View metadata, citation and similar papers at core.ac.uk brought to you by CORE Paperprovided by 48Elsevier Disc - Publisher Connector 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 # 2001 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 7 (Suppl. 3), 2±10 Paper 48 Disc 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