubMed]

85. Gustafsson I, Engstrand L, Cars O. In vitro pharmacodynamic studies of activities of ketolides HMR 3647 (Telithromycin) and HMR 3004 against extracellular or intracellular Helicobacter pylori. Antimicrob Agents Chemother 2001;45:353-5. [PubMed]

86. Gustafsson I, Hjelm E, Cars O. In vitro pharmacodynamics of the new ketolides HMR 3004 and HMR 3647 (Telithromycin) against Chlamydia pneumoniae. Antimicrob Agents Chemother 2000;44:1846-9. [PubMed]

87. Gustavson LE, Rieser M, Paris M. Abstract 4.03. The steady-state pharmacokinetics of ABT-773 at clinically-relevant doses. In: 6th International Conference on the Macrolides, Azalides, Streptogramins, Ketolides and Oxazolidinones. Bologna, Italy: 2002. [PubMed]

88. Hagberg L, Carbon C, van Rensburg DJ, Fogarty C, Dunbar L, Pullman J. Telithromycin in the treatment of community-acquired pneumonia: a pooled analysis. Respir Med 2003;97:625-33. [PubMed]

89. Hagberg L, Torres A, van Rensburg D, Leroy B, Rangaraju M, Ruuth E. Efficacy and tolerability of once-daily telithromycin compared with high-dose amoxicillin for treatment of community-acquired pneumonia. Infection 2002;30:378-86. [PubMed]

90. Hamilton-Miller JM, Shah S. Comparative in-vitro activity of ketolide HMR 3647 and four macrolides against gram-positive cocci of known erythromycin susceptibility status. J Antimicrob Chemother 1998;41:649-53. [PubMed]

91. Hamilton-Miller JM, Shah S. Patterns of phenotypic resistance to the macrolide-lincosamide-ketolide-streptogramin group of antibiotics in staphylococci. J Antimicrob Chemother 2000;46:941-9. [PubMed]

92. Hansen LH, Mauvais P, Douthwaite S. The macrolide-ketolide antibiotic binding site is formed by structures in domains II and V of 23S ribosomal RNA. Mol Microbiol 1999;31:623-31. [PubMed]

93. Hoban DJ, Doern GV, Fluit AC, Roussel-Delvallez M, Jones RN. Worldwide prevalence of antimicrobial resistance in Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the SENTRY Antimicrobial Surveillance Program, 1997-1999. Clin Infect Dis 2001;32 Suppl 2:S81-93. [PubMed]

94. Hoban DJ, Palatnick L, Weshnoweski B, Zhanel GG. Abstract P1259. Activity of telithromycin and oral comparators against 11 701 Canadian respiratory tract pathogens isolated from 1997 - 2000. In: 11th European Congress of Clinical Microbiology and Infectious Diseases. Istanbul, Turkey: 2001. [PubMed]

95. Hoban DJ, Wierzbowski AK, Nichol K, Zhanel GG. Macrolide-resistant Streptococcus pneumoniae in Canada during 1998-1999: prevalence of mef(A) and erm(B) and susceptibilities to ketolides. Antimicrob Agents Chemother 2001;45:2147-50. [PubMed]

96. Hoban DJ, Zhanel GG, Bellyou T, Karlowsky JA. Abstract 02.27. Telithromycin (HMR 3647) demonstrates excellent in vitro activity against clinical isolates of Streptococcus pyogenes and Streptococcus pneumoniae with M- and MLSB-resistance phenotypes. In: 5th International Conference on the Macrolides, Azalides, Streptogramins, Ketolides and Oxazolidinones. Seville, Spain: 2000. [PubMed]

97. Hoban DJ, Zhanel GG, Karlowsky JA. In vitro activity of the novel ketolide HMR 3647 and comparative oral antibiotics against Canadian respiratory tract isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Diagn Microbiol Infect Dis 1999;35:37-44. [PubMed]

98. Hoellman DB, Lin G, Jacobs MR, Appelbaum PC. Activity of HMR 3647 compared to those of six compounds against 235 strains of Enterococcus faecalis. Antimicrob Agents Chemother 1999;43:166-8. [PubMed]

99. Hoppe JE, Bryskier A. In vitro susceptibilities of Bordetella pertussis and Bordetella parapertussis to two ketolides (HMR 3004 and HMR 3647), four macrolides (azithromycin, clarithromycin, erythromycin A, and roxithromycin), and two ansamycins (rifampin and rifapentine). Antimicrob Agents Chemother 1998;42:965-6. [PubMed]

