In vitro activity of telavancin against recent Gram-positive clinical isolates: results of the Prospective European Surveillance Initiative

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1 Journal of Antimicrobial Chemotherapy (2008) 62, doi: /jac/dkn124 Advance Access publication 19 April 2008 In vitro activity of telavancin against recent Gram-positive clinical isolates: results of the Prospective European Surveillance Initiative Deborah C. Draghi 1, Bret M. Benton 2, Kevin M. Krause 2, Clyde Thornsberry 1, Chris Pillar 1 and Daniel F. Sahm 1 * 1 Eurofins Medinet, Inc., Dulles Technology Drive, Suite 200, Herndon, VA, USA; 2 Theravance, Inc., 901 Gateway Boulevard, South San Francisco, CA, USA Received 20 December 2007; returned 21 January 2008; revised 20 February 2008; accepted 27 February 2008 Objectives: Telavancin is a novel semi-synthetic lipoglycopeptide currently in late-stage clinical development for the treatment of serious infections due to Gram-positive bacteria. The objective of this study was to provide a baseline prospective assessment of its in vitro activity against a large and diverse collection of Gram-positive clinical isolates from Europe and Israel. Methods: Gram-positive clinical isolates, collected between October 2004 and December 2005 from 36 hospital laboratories in 15 countries, were tested by broth microdilution using CLSI methodology. Results: In total, 3206 isolates were collected. Telavancin had potent activity against Staphylococcus aureus and coagulase-negative staphylococci (MIC range to 2 mg/l), independent of resistance to methicillin or to multiple drugs. Telavancin had particularly strong activity against streptococcal isolates (MIC range to 0.5 mg/l), including penicillin-resistant and multiple drug-resistant Streptococcus pneumoniae and erythromycin non-susceptible b-haemolytic and viridans group streptococci. Telavancin also had excellent activity against vancomycin-susceptible enterococci (MIC mg/l), and although its MICs were elevated against VanA strains (Enterococcus faecalis MIC 90 8 mg/l and Enterococcus faecium MIC 90 4 mg/l), its MIC 90 was substantially lower than observed with available glycopeptides. Conclusions: Telavancin has potent in vitro activity against contemporary Gram-positive clinical isolates from diverse geographic areas in Europe and Israel. Keywords: susceptibility tests, Staphylococcus aureus, enterococci, Streptococcus spp. Introduction Drug resistance in Gram-positive pathogens is a continuing worldwide healthcare concern. Telavancin is a novel, investigational lipoglycopeptide that has demonstrated superior in vitro activity, when compared with currently available glycopeptides, against a range of clinically important Gram-positive bacteria including resistant organisms. 1 4 Against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis, telavancin was shown in several studies to be 2- to 8-fold more potent than vancomycin and 4- to 32-fold more potent than teicoplanin. 2 4 Telavancin also demonstrated activity against vancomycin-resistant enterococci (VRE). 2,4 Telavancin has a unique, multifunctional mechanism of action that appears to be responsible for its more rapid and extensive bactericidal activity observed relative to other available glycopeptides. 5 Like vancomycin, telavancin inhibits peptidoglycan biosynthesis by binding to the D-alanyl-D-alanine termini of peptidoglycan intermediates, thus disrupting late-stage steps in cell wall biosynthesis. In intact MRSA cells, telavancin was 14-fold as active as vancomycin in inhibiting peptidoglycan synthesis [50% inhibitory concentrations (IC 50 ) 0.14 and 2.0 mm, respectively]. 6 Additionally, telavancin interferes with bacterial cell membrane function, an activity not previously observed for glycopeptides. In MRSA cells, telavancin exposure resulted in concentration-dependent membrane depolarization... *Corresponding author. Tel: þ ; Fax: þ ; daniel.sahm@eurofinsmedinet.com # The Author Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 In vitro activity of telavancin against European and Israeli isolates and increased membrane permeability. 