Activity of Oritavancin against Gram-Positive Pathogens Causing Bloodstream Infections in the United States over 10 Years: Focus on Drug-Resistant Enterococcal Subsets (2010–2019)

ABSTRACT Oritavancin displayed potent and stable activity (MIC90 range of 0.06 to 0.5 mg/L) over a 10-year period (2010 to 2019) against Gram-positive pathogens that cause bloodstream infections (BSI), including methicillin-resistant Staphylococcus aureus (MRSA) and resistant subsets of Enterococcus spp. Daptomycin and linezolid were also active against methicillin-resistant S. aureus and vancomycin-resistant Enterococcus (VRE). Only oritavancin and linezolid remained active against Enterococcus faecium isolates displaying an elevated daptomycin MIC (i.e., 2 to 4 mg/L). Proportions of methicillin-resistant S. aureus and vancomycin-resistant Enterococcus within the respective S. aureus and enterococcal populations decreased over this period.

solubility and susceptibility to optochin (see the Table 1 footnotes for a list of all isolates included in the study). Susceptibility testing was performed by broth microdilution following CLSI methods (13), using either dry-form (2010 to 2014) (Thermo Fisher; Bedford, MA) or frozen-form (2015 to 2019) panels (JMI Laboratories). MIC interpretations were based on CLSI criteria (14).
S. aureus (48.7%) alone comprised almost half of Gram-positive pathogens. The proportion of methicillin resistance among S. aureus varied from 46.6% to 42.3%, and these rates appeared to trend lower over time (Table 2). This trend was also noted in other regional and national surveillance programs during the 2000s, likely as a result of an increasing emphasis on hospital infection prevention, stewardship programs, and activities directed toward healthcare quality improvement (2,(15)(16)(17)(18). Similarly, a progressive decrease in the rate of methicillin resistance among coagulase-negative Staphylococcus (MRCoNS) BSI was noted. Oritavancin MIC 50 values against S. aureus ranged from 0.015 to 0.03 mg/L, and MIC 90 values were 0.06 mg/L irrespective of methicillin susceptibility (  Table S1 in the supplemental material).
Enterococcus spp. comprised 18.8% (2,895 out of 15,403) of Gram-positive pathogens causing BSI, where E. faecalis was the most common species (59.0%), followed by E. faecium (37.4%). VRE rates within E. faecalis decreased over time, from 4.5% (2010 to 2011) to 2.2% (2018 to 2019). Likewise, vancomycin resistance (from 79.6% to 62.8%) and ampicillin resistance (from 92.6% to 79.2%) decreased in E. faecium (Table 2). Ampicillin resistance and VRE phenotypes were displayed by most E. faecium (87.3% were ampicillin resistant and 72.5% were VRE), whereas only 3.6% of E. faecalis were resistant to vancomycin and none were resistant to ampicillin (Table S2). The decline in VRE as a proportion of total enterococcal infections may be due to the same reasons as described above for MRSA (2,19). The past increase in VRE in the US was mostly due to the expansion of E. faecium clonal complex 17 (20). The increase in ampicillin and vancomycin susceptibility may indicate a change in the epidemiology of E. faecium causing BSI in the United States. However, this epidemiology information was not captured for this large collection.
Oritavancin inhibited 97.7% of VanA and 100% of VanB E. faecium at #0.12 mg/L. In contrast, only 32.7% of E. faecalis isolates displaying the VanA phenotype were inhibited by oritavancin at #0.12 mg/L. VRE E. faecalis showed oritavancin MIC 50 values ranging from 0.12 to 0.25 mg/L, whereas MIC 50 values ranged from 0.015 to 0.03 mg/L against VRE E. faecium. The greater activity of oritavancin against E. faecium compared to E. faecalis is not well understood. Expression of vanZ or changes in LiaS sensor kinase were reported as possible explanations (21).
Almost half (49.9%) of E. faecium displayed daptomycin MICs of 2 to 4 mg/L, and 9 (0.8%) isolates were resistant (MIC, $8 mg/L; Table 1). The rates of E. faecium displaying elevated daptomycin MICs showed a progressive decrease over the study years,   analysis provide evidence that multiple oritavancin doses may be beneficial in treating severe infections and can achieve serum concentrations above the E. faecalis susceptibility breakpoint of 0.12 mg/L, for over 4 weeks (22,23). However, clinical studies are needed to evaluate the relationship between PK and clinical outcomes with oritavancin treatment. Another study conducted by Belley and colleagues on the pharmacodynamic activity of oritavancin against daptomycin-nonsusceptible VRE E. faecium suggested that a multiple-dose strategy with oritavancin may be effective against daptomycin-nonsusceptible vancomycin-resistant E. faecium (24). Viridans group Streptococcus isolates displayed oritavancin MIC 50 /MIC 90 values of #0.008 to 0.015/0.06 to 0.25 mg/L and susceptibility rates of 93.8% to 100.0% over the study period, while beta-hemolytic Streptococcus showed oritavancin MIC 50 /MIC 90 values of 0.03 to 0.06/0.12 to 0.25 mg/L and susceptibility rates of 97.1% to 100.0%. The activity of oritavancin and comparator agents against Viridans group Streptococcus and beta-hemolytic Streptococcus are displayed in the supplemental material (Table S1).
In conclusion, we noted encouraging decreasing trends in MRSA and VRE rates. Oritavancin showed potent and consistent activity against Gram-positive pathogens that cause BSI in US from 2010 to 2019, including multidrug-resistant pathogens such as MRSA, MRCoNS, VRE, and E. faecium with elevated daptomycin MIC and reduced susceptibility to linezolid and daptomycin. Further studies are warranted to identify appropriate oritavancin dosing strategies and the role of oritavancin in the armamentarium against either susceptible or multidrug-resistant Gram-positive isolates causing BSI and other severe infections.

SUPPLEMENTAL MATERIAL
Supplemental material is available online only. SUPPLEMENTAL FILE 1, PDF file, 0.4 MB.

ACKNOWLEDGMENTS
We thank the following staff members at JMI Laboratories (North Liberty, IA, USA): A. Chen, M. Konrardy, J. Maher, M. Janechek, and J. Oberholser for technical support and/ or assistance with manuscript preparation.  (14) breakpoints.