Diagnostic Microbiology and Infectious Disease xxx (2014) xxx–xxx

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Antimicrobial activity of ceftaroline combined with avibactam tested against bacterial organisms isolated from acute bacterial skin and skin structure infections in United States medical centers (2010–2012) Robert K. Flamm ⁎, David J. Farrell, Helio S. Sader, Ronald N. Jones JMI Laboratories, North Liberty, IA, USA

a r t i c l e

i n f o

Article history: Received 10 October 2013 Received in revised form 2 January 2014 Accepted 5 January 2014 Available online xxxx Keywords: ABSSSI Staphylococcus aureus Enterobacteriaceae

a b s t r a c t Ceftaroline-avibactam and comparator agents were tested against clinical isolates collected at 174 medical centers from patients with acute bacterial skin and skin structure infection (ABSSSI) in the United States (USA) during 2010–2012. Isolates were processed at the medical centers and forwarded to a central laboratory for confirmatory identification and susceptibility testing using reference methods. Ceftarolineavibactam was highly active against methicillin-susceptible (MIC50/90, 0.25/0.25 μg/mL) and methicillinresistant Staphylococcus aureus (MRSA; MIC50/90, 0.5/1 μg/mL). Vancomycin, tigecycline, daptomycin, and linezolid were also active (N99.9% susceptible) against MRSA (51.4% of S. aureus), but activity against MRSA was decreased for erythromycin, levofloxacin, and clindamycin (10.8, 40.3, and 81.9% susceptible, respectively). β-Hemolytic streptococci were highly susceptible to β-lactam antimicrobials, including ceftaroline-avibactam (MIC50/90, ≤0.03/≤0.03 μg/mL). Ceftaroline-avibactam was very active against Escherichia coli and Klebsiella pneumoniae (MIC50/90, 0.03/0.06 and 0.06/0.25 μg/mL, respectively) including extended-spectrum β-lactamase (ESBL) screen–positive phenotypes (MIC50/90, 0.06/0.12 and 0.12/1 μg/mL, respectively). Susceptibility of ESBL screen–positive E. coli and K. pneumoniae was 100.0/97.9% for tigecycline and 99.2/56.1% for meropenem, respectively. Susceptibility to other agents for ESBL screen–positive E. coli and K. pneumoniae was decreased. Ceftaroline-avibactam exhibited a broad-spectrum of in vitro activity against isolates from patients in the USA with ABSSSI including MRSA, β-hemolytic streptococci, E. coli, and K. pneumoniae as well as ESBL screen–positive phenotype isolates and merits further study in clinical indications where these resistant organisms may be a concern. © 2014 Elsevier Inc. All rights reserved.

1. Introduction Acute bacterial skin and skin structure infections (ABSSSI) are common infections representing approximately 10% of hospital admissions (Dryden, 2010; Giordano et al., 2007; Stevens et al., 2005). ABSSSI can range from mild infections to serious and even lifethreatening infections (Dryden, 2010; Stevens et al., 2005). The most common bacterial causes of ABSSSI include Staphylococcus aureus and β-hemolytic streptococci (Dryden, 2010; Moet et al., 2007; Sader et al., 2013a; Stevens et al., 2005). In hospitals, S. aureus predominates as the major cause of ABSSSI (Dryden, 2010). Gram-negative bacteria, primarily Enterobacteriaceae and non-fermentative bacteria such as Pseudomonas aeruginosa may also cause ABSSSI (Dryden, 2010; Moet et al., 2007; Stevens et al., 2005). The emergence of resistance to multiple classes of antimicrobials in methicillin-resistant S. aureus and Gram-negative bacilli, especially in immunocompromised patients,

⁎ Corresponding author. Tel.: +1-319-665-3370; fax: +1-319-665-3371. E-mail address: robert-fl[email protected] (R.K. Flamm).

has added complexity to choosing appropriate initial therapy (Dryden, 2010; Moet et al., 2007). Ceftaroline-avibactam is a combination of the antibacterial ceftaroline and the novel non-β-lactam β-lactamase inhibitor avibactam (Castanheira et al., 2012; Goldstein et al., 2013; Livermore et al., 2012; Mushtaq et al., 2010; Sader et al., 2013b; Wiskirchen et al., 2011). Avibactam does not have intrinsic antibacterial activity; however, it does inhibit Class A and C and some Class D β-lactamases (Ehmann et al., 2012). When avibactam is combined with an active βlactam agent, such as ceftaroline, its ability to inhibit β-lactamases protects the activity of the β-lactam from β-lactamase degradation (Castanheira et al., 2012; Goldstein et al., 2013; Livermore et al., 2012; Mushtaq et al., 2010; Sader et al., 2013b; Wiskirchen et al., 2011). Ceftaroline fosamil, the prodrug of active ceftaroline, is a cephalosporin approved by the United States Food and Drug Administration (USA-FDA) and European Medicines Agency. Ceftaroline has broadspectrum bactericidal in vitro activity against resistant Gram-positive organisms, including methicillin-resistant S. aureus (MRSA) and multidrug-resistant (MDR) strains of Streptococcus pneumoniae (Flamm et al., 2012; Sader et al., 2013a; Saravolatz et al., 2011; Teflaro® Package Insert, 2012; Zinforo TM Package Insert, 2012).

