Diagnostic Microbiology and Infectious Disease xxx (2014) xxx–xxx
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In vitro activity of oritavancin against Gram-positive pathogens isolated in Canadian hospital laboratories from 2011 to 2013 J.A. Karlowsky ⁎, A.J. Walkty, M.R. Baxter, H.J. Adam, G.G. Zhanel Department of Medical Microbiology and Infectious Diseases, Faculty of Medicine, University of Manitoba, Winnipeg, Canada
a r t i c l e
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Article history: Received 11 August 2014 Received in revised form 3 September 2014 Accepted 5 September 2014 Available online xxxx Keywords: Oritavancin MRSA Skin and soft tissue infection
a b s t r a c t Gram-positive pathogens isolated in 15 Canadian hospital laboratories between 2011 and 2013 were tested for susceptibility to oritavancin and comparative antimicrobial agents using the Clinical and Laboratory Standards Institute broth microdilution method. Oritavancin demonstrated in vitro activity equivalent to, or more potent than, vancomycin, daptomycin, linezolid, and tigecycline against the isolates of methicillin-susceptible Staphylococcus aureus (n = 1460; oritavancin MIC90, 0.06 μg/mL; 99.7% oritavancin-susceptible), methicillin-resistant S. aureus (n = 427; oritavancin MIC90, 0.06 μg/mL; 99.5% oritavancin-susceptible), Streptococcus pyogenes (n = 132; oritavancin MIC90, 0.25 μg/mL; 99.2% oritavancin-susceptible), Streptococcus agalactiae (n = 156; oritavancin MIC90, 0.12 μg/mL; 100% oritavancin-susceptible), and Enterococcus faecalis (n = 304; oritavancin MIC90, 0.06 μg/mL; 98.7% oritavancin-susceptible) tested. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Oritavancin is a semisynthetic lipoglycopeptide that was approved by the US Food and Drug Administration (FDA) in August 2014 for the single-dose (1200 mg) intravenous treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by, or suspected to be caused by, susceptible Gram-positive bacteria, including methicillinresistant Staphylococcus aureus (MRSA). The availability of a singledose therapy to treat patients with ABSSSI may improve patient compliance with therapy and transform the management of these infections, which are among the commonest indications requiring prescription of intravenous antimicrobial agents (Chambers, 2014; Corey et al., 2014). Oritavancin's mechanism of action against Gram-positive pathogens involves the inhibition of 2 distinct steps in cell wall biosynthesis, namely, transglycosylation and transpeptidation. Oritavancin does this by binding to the terminal D-Ala-D-Ala of a nascent peptidoglycan chain and by complexing with the pentaglycine bridge (Zhanel et al., 2012). Unlike other glycopeptides, oritavancin is able to bind to depsipeptides including D-Ala-D-Lac, which facilitates its inhibition of cell wall biosynthesis even in organisms exhibiting VanA-type resistance (Zhanel et al., 2012). In addition, oritavancin disrupts bacterial cell membranes, dissipating membrane potential and increasing membrane permeability (Zhanel et al., 2012). Our knowledge that oritavancin has multiple mechanisms of action suggests, theoretically at least, that it should be ⁎ Corresponding author. Tel.: +1-204-237-2105; fax: +1-204-237-7678. E-mail address: [email protected] (J.A. Karlowsky).
less likely to select resistant organisms when introduced into widespread clinical use. Oritavancin's spectrum of activity includes methicillin-susceptible S. aureus (MSSA) and MRSA, methicillin-susceptible and methicillinresistant Staphylococcus epidermidis and other coagulase-negative staphylococci, streptococci including β-hemolytic streptococci, and penicillin-resistant Streptococcus pneumoniae as well as vancomycinsusceptible and vancomycin-resistant enterococci (Mendes et al., 2012; Mendes et al., 2014b). The current study adds to the scientific literature describing the in vitro activity of oritavancin by defining oritavancin MIC distributions for important Gram-positive pathogens in Canada, a treatment-naïve population where oritavancin is currently not licensed for sale, and by specifically characterizing oritavancin activity against genetically defined community-associated MRSA and healthcare-associated MRSA. 2. Materials and methods 2.1. Bacterial isolates From January 2011 to October 2013, 15 sentinel Canadian hospital laboratories were asked to submit consecutive pathogens (1 per patient) from blood (n = 100), respiratory (n = 100), urine (n = 25), and wound (n = 25) infections. All isolates collected were deemed clinically significant by the participating sites. Isolate inclusion was independent of patient age. Primary isolate identification was performed by the submitting site. Isolates were re-identified by the coordinating laboratory (Health Sciences Centre, Winnipeg, Canada) using morphological characteristics and spot tests. If an isolate identification made by the coordinating laboratory was not consistent with that provided by the submitting site, the isolate was removed from the study.
http://dx.doi.org/10.1016/j.diagmicrobio.2014.09.003 0732-8893/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Karlowsky JA, et al, In vitro activity of oritavancin against Gram-positive pathogens isolated in Canadian hospital laboratories from 2011 to 2013, Diagn Microbiol Infect Dis (2014), http://dx.doi.org/10.1016/j.diagmicrobio.2014.09.003
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JA. Karlowsky et al. / Diagnostic Microbiology and Infectious Disease xxx (2014) xxx–xxx
2.2. Antimicrobial susceptibility testing Isolates were tested for their susceptibility to all antimicrobial agents, except oritavancin, using in-house–prepared 96-well broth microdilution panels according to Clinical and Laboratory Standards Institute (CLSI) guidelines (CLSI, 2012; CLSI, 2014). The antimicrobial agents tested were obtained as laboratory-grade powders from their respective manufacturers. Stock solutions and dilutions were prepared as described by the CLSI (2012) in cationadjusted Mueller–Hinton broth (MHB) and MHB with 5% laked horse blood, as appropriate. MIC results for oritavancin were generated using frozen 96-well broth microdilution panels provided by The Medicines Company (St. Laurent, Quebec, Canada). Oritavancin was tested with each media type supplemented with 0.002% polysorbate-80 (CLSI, 2014). Quality control was performed following CLSI recommendations, and MICs were interpreted using CLSI M100-S24 (CLSI, 2014) breakpoints except for tigecycline (Tygacil® product monograph; Wyeth Pharmaceuticals, October 2013) and oritavancin (Orbactiv™ product monograph; The Medicines Company, August 2014) where US FDA–approved MIC breakpoints were used. Multidrug-resistant (MDR) phenotype was defined as concurrent resistance to 3 or more classes of antimicrobial agent (β-lactam, glycopeptide, macrolide, lincosamide, folate synthesis inhibitor, tetracycline, and glycylcycline). 2.3. Molecular characterization of isolates MRSA isolates were confirmed using the cefoxitin disk test (CLSI, 2014) and by PCR amplification of the mecA gene (McDonald et al., 2005). Other molecular methods, including Panton Valentine Leukocidin (PVL) analysis (McDonald et al., 2005) and staphylococcal protein A (spa) typing (Golding et al., 2008), were used to assign isolates to communityassociated (resembling USA300 and USA400) or healthcare-associated (resembling USA100/800, USA200, USA500, and USA600) groups. A high degree of concordance between spa types and epidemic clones has been documented (Golding et al., 2008). Vancomycin resistance in Enterococcus faecium and Enterococcus faecalis isolates was confirmed using the vancomycin agar dilution test (CLSI, 2014). All confirmed isolates of Vancomycin Resistant Enterococci (VRE) underwent further analysis to determine the type of vancomycin resistance present. A multiplex PCR method was used to detect the presence of vanA, vanB, vanC, vanD, or vanE (Boyd et al., 2004). 3. Results MIC results were generated for 2108 staphylococci, 288 β-hemolytic streptococci, and 413 enterococci (Table 1). Of the 427 isolates of MRSA identified, spa typing identified 156 isolates as community-associated MRSA (CA-MRSA) and 245 isolates as hospitalassociated MRSA (HA-MRSA); 26 isolates of MRSA demonstrated unique spa types and could not be assigned to either the CA-MRSA or the HA-MRSA group. Oritavancin was more potent than vancomycin, daptomycin, linezolid, and tigecycline against MSSA and MRSA, both CA-MRSA and HA-MRSA, as well as MDR and non-MDR S. aureus, inhibiting 90% of the isolates tested (MIC90) at a concentration of 0.06 μg/mL. Fig. 1A depicts comparative MIC distributions for oritavancin, daptomycin, and vancomycin for isolates of MRSA. All isolates of S. aureus tested had oritavancin MICs of ≤0.25 μg/mL; 99.7% (1892/1898) of isolates were susceptible to oritavancin and had an MIC ≤0.12 μg/mL. Against S. epidermidis, oritavancin (MIC90, 0.12 μg/mL) was also more potent than vancomycin, daptomycin, linezolid, and tigecycline, including both MDR and non-MDR isolates. Against β-hemolytic streptococci, oritavancin MICs (Streptococcus pyogenes, MIC90, 0.25 μg/mL; Streptococcus agalactiae, MIC90, 0.12 μg/mL) were comparable to daptomycin, and both agents were more potent than vancomycin, linezolid, and tigecycline. All isolates of S. agalactiae tested were susceptible to oritavancin and had MICs ≤0.25 μg/mL. One isolate of S. pyogenes was identified that was not susceptible to oritavancin (MIC, 0.5 μg/mL); 99.2% (131/132) of S. pyogenes were susceptible to oritavancin and had MICs ≤0.25 μg/mL. Fig. 1B depicts comparative MIC distributions for oritavancin, daptomycin, and vancomycin for isolates of S. pyogenes; oritavancin was unique in that it demonstrated a broad, nonGaussian MIC distribution for S. pyogenes and S. agalactiae. All isolates of E. faecalis tested were susceptible to vancomycin and had oritavancin MICs ≤0.5 μg/mL; 98.7% (300/304) of isolates were susceptible to oritavancin and had MICs ≤0.12 μg/mL. All isolates of vancomycin-susceptible E. faecium tested had oritavancin MICs ≤0.03 μg/mL; the highest oritavancin MIC detected among the 22 isolates of vancomycin-resistant E. faecium was 0.5 μg/mL.
