Oritavancin in vitro activity against contemporary Staphylococcus aureus isolates responsible for invasive community- and healthcare-associated infections among patients in the United States (2013–2014)

Diagnostic Microbiology and Infectious Disease xxx (2016) xxx–xxx

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Oritavancin in vitro activity against contemporary Staphylococcus aureus isolates responsible for invasive community- and healthcare-associated infections among patients in the United States (2013–2014) Leonard R. Duncan, Helio S. Sader, Robert K. Flamm, Ronald N. Jones, Rodrigo E. Mendes ⁎ JMI Laboratories, North Liberty, IA, USA

a r t i c l e

i n f o

Article history: Received 2 June 2016 Received in revised form 22 July 2016 Accepted 23 July 2016 Available online xxxx Keywords: MRSA ABSSSI Lipoglycopeptide

a b s t r a c t Oritavancin has been approved in the United States and European Union for the treatment of acute bacterial skin and skin structure infections caused by several Gram-positive pathogens including Staphylococcus aureus. In this study, the in vitro activity of oritavancin and comparator agents was assessed against 1008 isolates of contemporary invasive community- or healthcare-associated S. aureus (790 and 218 isolates, respectively). All sampled contemporary (2013–2014) S. aureus isolates were susceptible at ≤0.12 μg/mL to oritavancin (MIC50/90 values, 0.03/0.06 μg/mL), regardless of origin or susceptibility phenotype. © 2016 Elsevier Inc. All rights reserved.

Invasive Staphylococcus aureus infections are associated with significant morbidity and mortality (Dantes et al., 2013; Keynan and Rubinstein, 2013). Methicillin-resistant S. aureus (MRSA) infections are of particular concern, because they originate in both healthcare and community settings and can prove challenging for empiric therapy (Holland et al., 2014; Keynan and Rubinstein, 2013). Dantes et al. (2013) estimated that approximately 80,000 invasive MRSA infections occurred in the United States in 2011, with the majority being bloodstream infections (BSI). Vancomycin and daptomycin remain the front-line therapies for treatment of invasive MRSA infections (Holland et al., 2014; Keynan and Rubinstein, 2013). Oritavancin is a semisynthetic lipoglycopeptide derived from a series of naturally occurring vancomycin-like molecule, chloroeremomycin (Mendes et al., 2012). Oritavancin recently joined the anti–Gram-positive armamentarium with approvals from the US Food and Drug Administration (Orbactiv™, 2016) and European Medicines Agency (EMA, 2015) for the treatment for adults with acute bacterial skin and skin structure infections (ABSSSI). Oritavancin may be an attractive option for the treatment of serious infections in an outpatient setting (Lodise et al., 2016; Mitra et al., 2015; Tice, 2012), because it exhibits an extended terminal elimination half-life (Rubino et al., 2015) that allows for administration of a single intravenous dose in the treatment of ABSSSI. A previous study (Mendes et al., 2014) reported that oritavancin exhibited excellent in vitro activity against S. aureus BSI isolates (2008– 2012) collected in US and European hospitals. Here we extend those ⁎ Corresponding author: Tel.: +1-319-665-3370; fax: +1-319-665-3371. E-mail address: [email protected] (R.E. Mendes).