100. Jalava J, Kataja J, Seppala H, Huovinen P. In vitro activities of the novel ketolide telithromycin (HMR 3647) against erythromycin-resistant Streptococcus species. Antimicrob Agents Chemother 2001;45:789-93. [PubMed]

101. Johnson CN, Benjamin WH Jr, Gray BM, Crain MC, Edwards KM, Waites KB. In vitro activity of ABT-773, telithromycin and eight other antimicrobials against erythromycin-resistant Streptococcus pneumoniae respiratory isolates of children. Int J Antimicrob Agents 2001;18:531-5. [PubMed]

102. Jones RN, Biedenbach DJ. Antimicrobial activity of RU-66647, a new ketolide. Diagn Microbiol Infect Dis 1997;27:7-12. [PubMed]

103. Jung R, Bearden DT, Danziger LH. Abstract 2141. Effect of ABT-773 and other antimicrobial agents on the morphology and the release of interleukin-1B and Interleukin-8 against Haemophilus influenzae and Streptococcus pneumoniae in whole blood. In: 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, USA: 1999. [PubMed]

104. Jung R, Danziger LH, Pendland SL. Intracellular activity of ABT-773 and other antimicrobial agents against Legionella pneumophila. J Antimicrob Chemother 2002;49:857-61. [PubMed]

105. Kadota J, Ishimatsu Y, Iwashita T, Matsubara Y, Tomono K, Tateno M, Ishihara R, Muller-Serieys C, Kohno S. Intrapulmonary pharmacokinetics of telithromycin, a new ketolide, in healthy Japanese volunteers. Antimicrob Agents Chemother 2002;46:917-21. [PubMed]

105a. Kanathur N, Mathai MG, Byrd RP Jr, Fields CL, Roy TM. Simvastatin-diltiazem drug interaction resulting in rhabdomyolysis and hepatitis. Tenn Med. 2001;94:339-41. [PubMed]

106. Kaneko T, McMillen W, Sutcliffe J, Duignan J, Petitpas J. Abstract 1815. Synthesis and in vitro activity of C2-substituted C9-oxime ketolides. In: 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Canada: 2000. [PubMed]

107. Ketek. (telithromycin) briefing document for the FDA anti-infective drug products advisory committee. Aventis Pharma, Bridgewater, New Jersey, US; Executive Summary, January 2003. [PubMed]

108. Ketek. (telithromycin) briefing document for the FDA anti-infective drug products advisory committeeAventis Pharma, Bridgewater, New Jersey, US; Executive Summary, March 2001. [PubMed]

109. Khair OA, Andrews JM, Honeybourne D, Jevons G, Vacheron F, Wise R. Lung concentrations of telithromycin after oral dosing. J Antimicrob Chemother 2001;47:837-40. [PubMed]

110. Kim MK, Zhou W, Tessier PR, Xuan D, Ye M, Nightingale CH, Nicolau DP. Bactericidal effect and pharmacodynamics of cethromycin (ABT-773) in a murine pneumococcal pneumonia model. Antimicrob Agents Chemother 2002;46:3185-92. [PubMed]

111. Leclercq R. Abstract 1135. Resistance to ketolides: role of ribosomal modification and macrolide efflux. In: 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Canada: 2000. [PubMed]

112. Leroy B, Rangaraju M. Abstract 2224. High in vitro susceptibility of the ketolide telithromycin (HMR 3647) in clinical isolates of key respiratory pathogens. In: 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Canada: 2000. [PubMed]

113. Linglof T, Olsson-Liljequist B, Naaber P, Kaftyrea L. Abstract P886. Activity of telithromycin on S. pyogenes and S. pneumoniae in Russia and Estonia: an epidemiological study. In: 11th European Congress of Clinical Microbiology and Infectious Diseases. Istanbul, Turkey: 2001. [PubMed]

114. Lippert C, Andersen A, Sach S, Sultan E. Abstract P893. Telithromycin (HMR 3647) does not require dosage adjustment in patients with renal impairment. In: 11th European Congress of Clinical Microbiology and Infectious Diseases. Istanbul, Turkey: 2001. [PubMed]

115. Lippert C, Leese PT, Sultan E. Abstract P1269. Effect of gastric pH on the bioavailability of telithromycin (HMR 3647). In: 11th European Congress of Clinical Microbiology and Infectious Diseases. Istanbul, Turkey: 2001. [PubMed]