4. Discussion MRSA is well recognized as a leading cause of healthcare- and community-associated infections and poses significant challenges to patient care (Bordon et al., 2010; Nichol et al., 2013). CA-MRSA have now supplanted MSSA as the most common cause of ABSSSI in some regions in the United States (Moran et al., 2006). Many ABSSSI, although serious, can be treated on an outpatient basis (Moellering and Ferraro, 2012). The success of outpatient antimicrobial therapy for ABSSSI would be improved by access to more reliable oral anti-staphylococcal agents or parenteral agents that can be given infrequently to treat infections. Oritavancin is administered as a single-dose treatment for ABSSSI (Corey et al., 2014).
Published studies describing the in vitro activity of oritavancin have shown that it is active against healthcare-associated and communityassociated MRSA genotypes as well as against vancomycin-intermediate S. aureus (VISA), heteroresistant VISA (hVISA), vancomycin-resistant S. aureus, daptomycin-nonsusceptible S. aureus, MDR S. aureus, and mecC MRSA (Arhin et al., 2009; Arhin et al., 2014; Mendes et al., 2012; Mendes et al., 2014a). Clinical evidence to support the use of oritavancin against infections caused by VISA, hVISA, or Glycopeptide Intermediate S. aureus (GISA) isolates remains to be defined. The current study demonstrated a consistent MIC90, 0.06 μg/mL, for oritavancin for all isolates of MRSA tested as well as in subset analysis of healthcare-associated and community-associated MRSA and for MDR S. aureus (Table 1). Our results were similar to those reported by other investigators describing the in vitro activity of oritavancin against isolates from the United States and Europe (Mendes et al., 2012; Mendes et al., 2014a). Mendes et al. (2014a) also reported the MIC90 for oritavancin (0.12 μg/mL) that was 2-fold higher for isolates of S. aureus with elevated MICs for vancomycin (MIC, 2 μg/mL) and daptomycin (MIC, 1–4 μg/mL) than it was for isolates more susceptible to vancomycin and daptomycin (oritavancin MIC90, 0.06 μg/mL), an analysis made possible by the large number of isolates (n = 9115) tested. Arhin et al. (2012) reported a similar correlation between oritavancin and vancomycin MICs in staphylococci. In the current study, we observed MIC90 of 0.25 μg/mL and 0.12 μg/mL, respectively, for S. pyogenes and S. agalactiae (Table 1). Other investigators have reported similar MIC distributions (Arhin et al., 2009; Mendes et al., 2012) and that oritavancin activity against β-hemolytic streptococci was not influenced by concurrent macrolide non-susceptibility (Arhin et al., 2009). Oritavancin MICs are lower for S. pneumoniae and viridans group streptococci than for β-hemolytic streptococci (Arhin et al., 2009; Mendes et al., 2012; Mendes et al., 2014b). Oritavancin retains substantial in vitro activity against enterococci harboring commonly encountered vancomycin operons, including vanA, vanB, vanC, and vanD (Moellering and Ferraro, 2012). Oritavancin differs from teicoplanin, telavancin, and dalbavancin, which have activity against vancomycin-resistant enterococci containing the vanB operon because they do not induce its expression but lack activity against vanA containing enterococci because vanA is constitutively expressed (Moellering and Ferraro, 2012). In the current study, we observed that all isolates of enterococci were inhibited by oritavancin at a concentration of ≤0.5 μg/mL; however, oritavancin MICs were lower for vancomycinsusceptible E. faecium (MIC90, 0.015 μg/mL) than vancomycinsusceptible E. faecalis (MIC90, 0.06 μg/mL) or vancomycin-resistant E. faecium (MIC90, 0.12 μg/mL); our data confirm the reports of Arhin et al. (2009) and Mendes et al. (2012) who reported similar differences in oritavancin activity for enterococci. In conclusion, in this recent survey of Gram-positive clinical isolates collected in Canadian hospitals, we demonstrated that ≥99% of S. aureus (including MRSA), S. pyogenes, and enterococci were susceptible to oritavancin, vancomycin, and daptomycin. Based on MIC50 and MIC90 values, oritavancin demonstrated in vitro activity that was equivalent to or more potent than vancomycin and daptomycin against MSSA, MRSA, β-hemolytic streptococci, and enterococci. As in the past, the long-term success of a new agent such as oritavancin when introduced into clinical use will be dependent upon its safety in clinical practice as well as its prudent use to prevent resistance development. Acknowledgments The CANWARD study is supported in part by the University of Manitoba, Health Sciences Centre (Winnipeg, Manitoba, Canada), National Microbiology Laboratory (Winnipeg, Manitoba, Canada), and The Medicines Company (Parsippany, NJ, USA). The medical centers (investigators) that participated in the CANWARD study in from 2011 to 2013 were: Vancouver Hospital,
Please cite this article as: Karlowsky JA, et al, In vitro activity of oritavancin against Gram-positive pathogens isolated in Canadian hospital laboratories from 2011 to 2013, Diagn Microbiol Infect Dis (2014), http://dx.doi.org/10.1016/j.diagmicrobio.2014.09.003
JA. Karlowsky et al. / Diagnostic Microbiology and Infectious Disease xxx (2014) xxx–xxx
