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Microbiological profile of telithromycin, the first ketolide antimicrobial

D. Felmingham

GR Micro Ltd, London, UK

ABSTRACT Telithromycin, the first of the ketolide antimicrobials, has been specifically designed to provide potent activity against common and atypical/intracellular or cell-associated respiratory pathogens, including those that are

resistant to b-lactams and/or macrolide±lincosamide±streptograminB (MLSB) antimicrobials. Against Gram- positive cocci, telithromycin possesses more potent activity in vitro and in vivo than the macrolides

clarithromycin and azithromycin. It retains its activity against erm-(MLSB)ormef-mediated macrolide-resistant Streptococcus pneumoniae and Streptococcus pyogenes and against Staphylococcus aureus resistant to macrolides through

inducible MLSB mechanisms. Telithromycin also possesses high activity against the Gram-negative pathogens Haemophilus influenzae and Moraxella catarrhalis, regardless of b-lactamase production. In vitro, it shows similar activity to azithromycin against H. influenzae, while in vivo its activity against H. influenzae is higher than that of azithromycin. Telithromycin's spectrum of activity also extends to the atypical, intracellular and cell-associated pathogens Legionella pneumophila, Mycoplasma pneumoniae and Chlamydia pneumoniae. In vitro, telithromycin does

not induce MLSB resistance and it shows low potential to select for resistance or cross-resistance to other antimicrobials. These characteristics indicate that telithromycin will have an important clinical role in the Ahed empirical treatment of community-acquired respiratory tract infections. Bhed Clin Microbiol Infect 2001: 7 (Supplement 3): 2±10 Ched Dhed Ref marker Fig marker these agents. Resistance to penicillin, particularly among S. Table marker INTRODUCTION pneumoniae, H. influenzae and M. catarrhalis, has limited the Ref end Given the diverse etiology of community-acquired respiratory usefulness of both penicillins and cephalosporins. In addition, Ref start tract infections (RTIs) and the time required to establish a these agents do not offer activity against atypical pathogens. microbiological diagnosis, treatment is usually initiated Macrolide antimicrobials provide effective coverage against a empirically. In choosing appropriate antimicrobial therapy, much broader spectrum of respiratory pathogens and have the likely pathogens and their susceptibilities are major been particularly useful for the treatment of patients intolerant considerations. Streptococcus pneumoniae, Haemophilus influenzae, of b-lactams. However, resistance to macrolides among Gram- Moraxella catarrhalis and Streptococcus pyogenes are common positive cocci is increasing worldwide [1], and frequently bacterial causes of lower (LRTIs) and upper respiratory tract confers cross-resistance to all other antimicrobials of the

infections (URTIs). Other organisms that are implicated less macrolide±lincosamide±streptograminB (MLSB) class. New frequently, but should also be considered, include Staphylo- extended-spectrum fluoroquinolones with improved activity coccus aureus and the so-called `atypical' pathogens ± Chlamydia against Gram-positive pathogens have recently been licensed pneumoniae, Mycoplasma pneumoniae and Legionella pneumophila ± for treatment of RTIs, but early reports of emerging resistance which are emerging as an important cause of community- urge caution in their use [2]. Furthermore, these agents are not acquired pneumonia (CAP). licensed for use in children. The usefulness of currently available antimicrobial agents New classes of antimicrobial are therefore required which that are widely prescribed for these infections is being provide effective coverage against the key pathogens but also compromised by the changing etiology of RTIs and, perhaps retain activity against resistant isolates. Of the new agents that most importantly, by the increasing prevalence of resistance to are currently in development, telithromycin (HMR 3647) ± the first of the ketolide antimicrobials ± appears particularly Corresponding author and reprint requests: D. Felmingham, GR promising in this regard. Micro Ltd, 7±9 William Road, London NW1 3ER, UK The in vitro activity of telithromycin has been tested against Tel.: 020 738 87320 Fax: 020 738 87324 approximately 10 000 isolates of key respiratory pathogens. E-mail: [email protected] Highly consistent results have been obtained from many

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Felmingham Microbiological profile of telithromycin 3

laboratories worldwide, although only a selection of these patients with otitis media caused by penicillin-resistant studies will be included in this article. pneumococci [6].

