Antimicrobial Activity of Telavancin Tested In Vitro Against a Global Collection of Gram-Positive Pathogens,Including Multidrug-Resistant Isolates (2015–2017)

Bacterial isolates tested

A total of 24,408 nonduplicate consecutive Gram-positive clinical isolates from the SENTRY Antimicrobial Surveillance Program were submitted from 144 medical centers across 34 countries in North America (78 medical centers), Latin America (10 medical centers), Europe (41 medical centers), and the Asia-Pacific region (15 medical centers) (Supplementary Table S1). Supplementary Table S2 displays the number of isolates by species stratified by country of collection. Only one isolate per patient infection episode was included in the surveillance collection. Species identification was performed at the participating medical centers and confirmed at JMI Laboratories (North Liberty, IA) using matrix-assisted laser desorption ionization-time of flight mass spectrometry (Bruker, Billerica, MA) when necessary.

The isolates were collected primarily from bloodstream infections (5,184 isolates; 21.2% overall), skin and skin structure infections (10,300 isolates; 42.2% overall), pneumonia in hospitalized patients (5,156 isolates; 21.1% overall; this category includes patients hospitalized for any reason, who were diagnosed with pneumonia while hospitalized), urinary tract infections (1,000 isolates; 4.1% overall), intra-abdominal infections (721 isolates; 3.0% overall), community-acquired respiratory tract infection (1,045 isolates; 4.3% overall), and other infections (1,002 isolates; 4.1% overall), according to a standard surveillance design.

Table 1 lists the number of isolates collected per year for each major species and organism group. A total of 49 isolates were part of low prevalence species and were not considered further in this study. In 2017, the surveillance design for telavancin was restricted to the collection of S. aureus isolates from the United States (Table 1).

Minimal inhibitory concentration (MIC) values were also measured for 2 supplemental groups of S. aureus isolates, which were used to enrich the set of 484 ceftaroline-nonsusceptible S. aureus isolates collected from 2015 through 2017 as part of the SENTRY surveillance program for telavancin. First, a set of 50 randomly selected ceftaroline-nonsusceptible (MIC ≥2 μg/mL) S. aureus isolates collected in 2017 from Europe (n = 27), Latin America (n = 11), and the Asia-Pacific region (n = 12) was added to the SENTRY telavancin surveillance isolates to generate a combined set of 534 ceftaroline-nonsusceptible S. aureus isolates (Table 2). MIC values were also measured for a second set of 35 ceftaroline-resistant (MIC ≥4 μg/mL) S. aureus isolates that were collected globally from 2015 through 2017 (Table 2).

An isolate was considered MDR if it was nonsusceptible to ≥3 of the antimicrobials listed in Supplementary Table S3 (using Clinical and Laboratory Standards Institute [CLSI] interpretive criteria, where applicable). In general, these MDR definitions were patterned after the recommendations of Magiorakos et al., ¹¹ which were specified in that report; in this study, the definition was more restrictive for the MRSA subset, which was required to be nonsusceptible to ≥3 of the listed antimicrobials, in addition to oxacillin.

Susceptibility testing methods

Isolates were tested for antimicrobial susceptibility using broth microdilution methodology as per CLSI guidelines using frozen-form 96-well MIC panels. ¹² The testing medium was cation-adjusted Mueller-Hinton broth supplemented with 2.5–5% lysed horse blood for testing streptococci, supplemented with 50 mg/L calcium (Ca²⁺) for testing daptomycin, and supplemented with 0.002% polysorbate 80 for testing telavancin.^12,13 MIC results for telavancin and comparators were interpreted using CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint criteria, where published.^14,15

Concurrently tested American Type Culture Collection (ATCC) quality control strains included S. aureus ATCC 29213, Enterococcus faecalis ATCC 29212, and Streptococcus pneumoniae ATCC 49619. The inoculum densities during susceptibility testing were monitored by bacterial colony counts.