previous results by assessing oritavancin in vitro activity against more recent S. aureusUS BSI isolates (2013–2014) and investigate whether the origin of these isolates (healthcare-associated [HA] or communityassociated [CA]; David et al., 2008) influences oritavancin activity. This HA/CA MRSA distinction can be clinically relevant, because the 2 categories of isolates often differ in various aspects of morbidity/mortality and in their susceptibilities to non–β-lactam agents (Dantes et al., 2013; David et al., 2008; Keynan and Rubinstein, 2013). During the oritavancin resistance surveillance program (2013– 2014), a total of 1110S. aureus isolates were recovered from blood culture specimens. A total of 29 medical centers located in 22 states/25 cities in the 9US Census Bureau divisions (2–4 sites per region) contributed isolates (65–167 isolates per region).The isolates were identified by the participating laboratory, and these identifications were confirmed by the monitoring reference laboratory (JMI Laboratories, North Liberty, IA, USA) using standard algorithms with supporting data from Matrix-Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry analysis (Bruker Daltonics, Bremen, Germany). Susceptibility of S. aureus isolates to oritavancin and comparator agents was determined by the reference broth microdilution method following the Clinical and Laboratory Standards Institute (CLSI) guidelines (CLSI, 2015). Susceptibility testing was performed using panels manufactured by Thermo Fisher Scientific (Cleveland, OH, USA) that provide results equivalent to the CLSI-approved broth microdilution method supplemented with 0.002% polysorbate-80. Appropriate bacterial inoculum densities were confirmed by colony counts. Validation of the MIC values was performed by concurrent testing of CLSIrecommended quality control (QC) reference strains (S. aureus ATCC 29213 and Enterococcus faecalis ATCC 29212). All QC results were within

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Please cite this article as: Duncan LR, et al, Oritavancin in vitro activity against contemporary Staphylococcus aureus isolates responsible for invasive community- and healthcare-associated infections ..., Diagn Microbiol Infect Dis (2016), http://dx.doi.org/10.1016/j.diagmicrobio.2016.07.025

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L.R. Duncan et al. / Diagnostic Microbiology and Infectious Disease xxx (2016) xxx–xxx

published acceptable ranges (CLSI, 2016). MIC interpretations were based on CLSI susceptible breakpoint criteria (CLSI, 2016), which for oritavacin are equivalent to those of the FDA and European Committee on Antimicrobial Susceptibility Testing for S. aureus (≤0.12 μg/mL) (EUCAST, 2016; Orbactiv™, 2016). MRSA isolates that were resistant to 3 or more relevant drug classes (in addition to β-lactam agents) were defined as multidrug resistant (MDR). Briefly, an MRSA isolate was categorized as MDR if it had, in addition to oxacillin, a resistance phenotype (nonsusceptibility to daptomycin was applied) to 3 or more of the following drug classes (CLSI criteria): macrolides (erythromycin, ≥8 μg/mL), fluoroquinolones (levofloxacin, ≥4 μg/mL), lincosamides (clindamycin, ≥4 μg/mL [constitutive resistance only]), oxazolidinones (linezolid, ≥8 μg/mL), tetracyclines (tetracycline hydrochloride, ≥16 μg/mL), folate pathway inhibitors (trimethoprim-sulfamethoxazole [TMP-SMX], ≥4/76 μg/mL), or lipopeptides (daptomycin, ≥2 μg/mL[resistance to glycopeptides was not observed]). A large number of different criteria have been utilized to categorize MRSA infections as CA or HA (reviewed by David et al., 2008). For example, the Centers for Disease Control and Prevention considers an MRSA infection to be HA hospitalonset (HAHO) if the isolate is cultured from a specimen collected N48 hours after hospitalization. If an isolate is cultured from a specimen collected ≤48 hours after hospitalization: 1) the infection is characterized as HA communityonset (HACO) if the MRSA is recovered from a patient who satisfies the criteria for 1 or more “healthcare risk factors”—e.g., hospitalization during the previous year; or 2) the infection is categorized as CA if the patient lacks all of the associated healthcare risk factors (Kreisel et al., 2010; Morrison et al., 2006). Alternatively, various phenotypic and/or genotypic criteria (e.g., an MDR phenotype or the presence of SCCmecIV) have also been used to categorize MRSA isolates as CA and HA (David et al., 2008). Here, we used 2 different methods to categorize isolates as HAHO or CA. First, all isolates (regardless of methicillin-susceptible Staphylococcus aureus [MSSA] or MRSA phenotype) were categorized as CA when recovered from a patient specimen submitted to the local clinical laboratory ≤48 hours after hospital admission. Limited patient demographic information (e.g., healthcare risk factors) did not allow further HACO and CA infections, herein all categorized as CA. Incontrast, isolates recovered from a specimen submitted N48 hours after hospital admission were considered HAHO, herein defined as HA. By these criteria, 790 isolates were categorized as CA and 218 as HA (Tables 1 and 2). Time-ofisolation data were missing for the remaining 102 isolates; as such, they were omitted from all further analysis. Secondly, an MRSA isolate was categorized as HA if it exhibited an MDR phenotype and as CA if it exhibited a non-MDR phenotype (Table 3) (David et al., 2008), irrespective of time of isolation. All tested S. aureus isolates were determined to be susceptible to oritavancin, with MIC50/90 values of 0.03/0.06 μg/mL, regardless of oxacillin susceptibility pattern, CA/HA assignment (Tables 1 and 2), or MDR phenotype (Tables 1 and 3). These S. aureus MIC50/90 values are identical to those recently reported (Biedenbach et al., 2015). Comparator agents,

