Oritavancin in vitro activity against Gram-positive organisms from European medical centers: a 10-year longitudinal overview from the SENTRY Antimicrobial Surveillance Program (2010–2019)

Abstract To assess oritavancin in vitro activity against clinically relevant Gram-positive pathogens in European (EU) hospitals, a total of 51,531 consecutive and unique clinical isolates collected in 2010–2019 were evaluated. All isolates were tested by CLSI broth microdilution methods. The key resistance phenotypes differed considerably between Eastern Europe (E-EU) and Western Europe (W-EU), respectively: methicillin-resistant (MR) Staphylococcus aureus 27.7%/22.9%; multidrug resistant (MDR) S. aureus, 19.7%/15.2%; MR coagulase-negative staphylococci, 77.3%/61.9%; vancomycin-resistant enterococci (E. faecium), 44.2%/20.9%; and MDR E. faecium, 63.8%/55.4%. There were no substantive differences in oritavancin minimum inhibitory concentration (MIC) values for the different species/organism groups over time or by EU region. Oritavancin inhibited 99.9% and 99.1% of all S. aureus and coagulase-negative staphylococci at 0.12 mg/L, respectively, and all isolates of E. faecalis and E. faecium at ≤0.5 mg/L. Oritavancin susceptibility rates against β-hemolytic and Viridans group streptococci isolates were 98.1% and 99.4%, respectively. Oritavancin had potent activity in vitro against this contemporary collection of European Gram-positive isolates from 2010 to 2019.


Introduction
Antimicrobial resistance (AMR) is an ongoing problem with serious implications for medical progress [1][2][3].A global survey of AMR in 204 countries and territories found approximately 1.27 million deaths directly attributable to bacterial AMR in 2019 [2].These estimates indicated that bacterial AMR is a public health concern with a magnitude at least as large as major infectious diseases such as HIV and malaria [2].Compared to all other causes of mortality surveyed in the Global Burden of Disease 2019 survey, bacterial AMR was the third leading cause of death in 2019, behind only ischemic heart disease and stroke [2].
AMR surveillance programs track the main bacterial and fungal pathogens causing human infections and the spread of key resistant phenotypes among prevalent pathogens in areas of interest.These programs also assess the in vitro activity of new and established antimicrobial agents against these pathogens over time [1,3].Longitudinal surveys, such as those conducted by the SENTRY Surveillance Program [1-3], may serve as benchmarks for future studies after antimicrobial agents are approved for clinical use.
Whereas vancomycin has been used as the agent of last resort for many infections caused by these GPC, each of these species or organism groups can harbor vancomycin resistance mechanisms as well as resistance to other classes of agents [10][11][12][13][14][15].Vancomycin-resistance is frequently observed in Enterococcus faecium causing infections worldwide and increased thickness of the cell wall may decrease vancomycin-susceptibility or drive vancomycintolerance in S. aureus (VISA) as well as Streptococcus spp. in the clinical setting [11,[14][15][16].As a result, new antimicrobials with enhanced potency against MDR (resistant to �3 different classes of agents) GPC have been developed [12,13,[17][18][19][20].Importantly, vancomycin-resistant Enterococcus faecium, MRSA and vancomycin-non susceptible S. aureus are pathogens listed as high priority for research and development of new antibiotics by the World Health Organization (WHO) global priority list of drug-resistant pathogens [21].
Oritavancin 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 acute bacterial skin and skin structure infection (ABSSSI) due to susceptible GPC, including staphylococci, enterococci and streptococci [17,18,22,23].Oritavancin has been approved for clinical use by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the single dosing regimen of ABSSSI [12,18,19].Recently, the same oritavancin dose (1200 mg) with a shorter infusion time of 1 h (Kimyrsa TM ) was approved by the US FDA [24].
Previous studies have demonstrated potent activity of oritavancin against S. aureus, including MRSA as well as heterogeneous vancomycin-intermediate S. aureus (hVISA) and VISA isolates and vancomycinsusceptible and -resistant enterococci [4,10,[25][26][27][28][29][30].Compared to other drugs of the same class, oritavancin displays a triple mechanism of action.Not only does it inhibit peptidoglycan synthesis, oritavancin also interacts with the bacterial cell membrane causing depolarization and increased membrane permeability [17].The oritavancin mechanism of action contributes to its bactericidal activity and may also prevent the emergence of resistance when it is used clinically.
Previously, we documented the sustained potency of oritavancin against clinical isolates of GPC collected in Europe from 2008-2016 [5-8,27-29].The objective of this study was to expand on the previous analysis by examining the longitudinal stability of the potency of oritavancin as measured by CLSI broth microdilution (BMD) method in the context of the SENTRY Antimicrobial Surveillance Program for 2010-2019.