In vitro activity FACTORS INFLUENCING DETERMINATION OF We and others have tested the comparative in vitro activity of TELITHROMYCIN ACTIVITY IN VITRO telithromycin against penicillin-susceptible (MIC 4 0.12 When determining the in vitro activity of a compound relative mg/L), -intermediate (MIC 0.12±1 mg/L) and -resistant to other agents, it is important to consider any possible effects strains (MIC 5 2 mg/L) [4,7,8]. The results of these studies of laboratory conditions or media. suggest that telithromycin has more potent antipneumococcal For telithromycin, minimum inhibitory concentrations activity than any of the macrolides or other available (MICs) can be determined by either agar or broth dilution antimicrobials. The results of our study are presented in Table techniques [3]. Both techniques produce similar results (with 1 [4,9]. Against susceptible strains, telithromycin demonstrated the exception of anaerobes) and are minimally affected by the potent activity with an MIC90 of 0.015 mg/L. Its activity was choice of medium (Brain Heart infusion medium, Mueller± at least as high as that of clarithromycin, the most active of the Hinton broth or Isosensitest). The presence of divalent cations macrolides tested, and 4-fold greater than that of azithromycin. in the culture medium does not appear to influence Telithromycin's activity was unaffected by intermediate or full telithromycin MICs. Calcium ions (0±200 mg/L in the resistance to penicillin: MIC90 against resistant strains was presence of 20 mg/L magnesium) and magnesium ions (0± 0.008 mg/L. The activity of telithromycin and the macrolides 50 mg/L in the presence of 100 mg/L calcium) have little was also tested against these same susceptible strains in the effect on the activity of telithromycin. presence of CO2. In air enriched to 6% CO2, the MICs for all As seen with other antimicrobials, telithromycin MICs are tested compounds were slightly increased. Telithromycin and influenced by inoculum size: between 103 and 107 colony clarithromycin MIC values increased 2-to 3-fold.For forming units (cfu) there is an 8-fold difference in MICs azithromycin, the effect was much more pronounced with (increased MICs seen with higher inocula), while within the MIC values increasing approximately 16-fold. range 104±105 cfu, no more than a 2-fold difference is Macrolide resistance in S. pneumoniae occurs principally as a observed in telithromycin MICs. Telithromycin, like the result of one of two mechanisms: (i) target site modification macrolides, is somewhat less active in acidic media (pH 5.5) and (ii) efflux. Target site modification is genetically than in alkaline conditions (pH 8). However, over the range determined by the ermB (erythromycin A resistance methylase) 6.5±7.5, the typical pH of culture media, there is only a 2-to genes. The product of the ermB gene is an RNA methylase 4-fold variation in telithromycin activity. The presence of that modifies a key site of interaction of erythromycin A with

CO2 can cause up to a 4-fold increase in telithromycin MICs the ribosomal RNA (reviewed by Leclercq and Courvalin determined on agar [3,4]. This effect is recognized for [10]). Expression of the methylase can be constitutive or macrolides, and occurs because the growth rates of S. inducible and results in cross-resistance to all MLSB anti- pneumoniae and H. influenzae are increased in the presence of microbials. Elimination of macrolides from the cell by an