including vancomycin (MIC50/90, 1/1 μg/mL; 100% susceptible), daptomycin (MIC50/90, 0.25/0.5 μg/mL; 97.8–100% susceptible), and linezolid (MIC50/90, 1/1 μg/mL; 100% susceptible) that are frequently used to treat MRSA BSI were also active against all or nearly all analyzed isolates (Tables 2 and 3). However, oritavancin MIC50 and MIC90 results were 8fold lower than those of daptomycin and 16- to 32-fold lower than those of vancomycin or linezolid (Tables 2 and 3). Moreover, 4 isolates showed daptomycin MIC results of 2 to 4 μg/mL (i.e., nonsusceptible), against which oritavancin MIC values were 0.03 to 0.06 μg/mL (data not shown). Certain additional comparator agents, including tetracycline and TMP-SMX, demonstrated acceptable (i.e., N90% susceptible rates) antimicrobial coverage against most subsets (Tables 2 and 3). One notable exception was a modestly lower susceptibility rate of MDR isolates to TMP-SMX (87.8% susceptible; Table 3). Erythromycin showed suboptimal antimicrobial activity against MSSA (60.4–70.1% susceptible), and very limited coverage was observed against MRSA subsets (2.2–18.8% susceptible; Tables 2 and 3). Levofloxacin was active against CA-MSSA (MIC50/90, 0.25/0.5 μg/mL; 92.0% susceptible; Table 2). Other subsets of S. aureus demonstrated widely variable susceptibility rates to levofloxacin (0.7–84.2% susceptible; Tables 2 and 3). Finally, although MSSA isolates were mostly susceptible to clindamycin (91.1–95.6%), MRSA CA/HA subgroups categorized based on the 48-hour isolation criterion demonstrated poor coverage (61.5– 69.8% susceptible, inducible resistance not included in both groups; Table 2). However, a different pattern emerged when MRSA isolates were segregated based on the absence or presence of an MDR phenotype, which is another criterion that has been used to differentiate between CA- and HA-isolates (David et al., 2008); the non-MDR MRSA (approximately two-thirds of the tested MRSA isolates) was highly susceptible to clindamycin (97.0%; inducible resistance not included), whereas MRSA isolates with an MDR phenotype (approximately onethird of the tested MRSA isolates) demonstrated a markedly lower susceptibility to clindamycin (10.8%) (Table 3). These results might be explained by the fact that non-MDR MRSA consists largely of USA300 isolates, which in general are erythromycinresistant (intrinsic msrA) and clindamycinsusceptible (David and Daum, 2010; David et al., 2008; Maree et al., 2007), although some isolates can show clindamycin resistance because of acquisition of erm(A) and erm(C) (Tenover and Goering, 2009). Limitations of this study were the lack of additional comparator agents (e.g., telavancin, dalbavancin, and ceftaroline) with similar indications and the lack of demographic information to further identify HACO S. aureus bacteremia (Dantes et al., 2013). Its presence within CA-MRSA bacteremia can be inferred by the high prevalence (32.6%; 94/288) of MDR isolates within the CA population (48-hour criterion; Table 1). In addition, it can be noted that CA-MRSA and HA-MRSA displayed very similar susceptibility profiles, including those against erythromycin, clindamycin, and levofloxacin (48-hour criterion; Table 2). Data also indicate that a great proportion (61.5%; 72/117;