116. Luna VA, Roberts MC. In-vitro activities of 11 antibiotics against 75 strains of Streptococcus pneumoniae with reduced susceptibilities to penicillin isolated from patients in Washington State. J Antimicrob Chemother 1999;44:578-80. [PubMed]

117. Ma Z, Clark RF, Brazzale A, Wang S, Rupp MJ, Li L, Griesgraber G, Zhang S, Yong H, Phan LT, Nemoto PA, Chu DT, Plattner JJ, Zhang X, Zhong P, Cao Z, Nilius AM, Shortridge VD, Flamm R, Mitten M, Meulbroek J, Ewing P, Alder J, Or YS. Novel erythromycin derivatives with aryl groups tethered to the C-6 position are potent protein synthesis inhibitors and active against multidrug-resistant respiratory pathogens. J Med Chem 2001;44:4137-56. [PubMed]

118. Malathum K, Coque TM, Singh KV, Murray BE. In vitro activities of two ketolides, HMR 3647 and HMR 3004, against gram-positive bacteria. Antimicrob Agents Chemother 1999;43:930-6. [PubMed]

119. Mandell GL, Coleman E. Uptake, transport, and delivery of antimicrobial agents by human polymorphonuclear neutrophils. Antimicrob Agents Chemother 2001;45:1794-8. [PubMed]

120. Mankin A, Xiong L, Khaitovich P. Abstract 01.02. Interaction of macrolides and ketolides with the ribosome. In: 5th International Conference on the Macrolides, Azalides, Streptogramins, Ketolides and Oxazolidinones. Seville, Spain: 2000. [PubMed]

121. Martinez-Martinez L, Pascual A, Suarez AI, Perea EJ. In vitro activities of ketolide HMR 3647, macrolides, and clindamycin against Coryneform bacteria. Antimicrob Agents Chemother 1998;42:3290-2. [PubMed]

122. Mauvais P, Bonnefoy A. Abstract 02.10. Lack of in vitro MLSB resistance induction by the ketolide telithromycin (HMR 3647): role of the 3-keto group. In: 5th International Conference on the Macrolides, Azalides, Streptogramins, Ketolides and Oxazolidinones. Seville, Spain: 2000. [PubMed]

123. Mazzariol A, Esposito S, Ciammanco A, Miragliotta G, Muresu E, Necolettu P, Fontana R, Cornaglia G. Abstract 2148. Genotype analysis of macrolide resistance and activity of the new ketolide telithromycin (HMR 3647) on group A, C and G beta-hemolytic Streptococci. In: 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Canada: 2000. [PubMed]

124. Mazzariol A, Luzzaro F, Manno G, Rescaldani R, Ronchetti P, Crest W, Savoia D, Fontana R, Cornaglia G. Abstract 2147. Multicenter evaluation of telithromycin (HMR 3647) activity on Italian Streptococcus pneumoniae with different genotypes of erythromycin resistance. In: 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Canada:, 2000.  [PubMed]

125. Mikamo H, Hua YX, Sato Y, Hayasaki Y, Tamaya T. In vitro antibacterial activities of telithromycin, a new ketolide, against bacteria causing infections in obstetric and gynaecological patients. J Antimicrob Chemother 2000;46:332-4. [PubMed]

126. Miossec-Bartoli C, Pilatre L, Peyron P, N'Diaye EN, Collart-Dutilleul V, Maridonneau-Parini I, Diu-Hercend A. The new ketolide HMR3647 accumulates in the azurophil granules of human polymorphonuclear cells. Antimicrob Agents Chemother 1999;43:2457-62. [PubMed]

127. Mittermayer H, Jebelean C, Bocksrucker A, Binder L, Haditsch M, Watshinger R. Abstract 2145. Activity of telithromycin (HMR 3647) against erythromycin-susceptible and -resistant isolates of Streptococcus pneumoniae and Streptococcus pyogenes from Austria. In: 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Canada: 2000.  [PubMed]

128. Miyamoto N, Murakami S, Yajin K, Takebayashi S, Omura R, Maekawa H, Moribe I, Nakao Y, Kobayahi T, Baba S. Abstract 2144. Pharmacokinetic study of a new ketolide antimicrobial telithromycin (HMR 3647) in otorhinolaryngology. In: 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Canada: 2000. [PubMed]