6 Membrane perturbation by telavancin was dependent on its binding to peptidoglycan precursors, indicating selectivity for bacterial cells. 6 Following clinical success in Phase 2 studies in patients with complicated skin and skin structure infections (csssis; also called complicated skin and soft tissue infections), 7,8 telavancin is currently being evaluated by regulatory authorities in the USA, Canada and Europe for its safety and efficacy in the treatment of csssi. Patient enrolment has also been completed for two Phase 3 trials for the treatment of hospital-acquired pneumonia. The objective of the current surveillance study was to provide a prospective assessment of the in vitro activity of telavancin against a large and diverse collection of Gram-positive clinical isolates from Europe and Israel. This is the first prospective surveillance study of telavancin in these geographic areas. Materials and methods In total, 36 community, teaching and university hospital laboratories in 14 European countries (Belgium, Croatia, Czech Republic, France, Germany, Greece, Hungary, Ireland, Italy, Poland, Portugal, Slovakia, Spain and the UK) and Israel collected isolates between October 2004 and December Each laboratory was asked to submit 80 consecutive non-duplicate isolates of clinically relevant Gram-positive pathogens from lower respiratory tract, upper respiratory tract (Streptococcus pneumoniae only), skin and skin structure (non-s. pneumoniae only), wound (non-s. pneumoniae only) and blood specimens. The goal was to obtain 45 S. aureus, 5 coagulase-negative staphylococci (CoNS), 10 Enterococcus faecalis, 10 Enterococcus faecium, 5 S. pneumoniae and 5 other streptococci per centre. Isolates were collected from adult and paediatric patients and from both inpatients (including those in intensive care units) and outpatients. All isolates were transported to a central laboratory (Eurofins Medinet, Inc., Herndon, VA, USA) for re-identification and susceptibility testing. Susceptibility testing of telavancin and comparators was performed using the broth microdilution method in accordance with the CLSI (formerly NCCLS) guidelines 9 and microtitre trays were prepared by TREK Diagnostics (Cleveland, OH, USA). Telavancin was supplied by Theravance, Inc. (South San Francisco, CA, USA). The quality control strains E. faecalis ATCC 29212, E. faecalis ATCC 51299, S. aureus ATCC and S. pneumoniae ATCC were tested in parallel, 9 and results were required to meet the quality control limits specified by CLSI. 10 Categorical interpretation of susceptible, intermediate or resistant were applied to the test results using the 2005 CLSI criteria, 10 where applicable. Results Clinical isolates In total, 3206 isolates were collected. The isolates included 1785 S. aureus, 236 CoNS, 450 E. faecalis, 362 E. faecium, 179 S. pneumoniae, 67 viridans group streptococci, 54 Streptococcus pyogenes, 48Streptococcus agalactiae and 25 other b-haemolytic streptococci (groups C, G or F). The numbers of isolates collected from each country ranged from 64 (Poland) to 569 (Spain); the proportions of S. aureus isolates from each country ranged from 51% (Belgium) to 69% (Poland) [median: 57% (Greece)]. Most of the S. pneumoniae isolates (67%) were from the upper or lower respiratory tract. Most of the other organisms were from skin and skin structure infections (including wounds) or from blood (50% and 34% of other organisms, respectively). Nearly one-third (30%) of the S. aureus and 75% of the CoNS were methicillin-resistant (MR). Among the MRSA and MRCoNS, respectively, 93% and 68% were also resistant to ciprofloxacin, 55% and 44% to clindamycin, 38% and 58% to gentamicin and 3% and 51% to co-trimoxazole. Vancomycin resistance was seen in 22% of the E. faecium