Introduction

Staphylococcus aureus is the second most common cause of bloodstream infection (BSI), and is the most important cause of BSI-associated death [1]. Prevalence-based studies, such as the SENTRY Antimicrobial Surveillance Program, observed a rate of 44.3% of S. aureus [45.4% methicillin-resistant S. aureus (MRSA)] causing bacteremia in USA hospitals during the 2015 sampling year (unpublished JMI data). Among multicenter and population-based investigations, incidence rates of 15–40 per 100,000 population per year have been identified, with case-fatality rates of approximately 15–25% [1–3].

Telavancin is a once-daily parenteral semi-synthetic lipoglycopeptide agent approved in the United States, Europe, and Canada for clinical indications, such as complicated skin and skin structure infections and/or hospital-acquired and ventilator-associated bacterial pneumonia (see package inserts for a complete description of respective indications) [4]. The efficacy and safety of telavancin is also under evaluation for the treatment of subjects with complicated S. aureus bacteremia and S. aureus right-sided infective endocarditis (NCT02208063) [5]. The in vitro activity of telavancin has been monitored and reported previously. However, this study evaluated the telavancin activity against a recent and global collection of S. aureus bacteremia isolates, including those responsible for endocarditis, to support the sought-after bacteremia/endocarditis clinical indications.

Materials and methods

This study included a total of 4191 S. aureus (1490 MRSA), which were unique (one per patient) clinical isolates recovered from blood samples collected during 2011–2014 in a global network of hospitals in the North America (2150 isolates), Europe (1283), Latin America (473), and Asia-Pacific (APAC; 285) regions. All isolates were deemed responsible for BSI, including endocarditis, by the participating site according to local guidelines. Isolates that met the protocol selection criteria had the bacterial identification initially performed by the participating laboratory, which submitted isolates to a central monitoring laboratory (JMI Laboratories, North Liberty, IA, USA), as part of the SENTRY Antimicrobial Surveillance Program. Bacterial identification was subsequently confirmed by the reference monitoring laboratory by standard algorithms. Isolates showing questionable phenotypic and/or biochemical results had the bacterial identification confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS; Bruker Daltonics, Bremen, Germany).

Isolates were tested for susceptibility by broth microdilution following the Clinical and Laboratory Standards Institute (CLSI) M07-A10 document [6]. Testing was performed using panels manufactured by Thermo Fisher Scientific (Cleveland, OH, USA). These validated panels provide minimum inhibitory concentration (MIC) results equivalent to the CLSI-approved broth microdilution method, which includes 0.002% polysorbate 80 in the testing media [6]. Bacterial inoculum density was monitored by colony counts to assure an adequate number of cells for each testing event. Quality of the MIC values was assured by concurrent testing of CLSI-recommended quality control (QC) reference strains (S. aureus ATCC 29213 and Enterococcus faecalis ATCC 29212) [6]. All QC results were within published acceptable ranges [6]. MIC interpretations for comparator agents were based on the CLSI M100-S26 [7] and European Committee on Antimicrobial Susceptibility Testing (EUCAST) [8] criteria, as available. Data analysis was performed by grouping isolates based on infection type, geographic region, and community-acquired (CA) and healthcare-associated (HA) origin based on the Centers for Disease Control and Prevention (CDC) criteria [9] and antimicrobial susceptibility phenotype. The latter applied the oxacillin breakpoint for grouping methicillin-susceptible (MSSA) and -resistant (MRSA) isolates and the vancomycin MIC results for segregating S. aureus between those with vancomycin MIC values of ≤1 or 2–4 μg/ml. Isolates were also categorized based on multidrug resistance (MDR), defined as MRSA isolates (methicillin [oxacillin]-resistant) resistant to an additional three or more drug classes (see Table 2 for a complete list of antimicrobials utilized).