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Table 1 In vitro activity of oritavancin and comparators against staphylococci, β-hemolytic streptococci, and enterococci isolated in 15 Canadian hospital laboratories from 2011 to 2013. MIC determination
MIC interpretation
Organism/phenotypea (n)
Antimicrobial Agent
MIC50 (μg/mL)
MIC90 (μg/mL)
MIC range (μg/mL)
% Susceptible
% Intermediate
% Resistant
MSSA (1460)
Oritavancinb Vancomycin Daptomycin Linezolid Tigecyclinec Doxycycline SXT Clindamycin Clarithromycin Moxifloxacin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Doxycycline SXT Clindamycin Clarithromycin Moxifloxacin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Doxycycline SXT Clindamycin Clarithromycin Moxifloxacin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Doxycycline SXT Clindamycin Clarithromycin Moxifloxacin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Doxycycline SXT Clindamycin Clarithromycin Moxifloxacin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Doxycycline SXT Clindamycin Clarithromycin Moxifloxacin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Doxycycline SXT Clindamycin Clarithromycin Moxifloxacin Oritavancin Vancomycin Daptomycin
0.03 0.5 0.25 2 0.12 ≤0.12 ≤0.12 ≤0.12 0.25 ≤0.06 0.03 1 0.25 2 0.12 ≤0.12 ≤0.12 ≤0.12 N32 4 0.03 0.5 0.25 2 0.12 ≤0.12 ≤0.12 ≤0.12 32 2 0.03 1 0.25 2 0.12 ≤0.12 ≤0.12 8 N32 8 0.03 1 0.25 2 0.12 ≤0.12 ≤0.12 ≤0.12 N32 8 0.03 0.5 0.25 2 0.12 ≤0.12 ≤0.12 ≤0.12 0.25 ≤0.06 0.06 1 0.25 0.5 0.12 0.25 2 ≤0.12 N32 1 0.12 1 0.25
0.06 1 0.25 4 0.25 0.25 ≤0.12 ≤0.12 N32 0.25 0.06 1 0.5 4 0.25 1 ≤0.12 N8 N32 N16 0.06 1 0.5 4 0.25 ≤0.12 ≤0.12 N8 N32 2 0.06 1 0.5 4 0.5 1 ≤0.12 N8 N32 N16 0.06 1 0.5 4 0.25 2 ≤0.12 N8 N32 N16 0.06 1 0.25 4 0.25 ≤0.12 ≤0.12 ≤0.12 N32 0.25 0.12 2 0.25 1 0.25 1 8 N8 N32 N16 0.12 2 0.25
≤0.004–0.25 ≤0.12–2 ≤0.03–1 ≤0.12–4 0.06–1 ≤0.12–16 ≤0.12 to N8 ≤0.12 to N8 ≤0.03 to N32 ≤0.06 to N16 ≤0.004–0.25 0.5–2 0.12–2 0.5–4 0.06–2 ≤0.12–16 ≤0.12 to N8 ≤0.12 to N8 ≤0.03 to N32 ≤0.06 to N16 ≤0.004–0.25 0.5–2 0.25–2 1–4 0.06–0.5 ≤0.12–2 ≤0.12–1 ≤0.12 to N8 0.12 to N32 ≤0.06–16 0.008–0.25 0.5–1 0.12–0.5 0.5–4 0.06–2 ≤0.12–16 ≤0.12 to N8 ≤0.12 to N8 ≤0.03 to N32 ≤0.06 to N16 0.008–0.25 0.5–2 0.12–2 0.5–4 0.06–2 ≤0.12–16 ≤0.12 to N8 ≤0.12 to N8 ≤0.03 to N32 ≤0.06 to N16 ≤0.004–0.25 ≤0.12–2 ≤0.03–1 ≤0.12–4 0.06–1 ≤0.12–16 ≤0.12 to N8 ≤0.12 to N8 ≤0.03 to N32 ≤0.06 to N16 0.008–0.5 ≤0.12–2 ≤0.03–0.5 ≤0.12–4 ≤0.03–1 ≤0.12–32 ≤0.12 to N8 ≤0.12 to N8 ≤0.03 to N32 ≤0.06 to N16 0.015–0.25 1–2 ≤0.03–0.5
99.7d 100 100 100 99.8f 98.7 99.5 95.5 76.9 91.1 99.5g 100 99.8h 100 98.4i 98.1 97.2 66.0 20.0 21.1 99.4g 100 99.4h 100 100 100 100 89.0 31.8 32.5 99.6g 100 100 100 97.1i 96.8 95.1 49.8 9.0 6.5 99.4g 100 99.7h 100 97.9i 95.8 96.1 45.1 0.9 3.0 99.7d 100 100 100 100 99.2 99.5 98.3 77.7 91.0 NA 100 100 100 NA 95.5 56.6 56.1 32.6 45.3 NA 100 100
-e 0 0.9 0.1 0.7 0.9 0 0.7 0 0.9 5.1 0 0 0 0.7 11.7 0 1.2 0 1.2 1.2 0 1.2 0 0 0 0 0.7 0.2 0.9 2.2 NA 0 NA 3.2
0 0 0.4 0.5 4.4 22.4 8.0 0 0 1.2 2.8 34.0 79.1 73.8 0 0 0 0 11.0 67.5 55.8 0 0 2.0 4.9 50.2 89.8 92.3 0 0 3.0 3.9 54.9 99.1 97.0 0 0 0.1 0.5 1.5 21.4 6.8 NA 0 0 NA 1.3 43.4 42.5 67.0 47.5 NA 0 -
MRSA (427)
CA-MRSA (156)
HA-MRSA (245)
MDR S. aureus (337)
Non-MDR S. aureus (1550)
S. epidermidis (221)
MDR S. epidermidis (85)
1.4 0.4 7.2 NA 0 -
(continued on next page)
Please cite this article as: Karlowsky JA, et al, In vitro activity of oritavancin against Gram-positive pathogens isolated in Canadian hospital laboratories from 2011 to 2013, Diagn Microbiol Infect Dis (2014), http://dx.doi.org/10.1016/j.diagmicrobio.2014.09.003
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JA. Karlowsky et al. / Diagnostic Microbiology and Infectious Disease xxx (2014) xxx–xxx
Table 1 (continued) MIC determination a
Organism/phenotype (n)
Non-MDR S. epidermidis (136)
S. pyogenes (132)
S. agalactiae (156)
E. faecalis (304)
Vancomycin-susceptible E. faecium (87)
Vancomycin-resistant E. faecium (22)o
MIC interpretation
Antimicrobial Agent
MIC50 (μg/mL)
MIC90 (μg/mL)
MIC range (μg/mL)
% Susceptible
% Intermediate
% Resistant
Linezolid Tigecycline Doxycycline SXT Clindamycin Clarithromycin Moxifloxacin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Doxycycline SXT Clindamycin Clarithromycin Moxifloxacin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Clindamycin Clarithromycin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Clindamycin Clarithromycin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Doxycycline Ciprofloxacin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Doxycycline Ciprofloxacin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Doxycycline Ciprofloxacin
1 0.25 0.5 4 N8 N32 4 0.06 1 0.25 0.5 0.12 0.25 ≤0.12 ≤0.12 4 ≤0.06 0.03 0.5 0.06 1 ≤0.015 ≤0.12 ≤0.03 0.03 0.5 0.25 1 0.03 ≤0.12 ≤0.03 0.03 1 1 2 0.12 8 1 0.008 0.5 1 2 0.12 ≤0.12 N16 0.008 N32 1 2 0.12 2 N16
1 0.25 1 8 N8 N32 N16 0.12 1 0.25 1 0.25 1 4 N8 N32 16 0.25 0.5 0.12 2 0.06 ≤0.12 ≤0.03 0.12 0.5 0.25 2 0.06 N64 32 0.06 2 2 4 0.12 16 N16 0.015 1 2 4 0.12 8 N16 0.12 N32 2 4 0.25 8 N16
≤0.12–2 0.06–1 ≤0.12–16 ≤0.12 to N8 ≤0.12 to N8 ≤0.03 to N32 ≤0.06 to N16 0.008–0.5 ≤0.12–2 ≤0.03–0.5 0.25–4 ≤0.03–1 ≤0.12–32 ≤0.12 to N8 ≤0.12 to N8 ≤0.03 to N32 ≤0.06 to N16 ≤0.0005–0.5 0.25–1 ≤0.03–0.12 0.25–4 ≤0.015–0.25 ≤0.12 to N64 ≤0.03 to N32 0.001–0.25 0.25–1 ≤0.03–0.5 0.25–2 ≤0.015–1 ≤0.12 to N64 ≤0.03 to N32 ≤0.004–0.5 0.25–4 ≤0.03–4 0.5–4 ≤0.03–0.5 ≤0.12–32 0.25 to N16 ≤0.004–0.03 0.25–2 ≤0.03–4 1–4 ≤0.03–0.25 ≤0.12–16 0.25 to N16 ≤0.004–0.5 32 to N32 0.25–2 1–4 0.06–0.5 ≤0.12–16 N16