and 5% of the E. faecalis isolates; most of the resistant isolates expressed the VanA phenotype (i.e. resistance to teicoplanin). More than 40% of the enterococci had high-level resistance to streptomycin and gentamicin, and.80% of the E. faecium isolates were ampicillin-resistant. Among S. pneumoniae isolates, 16% were resistant to penicillin and 31% were resistant to multiple drugs. Of the penicillin-resistant pneumococci, 68% to clindamycin, 89% to erythromycin, 57% to tetracycline and 82% to co-trimoxazole. Among b-haemolytic and viridans group streptococci, 20% and 43%, respectively, were non-susceptible to erythromycin and the rate of resistance to tetracycline was also high in these organisms (20% to.40%). Susceptibility to telavancin Telavancin had potent in vitro activity against staphylococcal, streptococcal and enterococcal isolates (Table 1). Its activity against S. aureus was similar for methicillin-susceptible S. aureus (MSSA) and MRSA isolates; the MIC 90 values were 0.25 and 0.5 mg/l, respectively. Only 8/1238 isolates of MSSA (0.6%) and 16/547 isolates of MRSA (2.9%) were found to have the highest MIC values observed (1 mg/l). Similarly, the telavancin MIC 90 values for methicillin-susceptible and MRCoNS were 0.25 and 0.5 mg/l, respectively (Table 1). The MIC 90 values of vancomycin, teicoplanin, daptomycin, linezolid and quinupristin/dalfopristin for MSSA and MRSA were all higher than those values of telavancin; against the CoNS, the MIC 90 values of vancomycin, teicoplanin and linezolid were higher than those values of telavancin. Among the staphylococci collected, there were three S. aureus and four CoNS isolates that were non-susceptible to either daptomycin or linezolid; the telavancin MIC values for these strains ranged from 0.12 to 1 mg/l (Table 2). Table 1 also shows the MICs (MIC 50, MIC 90 and range) of telavancin and selected comparators for vancomycin-susceptible enterococci (VSE) and VRE (VanA). Telavancin MICs ranged from 0.03 to 1.0 mg/l for VSE; the MIC 90 values were 0.5 and 0.25 mg/l, respectively, for vancomycin-susceptible E. faecalis and E. faecium, which were comparable with those of teicoplanin and somewhat lower than those of vancomycin, daptomycin and linezolid. Only 18/426 isolates of vancomycin-susceptible E. faecalis (4.2%) and 3/276 isolates of vancomycin-susceptible E. faecium (1.1%) were found to have the highest MIC values observed (1 mg/l). Against VanA VRE isolates (characterized as being resistant to both vancomycin and teicoplanin), the telavancin MIC values were higher (0.5 8 mg/l) than for VSE strains, although considerably lower than those of teicoplanin (MIC 90 values.128 mg/l) and vancomycin (MIC 90 values 512 mg/l) for the VanA strains. Against seven VanB (teicoplanin-susceptible and vancomycin-resistant) isolates, the MIC values of telavancin ranged from 0.12 to 2 mg/l, comparable with the MIC values of teicoplanin, daptomycin and 117

3 Draghi et al. Table 1. Activity of telavancin and selected comparators against Gram-positive clinical isolates from Europe and Israel MIC (mg/l) Organism (no. tested) Agent range 50% 90% S. aureus, methicillin-susceptible (1238) telavancin vancomycin teicoplanin linezolid daptomycin 0.03 to quinupristin/dalfopristin gentamicin 0.06 to co-trimoxazole a 0.5 to S. aureus, methicillin-resistant (547) telavancin vancomycin teicoplanin linezolid 0.5 to daptomycin 0.25 to quinupristin/dalfopristin 0.12 to gentamicin 0.12 to co-trimoxazole a 0.5 to Coagulase-negative staphylococci, b methicillin-susceptible (60) telavancin vancomycin teicoplanin linezolid daptomycin quinupristin/dalfopristin Coagulase-negative staphylococci, b methicillin-resistant (176) telavancin vancomycin teicoplanin linezolid 0.5 to daptomycin 0.12 to quinupristin/dalfopristin 0.12 to E. faecalis, vancomycin-susceptible (426) telavancin vancomycin teicoplanin linezolid daptomycin quinupristin/dalfopristin ampicillin E. faecalis, vancomycin-resistant (VanA) (23) telavancin vancomycin 256 to teicoplanin 32 to linezolid daptomycin quinupristin/dalfopristin ampicillin E. faecium, vancomycin-susceptible (276) telavancin vancomycin teicoplanin linezolid daptomycin quinupristin/dalfopristin ampicillin 0.25 to E. faecium, vancomycin-resistant (VanA) (73) telavancin vancomycin 64 to teicoplanin 32 to linezolid Continued 118