CO2 rather than by any effect of CO2 on acidity of the growth efflux pump (M-type resistance), encoded by the mefA gene medium. Telithromycin's activity against anaerobic organisms [11], only confers resistance to 14-and 15-memberedring is also influenced by CO2. Credito et al. [5] have shown that macrolides. The activity of telithromycin against strains of S. this effect can be overcome by using Oxyrase (Oxyrase Inc., pneumoniae resistant to erythromycin A through these Mansfield, OH, USA) in the culture to prevent the mechanisms has been tested in comparison with erythromycin introduction of CO2. A and the lincosamide, clindamycin [9] (Table 1). Telithro- mycin showed excellent activity (MIC range 0.06±1 mg/L) against strains of S. pneumoniae resistant to macrolides as a ACTIVITY AGAINST COMMON RESPIRATORY PATHOGENS result of target site modification (methylation). The corre- sponding values for erythromycin A and clindamycin were Streptococcus pneumoniae well in excess of any concentrations that could be attained Streptococcus pneumoniae is the predominant bacterial pathogen therapeutically. Telithromycin also demonstrated excellent of RTIs. Penicillin resistance is highly prevalent among activity against strains resistant to macrolides through an efflux pneumococci with levels of 50% or more now being reported mechanism (MIC range 0.12±0.5 mg/L). in some countries (e.g. France, Spain, Hong Kong) [1]. Time±kill analysis experiments demonstrate concentration- Effective coverage against resistant isolates is essential to ensure dependent bactericidal activity for telithromycin against bacterial eradication and has been linked to clinical outcome in S. pneumoniae at concentrations at or above the MIC (0.016

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Table 1 Comparative in vitro activity of telithromycin against penicillin-resistant and erythromycin A-resistant isolates of S. pneumoniae

MICs (mg/L) ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ

MIC50 MIC90 Range

Penicillin susceptibility (adapted from [4]) Penicillin susceptible (n = 21) Erythromycin A 0.06 0.12 0.03±0.12 Clarithromycin 0.015 0.015 0.015±0.03 Azithromycin 0.06 0.06 0.015±0.06 Telithromycin 0.008 0.015 0.008±0.015

Penicillin intermediate (n = 20) Erythromycin A 0.12 0.12 0.03±0.12 Clarithromycin 0.015 0.015 0.015±0.03 Azithromycin 0.06 0.06 0.015±0.06 Telithromycin 0.008 0.015 0.004±0.015

Penicillin resistant (n = 20) Erythromycin A 0.12 0.12 0.015±0.12 Clarithromycin 0.015 0.015 0.015±0.03 Azithromycin 0.06 0.06 0.015±0.06 Telithromycin 0.008 0.008 0.008±0.03

Erythromycin A resistance [9]

Constitutive MLSB (erm)(n = 21) Erythromycin A 512 4 512 16±4 512 Clindamycin 128 256 32±512 Telithromycin 0.06 1 0.06±1

Inducible MLSB (erm)(n =9) Erythromycin A 128 512 2±512 Clindamycin 8 64 0.25±64 Telithromycin 0.06 0.5 0.06±1

Efflux (mef)(n =3) Erythromycin A ± ± 2±4 Clindamycin ± ± All 0.06 Telithromycin ± ± 0.12±0.5

mg/L). Otsuki and colleagues [12] showed significant rates of (PD50) infected with erythromycin A-susceptible pneumo- killing over the first 4 h with telithromycin. In similar cocci. The macrolides erythromycin A, clarithromycin and experiments, we have demonstrated a 99% reduction in azithromycin were at least 5-fold less potent. Telithromycin viability within 12±24 h at 2 6 MIC [13]. Telithromycin's also demonstrated good efficacy against infections caused by bactericidal activity is greater than that of azithromycin and in macrolide-resistant strains (PD50 6.5 mg/kg and 4 mg/kg, general tends to be more concentration dependent than that of respectively), while the macrolides tested offered no protec- the macrolides. It retains bactericidal activity against erythro- tion (PD50 4 50 mg/kg). mycin A-resistant strains, albeit at a slightly lower level than against susceptible strains (Figure 1). Azithromycin, in Potential for development of resistance contrast, shows no bactericidal activity against erythromycin Experiments in vitro indicate that telithromycin does not

A-resistant isolates. induce MLSB resistance in pneumococci [15]. Spontaneous resistance to telithromycin appears to occur with low In vivo activity frequency in vitro. Furthermore, the compound has shown Telithromycin's excellent antipneumococcal activity in vitro low potential to select for resistance or cross-resistance during translates well in animal models (Figure 2a). Using a mouse serial passage experiments [16]. In inducibly erythromycin A- septicemia model, Agouridas and coworkers [14] showed that resistant strains of S. pneumoniae, telithromycin selected for a dose of 1 mg/kg telithromycin protected 50% of animals constitutive resistance to erythromycin A considerably more