100 NA 96.5 15.3 15.3 6.0 4.7 NA 100 100 100 NA 94.8 82.4 81.6 49.3 70.6 99.2j 100 100 98.5k 100 99.2 94.7 100 100 100 100 99.4l 83.3 69.9 98.7m 100 100 89.4 99.3n 38.5 67.4 NA 100 100 83.9 NA 86.2 11.8 NA 0 100 81.8 NA 77.3 0
NA 1.2 0 0 1.2 NA 0 NA 4.4 2.2 0.7 11.0 0 0 0.7 4.5 0 10.6
0 NA 2.3 84.7 84.7 94.0 94.1 NA 0 0 NA 0.8 17.6 16.2 50.0 18.4 0.8 5.3 16.0 25.6 0 0 0.7 19.4 28.6 NA 0 0 NA 8.0 88.2 NA 100 0 NA 9.1 100
42.1 4.0 NA 0 16.1 NA 5.8 0 NA 0 18.2 NA 13.6 0
SXT = trimethoprim-sulfamethoxazole; NA = currently MIC breakpoints are not available. a MDR, defined as resistance to 3 or more classes of antimicrobial agents (β-lactam, glycopeptide, macrolide, lincosamide, folate synthesis inhibitor, fluoroquinolone, tetracycline, and glycylcycline). spa typing identified 156 CA-MRSA and 245 HA-MRSA; 26 isolates of MRSA demonstrated unique spa types and could not be assigned to either the CA-MRSA or the HAMRSA group. b Oritavancin US FDA breakpoints: S. aureus, ≤0.12 μg/mL (susceptible); Streptococcus spp. other than S. pneumoniae, ≤0.25 μg/mL (susceptible); and E. faecalis (vancomycin-susceptible), ≤0.12 μg/mL (susceptible). c Tigecycline US FDA breakpoints: S. aureus, ≤0.5 μg/mL (susceptible); Streptococcus spp. other than S. pneumoniae, ≤0.25 μg/mL (susceptible); and E. faecalis (vancomycin-susceptible), ≤0.25 μg/mL (susceptible). d Four isolates of MSSA were non-susceptible to oritavancin (MIC, 0.25 μg/mL) and were non-MDR isolates. e -, MIC breakpoints for intermediate and resistant categories have not been not defined by CLSI (2014) or US FDA. An isolate with an MIC exceeding the susceptible breakpoint is defined as non-susceptible. f Three isolates of MSSA were non-susceptible to tigecycline (MIC, N0.5 μg/mL). g Two isolates of MRSA were non-susceptible to oritavancin (MIC, 0.25 μg/mL) and were MDR isolates; 1 isolate was CA-MRSA and 1 isolate was HA-MRSA. h One isolate of MRSA (CA-MRSA) was non-susceptible to daptomycin (MIC, N1 μg/mL). i Seven isolates of MRSA (all HA-MRSA) were non-susceptible to tigecycline (MIC, N0.5 μg/mL). j One isolate of MSSA was non-susceptible to oritavancin (MIC, 0.5 μg/mL). k Two isolates of S. pyogenes were non-susceptible to linezolid (MIC, N2 μg/mL). l One isolate of S. agalactiae was non-susceptible to tigecycline (MIC, N0.25 μg/mL). m Four isolates of E. faecalis were non-susceptible to oritavancin (MIC, N0.25 μg/mL). n Two isolates of E. faecalis were non-susceptible to tigecycline (MIC, N0.25 μg/mL). o All 22 isolates of vancomycin-resistant E. faecium were vanA-positive by PCR testing.
Please cite this article as: Karlowsky JA, et al, In vitro activity of oritavancin against Gram-positive pathogens isolated in Canadian hospital laboratories from 2011 to 2013, Diagn Microbiol Infect Dis (2014), http://dx.doi.org/10.1016/j.diagmicrobio.2014.09.003
JA. Karlowsky et al. / Diagnostic Microbiology and Infectious Disease xxx (2014) xxx–xxx
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Fig. 1. MIC distributions for oritavancin, daptomycin, and vancomycin for (A) MRSA and (B) S. pyogenes.
Vancouver, British Columbia (Dr D. Roscoe); University of Alberta Hospital, Edmonton, Alberta (Drs R. Rennie and J. Fuller); Royal University Hospital, Saskatoon, Saskatchewan (Dr J. Blondeau); Health Sciences Centre, Winnipeg, Manitoba (Drs D. Hoban/G. Zhanel); London Health Sciences Centre, London, Ontario (Dr Z. Hussain); University Health Network and Mount Sinai Hospital, Toronto, Ontario (Dr S. Poutanen); St. Michael's Hospital, Toronto, Ontario (Dr L. Matukas); Children's Hospital of Eastern Ontario, Ottawa, Ontario (Dr F. Chan); The Ottawa Hospital, Ottawa, Ontario (Dr M. Desjardins); Royal Victoria Hospital, Montreal, Quebec (Dr V. Loo); Montreal General Hospital, Montreal, Quebec (Dr V. Loo); Hôpital Maisonneuve-Rosemont, Montreal, Quebec (Dr M. Laverdière); Centre Hospitalier Régional de Trois Rivières, Pavillon Sainte Marie, Trois Rivières, Quebec (Dr M. Goyette); Hôpital de la Cité-de-la-Santé, Laval, Quebec (Dr M. Bergevin); L’Hôtel-Dieu de Quebec, Quebec City, Quebec (Dr R. Pelletier); South-East Regional Health Authority, Moncton, New Brunswick (Dr M. Kuhn); and Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia (Dr R. Davidson).
References Arhin FF, Sarmiento I, Parr Jr TR, Moeck G. Comparative in vitro activity of oritavancin against Staphylococcus aureus strains that are resistant, intermediate or heteroresistant to vancomycin. J Antimicrob Chemother 2009;64:868–70. Arhin FF, Draghi DC, Pillar CM, Moeck G, Sahm DF. Correlation between oritavancin and vancomycin minimum inhibitory concentrations in staphylococci. Int J Antimicrob Agents 2012;40:562–3. Arhin FF, Sarmiento I, Moeck G. In vitro activities of oritavancin and comparators against methicillin-resistant Staphylococcus aureus (MRSA) isolates harbouring the novel mecC gene. Int J Antimicrob Agents 2014;44:65–8. Bordon JM, Master RN, Clark RB, Karlowsky JA, Klotchko A, Duvvuri P, et al. Methicillinresistant Staphylococcus aureus resistance to non-β-lactam antimicrobials in the United States from 1996 to 2008. Diagn Microbiol Infect Dis 2010;67:395–8.