4 In vitro activity of telavancin against European and Israeli isolates Table 1. Continued Organism (no. tested) Agent MIC (mg/l) range 50% 90% daptomycin quinupristin/dalfopristin ampicillin 8 to S. pyogenes (54) telavancin vancomycin penicillin linezolid daptomycin levofloxacin co-trimoxazole a S. agalactiae (48) telavancin vancomycin penicillin levofloxacin linezolid daptomycin co-trimoxazole a 0.06 to Streptococcus spp., groups C, F and G (25) telavancin vancomycin penicillin levofloxacin erythromycin to linezolid daptomycin co-trimoxazole a Streptococcus spp., viridans group (67) telavancin vancomycin penicillin 0.06 to levofloxacin 0.25 to linezolid daptomycin 0.03 to co-trimoxazole a 0.06 to S. pneumoniae, penicillin-susceptible (125) telavancin vancomycin penicillin levofloxacin 0.25 to linezolid co-trimoxazole a 0.06 to tetracycline 0.06 to S. pneumoniae, penicillin-non-susceptible c (54) telavancin vancomycin penicillin 0.12 to erythromycin 0.03 to levofloxacin linezolid co-trimoxazole a 0.06 to tetracycline 0.06 to a MICs expressed as concentration of trimethoprim. b Includes S. capitis (5), S. cohnii (1), S. epidermidis (130), S. haemolyticus (25), S. hominis (9), S. saprophyticus (2), S. simulans (5), S. warneri (6), S. xylosus (3) and unspeciated (50). c Includes penicillin-intermediate and -resistant isolates. 119

5 Draghi et al. Table 2. Activity of telavancin against selected Gram-positive clinical isolates from Europe and Israel not susceptible to daptomycin and/or linezolid MIC (mg/l) Organism Phenotype ID number telavancin vancomycin linezolid daptomycin S. aureus DAP NS S. aureus DAP NS S. aureus LZD NS CoNS (non-speciated) DAP NS CoNS (non-speciated) DAP NS S. epidermidis LZD NS S. epidermidis LZD NS E. faecium DAP NS E. faecium DAP NS ID, identification; DAP, daptomycin; NS, non-susceptible; LZD, linezolid; CoNS, coagulase-negative staphylococci. linezolid (data not shown). When all VSE and VRE isolates are considered together, the MIC distribution of telavancin is bimodal. This is illustrated in Figure 1, which also demonstrates that the second mode is accounted for by the MIC distribution for vancomycin-resistant isolates. Among the enterococci collected, two E. faecium isolates were non-susceptible to daptomycin; the telavancin MICs for these strains were both 0.12 mg/l (Table 2). Table 1 also illustrates the MICs of telavancin and comparators for streptococci. Among all agents tested, telavancin had the greatest potency against S. pneumoniae, with an MIC 90 of 0.03 mg/l, regardless of resistance to penicillin or other agents. Telavancin demonstrated consistently potent activity against b-haemolytic streptococci (MIC mg/l) and viridans group streptococci (MIC mg/l), regardless of their susceptibility to erythromycin. Vancomycin, levofloxacin, linezolid and daptomycin all demonstrated less potent activity against the b-haemolytic and viridans group streptococci relative to telavancin. The MIC 90 values of penicillin for the b-haemolytic streptococci were 0.06 mg/l; 25% of the viridans group streptococci were resistant to or had intermediate susceptibility to penicillin. Among other comparators, clindamycin and telithromycin were most affected by susceptibility to erythromycin (data not shown). Discussion In this report, we describe the results of a large multinational surveillance initiative specifically designed to provide a benchmark for the activity of telavancin. This was the first prospective surveillance study of this new agent in European countries and Israel. More than 3000 Gram-positive organisms were collected from diverse geographic and demographic environments to obtain a robust, representative sample of contemporary isolates. The activity of telavancin was assessed in the context of other Gram-positive agents and resistance phenotypes. We noted that resistance to established antimicrobial agents among the isolates was consistent with rates reported in previous European and international studies Importantly, the activity of telavancin was similar to that previously reported in smaller, retrospective surveillance studies. 