JAC Advance Access originally published online on June 22, 2007
Journal of Antimicrobial Chemotherapy 2007 60(2):406-409; doi:10.1093/jac/dkm211
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Comparative activity of telavancin against isolates of community-associated methicillin-resistant Staphylococcus aureus
Department of Internal Medicine, St John Hospital and Medical Center, Detroit, MI, USA
* Corresponding author. Tel: +1-313-343-3362; Fax: +1-313-343-7784; E-mail: louis.saravolatz{at}stjohn.org
Received 23 February 2007; returned 6 April 2007; revised 15 May 2007; accepted 17 May 2007
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Abstract |
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Objectives: This study compared the activity of telavancin, a novel multivalent lipoglycopeptide with rapid bactericidal activity, with those of five standard antibiotics for methicillin-resistant Staphylococcus aureus (MRSA) against isolates of community-associated MRSA (CA-MRSA).
Methods: Microdilution tests performed according to CLSI guidelines using cation-adjusted Mueller–Hinton broth were used to determine the MIC values of telavancin, quinupristin/dalfopristin, vancomycin, trimethoprim/sulfamethoxazole, linezolid and daptomycin versus 60 CA-MRSA isolates. MBC values of telavancin were determined according to CLSI guidelines and American Society for Microbiology standards. PFGE was performed using the restriction enzyme SmaI. Samples from three predominant pulsed-field types were typed by multilocus sequence typing. Staphylococcal cassette chromosome mec typing was determined by multiplex PCR. The Panton-Valentine leucocidin (PVL) genes (lukS-PV and lukF-PV) were identified by PCR.
Results: The telavancin MIC90 and MBC90 values for this collection of 60 CA-MRSA isolates were 0.5 and 1 mg/L, respectively, with MIC and MBC values both ranging from 0.25 to 1 mg/L. Telavancin was found to be bactericidal in this study, as its MBC was no more than 2-fold higher than its MIC for all CA-MRSA isolates tested except one. (A single isolate yielded an MBC/MIC ratio of 4.) PVL- and non-PVL-producing strains demonstrated similar susceptibility to telavancin and comparator agents.
Conclusions: Based on in vitro activity, telavancin should be an effective agent against CA-MRSA.
Keywords: CA-MRSA , PVL , S. aureus
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Introduction |
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Reports of methicillin-resistant Staphylococcus aureus (MRSA) originating in the community among people without traditional MRSA risk factors are increasing across geographically diverse regions.1,2 First described in the 1980s, MRSA infections acquired in the community traditionally have been associated with recent hospitalization or other contact with a healthcare facility, prolonged or recent antibiotic therapy, or injection drug use.3 Community-acquired MRSA (CA-MRSA) infections have also appeared with greater frequency among athletic teams and in prison populations or in lower socioeconomic strata. However, not only has the incidence of CA-MRSA increased in several communities among those lacking established risk factors for infection, but strains of CA-MRSA recently have emerged as a cause of infections in healthcare facilities.2,4
The increasing incidence and emergence of CA-MRSA in healthcare settings combined with the inadvisability of relying solely on ß-lactam antibiotics as empirical therapy for severe infections that may be staphylococcal in origin, underscore the need to pursue novel strategies for effectively treating CA-MRSA infections. Telavancin is a novel lipoglycopeptide with rapid bactericidal activity and multiple mechanisms of action against MRSA and other Gram-positive bacteria.5,6 To investigate the therapeutic potential of telavancin in CA-MRSA and further our understanding of the epidemiology of CA-MRSA infections, we performed an in vitro study on 60 CA-MRSA isolates obtained from our institution, comparing the activity of telavancin with that of five standard antibiotics. We assessed the comparative in vitro activity of telavancin against both Panton-Valentine leucocidin (PVL)- and non-PVL-producing strains of CA-MRSA.
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Materials and methods |
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CA-MRSA isolates
Sixty strains of MRSA, meeting the CDC definition of CA-MRSA previously described,1 were isolated from 60 patients admitted to St John Hospital and Medical Center, Detroit, MI, USA, from 1 July 2003 to 1 December 2005 who were found to have a culture positive for MRSA within 48 h of admission, as recorded in the microbiology laboratory database. MRSA isolates were identified using the Vitek 2 system (bioMérieux, Durham, NC, USA). There were no duplicate isolates from patients.