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Felmingham Microbiological profile of telithromycin 5

PenS EryS S. pneumoniae (a) S. pneumoniae >50 >50 >50 Counts (log CFU/mL) 50 10 Telithromycin 10 45 Erythromycin A Clarithromycin 9 40 Azithromycin 8 Control 35 TEL at 2 x MIC 7 TEL at 4 x MIC 30 6 TEL at 8 x MIC (mg/kg) 25 5 AZI at 2 x MIC 50

AZI at 4 x MIC PD 20 4 AZI at 8 x MIC 15 3 2 10 7.5 6 6.5 1 5 4 0 1 0 -5 0 5 10 15 20 25 30 Ery-S Ery-cR Ery-iR

Time (hours) (b) H. influenzae >300 >300 300 PenS EryR S. pneumoniae

Counts (log CFU/mL) 10 250 230 10 200 9 200 8 150 145 7 (mg/kg) 120 50 6 100 PD 100 94 5 4 52 50 40 3 25 2 0 1 β-lactamase Amp-R β-lactamase 0 negative β-lactamase positive negative -5 0 5 10 15 20 25 30

Time (hours) Fig 2 Protective effect of telithromycin in disseminated murine infections caused by (a) erythromycin A-susceptible and -resistant S. Fig 1 Time±kill profile of the in vitro activity of telithromycin against pneumoniae and (b) b-lactamase-negative, b-lactamase-positive and erythromycin A-susceptible and -resistant strains of S. pneumoniae ampicillin-resistant b-lactamase-negative H. influenzae (adapted from S (adapted from [13]). CFU, colony-forming units; Pen , penicillin [14]). PD50, dose that protects 50% of animals; Ery-S, erythromycin A susceptible; EryR, erythromycin A resistant. susceptible (MIC = 0.02 mg/L); Ery-cR, erythromycin A constitutively resistant (MIC 4 40 mg/L); Ery-iR, erythromycin A inducibly resistant (MIC = 10 mg/L); Amp-R, ampicillin resistant. slowly than josamycin, to a substantially lesser extent and at a Streptococcus pyogenes lower frequency (Figure 3). These results suggest a lower likelihood of resistance developing through the clinical use of Streptococcus pyogenes (Group A b-hemolytic streptococci) is the telithromycin. It has been suggested that this property of predominant bacterial pathogen of tonsillopharyngitis, parti- telithromycin reflects its unique mechanism of action. cularly among children. It is also implicated in otitis media. Telithromycin binds to two regions on the bacterial ribosome Infections caused by S. pyogenes can lead to more serious and hence mutation or modification (e.g. methylation) of a complications if not treated effectively. As yet, S. pyogenes has single target site may be insufficient to disrupt binding [17]. been unaffected by resistance to penicillin, which remains the

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700 and is caused by a similar mechanism (encoded by erm genes) as Josamycin 600 in pneumococci (reviewed by Leclercq and Courvalin [10]). 500 Telithromycin has excellent activity against S. pyogenes (MIC range 0.008±0.06 mg/L) (Table 2). Its activity is 4-fold 400 higher than that of erythromycin A or azithromycin, and of 300

MIC (mg/L) the same order as clarithromycin, the most active of the 200 macrolides against S. pyogenes in vitro [4]. Telithromycin retains Telithromycin 100 activity against constitutively MLSB resistant strains, albeit at a 0.6 1.2 10 slightly lower level: MIC range 0.03±4 mg/L. Both 0 01234567 erythromycin A and the lincosamide clindamycin have greatly No. of transfers reduced activity against constitutively resistant isolates (MIC ranges 128±4 512 mg/L and 64±256 mg/L, respectively) [9]. Fig 3 Selection of resistance in inducibly erythromycin A-resistant S. Strains affected by efflux-mediated erythromycin A resistance pneumoniae with telithromycin and josamycin (adapted from [16]). are also highly susceptible to telithromycin (MIC range 0.03± 0.5 mg/L) [9]. treatment of choice for tonsillopharyngitis. Erythromycin A resistance, in contrast, is increasing rapidly in some geogra- phical areas and levels of up to 25% have been reported in Staphylococcus aureus Italy, Finland and Canada [18±20]. Efflux resistance, encoded by the mefA gene, accounts for the majority of erythromycin Streptococcus aureus is a major human pathogen but accounts for