1 4 Figure 1. Telavancin MIC distribution against enterococci (n ¼ 812). Black bars, all enterococci; grey bars, vancomycin-resistant isolates of the VanA (n ¼ 96) and VanB (n ¼ 7) phenotype. Telavancin exhibited potent in vitro activity against all staphylococcal isolates tested, regardless of resistance to other antimicrobial classes. Among the comparators, only co-trimoxazole had equivalent or lower MIC 90 values (0.5 mg/l) for S. aureus; however, a small amount of resistance to this agent (3%) was seen. In particular, the MIC 90 values of telavancin against MRSA and MRCoNS were lower than the MIC 90 values of currently available glycopeptides (vancomycin and teicoplanin). Against CoNS, only daptomycin and quinupristin/dalfopristin had activity comparable to that of telavancin. Based on the MIC 90 values, telavancin was 4-fold more active as vancomycin against Van-S enterococci. Although it was somewhat less active against VanA strains, the telavancin MIC 90 values were at least 16-fold lower than those of teicoplanin and 64-fold lower than those of vancomycin against these isolates. The potency of telavancin against VanA strains was comparable to that of non-glycopeptide agents such as linezolid and daptomycin and to that of quinupristin/dalfopristin against VanA E. faecium, but less potent than linezolid and daptomycin against VanA E. faecalis. Isolates with resistance to the most recent and highly active Gram-positive agents, linezolid and daptomycin, though 120

6 In vitro activity of telavancin against European and Israeli isolates infrequently encountered, are of significant clinical interest. As shown in this study, no alteration in the in vitro activity of telavancin was observed against the few linezolid non-susceptible isolates (S. aureus and S. epidermidis) or daptomycin nonsusceptible isolates (S. aureus, CoNS and E. faecium) encountered in this study. Telavancin demonstrated very potent and consistent antistreptococcal activity, greater than the activity observed with most of the comparators, against all species and resistance phenotypes. In particular, the MIC 90 value of telavancin was 0.03 mg/l for isolates of S. pneumoniae that were not susceptible to penicillin, which was considerably lower than those of all comparators. Among the agents tested, only penicillin showed comparable activity to telavancin against the b-haemolytic streptococci. In conclusion, telavancin demonstrated potent in vitro activity against contemporary Gram-positive clinical isolates from Europe and Israel. The activity of telavancin was not affected by resistance to other classes of antibiotics, including the new lipopeptide and oxazolidinone class agents daptomycin and linezolid, respectively. As clinical development of telavancin continues, this first prospective surveillance study will serve as a useful benchmark. Funding This study was funded by Theravance, Inc., 901 Gateway Boulevard, South San Francisco, CA, USA. Editorial assistance was provided by Matthew Smith, PhD, and funded by Astellas Pharma, Inc. Transparency declarations D. C. D., C. T., C. P. and D. F. S. are employees of Eurofins Medinet, Inc., which received funding from Theravance, Inc. D. C. D., C. T. and C. P. do not own stock or options in any company involved in the study. D. F. S. owns stock in Eurofins Medinet, Inc. B. M. B. and K. M. 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