Telavancin Activity Against a Global Collection of Staphylococcus aureus Clinical Isolates (2013–2015)

Telavancin had MIC50, MIC90, and MIC100 values of 0.03, 0.06, and 0.12 μg/mL, respectively, against methicillinsusceptible (MSSA), methicillin-resistant (MRSA), and MRSA multidrug-resistant (MDR) subsets of Staphylococcus aureus. Isolates with elevated vancomycin MIC values (2 μg/mL) resulted in a telavancin MIC50 (0.06 μg/mL) 2-fold higher than isolates with lower vancomycin MIC results (telavancin MIC50, 0.03 μg/mL). However, telavancin had MIC90 and MIC100 results of 0.06 and 0.12 μg/mL (100% susceptible), respectively, regardless of methicillin-resistance phenotype.


Introduction
Among bacterial pathogens that cause healthcareassociated (HAI) and community-associated (CAI) infections, Staphylococcus aureus has proven to be a highly adaptable pathogen, fully capable of acquiring multiple resistance mechanisms as well as increased virulence [1]. The multidrugresistant (MDR) capacity of S. aureus, especially healthcareassociated methicillin-resistant S. aureus (HA-MRSA), coupled with concerns regarding the adequacy of vancomycin in treating complicated staphylococcal infections has prompted the development of several new agents with potent activity against MRSA, methicillin-susceptible S. aureus (MSSA), and MDR MRSA, including strains with elevated vancomycin MIC values [1][2][3][4][5][6][7].
S. aureus continues to be a leading cause of septicemia, osteoarticular infections, skin and skin structure infections (SSSI), pleuropulmonary infections, and device-related infections [1,8]. Whereas infection rates from MRSA appear to have stabilized or even decreased in industrialized countries, concerns regarding suboptimal responses to glycopeptides, the slow bactericidal activity of vancomycin, the emergence of isolates with reduced susceptibility to vancomycin and daptomycin on therapy, and possible MIC creep among susceptible isolates complicate managing S. aureus infections [1,3,4,6,7,9,10].
Telavancin is a parenteral, bactericidal, semisynthetic lipoglycopeptide agent that has been shown to be non-inferior to vancomycin in Phase 3 clinical trials of adult patients with complicated skin and skin structure infections (cSSSI). Telavancin also was shown to be non-inferior to vancomycin in treating hospital-acquired bacterial pneumonia (HABP), including ventilator-associated bacteria pneumonia (VABP), due to susceptible gram-positive pathogens and S. aureus, respectively [5,11,12] Telavancin has been approved for clinical use by the United States (US) Food and Drug Administration (FDA) in the once-daily treatment of cSSSI and HABP/VABP. This agent has demonstrated comparable efficacy to vancomycin in a limited number of patients with either cSSSI or HABP/VABP and concurrent S. aureus bacteremia [13,14].
Previous studies demonstrated potent telavancin activity against S. aureus that included methicillin-resistant (MRSA) strains, heterogeneous vancomycin-intermediate S. aureus (hVISA) and VISA isolates, and vancomycin-susceptible Enterococcus faecalis [5]. Not only does telavancin inhibit peptidoglycan synthesis, it also interacts with the bacterial cell membrane causing depolarization and increased membrane permeability [5]. This dual mechanism of action contributes to the bactericidal activity of telavancin and might also prevent emerging resistance when it is used clinically. In fact, only 1 report has been published about in vivo development of a nonsusceptible phenotype during telavancin therapy [5].
The sustained potency of telavancin versus S. aureus strains collected in Europe from 2007 to 2008 [15] and in the United States from 2011 to 2013 [16] has been documented. The objective of the present study was to expand on the studies of Mendes et al. [15,16] by including 22,406 S. aureus clinical isolates from 77 US medical centers; 2 Canadian medical centers; and the rest of the world (ROW) with 39 medical centers in 19 European countries/regions, 10 medical centers in 4 Latin American countries, and 19 Asian-Pacific medical centers in 9 countries for the years 2013 to 2015. All testing was performed using the revised CLSI method with the new quality control (QC) MIC ranges and interpretive criteria [17,18].

Materials and Methods
Isolates included in this study were part of the 2013-2015 US and ROW SENTRY Antimicrobial Surveillance Program, which monitors antimicrobial resistance and prevalence of pathogens causing bloodstream infections (BSI), communityacquired pneumonia, pneumonia in hospitalized patients, SSSI, intra-abdominal infections (IAI), and urinary tract infections (UTI). Participating sites follow instructions specific for each protocol to select and include consecutive and unique (1 per patient) isolates that were deemed clinically relevant based on local criteria until they reached a target number of 250-500 pathogens per site (depending on hospital size). Isolates that met the selection criteria for each of the 6 specific protocols were initially identified by the participant laboratory using local practices and were submitted to the coordinating monitoring laboratory (JMI Laboratories, North Liberty, Iowa, USA). Isolate bacterial identifications were confirmed by standard methods per Murray et al. [19]. Isolates showing questionable phenotypic and/or biochemical results had their identification confirmed by matrix-assisted laser desorption ionization-time of flight mass spectrometry (Bruker Daltonics, Bremen, Germany).

Conclusions
In this in vitro study, telavancin maintained potent activity against S. aureus, including isolates with decreased susceptibility to comparator agents, and maintained MIC 90 and MIC , results of 0.06 and 0.12 μg/mL, respectively, against all examined resistant isolate subsets that included MRSA (100.0% susceptible). In addition, the telavancin potency observed was at least 8-fold greater than tested comparators. These results confirm telavancin had more potent activity when compared to earlier studies [22][23][24] that underestimated the potency of the drug due to solubility and drug binding to plastic trays during susceptibility testing [20].