A-resistant isolates; however, MLSB resistance is also common 5 10% of community-acquired RTIs. The majority of strains

Table 2 In vitro activity of telithromycin against erythromycin A-susceptible and -resistant isolates of S. pyogenes and S. aureus (adapted from [4]; [9])

MICs (mg/L) ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ

MIC50 MIC90 Range

S. pyogenes Erythromycin A susceptible (n = 24) Erythromycin A 0.06 0.06 0.03±8 Clarithromycin 0.015 0.015 0.015±4 Azithromycin 0.06 0.12 0.06±64 Telithromycin 0.015 0.015 0.008±0.06

Constitutive MLSB (erm)(n = 21) Erythromycin A 4512 4512 128±4 512 Clindamycin 128 128 64±256 Telithromycin 0.5 4 0.03±4

Efflux (mef)(n = 21) Erythromycin A 8 8 1±8 Clindamycin 0.030.030.03 ±0.5 Telithromycin 0.25 0.5 0.03±0.5

S. aureus Erythromycin A susceptible (n = 27) Erythromycin A 0.25 0.5 0.25±0.5 Clarithromycin 0.25 0.25 0.12±0.25 Azithromycin 1 1 0.5±1 Telithromycin 0.12 0.12 0.06±0.12

Erythromycin A resistant (n = 22) Erythromycin A 5128 5128 4±5128 Clarithromycin 5128 5128 4±5128 Azithromycin 5128 5128 16±5128 Telithromycin 0.12 5128 0.06±5128

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Felmingham Microbiological profile of telithromycin 7

produce b-lactamase and MLSB resistance is estimated to affect unaffected by b-lactamase production. MIC values for H. as many as 20% of strains [21]. influenzae are increased in the presence of CO2 (6%) by one 2- Against erythromycin A-susceptible strains of S. aureus, fold dilution factor. Telithromycin also shows concentration- telithromycin shows very high activity (MIC range 0.06±0.12 dependent bactericidal activity against H. influenzae over the mg/L), superior to the macrolides (Table 2). Although it first 4 h at concentrations equal to and greater than its MIC retains activity against isolates expressing inducible MLSB (Figure 4) [12]. resistance, telithromycin is inactive against constitutively resistant strains (MIC90 5 128 mg/L) [4]. In vivo activity The comparative activity of telithromycin has also been investigated in the murine model of septicaemia [14] (Figure Haemophilus influenzae 2b). Telithromycin showed superior potency to azithromycin Haemophilus influenzae is a major pathogen in RTIs, particularly in acute exacerbations of chronic bronchitis. 10 MIC: 1 mg/mL Control b-lactamase production is the most significant resistance 9 0.25 MIC 0.5 MIC mechanism affecting this organism. Susceptibility to macro- 8 7 lides remains relatively constant, with azithromycin being the 6 MIC most active of these agents in vitro. 5 2 MIC 4 4 MIC In vitro activity 3

Log of viable cells/mL Log of viable 2 Telithromycin's activity against H. influenzae (MIC range 0.5± 0 2 mg/L) is somewhat lower than against Gram-positive cocci 01234 Incubation time (hours) (Table 3) [4]. It is, however, similar to that of azithromycin and significantly greater than that of erythromycin A and Fig 4 Time±kill profile of the in vitro activity of telithromycin against H. clarithromycin. Both telithromycin and the macrolides are influenzae (adapted from [12]).