For an infection to be defined as an MRSA infection in this study, the following criteria had to be met by careful chart review: clinical evidence of infection, identification of MRSA from a sterile body site or from drainage obtained at a non-sterile site having evidence of infection and no identification of other pathogens involved. Cultures were performed on samples collected from blood (n = 26), wound or tissue (n = 31), sputum (n = 1), catheter tip (n = 1), or percutaneous endoscopic gastrostomy site (n = 1). To avoid including nosocomial strains of MRSA, we excluded isolates from patients with cultures positive for MRSA after 48 h of hospitalization.
PFGE was performed on all isolates, using the SmaI restriction endonuclease, and the findings were interpreted according to standard guidelines.1,4 Specimens from three predominant pulsed-field types, designated A, C and D, were typed by multilocus sequence typing.1 Staphylococcal cassette chromosome (SCC) mec types were determined by a multiplex PCR method.1,4 The results were verified by PCR amplification of the cassette chromosome recombinase (ccr) gene and mec class type.1 The PVL genes lukS-PV and lukF-PV were identified by PCR.1
Antimicrobials and in vitro susceptibility testing
The following antimicrobials were obtained in powder form and used in the in vitro experiments: telavancin (Theravance, Inc., South San Francisco, CA, USA), quinupristin/dalfopristin (King Pharmaceuticals, Inc., Cary, NC, USA), vancomycin (Eli Lilly and Company, Indianapolis, IN, USA), trimethoprim/sulfamethoxazole (Sigma-Aldrich Corporation, St Louis, MO, USA), linezolid (Pharmacia Corporation, Kalamazoo, MI, USA) and daptomycin (Cubist Pharmaceuticals, Lexington, MA, USA).
Microdilution tests using cation-adjusted Mueller–Hinton broth were used to determine the MICs of telavancin, quinupristin/dalfopristin, vancomycin, trimethoprim/sulfamethoxazole and linezolid for all isolates. For the determination of the MIC of daptomycin, additional calcium was added to bring the concentration of calcium to 50 mg/L. MIC values were determined in accordance with CLSI (formerly NCCLS) guidelines.7 In keeping with these guidelines MIC values were read visually as the lowest drug concentration well with no visible bacterial growth. The MBC values of telavancin for all isolates were also determined according to CLSI guidelines.
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Results |
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Molecular analyses
Molecular analyses indicated that 32 of the 60 isolates tested had the same profile as USA300, a MRSA clone identified as the predominant cause of CA-MRSA infections in the United States, and that they carried the SCCmec type IV allele, considered a marker for CA-MRSA,2,4 and harboured PVL genes (Table 1).
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PFGE profiles of representative isolates were generated from strains that were isolated on more than one occasion. The PFGE pattern from isolate A was indistinguishable from that of USA300. Additionally, MRSA clone USA100 and the sample PFGE strain E possessed identical PFGE profiles. A dendrogram analysis of the representative pulsed-field types was performed and showed the degree of relatedness; the most common isolate, designated A, was found in 32 patients and was identical to USA300, and the second most common isolate, E, was found in 6 patients and was identical to USA100. Based on the dendrogram, the remaining isolates were unrelated. Multilocus sequencing results were: strain A (3-3-1-1-4-4-3), strain C (10-2-23-6-10-3-2), strain D (1-4-1-4-12-1-1).
Telavancin was highly active against all 60 CA-MRSA isolates (Table 2). The MIC and MBC ranges of telavancin both equalled 0.25–1 mg/L, and the MIC90 and MBC90 values of telavancin were 0.5 and 1 mg/L, respectively. Telavancin was found to be bactericidal in this study, as its MBC was no more than 2-fold higher than its MIC for all CA-MRSA isolates tested except one. For example, the telavancin MBC/MIC ratios were 
4 for all 60 isolates tested, 1 for 34 strains (57%) and 2 for 25 strains (42%). A single isolate yielded an MBC/MIC ratio of 4. Similar in vitro activity for telavancin and comparator agents was observed among CA-MRSA isolates having the same profile as USA300 (n = 32) and among non-PVL-producing CA-MRSA isolates (n = 28). Only one strain demonstrated resistance to trimethoprim/sulfamethoxazole; the MIC and MBC of telavancin for this strain were 0.5 and 1 mg/L, respectively.