129. Morosini MI, Canton R, Loza E, Negri MC, Galan JC, Almaraz F, Baquero F. In vitro activity of telithromycin against Spanish Streptococcus pneumoniae isolates with characterized macrolide resistance mechanisms. Antimicrob Agents Chemother 2001;45:2427-31. [PubMed]

130. Morrissey I, Trezise E, Tsa N, Robbins MJ, Hopkirk S, Oram M, Bryskier A, Felmingham D. Abstract 2149. The comparative in vitro activity of telithromycin (HMR 3647) against isolates of Streptococcus pyogenes (Lancefield serogroup A) circulating in Great Britain, Northern Ireland and the Republic of Ireland during late 1999. In: 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Canada: 2000. [PubMed]

131. Muller-Serieys C, Soler P, Cantalloube C, Lemaitre F, Gia HP, Brunner F, Andremont A. Bronchopulmonary disposition of the ketolide telithromycin (HMR 3647). Antimicrob Agents Chemother 2001;45:3104-8. [PubMed]

132. Munckhof WJ, Borlace G, Turnidge JD. Postantibiotic suppression of growth of erythromycin A-susceptible and -resistant gram-positive bacteria by the ketolides telithromycin (HMR 3647) and HMR 3004. Antimicrob Agents Chemother 2000;44:1749-53. [PubMed]

133. Nagai K, Appelbaum PC, Davies TA, Kelly LM, Hoellman DB, Andrasevic AT, Drukalska L, Hryniewicz W, Jacobs MR, Kolman J, Miciuleviciene J, Pana M, Setchanova L, Thege MK, Hupkova H, Trupl J, Urbaskova P. Susceptibilities to telithromycin and six other agents and prevalence of macrolide resistance due to L4 ribosomal protein mutation among 992 Pneumococci from 10 central and Eastern European countries. Antimicrob Agents Chemother 2002;46:371-7. [PubMed]

134. Nagai K, Appelbaum PC, Davies TA, Kelly LM, Hoellman DB, Andrasevic AT, Drukalska L, Hryniewicz W, Jacobs MR, Kolman J, Miciuleviciene J, Pana M, Setchanova L, Thege MK, Hupkova H, Trupl J, Urbaskova P. Susceptibility to telithromycin in 1,011 Streptococcus pyogenes isolates from 10 central and Eastern European countries. Antimicrob Agents Chemother 2002;46:546-9. [PubMed]

135. Nagai K, Davies TA, Appelbaum PC, Hryniewicz W, Drukalska L, Jacobs MR, Kolman J, Miciuleviciene J, Pana M, Setchanova L, Tambic A, Konkoly Thege M, Trupl J, Urbaskova P. Abstract 0138. Mechanism of macrolide resistance in Streptococcus pneumoniae and Streptococcus pyogenes from central and eastern European countries. In: 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada: 2000. [PubMed]

136. Namour F, Wessels DH, Pascual MH, Reynolds D, Sultan E, Lenfant B. Pharmacokinetics of the new ketolide telithromycin (HMR 3647) administered in ascending single and multiple doses. Antimicrob Agents Chemother 2001;45:170-5. [PubMed]

137. Negri MC, Loza E, Canton R, Morosini MI, Galan JC, Almaraz F, Baquero F. Abstract 2155. Activity of telithromycin (HMR 3647) against susceptible and well-characterized erythromycin A-resistant isolates of Streptococcus pyogenes. In: 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Canada: 2000. [PubMed]

138. Neuhauser MM, Prause JL, Danziger LH, Pendland SL. Postantibiotic effects of ABT-773 and amoxicillin-clavulanate against Streptococcus pneumoniae and Haemophilus influenzae. Antimicrob Agents Chemother 2001;45:3613-5. [PubMed]

139. Nilius AM, Bui MH, Almer L, Hensey-Rudloff D, Beyer J, Ma Z, Or YS, Flamm RK. Comparative in vitro activity of ABT-773, a novel antibacterial ketolide. Antimicrob Agents Chemother 2001;45:2163-8. [PubMed]

140. Nilius AM, Hensey-Rudloff DM, Reimann MA, Flamm RK. Comparison of selection for mutants with reduced susceptibility to ABT-773, erythromycin and rifampicin in respiratory tract pathogens. J Antimicrob Chemother 2002;49:831-6. [PubMed]