Table 3 In vitro activity of telithromycin MICs (mg/L) against b-lactamase-positive and -negative ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ H. influenzae and M. catarrhalis (adapted

MIC50 MIC90 Range from [4])

H. influenzae b-lactamase-negative (n = 20) Erythromycin 4 8 2±8 Clarithromycin 4 8 2±16 Azithromycin 1 1 0.25±2 Telithromycin 1 2 0.5±2

b-lactamase-positive (n = 24) Erythromycin 4 4 2±8 Clarithromycin 4 8 2±8 Azithromycin 0.5 1 0.25±1 Telithromycin 1 2 0.5±2

M. catarrhalis b-lactamase-negative (n = 21) Erythromycin 0.12 0.25 0.03±0.25 Clarithromycin 0.030.06 0.015±0.06 Azithromycin 0.030.030.015±0.03 Telithromycin 0.06 0.06 0.008±0.06

b-lactamase-positive (n = 24) Erythromycin 0.12 0.25 0.06±1 Clarithromycin 0.06 0.06 0.015±0.12 Azithromycin 0.030.030.008±0.03 Telithromycin 0.06 0.06 0.008±0.12

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against all strains tested (b-lactamase negative, b-lactamase ACTIVITY AGAINST ATYPICAL RESPIRATORY PATHOGENS positive and ampicillin-resistant b-lactamase negative). Ery- Legionella pneumophila thromycin A and clarithromycin demonstrated poor activity in vivo against H. influenzae. Legionella pneumophila is estimated to cause as many as 30% of cases of CAP [22]. Infections are often severe and life- threatening. It is an intracellular pathogen and antimicrobials Moraxella catarrhalis must attain significant intracellular concentrations in order to Moraxella catarrhalis is implicated in acute exacerbation of be efficacious. chronic bronchitis and acute maxillary sinusitis. Greater than The activity of telithromycin against Legionella spp. in vitro 90% of isolates of this organism are reported to produce has been investigated in comparison with macrolides and other b-lactamase [1]. antimicrobial agents, including the newer fluoroquinolones, Telithromycin offers potent activity against both b- levofloxacin and moxifloxacin [23] (Table 4). Telithromycin lactamase-negative and b-lactamase-positive strains of M. has potent activity against Legionella spp. (MIC range 4 catarrhalis (Table 3) [4]. Its MIC90 (0.06 mg/L) is comparable 0.004±0.12 mg/L), greater than that of erythromycin A and with those of azithromycin and clarithromycin, and at least 4- comparable with that of levofloxacin and moxifloxacin. fold lower than that of erythromycin A. Moraxella catarrhalis is notoriously difficult to work with in In vivo activity time±kill experiments as a result of bacterial clumping. Telithromycin is also active against L. pneumophila in vivo. Telithromycin (at 86MIC) shows bactericidal activity after Edelstein and Edelstein [26] investigated the effect of 12±24 h against this organism, although its activity is lower telithromycin on the survival of guinea pigs infected intra- than that observed against S. pneumoniae and H. influenzae [13]. tracheally with L. pneumophila. Animals received telithromycin Azithromycin showed slightly higher bactericidal activity 10 mg/kg once or twice daily, erythromycin A 30 mg/kg against M. catarrhalis; however, the reduction in log counts twice daily or saline for 5 days. All 32 animals that received was less than 3-fold after 24 h at 86MIC. The activity of both telithromycin survived up to 14 days postinfection, regardless telithromycin and azithromycin was reduced against of the dosing frequency. In the erythromycin A-treated group b-lactamase-positive strains. of animals, two of 16 animals died at 6±8 days postinfection.

Table 4 Activity of telithromycin against atypical respiratory pathogens [4,23±25] MIC (mg/L) ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ

MIC50 MIC90 Range

Legionella spp. (n =30a) Telithromycin 0.015 0.03 40.004±0.12 Erythromycin A 0.12 0.12 0.06±0.5 Clarithromycin 40.004 40.004 40.004±0.03 Roxithromycin 0.06 0.12 0.03±0.25 Levofloxacin 0.015 0.030.015±0.06 Moxifloxacin 0.030.06 0.03 ±0.12 Rifampicin 40.0005 0.008 40.0005±0.015

M. pneumoniae (n = 29) Telithromycin 0.001 0.004 0.00025±0.015 Clarithromycin 0.004 0.015 0.005±0.015 Azithromycin 0.004 0.008 0.001±0.015

C. pneumoniae (n = 19) Telithromycin 0.06 0.25 0.03±2 Roxithromycin 0.25 0.5 0.06±2 Erythromycin A 0.12 0.25 0.015±0.25 Azithromycin 0.12 0.25 0.015±0.5

aIncludes 21 isolates of L. pneumophila.