Boyd DA, Kibsey P, Roscoe D, Mulvey MR. Enterococcus faecium N03-0072 carries a new VanD-type vancomycin resistance determinant: characterization of the VanD5 operon. J Antimicrob Chemother 2004;54:680–3. Chambers HF. Pharmacology and the treatment of complicated skin and skin-structure infections. N Engl J Med 2014;370:2238–9. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically – Ninth Edition: Approved Standard M07-A9. Wayne, PA: CLSI; 2012. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing. Twenty-Fourth Informational Supplement. Document M100-S24. Wayne, PA: CLSI; 2014. Corey GR, Kabler H, Mehra P, Gupta S, Overcash JS, Porwal A, et al. Single-dose oritavancin in the treatment of acute bacterial skin infections. N Engl J Med 2014;370:2180–90. Golding GR, Campbell JL, Spreitzer DJ, Veyhl J, Surynicz K, Simor A, et al. Canadian Nosocomial Infection Surveillance Program. A preliminary guideline for the assignment of methicillin-resistant Staphylococcus aureus to a Canadian pulsed-field gel electrophoresis epidemic type using spa typing. Can J Infect Dis Med Microbiol 2008;19:273–81. McDonald RR, Antonishyn NA, Hansen T, Snook LA, Nagle E, Mulvey MR, et al. Development of a triplex real-time PCR assay for detection of Panton-Valentine Leukocidin toxin genes in clinical isolates of methicillin-resistant Staphylococcus aureus. J Clin Microbiol 2005;43:6147–9. Mendes RE, Farrell DJ, Sader HS, Jones RN. Oritavancin microbiologic features and activity results from the surveillance program in the United States. Clin Infect Dis 2012; 54(Suppl 3):S203–13. Mendes RE, Sader HS, Flamm RK, Farrell DJ, Jones RN. Oritavancin activity against Staphylococcus aureus causing invasive infections in U.S. and European hospitals: a 5-year international surveillance program. Antimicrob Agents Chemother 2014a;58:2921–4. Mendes RE, Sader HS, Flamm RK, Jones RN. Activity of oritavancin tested against uncommonly isolated Gram-positive pathogens responsible for documented infections in hospitals worldwide. J Antimicrob Chemother 2014b;69:1579–81. Moellering Jr RC, Ferraro MJ. Introduction: solving the clinical problem of vancomycin resistance. Clin Infect Dis 2012;54(Suppl. 3):S201–2. Moran GJ, Krishnadasan A, Gorwitz RJ, Fosheim GE, McDougal LK, Carey RB, et al. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med 2006;355:666–74. Nichol KA, Adam HJ, Roscoe DL, Golding GR, Lagace-Wiens PRS, Hoban DJ, et al. Changing epidemiology of methicillin-resistant Staphylococcus aureus in Canada. J Antimicrob Chemother 2013;68(Suppl 1):i47–55. Zhanel GG, Schweizer F, Karlowsky JA. Oritavancin: mechanism of action. Clin Infect Dis 2012;54(Suppl 3):S214–9.
Please cite this article as: Karlowsky JA, et al, In vitro activity of oritavancin against Gram-positive pathogens isolated in Canadian hospital laboratories from 2011 to 2013, Diagn Microbiol Infect Dis (2014), http://dx.doi.org/10.1016/j.diagmicrobio.2014.09.003
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In vitro activity of oritavancin against Gram-positive pathogens isolated in Canadian hospital laboratories from 2011 to 2013 J.A. Karlowsky ⁎, A.J. Walkty, M.R. Baxter, H.J. Adam, G.G. Zhanel Department of Medical Microbiology and Infectious Diseases, Faculty of Medicine, University of Manitoba, Winnipeg, Canada
a r t i c l e
i n f o
Article history: Received 11 August 2014 Received in revised form 3 September 2014 Accepted 5 September 2014 Available online xxxx Keywords: Oritavancin MRSA Skin and soft tissue infection
a b s t r a c t Gram-positive pathogens isolated in 15 Canadian hospital laboratories between 2011 and 2013 were tested for susceptibility to oritavancin and comparative antimicrobial agents using the Clinical and Laboratory Standards Institute broth microdilution method. Oritavancin demonstrated in vitro activity equivalent to, or more potent than, vancomycin, daptomycin, linezolid, and tigecycline against the isolates of methicillin-susceptible Staphylococcus aureus (n = 1460; oritavancin MIC90, 0.06 μg/mL; 99.7% oritavancin-susceptible), methicillin-resistant S. aureus (n = 427; oritavancin MIC90, 0.06 μg/mL; 99.5% oritavancin-susceptible), Streptococcus pyogenes (n = 132; oritavancin MIC90, 0.25 μg/mL; 99.2% oritavancin-susceptible), Streptococcus agalactiae (n = 156; oritavancin MIC90, 0.12 μg/mL; 100% oritavancin-susceptible), and Enterococcus faecalis (n = 304; oritavancin MIC90, 0.06 μg/mL; 98.7% oritavancin-susceptible) tested. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Oritavancin is a semisynthetic lipoglycopeptide that was approved by the US Food and Drug Administration (FDA) in August 2014 for the single-dose (1200 mg) intravenous treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by, or suspected to be caused by, susceptible Gram-positive bacteria, including methicillinresistant Staphylococcus aureus (MRSA). The availability of a singledose therapy to treat patients with ABSSSI may improve patient compliance with therapy and transform the management of these infections, which are among the commonest indications requiring prescription of intravenous antimicrobial agents (Chambers, 2014; Corey et al., 2014). Oritavancin's mechanism of action against Gram-positive pathogens involves the inhibition of 2 distinct steps in cell wall biosynthesis, namely, transglycosylation and transpeptidation. Oritavancin does this by binding to the terminal D-Ala-D-Ala of a nascent peptidoglycan chain and by complexing with the pentaglycine bridge (Zhanel et al., 2012). Unlike other glycopeptides, oritavancin is able to bind to depsipeptides including D-Ala-D-Lac, which facilitates its inhibition of cell wall biosynthesis even in organisms exhibiting VanA-type resistance (Zhanel et al., 2012). In addition, oritavancin disrupts bacterial cell membranes, dissipating membrane potential and increasing membrane permeability (Zhanel et al., 2012). Our knowledge that oritavancin has multiple mechanisms of action suggests, theoretically at least, that it should be ⁎ Corresponding author. Tel.: +1-204-237-2105; fax: +1-204-237-7678. E-mail address: [email protected] (J.A. Karlowsky).
less likely to select resistant organisms when introduced into widespread clinical use. Oritavancin's spectrum of activity includes methicillin-susceptible S. aureus (MSSA) and MRSA, methicillin-susceptible and methicillinresistant Staphylococcus epidermidis and other coagulase-negative staphylococci, streptococci including β-hemolytic streptococci, and penicillin-resistant Streptococcus pneumoniae as well as vancomycinsusceptible and vancomycin-resistant enterococci (Mendes et al., 2012; Mendes et al., 2014b). The current study adds to the scientific literature describing the in vitro activity of oritavancin by defining oritavancin MIC distributions for important Gram-positive pathogens in Canada, a treatment-naïve population where oritavancin is currently not licensed for sale, and by specifically characterizing oritavancin activity against genetically defined community-associated MRSA and healthcare-associated MRSA. 2. Materials and methods 2.1. Bacterial isolates From January 2011 to October 2013, 15 sentinel Canadian hospital laboratories were asked to submit consecutive pathogens (1 per patient) from blood (n = 100), respiratory (n = 100), urine (n = 25), and wound (n = 25) infections. All isolates collected were deemed clinically significant by the participating sites. Isolate inclusion was independent of patient age. Primary isolate identification was performed by the submitting site. Isolates were re-identified by the coordinating laboratory (Health Sciences Centre, Winnipeg, Canada) using morphological characteristics and spot tests. If an isolate identification made by the coordinating laboratory was not consistent with that provided by the submitting site, the isolate was removed from the study.