Telavancin and comparator activities against S. aureus

Telavancin exhibited MIC₉₀ values of 0.06 μg/mL against the full global set of S. aureus isolates and the MRSA subset (44.4% of the full set), and all isolates were susceptible to telavancin (Table 2). The MIC_50/90 results for telavancin tested against the full S. aureus isolate set were identical to results from global surveillance data derived from isolates collected from 2011 through 2014.^10,16–19 For the full S. aureus isolate set, telavancin activity did not vary by continent; the MIC₅₀ value increased twofold to 0.06 μg/mL for MRSA isolates from Latin American (data not shown).

MIC data for comparator antimicrobials tested against the full S. aureus and MRSA isolate sets are shown in Table 3. No VISA isolates were observed in this study. In total, 2.7% of the S. aureus isolates were nonsusceptible to ceftaroline, but this value increased to 6.2% among the MRSA subset (Table 3).

We further explored the antimicrobial activities of telavancin and comparator agents by testing subsets of S. aureus isolates that were ceftaroline nonsusceptible or ceftaroline resistant (see Materials and Methods section) (Tables 2 and 4). The telavancin MIC₉₀ values were identical for the full S. aureus and ceftaroline-nonsusceptible S. aureus isolate sets (both MIC₉₀ values, 0.06 mg/mL), only increased twofold (MIC₉₀ value, 0.12 mg/mL) against the ceftaroline-resistant subset, and all isolates remained susceptible to telavancin (Table 2). In addition to telavancin, the ceftaroline-nonsusceptible and ceftaroline-resistant S. aureus subsets were also highly susceptible (97.2% to 100%) to daptomycin, linezolid, trimethoprim-sulfamethoxazole, and vancomycin (Table 4).

Notably, the telavancin MIC₉₀ value and susceptibility rate for the MDR MRSA subset were identical to the corresponding values for the full isolate set (Table 2). In addition to telavancin, the MDR MRSA subset was >90% susceptible to daptomycin, linezolid, teicoplanin, trimethoprim-sulfamethoxazole, and vancomycin (Table 5). Overall, the MDR MRSA subset was 81.8% susceptible to ceftaroline, but this activity varied by geographical region from a low of 39.1% susceptible in the Asia-Pacific to a high of 85.7% susceptible in North America (Fig. 1). A similar trend of lower ceftaroline susceptibility among isolates from the Asia-Pacific and Latin American regions was also observed for the full MRSA subset (North America, 95.6% susceptible; Europe, 89.4% susceptible; Asia-Pacific, 72.8% susceptible; and Latin America, 76.1% susceptible) (data not shown).

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FIG. 1.

Telavancin and ceftaroline activity against multidrug-resistant MRSA isolates collected from 2015 through 2017 stratified by global region. MRSA, methicillin-resistant Staphylococcus aureus. Color images are available online.

Telavancin and comparator activities against coagulase-negative staphylococci

Telavancin exhibited potent activity (MIC₉₀ value, 0.06 μg/mL) against the full set of coagulase-negative staphylococci (CoNS) isolates, the methicillin-resistant Staphylococcus epidermidis subset, and the MDR CoNS subset (Table 2), and these results were similar or identical to corresponding surveillance data reported for isolates collected from 2011 through 2014.^10,16–19 The telavancin MIC_50/90 values for the CoNS isolates were identical for all regions studied (data not shown). MIC data for comparator antimicrobials tested against the full CoNS isolate set are shown in Supplementary Table S4. The MDR CoNS subset was ≥89.8% susceptible to daptomycin, linezolid, teicoplanin, and vancomycin, but telavancin was at least eightfold more potent by MIC_50/90 values than any of these comparator agents (Table 5).