Clinical isolates
A total of 51,531 clinical isolates deemed to be the primary organism responsible for clinical infections per local guidelines were included in the study (Table 1).Isolates originated from 54 sites in Europe.Eastern Europe (E-EU) included 11 sites and 9,450 isolates from Greece, Israel, Poland, Russia, Turkey and Ukraine.Western Europe (W-EU) included 43 sites and 42,081 isolates from Belgium, France, Germany, Ireland, Italy, Portugal, Spain, Sweden, Switzerland and the UK.These pathogens were submitted to the coordinating monitoring laboratory (JMI Laboratories, North Liberty, Iowa, USA), where bacterial identifications were confirmed by standard algorithms and VitekV R 2 (2010-2012; bioM� erieux, Hazelwood, Missouri, USA) or MALDI-TOF-MS (2013-2019; Bruker Daltonics, Bremen, Germany).

Antimicrobial susceptibility testing
Isolates were tested for susceptibility by broth microdilution following the Clinical and Laboratory Standards Institute (CLSI) M07 document current in place for each year using dry-form (2010-2014; ThermoFisher Scientific; Bedford, MA, USA) or frozen-form (2015-2019; JMI Laboratories) panels [31].Quality assurance was performed by concurrently testing the following CLSI-recommended strains: Enterococcus faecalis ATCC 29212, S. aureus ATCC 29213 and S. pneumoniae ATCC 49619 [32].EUCAST-approved interpretive breakpoint criteria were utilized for oritavancin: susceptible breakpoints of �0.12 mg/L were used for S. aureus and �0.25 mg/L were used for b-hemolytic (BHS) and Viridans group (VGS) streptococci.MIC interpretations for comparator agents were based on EUCAST [33] breakpoint criteria.

Overall activity of oritavancin
The MIC distribution for oritavancin for each of the organisms and key resistant phenotypes of GPC from EU medical centers for 2010-2019 are shown in Table 2.The distributions, modal MIC and MIC 50/90 values for each of the organism groups were identical for E-EU and W-EU isolates and were combined for purposes of this analysis.
Overall, oritavancin showed modal MIC, MIC 50 and MIC 90 results of 0.03, 0.03 and 0.06 mg/L when tested against S. aureus, regardless of the methicillin susceptibility, MDR phenotype, or geographic region (99.8% of E-EU and W-EU isolates inhibited at �0.12 mg/L; Table 2).Methicillin-susceptible, coagulase-negative staphylococcal (MS-CoNS) isolates from EU demonstrated an MIC 50 value for oritavancin (MIC 50 , 0.015 mg/L) that was slightly lower than that for MR-CoNS isolates (MIC 50 , 0.03 mg/L; Table 2).A total of 78.9% and 63.1% of CoNS from E-EU and W-EU, respectively, were methicillin resistant (MR-CoNS) (data not shown): 99.0% of MR-CoNS were susceptible to oritavancin at the S. aureus breakpoint of �0.12 mg/L (Table 2).

Activity of oritavancin and comparator agents against S. aureus and Enterococcus spp. isolates from E-EU and W-EU
Table 3 shows the MIC 50/90 results and the percentage of each species that were susceptible or resistant to oritavancin and comparator antimicrobial agents (limited to S. aureus and Enterococcus spp.) in the 2010-2019 SENTRY program for Europe.The MIC 50/90 values for oritavancin and each species did not vary by more than one two-fold dilution step over time and were comparable between E-EU and W-EU isolates.

Discussion
This study evaluated the in vitro activity of oritavancin and comparators against a 10-year collection of  identical for pathogens from both EU regions.Although oritavancin displayed very high percentage of susceptibility against GP pathogens a responsible use of the drug to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria is an important recommendation [24].Overall, oritavancin activity was essentially unchanged over the 10-year period and was comparable for isolates from E-EU and W-EU.The in vitro potency of oritavancin based on MIC 90 values was greater than that of the tested comparators for each of the key resistant pathogens.Oritavancin inhibited 95.7% of MRSA isolates with reduced susceptibility to vancomycin (MIC, 2 mg/L) at the EUCAST-approved breakpoint of �0.12 mg/L.Equivalent potency results were observed for oritavancin when tested against isolates from E-EU and W-EU, with marginal differences for E. faecium.The data presented here confirm and extend the previously reported conclusions of the SENTRY Program for GPC isolates from EU [5-8, [27][28][29] as well as those of other investigators [4, 10,30].

Table 1 .
Distribution of main Gram-positive species and organism groups total and by year as part of the surveillance studies.

Table 2 .
Antimicrobial activity of oritavancin tested against the main organisms and organism groups.

Table 3 .
Antimicrobial activity of oritavancin and comparator agents tested against S. aureus and Enterococcus spp.from Western and Eastern Europe.
W-EU(11.7 attributable deaths/100,000).Despite the differences in the frequency of these important pathogens, the in vitro potency of oritavancin was virtually

Table 3 .
Continued.Note: HL: high-level resistance.Number of isolates in each organism group is written in italic.