141. Norrby SR, Rabie WJ, Bacart P, Mueller O, Leroy B, Rangaraju M, Butticaz-Iroudayassamy E. Efficacy of short-course therapy with the ketolide telithromycin compared with 10 days of penicillin V for the treatment of pharyngitis/tonsillitis. Scand J Infect Dis 2001;33:883-90. [PubMed]

142. Novotny GW, Andersen NM, Poehlsgaard J. Abstract P480. Telithromycin interacts directly with the base of A752 in domain II of 23S ribosomal RNA, in contrast to erythromycin and clarithromycin. In: 11th European Congress of Clinical Microbiology and Infectious Diseases. Istanbul, Turkey: 2001. [PubMed]

143. Odenholt I, Lowdin E, Cars O. Pharmacodynamics of telithromycin In vitro against respiratory tract pathogens. Antimicrob Agents Chemother 2001;45:23-9. [PubMed]

144. Okamoto H, Miyazaki S, Tateda K, Ishii Y, Yamaguchi K. Comparative in vitro activity of telithromycin (HMR 3647), three macrolides, amoxycillin, cefdinir and levofloxacin against gram-positive clinical isolates in Japan. J Antimicrob Chemother 2000;46:797-802. [PubMed]

145. Or YS, Clark RF, Wang S, Chu DT, Nilius AM, Flamm RK, Mitten M, Ewing P, Alder J, Ma Z. Design, synthesis, and antimicrobial activity of 6-O-substituted ketolides active against resistant respiratory tract pathogens. J Med Chem 2000;43:1045-9. [PubMed]

146. Pankuch GA, Hoellman DB, Lin G, Bajaksouzian S, Jacobs MR, Appelbaum PC. Activity of HMR 3647 compared to those of five agents against Haemophilus influenzae and moraxella catarrhalis by MIC determination and time-kill assay. Antimicrob Agents Chemother 1998;42:3032-4. [PubMed]

147. Pankuch GA, Visalli MA, Jacobs MR, Appelbaum PC. Susceptibilities of penicillin- and erythromycin-susceptible and -resistant pneumococci to HMR 3647 (RU 66647), a new ketolide, compared with susceptibilities to 17 other agents. Antimicrob Agents Chemother 1998;42:624-30. [PubMed]

148. Pascual A, Ballesta S, Garcia I, Perea EJ. Uptake and intracellular activity of ketolide HMR 3647 in human phagocytic and non-phagocytic cells. Clin Microbiol Infect 2001;7:65-9. [PubMed]

149. Pendland SL, Prause JL, Neuhauser MM, Boyea N, Hackleman JM, Danziger LH. In vitro activities of a new ketolide, ABT-773, alone and in combination with amoxicillin, metronidazole, or tetracycline against Helicobacter pylori. Antimicrob Agents Chemother 2000;44:2518-20. [PubMed]

150. Perret C, Lenfant B, Weinling E, Wessels DH, Scholtz HE, Montay G, Sultan E. Pharmacokinetics and absolute oral bioavailability of an 800-mg oral dose of telithromycin in healthy young and elderly volunteers. Chemotherapy 2002;48:217-23. [PubMed]

151. Phan LT, Clark RF, Rupp M, Or YS, Chu DT, Ma Z. Synthesis of 2-fluoro-6-O-propargyl-11,12-carbamate ketolides. A novel class of antibiotics. Org Lett 2000;2:2951-4. [PubMed]

152. Piper KE, Rouse MS, Steckelberg JM, Wilson WR, Patel R. Ketolide treatment of Haemophilus influenzae experimental pneumonia. Antimicrob Agents Chemother 1999;43:708-10. [PubMed]

153. Pletz MW, Preechachatchaval V, Bulitta J, Allewelt M, Burkhardt O, Lode H. ABT-773: pharmacokinetics and interactions with ranitidine and sucralfate. Antimicrob Agents Chemother 2003;47:1129-31. [PubMed]

154. Pluim J, Sultan E, Leroy B. Abstract P1263. Population pharmacokinetics support the convenient once-daily 800 mg dosage of telithromycin in patients with upper and lower RTIs, including special populations. In: 11th European Congress of Clinical Microbiology and Infectious Diseases. Istanbul, Turkey: 2001. [PubMed]

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156. Pradhan RS, Gustavson LE, Londo DD, Zhang Y, Zhang J, Paris MM. Abstract 2138. The bioavailability of ABT-773 is unaffected by food. In: 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Canada: 2000. [PubMed]

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