Table 1 Antimicrobial activity and MIC distribution of oritavancin against S. aureus responsible for invasive CA and HA infections among patients in the United States (2013–2014). MIC (μg/mL) S. aureus

All MSSA MRSA MDR Non-MDR a

Number (cumulative %) inhibited at oritavancin MIC (μg/mL)

Origin (no. tested) CAa (790) HAa (218) CA (502) HA (101) CA (288) HA (117) CA (94) HA (45) CA (194) HA (72)

50%

90%

≤0.004

0.008

0.015

0.03

0.06

0.12

0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03

0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06

1 (0.1) 1 (0.5) 0 (0.0) 0 (0.0) 1 (0.3) 1 (0.9) 1 (1.1) 0 (0.0) 0 (0.0) 1 (1.4)

26 (3.4) 6 (3.2) 18 (3.6) 1 (1.0) 8 (3.1) 5 (5.1) 6 (7.4) 1 (2.2) 2 (1.0) 4 (6.9)

234 (33.0) 63 (32.1) 138 (31.1) 28 (28.7) 96 (36.5) 35 (35.0) 28 (37.2) 10 (24.4) 68 (36.1) 25 (41.7)

315 (72.9) 89 (72.9) 208 (72.5) 43 (71.3) 107 (73.6) 46 (74.4) 41 (80.9) 21 (71.1) 66 (70.1) 25 (76.4)

181 (95.8) 53 (97.2) 119 (96.2) 26 (97.0) 62 (95.1) 27 (97.4) 13 (94.7) 13 (100.0) 49 (95.4) 14 (95.8)

33 (100.0) 6 (100.0) 19 (100.0) 3 (100.0) 14 (100.0) 3 (100.0) 5 (100.0) 9 (100.0) 3 (100.0)

CA and HA designations were based on time of culture (48-hour isolation criterion).

Please cite this article as: Duncan LR, et al, Oritavancin in vitro activity against contemporary Staphylococcus aureus isolates responsible for invasive community- and healthcare-associated infections ..., Diagn Microbiol Infect Dis (2016), http://dx.doi.org/10.1016/j.diagmicrobio.2016.07.025

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Table 2 Antimicrobial activity of oritavancin and comparator agents against MSSA and MRSA isolates responsible for invasive CA and HA infections among patients in the United States (2013– 2014). CAa (790 isolates)

HAa (218 isolates)

MSSA (502)

MRSA (288) %Sb

MIC (μg/mL) Antimicrobial agent

50%

90%

Oritavancin Vancomycin Daptomycin Linezolid Erythromycin Clindamycin Levofloxacin Tetracycline TMP-SMX

0.03 1 0.25 1 0.25 ≤0.25 0.25 ≤0.5 ≤0.5

0.06 1 0.5 1 N16 ≤0.25 0.5 ≤0.5 ≤0.5

MSSA (101) %Sb

MIC (μg/mL)

100.0 100.0 99.8 100.0 70.1 95.6 92.0 97.8 99.6

50%

90%

0.03 1 0.25 1 N16 ≤0.25 4 ≤0.5 ≤0.5

0.06 1 0.5 1 N16 N2 N4 1 ≤0.5

100.0 100.0 98.6 100.0 13.9 69.8 29.2 95.8 95.1

MRSA (117)