Results and discussion

Overall, S. aureus isolates were 100.0% susceptible to telavancin and had the highest MIC50, MIC90, and MIC100 results of 0.03, 0.06, and 0.12 μg/ml, respectively. Equivalent MIC values (MIC50/90, 0.03/0.06 μg/ml) were obtained for telavancin against isolates from different infection types (i.e., BSI and endocarditis), MSSA and MRSA isolates, as well as MRSA from CA and HA origins (Table 1). Telavancin (MIC50/90, 0.03/0.06 μg/ml) had similar potency against all S. aureus and the MRSA subsets from North America and Europe. The isolates from the APAC and Latin America regions had slightly higher MIC50 values (MIC50/90, 0.06/0.06 μg/ml), although the MIC90 and MIC100 results remained identical to those obtained for the overall MSSA population (Table 1).

Table 1 Antimicrobial activity and minimum inhibitory concentration (MIC) distributions for telavancin when tested against Staphylococcus aureus clinical isolates, as part of the international telavancin surveillance program
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MRSA with vancomycin MIC values of 2–4 μg/ml and the MDR subset had telavancin MIC50 results of 0.06 μg/ml, which was 2-fold higher than the telavancin MIC50 results (MIC50, 0.03 μg/ml) for the isolates exhibiting vancomycin MIC values at ≤1 μg/ml or a non-MDR phenotype. Even though the MIC50 was higher in these resistant subgroups, telavancin still inhibited all isolates at the susceptible breakpoint of ≤0.12 μg/ml (Table 1). Daptomycin (MIC50/90, 0.5/1 μg/ml; Table 2) also demonstrated higher MIC results when tested against MRSA exhibiting vancomycin MIC values of 2–4 μg/ml compared with those isolates with vancomycin MIC values of ≤1 μg/ml (data not shown).

Table 2 Antimicrobial activity of telavancin and comparator agents tested against a global collection of resistant subsets of S. aureus clinical isolates responsible for bloodstream infections, including endocarditis
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Overall, telavancin showed MIC50 results 8-fold lower than daptomycin (MIC50/90, 0.25/0.5 μg/ml) and up to 32-fold lower than vancomycin (MIC50/90, 1/1 μg/ml) against bacteremia MRSA, including those causing endocarditis (Fig. 1 and Table 2). Similarly, the telavancin MIC results (MIC50/90, 0.06/0.06 μg/ml) were 4- to 8-fold lower than those obtained by daptomycin (MIC50/90, 0.25/0.5 μg/ml) and 16-fold lower than vancomycin (MIC50/90, 1/1 μg/ml) against the MRSA MDR subset (Table 2). When tested against the MRSA subset displaying decreased susceptibility to vancomycin (MIC, 2–4 μg/ml), telavancin (MIC50/90, 0.06/0.12 μg/ml) and daptomycin (MIC50/90, 0.5/1 μg/ml) were the most potent agents; however, telavancin was 8-fold more potent than daptomycin (Table 2).

Fig. 1
figure 1

Telavancin, daptomycin, and vancomycin minimum inhibitory concentration (MIC) distributions obtained against all bacteremia methicillin-resistant Staphylococcus aureus (MRSA). Data are presented as the cumulative percentage of isolates inhibited at each MIC (μg/ml). MIC50 differences between drugs are depicted

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Telavancin demonstrated potent in vitro activity against this contemporary global collection of S. aureus causing bacteremia, including resistant subsets and isolates causing endocarditis. In addition, telavancin had in vitro potency at least 4-fold greater than other clinically available comparator antimicrobial agents (daptomycin and vancomycin) recommended by the current Infectious Diseases Society of America (IDSA) guidelines for the treatment of bacteremia caused by MRSA and MDR subsets [10]. These in vitro results support further investigations of telavancin as a candidate for the treatment of bacteremia caused by S. aureus and resistant subsets, including those isolates responsible for endocarditis [11]. Moreover, the results obtained for telavancin corroborate those reported previously and indicate sustained in vitro potency over time against S. aureus isolates causing infections in hospitals worldwide [12–14].