Telavancin and comparator activities against the enterococci

The overall vancomycin resistance rate was 4.8% for the set of E. faecalis isolates (Supplementary Table S4). Telavancin exhibited potent antimicrobial activity (MIC₉₀ value, 0.25 μg/mL) against the full E. faecalis isolate set (Table 2), and by MIC₉₀ value, telavancin was fourfold to eightfold more potent than ampicillin (MIC₉₀ value, 1 μg/mL), daptomycin (MIC₉₀ value, 1 μg/mL), linezolid, (MIC₉₀ value, 2 μg/mL), and vancomycin (MIC₉₀ value, 2 μg/mL) (Supplementary Table S4). The telavancin MIC₉₀ value against the vancomycin-susceptible E. faecalis subset was unchanged compared to the full isolate set (Table 2). The MIC₉₀ value reported for the vancomycin-susceptible E. faecalis isolates tested in this study (MIC₉₀ value, 0.25 μg/mL) was similar to that reported for isolates collected from 2011 to 2012 (MIC₉₀ value, 0.12 μg/mL), ¹⁶ and 99.9% of the current vancomycin-susceptible isolates remained susceptible to telavancin (Table 2).

All 49 E. faecalis isolates with telavancin MIC values of ≥2 μg/mL exhibited a VanA resistance phenotype (Table 2). In contrast, telavancin retained activity against the subset of 6 isolates that exhibited a VanB resistance phenotype (telavancin MIC range, 0.12–0.25 μg/mL) (Table 2). Telavancin activity was lower against the subset of 52 MDR E. faecalis isolates (MIC₉₀ value, >2 μg/mL), because the subset was 100% resistant to vancomycin and predominately exhibited a VanA phenotype (Table 2 and data not shown). The MDR E. faecalis subset remained 100% susceptible to ampicillin, daptomycin, and linezolid (data not shown).

Most Enterococcus faecium isolates were resistant to vancomycin (62.1% resistant) (Supplementary Table S4). As expected, telavancin exhibited weak activity against the full E. faecium isolate set (MIC₉₀ value, >2 μg/mL) (Supplementary Table S4), but exhibited potent activity against the vancomycin-susceptible subset (MIC₉₀ value, 0.06 μg/mL) (Table 2).

Telavancin and comparator activities against S. pneumoniae

Telavancin was highly active against the full S. pneumoniae isolate set (MIC₉₀ value, 0.015 μg/mL) (Table 2), and this activity was unchanged when compared to data from global isolates collected between 2011 and 2014.^10,16,18,19 MIC data for comparator antimicrobials tested against the full S. pneumoniae isolate set are shown in Supplementary Table S4. The MDR subset of S. pneumoniae isolates exhibited decreased susceptibility to ceftriaxone (18.2% nonsusceptible using non-meningitis breakpoints), penicillin (24.7% nonsusceptible using parenteral, non-meningitis breakpoints), and several other antimicrobials (Table 5), but telavancin activity was unchanged compared to the full isolate set (Table 2). The MDR S. pneumoniae subset was ≥95.8 susceptible to ceftaroline, levofloxacin, linezolid, and vancomycin (Table 5).

Telavancin and comparator activities against BHS and VGS

The full BHS isolate set and the Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus dysgalactiae subsets were all 100% susceptible to telavancin (Table 2) (MIC₉₀ value, 0.03 μg/mL for each species and the full isolate set). The full VGS isolate set was 99.0% susceptible to telavancin (MIC₉₀ value, 0.03 μg/mL) (Table 2). The MIC₉₀ values for the full BHS and VGS isolate sets did not vary by more than twofold when the data were stratified by continent (data not shown). These data were identical or nearly identical to the corresponding values observed for analogous isolate sets collected and tested from 2011 through 2014.^10,16–19 MIC data for comparator antimicrobials tested against the full BHS and VGS isolate sets are shown in Supplementary Table S4. The MIC₉₀ value for the MDR BHS subset (0.03 μg/mL) was unchanged compared to the full isolate set, and the MIC₉₀ value for the MDR VGS subset (0.06 μg/mL) only increased twofold compared to the full isolate set (Table 2).