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Felmingham Microbiological profile of telithromycin 9

pathogens, telithromycin shows similar in vitro activity to Mycoplasma pneumoniae azithromycin, while its activity in vivo against H. influenzae is

Mycoplasma pneumoniae accounts for 5 10% of cases of CAP higher. Telithromycin retains activity against erm-(MLSB)or [27]. It is more common in children and young adults and mef-mediated macrolide-resistant S. pneumoniae and S. pyogenes generally causes mild pneumonia. As M. pneumoniae has no cell and against S. aureus expressing erm-mediated inducible wall, b-lactams are inactive against this organism. resistance. Furthermore, it demonstrates low potential to Mycoplasma pneumoniae is extremely susceptible to telithro- induce or select for resistance or cross-resistance. These properties suggest that telithromycin will have an important mycin (Table 4). Telithromycin MIC90 against 21 isolates of M. pneumoniae was 0.004 mg/L (range 0.00025±0.015 mg/L) clinical role in the treatment of community-acquired RTIs. [4,24]. The activity of telithromycin was 2-to 3-foldhigher than that of clarithromycin or azithromycin, which are known REFERENCES to provide good coverage against this organism. 1. Felmingham D, GruÈneberg RN, and the Alexander Project Group. The Alexander Project 1996±97: latest susceptibility data from this international Chlamydia pneumoniae study of bacterial pathogens from community-acquired lower respiratory tract infections. J AntimicrobChemother 2000; 45: 191±203. Chlamydia pneumoniae is now recognized as an important cause 2. Chen DK, McGreer A, De Azavedo JC, Low DE. Decreased susceptibility of CAP, and some reports estimate that its involvement may of Streptococcus pneumoniae to fluoroquinolones in Canada. N Engl J Med be as high as 40% [28]. Chlamydia pneumoniae is an obligate 1999; 341: 233±9. intracellular pathogen. 3. Davies TA, Kelly LM, Jacobs MR, Appelbaum PC. Antipneumococcal activity of telithromycin by agar dilution, microdilution, E test and disk The intracellular activity of telithromycin against C. diffusion methodologies. J Clin Microbiol 2000; 38: 1444±8. pneumoniae has been studied in an infected human hepatocyte 4. Felmingham D, Robbins MJ, Leakey A et al. The comparative in vitro cell line [25]. Telithromycin showed excellent activity against activity of HMR 3647, a ketolide antimicrobial, against clinical bacterial C. pneumoniae (MIC range 0.03±2 mg/L), comparable with isolates. In: Abstracts of the 37th Interscience Conference on Antimicrobial Agents that of macrolides (Table 4). It also demonstrated chlamydi- and Chemotherapy, Toronto, Ontario, Canada, 28 September±1 October, 1997. Washington DC: American Society for Microbiology, 2000, abstract F166. cidal activity with a minimum chlamydicidal concentration of 5. Credito KL, Ednie LM, Jacobs MR, Appelbaum PC. 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10 Clinical Microbiology and Infection, Volume 7, Supplement 3, 2001

Abstracts of the 38th Interscience Conference on Antimicrobial Agents and antibiotics: results of a collaborative surveillance study. J Antimicrob Chemotherapy, San Diego, CA, USA, 24±27 September 1998. Washington Chemother 1996; 38: 97±106. DC: American Society for Microbiology, 2000: 207, abstract E133. 22. Falco V, FernaÂndez de Sevilla T, Alegre J, Ferrer A, MartõÂnez VaÂsquez JM. 14. Agouridas C, Bonnefoy A, Chantot JF. In vivo antibacterial activity of Legionella pneumophila. A cause of severe community-acquired pneumonia. HMR 3647, a novel ketolide highly active against respiratory pathogens Chest 1991; 100: 1007±11. [Abstract 1.11]. In: Prog. 4th International Conference on the Macrolides, 23. SchuÈlin T, Wennersten CB, Ferraro MJ, Moellering RC, Eliopoulous GM. Azalides, Streptogramins and Ketolides, 21±23 January 1998, Barcelona, Spain. Susceptibilities of Legionella spp. to newer antimicrobials in vitro. Antimicrob 15. Bonnefoy A, Girard AM, Agouridas C, Chantot JF. Ketolides lack Agents Chemother 1998; 42: 1520±3.