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Please cite this article as: Karlowsky JA, et al, In vitro activity of oritavancin against Gram-positive pathogens isolated in Canadian hospital laboratories from 2011 to 2013, Diagn Microbiol Infect Dis (2014), http://dx.doi.org/10.1016/j.diagmicrobio.2014.09.003
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2.2. Antimicrobial susceptibility testing Isolates were tested for their susceptibility to all antimicrobial agents, except oritavancin, using in-house–prepared 96-well broth microdilution panels according to Clinical and Laboratory Standards Institute (CLSI) guidelines (CLSI, 2012; CLSI, 2014). The antimicrobial agents tested were obtained as laboratory-grade powders from their respective manufacturers. Stock solutions and dilutions were prepared as described by the CLSI (2012) in cationadjusted Mueller–Hinton broth (MHB) and MHB with 5% laked horse blood, as appropriate. MIC results for oritavancin were generated using frozen 96-well broth microdilution panels provided by The Medicines Company (St. Laurent, Quebec, Canada). Oritavancin was tested with each media type supplemented with 0.002% polysorbate-80 (CLSI, 2014). Quality control was performed following CLSI recommendations, and MICs were interpreted using CLSI M100-S24 (CLSI, 2014) breakpoints except for tigecycline (Tygacil® product monograph; Wyeth Pharmaceuticals, October 2013) and oritavancin (Orbactiv™ product monograph; The Medicines Company, August 2014) where US FDA–approved MIC breakpoints were used. Multidrug-resistant (MDR) phenotype was defined as concurrent resistance to 3 or more classes of antimicrobial agent (β-lactam, glycopeptide, macrolide, lincosamide, folate synthesis inhibitor, tetracycline, and glycylcycline). 2.3. Molecular characterization of isolates MRSA isolates were confirmed using the cefoxitin disk test (CLSI, 2014) and by PCR amplification of the mecA gene (McDonald et al., 2005). Other molecular methods, including Panton Valentine Leukocidin (PVL) analysis (McDonald et al., 2005) and staphylococcal protein A (spa) typing (Golding et al., 2008), were used to assign isolates to communityassociated (resembling USA300 and USA400) or healthcare-associated (resembling USA100/800, USA200, USA500, and USA600) groups. A high degree of concordance between spa types and epidemic clones has been documented (Golding et al., 2008). Vancomycin resistance in Enterococcus faecium and Enterococcus faecalis isolates was confirmed using the vancomycin agar dilution test (CLSI, 2014). All confirmed isolates of Vancomycin Resistant Enterococci (VRE) underwent further analysis to determine the type of vancomycin resistance present. A multiplex PCR method was used to detect the presence of vanA, vanB, vanC, vanD, or vanE (Boyd et al., 2004). 3. Results MIC results were generated for 2108 staphylococci, 288 β-hemolytic streptococci, and 413 enterococci (Table 1). Of the 427 isolates of MRSA identified, spa typing identified 156 isolates as community-associated MRSA (CA-MRSA) and 245 isolates as hospitalassociated MRSA (HA-MRSA); 26 isolates of MRSA demonstrated unique spa types and could not be assigned to either the CA-MRSA or the HA-MRSA group. Oritavancin was more potent than vancomycin, daptomycin, linezolid, and tigecycline against MSSA and MRSA, both CA-MRSA and HA-MRSA, as well as MDR and non-MDR S. aureus, inhibiting 90% of the isolates tested (MIC90) at a concentration of 0.06 μg/mL. Fig. 1A depicts comparative MIC distributions for oritavancin, daptomycin, and vancomycin for isolates of MRSA. All isolates of S. aureus tested had oritavancin MICs of ≤0.25 μg/mL; 99.7% (1892/1898) of isolates were susceptible to oritavancin and had an MIC ≤0.12 μg/mL. Against S. epidermidis, oritavancin (MIC90, 0.12 μg/mL) was also more potent than vancomycin, daptomycin, linezolid, and tigecycline, including both MDR and non-MDR isolates. Against β-hemolytic streptococci, oritavancin MICs (Streptococcus pyogenes, MIC90, 0.25 μg/mL; Streptococcus agalactiae, MIC90, 0.12 μg/mL) were comparable to daptomycin, and both agents were more potent than vancomycin, linezolid, and tigecycline. All isolates of S. agalactiae tested were susceptible to oritavancin and had MICs ≤0.25 μg/mL. One isolate of S. pyogenes was identified that was not susceptible to oritavancin (MIC, 0.5 μg/mL); 99.2% (131/132) of S. pyogenes were susceptible to oritavancin and had MICs ≤0.25 μg/mL. Fig. 1B depicts comparative MIC distributions for oritavancin, daptomycin, and vancomycin for isolates of S. pyogenes; oritavancin was unique in that it demonstrated a broad, nonGaussian MIC distribution for S. pyogenes and S. agalactiae. All isolates of E. faecalis tested were susceptible to vancomycin and had oritavancin MICs ≤0.5 μg/mL; 98.7% (300/304) of isolates were susceptible to oritavancin and had MICs ≤0.12 μg/mL. All isolates of vancomycin-susceptible E. faecium tested had oritavancin MICs ≤0.03 μg/mL; the highest oritavancin MIC detected among the 22 isolates of vancomycin-resistant E. faecium was 0.5 μg/mL.
4. Discussion MRSA is well recognized as a leading cause of healthcare- and community-associated infections and poses significant challenges to patient care (Bordon et al., 2010; Nichol et al., 2013). CA-MRSA have now supplanted MSSA as the most common cause of ABSSSI in some regions in the United States (Moran et al., 2006). Many ABSSSI, although serious, can be treated on an outpatient basis (Moellering and Ferraro, 2012). The success of outpatient antimicrobial therapy for ABSSSI would be improved by access to more reliable oral anti-staphylococcal agents or parenteral agents that can be given infrequently to treat infections. Oritavancin is administered as a single-dose treatment for ABSSSI (Corey et al., 2014).