MIC (μg/mL) 50%

90%

0.03 1 0.25 1 0.25 ≤0.25 0.25 ≤0.5 ≤0.5

0.06 1 0.5 1 N16 ≤0.25 4 ≤0.5 ≤0.5

%Sb

100.0 100.0 100.0 100.0 60.4 91.1 84.2 96.0 99.0

%Sb

MIC (μg/mL) 50%

90%

0.03 1 0.25 1 N16 ≤0.25 N4 ≤0.5 ≤0.5

0.06 1 0.5 1 N16 N2 N4 2 ≤0.5

100.0 100.0 100.0 100.0 11.1 61.5 20.5 95.7 94.0

MSSA = methicillin‐susceptible S. aureus; MRSA = methicillin‐resistant S. aureus; TMP‐SMX=trimethoprim‐sulfamethoxazole. a CA and HA designations were based on time of culture (48-hour isolation criterion). b Susceptible (S) breakpoint criteria for oritavancin according to CLSI (2016) and EUCAST (2016) (≤0.12 μg/mL for S). Breakpoint criteria for comparator agents were those from the CLSI (CLSI, 2016). Clindamycin susceptibility rates include inducible resistance phenotype.

Table 1) of historically community-based clones (e.g., USA300; nonMDR) have invaded the healthcare setting and are now successful nosocomial pathogens, a phenomenon that has been documented by several studies (Jenkins et al., 2009; Klevens et al., 2007; Popovich et al., 2008; Seybold et al., 2006). These data suggest that the typical 48-hour criterion used to assign CA or HA status may no longer reliably differentiate between historically CA (e.g., USA300) and hospital-associated (e.g., USA100) clones. The observation that oritavancin displayed potent in vitro activity against a contemporary collection of S. aureus isolates causing invasive infections in US hospitals is fully consistent with our previous report that analyzed US and European S. aureus blood culture isolates collected between 2008 and 2012 (Mendes et al., 2014);in both studies, oritavancin exhibited excellent activity with MIC50/90 values of 0.03/ 0.06 μg/mL. In conclusion, oritavancin displayed potent activity against S. aureus BSI isolates that were characterized as CA or HA by 2 different criteria.Although vancomycin, daptomycin, linezolid, and tetracycline also demonstrated good in vitro coverage against all isolate subsets analyzed, the in vitro potency of oritavancin was consistently greater (8-

Table 3 Antimicrobial activity of oritavancin and comparator agents against HA and CA (based on MDR phenotype) MRSA isolates responsible for bacteremia in patients in the United States (2013–2014). MRSA (405) CAa (non-MDR) (266) MIC (μg/ml) Antimicrobial agent

50%

90%

Oritavancin Vancomycin Daptomycin Linezolid Erythromycin Clindamycin Levofloxacin Tetracycline TMP-SMX

0.03 1 0.25 1 N16 ≤0.25 4 ≤0.5 ≤0.5

0.06 1 0.5 1 N16 ≤0.25 N4 ≤0.5 ≤0.5

HAa (MDR) (139) %S

b

100.0 100.0 99.6 100.0 18.8 97.0 40.2 96.6 98.5

MIC (μg/ml) 50%

90%

0.03 1 0.25 1 N16 N2 N4 ≤0.5 ≤0.5

0.06 1 0.5 1 N16 N2 N4 2 N4

%Sb

100.0 100.0 97.8 100.0 2.2 10.8 0.7 94.2 87.8

MDR=multidrug‐resistant, defined as MRSA (methicillin [oxacillin]‐resistant) resistant to three or more drug classes in addition to β‐lactam agents. TMP‐SMX=trimethoprim‐ sulfamethoxazole. a CA and HA designations were based on MDR/non-MDR phenotype. b Susceptible (S) breakpoint criteria for oritavancin according to CLSI (2016) and EUCAST (2016) (≤0.12 μg/mL for S). Breakpoint criteria for comparator agents were those from CLSI (CLSI, 2016). Clindamycin susceptibility rates include inducible resistance phenotype.

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