inducibility properties of MLSB resistance phenotype. J AntimicrobChe- 24. BeÂbeÂar CM, Renaudin H, Aydin MD, Chantot JF, BeÂbeÂar C. In vitro mother 1997; 40: 85±90. activity of ketolides against mycoplasmas. J AntimicrobChemother 1997; 39: 16. Bonnefoy A, Agouridas C, Chantot JF. HMR 3647: antibacterial activity of 669±70. resistance [Abstract 1.24]. In: Prog. 4th International Conference on the 25. Roblin PM, Hammerschlag MR. In vitro activity of a new ketolide Macrolides, Azalides, Streptogramins and Ketolides, 21±23 January 1998, antibiotic, HMR 3647, against Chlamydia pneumoniae. AntimicrobAgents Barcelona, Spain. Chemother 1998; 42: 1515±6. 17. Douthwaite S, Hansen LH, Mauvais P. Macrolide±ketolide inhibition of 26. Edelstein PH, Edelstein MAC. In vitro activity of the ketolide HMR 3647 MLS-resistant ribosomes is improved by alternative drug interaction with (RU 66647) for Legionella spp., its pharmacokinetics in guinea pigs, and use domain II of 23S rRNA. Mol Microbiol 2000; 36: 183±93. of the drug to treat guinea pigs with Legionella pneumophila pneumonia. 18. Cocuzza CE, Tomasini A, Renzetti D et al. Ketolide (HMR 3647) in vitro AntimicrobAgents Chemother 1999; 43: 90±5. activity on 4000 strains of Streptococcus pyogenes is northern Italy [Abstract 27. Fang G-D, Fine M, Orloff J et al. New and emerging etiologies for 1.06]. In: Prog. 4th International Conference on the Macrolides, Azalides, community-acquired pneumonia with implications for therapy. A Streptogramins and Ketolides, 21±23 January, 1998, Barcelona, Spain. prospective multicenter study of 359 cases. Medicine 1990; 69: 307±16. 19. SeppaÈlaÈ H, Klaukka T, Vuopio-Varkila J et al. The effect of changes in the 28. Kauppinen M, Saikku P. Pneumonia due to Chlamydia pneumoniae: consumption of macrolide antibiotics on erythromycin resistance in Group prevalence, clinical features, diagnosis and treatment. Clin Infect Dis 1995; A streptococci in Finland. New Engl J Med 1997; 337: 441±6. 21: 244±52. 20. Hoban D, Palatnick L, Weshnoweski B et al. The novel ketolide HMR 3647 29. Dubois J, St-Pierre C. Telithromycin comparative bactericidal activity and is highly active against worldwide isolates of Streptococcus pneumoniae and postantibiotic effect (PAE) against respiratory pathogens [abstract WeP96]. Streptococcus pyogenes [Abstract 1.04]. In: Prog. 4th International Conference on the 10th European Congress on Clinical Microbiology and Infectious Diseases, Macrolides, Azalides, Streptogramins and Ketolides, 21±23 January 1998, Stockholm, Sweden 28±31 May 2000. Clin Microbiol Infect 2000; 6 (Suppl. Barcelona, Spain. 1): 85. 21. Schito GC, Debbia EA, Pesce A, and the Alexander Project Collaborative 30. Drusano G. Pharmacodynamic and pharmacokinetic considerations in Group. Susceptibility of respiratory strains of Staphylococcus aureus to 15 antimicrobial selection. Clin Microbiol Infect 2001; 7 (Suppl. 3): 24±29.

# 2001 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 7 (Suppl. 3), 2±10