Published studies describing the in vitro activity of oritavancin have shown that it is active against healthcare-associated and communityassociated MRSA genotypes as well as against vancomycin-intermediate S. aureus (VISA), heteroresistant VISA (hVISA), vancomycin-resistant S. aureus, daptomycin-nonsusceptible S. aureus, MDR S. aureus, and mecC MRSA (Arhin et al., 2009; Arhin et al., 2014; Mendes et al., 2012; Mendes et al., 2014a). Clinical evidence to support the use of oritavancin against infections caused by VISA, hVISA, or Glycopeptide Intermediate S. aureus (GISA) isolates remains to be defined. The current study demonstrated a consistent MIC90, 0.06 μg/mL, for oritavancin for all isolates of MRSA tested as well as in subset analysis of healthcare-associated and community-associated MRSA and for MDR S. aureus (Table 1). Our results were similar to those reported by other investigators describing the in vitro activity of oritavancin against isolates from the United States and Europe (Mendes et al., 2012; Mendes et al., 2014a). Mendes et al. (2014a) also reported the MIC90 for oritavancin (0.12 μg/mL) that was 2-fold higher for isolates of S. aureus with elevated MICs for vancomycin (MIC, 2 μg/mL) and daptomycin (MIC, 1–4 μg/mL) than it was for isolates more susceptible to vancomycin and daptomycin (oritavancin MIC90, 0.06 μg/mL), an analysis made possible by the large number of isolates (n = 9115) tested. Arhin et al. (2012) reported a similar correlation between oritavancin and vancomycin MICs in staphylococci. In the current study, we observed MIC90 of 0.25 μg/mL and 0.12 μg/mL, respectively, for S. pyogenes and S. agalactiae (Table 1). Other investigators have reported similar MIC distributions (Arhin et al., 2009; Mendes et al., 2012) and that oritavancin activity against β-hemolytic streptococci was not influenced by concurrent macrolide non-susceptibility (Arhin et al., 2009). Oritavancin MICs are lower for S. pneumoniae and viridans group streptococci than for β-hemolytic streptococci (Arhin et al., 2009; Mendes et al., 2012; Mendes et al., 2014b). Oritavancin retains substantial in vitro activity against enterococci harboring commonly encountered vancomycin operons, including vanA, vanB, vanC, and vanD (Moellering and Ferraro, 2012). Oritavancin differs from teicoplanin, telavancin, and dalbavancin, which have activity against vancomycin-resistant enterococci containing the vanB operon because they do not induce its expression but lack activity against vanA containing enterococci because vanA is constitutively expressed (Moellering and Ferraro, 2012). In the current study, we observed that all isolates of enterococci were inhibited by oritavancin at a concentration of ≤0.5 μg/mL; however, oritavancin MICs were lower for vancomycinsusceptible E. faecium (MIC90, 0.015 μg/mL) than vancomycinsusceptible E. faecalis (MIC90, 0.06 μg/mL) or vancomycin-resistant E. faecium (MIC90, 0.12 μg/mL); our data confirm the reports of Arhin et al. (2009) and Mendes et al. (2012) who reported similar differences in oritavancin activity for enterococci. In conclusion, in this recent survey of Gram-positive clinical isolates collected in Canadian hospitals, we demonstrated that ≥99% of S. aureus (including MRSA), S. pyogenes, and enterococci were susceptible to oritavancin, vancomycin, and daptomycin. Based on MIC50 and MIC90 values, oritavancin demonstrated in vitro activity that was equivalent to or more potent than vancomycin and daptomycin against MSSA, MRSA, β-hemolytic streptococci, and enterococci. As in the past, the long-term success of a new agent such as oritavancin when introduced into clinical use will be dependent upon its safety in clinical practice as well as its prudent use to prevent resistance development. Acknowledgments The CANWARD study is supported in part by the University of Manitoba, Health Sciences Centre (Winnipeg, Manitoba, Canada), National Microbiology Laboratory (Winnipeg, Manitoba, Canada), and The Medicines Company (Parsippany, NJ, USA). The medical centers (investigators) that participated in the CANWARD study in from 2011 to 2013 were: Vancouver Hospital,
Please cite this article as: Karlowsky JA, et al, In vitro activity of oritavancin against Gram-positive pathogens isolated in Canadian hospital laboratories from 2011 to 2013, Diagn Microbiol Infect Dis (2014), http://dx.doi.org/10.1016/j.diagmicrobio.2014.09.003
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Table 1 In vitro activity of oritavancin and comparators against staphylococci, β-hemolytic streptococci, and enterococci isolated in 15 Canadian hospital laboratories from 2011 to 2013. MIC determination
MIC interpretation
Organism/phenotypea (n)
Antimicrobial Agent
MIC50 (μg/mL)
MIC90 (μg/mL)
MIC range (μg/mL)
% Susceptible
% Intermediate
% Resistant
MSSA (1460)
Oritavancinb Vancomycin Daptomycin Linezolid Tigecyclinec Doxycycline SXT Clindamycin Clarithromycin Moxifloxacin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Doxycycline SXT Clindamycin Clarithromycin Moxifloxacin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Doxycycline SXT Clindamycin Clarithromycin Moxifloxacin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Doxycycline SXT Clindamycin Clarithromycin Moxifloxacin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Doxycycline SXT Clindamycin Clarithromycin Moxifloxacin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Doxycycline SXT Clindamycin Clarithromycin Moxifloxacin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Doxycycline SXT Clindamycin Clarithromycin Moxifloxacin Oritavancin Vancomycin Daptomycin
0.03 0.5 0.25 2 0.12 ≤0.12 ≤0.12 ≤0.12 0.25 ≤0.06 0.03 1 0.25 2 0.12 ≤0.12 ≤0.12 ≤0.12 N32 4 0.03 0.5 0.25 2 0.12 ≤0.12 ≤0.12 ≤0.12 32 2 0.03 1 0.25 2 0.12 ≤0.12 ≤0.12 8 N32 8 0.03 1 0.25 2 0.12 ≤0.12 ≤0.12 ≤0.12 N32 8 0.03 0.5 0.25 2 0.12 ≤0.12 ≤0.12 ≤0.12 0.25 ≤0.06 0.06 1 0.25 0.5 0.12 0.25 2 ≤0.12 N32 1 0.12 1 0.25
0.06 1 0.25 4 0.25 0.25 ≤0.12 ≤0.12 N32 0.25 0.06 1 0.5 4 0.25 1 ≤0.12 N8 N32 N16 0.06 1 0.5 4 0.25 ≤0.12 ≤0.12 N8 N32 2 0.06 1 0.5 4 0.5 1 ≤0.12 N8 N32 N16 0.06 1 0.5 4 0.25 2 ≤0.12 N8 N32 N16 0.06 1 0.25 4 0.25 ≤0.12 ≤0.12 ≤0.12 N32 0.25 0.12 2 0.25 1 0.25 1 8 N8 N32 N16 0.12 2 0.25
≤0.004–0.25 ≤0.12–2 ≤0.03–1 ≤0.12–4 0.06–1 ≤0.12–16 ≤0.12 to N8 ≤0.12 to N8 ≤0.03 to N32 ≤0.06 to N16 ≤0.004–0.25 0.5–2 0.12–2 0.5–4 0.06–2 ≤0.12–16 ≤0.12 to N8 ≤0.12 to N8 ≤0.03 to N32 ≤0.06 to N16 ≤0.004–0.25 0.5–2 0.25–2 1–4 0.06–0.5 ≤0.12–2 ≤0.12–1 ≤0.12 to N8 0.12 to N32 ≤0.06–16 0.008–0.25 0.5–1 0.12–0.5 0.5–4 0.06–2 ≤0.12–16 ≤0.12 to N8 ≤0.12 to N8 ≤0.03 to N32 ≤0.06 to N16 0.008–0.25 0.5–2 0.12–2 0.5–4 0.06–2 ≤0.12–16 ≤0.12 to N8 ≤0.12 to N8 ≤0.03 to N32 ≤0.06 to N16 ≤0.004–0.25 ≤0.12–2 ≤0.03–1 ≤0.12–4 0.06–1 ≤0.12–16 ≤0.12 to N8 ≤0.12 to N8 ≤0.03 to N32 ≤0.06 to N16 0.008–0.5 ≤0.12–2 ≤0.03–0.5 ≤0.12–4 ≤0.03–1 ≤0.12–32 ≤0.12 to N8 ≤0.12 to N8 ≤0.03 to N32 ≤0.06 to N16 0.015–0.25 1–2 ≤0.03–0.5
99.7d 100 100 100 99.8f 98.7 99.5 95.5 76.9 91.1 99.5g 100 99.8h 100 98.4i 98.1 97.2 66.0 20.0 21.1 99.4g 100 99.4h 100 100 100 100 89.0 31.8 32.5 99.6g 100 100 100 97.1i 96.8 95.1 49.8 9.0 6.5 99.4g 100 99.7h 100 97.9i 95.8 96.1 45.1 0.9 3.0 99.7d 100 100 100 100 99.2 99.5 98.3 77.7 91.0 NA 100 100 100 NA 95.5 56.6 56.1 32.6 45.3 NA 100 100
-e 0 0.9 0.1 0.7 0.9 0 0.7 0 0.9 5.1 0 0 0 0.7 11.7 0 1.2 0 1.2 1.2 0 1.2 0 0 0 0 0.7 0.2 0.9 2.2 NA 0 NA 3.2
0 0 0.4 0.5 4.4 22.4 8.0 0 0 1.2 2.8 34.0 79.1 73.8 0 0 0 0 11.0 67.5 55.8 0 0 2.0 4.9 50.2 89.8 92.3 0 0 3.0 3.9 54.9 99.1 97.0 0 0 0.1 0.5 1.5 21.4 6.8 NA 0 0 NA 1.3 43.4 42.5 67.0 47.5 NA 0 -
MRSA (427)
CA-MRSA (156)
HA-MRSA (245)
MDR S. aureus (337)
Non-MDR S. aureus (1550)