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Although CLSI breakpoints are not available at this time, telavancin achieves serum concentration levels that would inhibit all isolates after usual dosage.8
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Discussion |
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Telavancin demonstrated bactericidal activity against all 60 CA-MRSA isolates in this study, including 32 possessing the SCCmec type IV allele, PVL genes and the same profile as USA300. Among isolates studied telavancin showed in vitro activity as good as comparator agents and thus offers notable therapeutic potential for CA-MRSA. In addition, other investigators have already demonstrated the excellent activity of telavancin against glycopeptide-intermediate staphylococcal species and vancomycin-resistant S. aureus.8 Telavancin has demonstrated efficacy similar to that of standard therapy in Phase 2 trials for the treatment of complicated skin and skin structure infections caused by Gram-positive bacteria.9 Recently, the pooled results of two multinational, randomized, double-blinded Phase 3 trials in 1867 patients further demonstrated the efficacy of telavancin in complicated skin and skin structure infections caused by suspected or confirmed Gram-positive pathogens.10 For the treatment of such infections, telavancin in both studies was found to be comparable to the mainstay MRSA antibiotic vancomycin. Telavancin achieved the primary end point of non-inferiority to vancomycin in clinical cure rate in clinically evaluable patients. In patients infected with MRSA in all study populations, however, the clinical, microbiological and overall therapeutic response rates consistently favoured telavancin.
With CA-MRSA infections in healthcare settings on the rise2 and severe infections caused by CA-MRSA becoming less rare, a novel antimicrobial such as telavancin, which has demonstrated activity against both PVL- and non-PVL-producing strains of CA-MRSA in our study, may be an effective alternative in the treatment of CA-MRSA in nosocomial and community populations alike.
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External funding |
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This work was sponsored by a grant from Theravance, Inc., South San Francisco, CA, USA.
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L. D. S. has received consulting fees from Theravance, Inc., Johnson and Johnson and Pfizer Inc. and participates in the speakers' bureau for Merck and Schering Inc.; J. P.—none to declare; L. B. J. has received consulting fees from Theravance, Inc. and has participated in speakers' bureaus for Pfizer.
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Acknowledgements |
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Portions of this work were presented at the Forty-sixth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, USA, 2006 (poster E-0716).
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References |
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1 Johnson LB, Saeed S, Pawlak J, et al. Clinical and laboratory features of community-associated methicillin-resistant Staphylococcus aureus: is it really new? Infect Control Hosp Epidemiol (2006) 27:133–8.[CrossRef][Medline]
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Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med (2006) 355:666–74.
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Saravolatz LD, Markowitz N, Arking L, et al. Methicillin-resistant Staphylococcus aureus. Epidemiologic observations during a community-acquired outbreak. Ann Intern Med (1982) 96:11–6.
4 Johnson LB, Venugopal AA, Pawlak J, et al. Emergence of community-associated methicillin-resistant Staphylococcus aureus infection among patients with end-stage renal disease. Infect Control Hosp Epidemiol (2006) 27:1057–62.[CrossRef][Medline]
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Higgins DL, Chang R, Debabov DV, et al. Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother (2005) 49:1127–34.
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Shaw JP, Seroogy J, Kaniga K, et al. Pharmacokinetics, serum inhibitory and bactericidal activity, and safety of telavancin in healthy subjects. Antimicrob Agents Chemother (2005) 49:195–201.
7 National Committee for Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically—Sixth Edition: Approved Standard M7-A6 (2003) Wayne, PA, USA: NCCLS.
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Leuthner KD, Cheung CM, Rybak MJ. Comparative activity of the new lipoglycopeptide telavancin in the presence and absence of serum against 50 glycopeptide non-susceptible staphylococci and three vancomycin-resistant Staphylococcus aureus. J Antimicrob Chemother (2006) 58:338–43.
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Stryjewski ME, Chu VH, O'Riordan WD, et al. Telavancin versus standard therapy for treatment of complicated skin and skin structure infections caused by gram-positive bacteria: FAST 2 study. Antimicrob Agents Chemother (2006) 50:862–7.
10 Corey G, Stryjewski ME, O'Riordan WD, et al. Telavancin for the treatment of complicated skin and skin structure infections: results of the ATLAS study. In: Forty-fourth Annual Meeting of the Infectious Diseases Society of America (IDSA), Toronto, Ontario, Canada, 2007. Poster LB-17.
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