S. epidermidis (221)
MDR S. epidermidis (85)
1.4 0.4 7.2 NA 0 -
(continued on next page)
Please cite this article as: Karlowsky JA, et al, In vitro activity of oritavancin against Gram-positive pathogens isolated in Canadian hospital laboratories from 2011 to 2013, Diagn Microbiol Infect Dis (2014), http://dx.doi.org/10.1016/j.diagmicrobio.2014.09.003
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Table 1 (continued) MIC determination a
Organism/phenotype (n)
Non-MDR S. epidermidis (136)
S. pyogenes (132)
S. agalactiae (156)
E. faecalis (304)
Vancomycin-susceptible E. faecium (87)
Vancomycin-resistant E. faecium (22)o
MIC interpretation
Antimicrobial Agent
MIC50 (μg/mL)
MIC90 (μg/mL)
MIC range (μg/mL)
% Susceptible
% Intermediate
% Resistant
Linezolid Tigecycline Doxycycline SXT Clindamycin Clarithromycin Moxifloxacin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Doxycycline SXT Clindamycin Clarithromycin Moxifloxacin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Clindamycin Clarithromycin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Clindamycin Clarithromycin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Doxycycline Ciprofloxacin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Doxycycline Ciprofloxacin Oritavancin Vancomycin Daptomycin Linezolid Tigecycline Doxycycline Ciprofloxacin
1 0.25 0.5 4 N8 N32 4 0.06 1 0.25 0.5 0.12 0.25 ≤0.12 ≤0.12 4 ≤0.06 0.03 0.5 0.06 1 ≤0.015 ≤0.12 ≤0.03 0.03 0.5 0.25 1 0.03 ≤0.12 ≤0.03 0.03 1 1 2 0.12 8 1 0.008 0.5 1 2 0.12 ≤0.12 N16 0.008 N32 1 2 0.12 2 N16
1 0.25 1 8 N8 N32 N16 0.12 1 0.25 1 0.25 1 4 N8 N32 16 0.25 0.5 0.12 2 0.06 ≤0.12 ≤0.03 0.12 0.5 0.25 2 0.06 N64 32 0.06 2 2 4 0.12 16 N16 0.015 1 2 4 0.12 8 N16 0.12 N32 2 4 0.25 8 N16
≤0.12–2 0.06–1 ≤0.12–16 ≤0.12 to N8 ≤0.12 to N8 ≤0.03 to N32 ≤0.06 to N16 0.008–0.5 ≤0.12–2 ≤0.03–0.5 0.25–4 ≤0.03–1 ≤0.12–32 ≤0.12 to N8 ≤0.12 to N8 ≤0.03 to N32 ≤0.06 to N16 ≤0.0005–0.5 0.25–1 ≤0.03–0.12 0.25–4 ≤0.015–0.25 ≤0.12 to N64 ≤0.03 to N32 0.001–0.25 0.25–1 ≤0.03–0.5 0.25–2 ≤0.015–1 ≤0.12 to N64 ≤0.03 to N32 ≤0.004–0.5 0.25–4 ≤0.03–4 0.5–4 ≤0.03–0.5 ≤0.12–32 0.25 to N16 ≤0.004–0.03 0.25–2 ≤0.03–4 1–4 ≤0.03–0.25 ≤0.12–16 0.25 to N16 ≤0.004–0.5 32 to N32 0.25–2 1–4 0.06–0.5 ≤0.12–16 N16
100 NA 96.5 15.3 15.3 6.0 4.7 NA 100 100 100 NA 94.8 82.4 81.6 49.3 70.6 99.2j 100 100 98.5k 100 99.2 94.7 100 100 100 100 99.4l 83.3 69.9 98.7m 100 100 89.4 99.3n 38.5 67.4 NA 100 100 83.9 NA 86.2 11.8 NA 0 100 81.8 NA 77.3 0
NA 1.2 0 0 1.2 NA 0 NA 4.4 2.2 0.7 11.0 0 0 0.7 4.5 0 10.6
0 NA 2.3 84.7 84.7 94.0 94.1 NA 0 0 NA 0.8 17.6 16.2 50.0 18.4 0.8 5.3 16.0 25.6 0 0 0.7 19.4 28.6 NA 0 0 NA 8.0 88.2 NA 100 0 NA 9.1 100
42.1 4.0 NA 0 16.1 NA 5.8 0 NA 0 18.2 NA 13.6 0
SXT = trimethoprim-sulfamethoxazole; NA = currently MIC breakpoints are not available. a MDR, defined as resistance to 3 or more classes of antimicrobial agents (β-lactam, glycopeptide, macrolide, lincosamide, folate synthesis inhibitor, fluoroquinolone, tetracycline, and glycylcycline). spa typing identified 156 CA-MRSA and 245 HA-MRSA; 26 isolates of MRSA demonstrated unique spa types and could not be assigned to either the CA-MRSA or the HAMRSA group. b Oritavancin US FDA breakpoints: S. aureus, ≤0.12 μg/mL (susceptible); Streptococcus spp. other than S. pneumoniae, ≤0.25 μg/mL (susceptible); and E. faecalis (vancomycin-susceptible), ≤0.12 μg/mL (susceptible). c Tigecycline US FDA breakpoints: S. aureus, ≤0.5 μg/mL (susceptible); Streptococcus spp. other than S. pneumoniae, ≤0.25 μg/mL (susceptible); and E. faecalis (vancomycin-susceptible), ≤0.25 μg/mL (susceptible). d Four isolates of MSSA were non-susceptible to oritavancin (MIC, 0.25 μg/mL) and were non-MDR isolates. e -, MIC breakpoints for intermediate and resistant categories have not been not defined by CLSI (2014) or US FDA. An isolate with an MIC exceeding the susceptible breakpoint is defined as non-susceptible. f Three isolates of MSSA were non-susceptible to tigecycline (MIC, N0.5 μg/mL). g Two isolates of MRSA were non-susceptible to oritavancin (MIC, 0.25 μg/mL) and were MDR isolates; 1 isolate was CA-MRSA and 1 isolate was HA-MRSA. h One isolate of MRSA (CA-MRSA) was non-susceptible to daptomycin (MIC, N1 μg/mL). i Seven isolates of MRSA (all HA-MRSA) were non-susceptible to tigecycline (MIC, N0.5 μg/mL). j One isolate of MSSA was non-susceptible to oritavancin (MIC, 0.5 μg/mL). k Two isolates of S. pyogenes were non-susceptible to linezolid (MIC, N2 μg/mL). l One isolate of S. agalactiae was non-susceptible to tigecycline (MIC, N0.25 μg/mL). m Four isolates of E. faecalis were non-susceptible to oritavancin (MIC, N0.25 μg/mL). n Two isolates of E. faecalis were non-susceptible to tigecycline (MIC, N0.25 μg/mL). o All 22 isolates of vancomycin-resistant E. faecium were vanA-positive by PCR testing.
Please cite this article as: Karlowsky JA, et al, In vitro activity of oritavancin against Gram-positive pathogens isolated in Canadian hospital laboratories from 2011 to 2013, Diagn Microbiol Infect Dis (2014), http://dx.doi.org/10.1016/j.diagmicrobio.2014.09.003
JA. Karlowsky et al. / Diagnostic Microbiology and Infectious Disease xxx (2014) xxx–xxx
5
Fig. 1. MIC distributions for oritavancin, daptomycin, and vancomycin for (A) MRSA and (B) S. pyogenes.
Vancouver, British Columbia (Dr D. Roscoe); University of Alberta Hospital, Edmonton, Alberta (Drs R. Rennie and J. Fuller); Royal University Hospital, Saskatoon, Saskatchewan (Dr J. Blondeau); Health Sciences Centre, Winnipeg, Manitoba (Drs D. Hoban/G. Zhanel); London Health Sciences Centre, London, Ontario (Dr Z. Hussain); University Health Network and Mount Sinai Hospital, Toronto, Ontario (Dr S. Poutanen); St. Michael's Hospital, Toronto, Ontario (Dr L. Matukas); Children's Hospital of Eastern Ontario, Ottawa, Ontario (Dr F. Chan); The Ottawa Hospital, Ottawa, Ontario (Dr M. Desjardins); Royal Victoria Hospital, Montreal, Quebec (Dr V. Loo); Montreal General Hospital, Montreal, Quebec (Dr V. Loo); Hôpital Maisonneuve-Rosemont, Montreal, Quebec (Dr M. Laverdière); Centre Hospitalier Régional de Trois Rivières, Pavillon Sainte Marie, Trois Rivières, Quebec (Dr M. Goyette); Hôpital de la Cité-de-la-Santé, Laval, Quebec (Dr M. Bergevin); L’Hôtel-Dieu de Quebec, Quebec City, Quebec (Dr R. Pelletier); South-East Regional Health Authority, Moncton, New Brunswick (Dr M. Kuhn); and Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia (Dr R. Davidson).
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Please cite this article as: Karlowsky JA, et al, In vitro activity of oritavancin against Gram-positive pathogens isolated in Canadian hospital laboratories from 2011 to 2013, Diagn Microbiol Infect Dis (2014), http://dx.doi.org/10.1016/j.diagmicrobio.2014.09.003