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Please cite this article as: Flamm RK, et al, Antimicrobial activity of ceftaroline combined with avibactam tested against bacterial organisms isolated from acute bacterial ski..., Diagn Microbiol Infect Dis (2014), http://dx.doi.org/10.1016/j.diagmicrobio.2014.01.003

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R.K. Flamm et al. / Diagnostic Microbiology and Infectious Disease xxx (2014) xxx–xxx

Ceftaroline also has activity against many Enterobacteriaceae; however, it is not active against extended-spectrum β-lactamase (ESBL) phenotype strains (Flamm et al., 2012; Sader et al., 2013a; Saravolatz et al., 2011). Adding avibactam to ceftaroline expands the activity to include ESBL and cephalosporinase phenotype strains (Castanheira et al., 2012; Flamm et al., 2012; Livermore et al., 2012; Mushtaq et al., 2010; Sader et al., 2013a; Wiskirchen et al., 2011). In an effort to better understand the activity of ceftarolineavibactam when tested against ABSSSI pathogens in the USA and to provide information on the baseline level of activity for this agent, a surveillance program to assess ceftaroline-avibactam and comparator agents was performed. Herein, we report the results for a 3-year period (2010–2012) describing the activities against 14,504 isolates from documented ABSSSI collected from patients in 174 different medical centers.

2. Materials and methods 2.1. Organism collection Organisms were collected from patients with ABSSSI (1 per patient episode). A total of 14,504 were tested against ceftaroline-avibactam as listed in Table 1. The study protocol predetermined the target numbers of strains for each of the requested bacterial species that sites were to collect. One hundred seventy-four different medical centers representing all 9 USA census bureau regions submitted isolates during the time period 2010–2012; 65 medical centers (5–10 medical centers per region, 37 states in 2010), 67 medical centers (5– 12 medical centers per region, 37 states in 2011), and 163 medical centers (7–27 medical centers per region, 47 states in 2012). Isolates were sent to a central reference laboratory (JMI Laboratories, North Liberty, IA, USA) for confirmatory identification and reference susceptibility testing.

2.2. Susceptibility testing Susceptibility testing was performed for ceftaroline-avibactam and selected comparator agents by reference broth microdilution methods as described by the CLSI document M07-A9 (CLSI, 2012). Avibactam was tested at a fixed concentration of 4 μg/mL. CLSI interpretive criteria were applied per M100-S23 (CLSI, 2013) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) interpretations were based on EUCAST breakpoint table v.3.0, January 2013 (EUCAST, 2013). USA-FDA breakpoint criteria for tigecycline were applied, when available (Tygacil® Package Insert, 2012). The susceptibility test medium used was cation-adjusted MuellerHinton broth; however, for β-hemolytic streptococci, supplementation with 2.5–5% lysed horse blood was done (CLSI, 2012). Quality control (QC) strains were tested concurrently and included S. aureus ATCC 29213, Enterococcus faecalis ATCC 29212, S. pneumoniae ATCC 49619, and Escherichia coli ATCC 25922 and 35218. All QC results were within published CLSI ranges (CLSI, 2013). E. coli and Klebsiella spp. isolates were identified as phenotypically positive by a screening test for ESBL production when ceftriaxone or ceftazidime or aztreonam MIC values were ≥2 μg/mL (CLSI, 2013). Although an ESBL confirmation test was not performed and other β-lactamases, such as AmpC and K. pneumoniae carbapenemases (KPC), may also produce an “ESBL-phenotype”, these strains were grouped together because they usually demonstrate resistance to various broad-spectrum βlactam compounds. As part of a specific program to examine the diversity of β-lactamases found in Gram-negative bacteria in the USA during 2012, Gram-negative bacteria that occurred in skin and skin structure infections collected during 2012 that were positive by the screening method for ESBL phenotype were evaluated further for the presence of broad-spectrum β-lactamases as previously described using a commercial microarray-based assay Check-MDR CT101 kit (Check-points, Wageningen, Netherlands) (Castanheira et al., 2013; Castanheira et al., 2014). This kit has the capability to detect CTX-M

Table 1 Summary of ceftaroline-avibactam activity tested against bacterial isolates from patients with acute bacterial skin and skin structure infections from the USA (2010–2012). Organism

No. of isolates

S. aureus MSSA MRSA CoNS β-hemolytic streptococci Streptococcus pyogenes Streptococcus agalactiae Other streptococci Viridans group streptococci E. coli ESBL screen–negative phenotype ESBL screen–positive phenotype Meropenem-susceptible (MIC, ≤1 μg/mL) Meropenem-non-susceptible (MIC, ≥2 μg/mL) K. pneumoniae ESBL screen–negative phenotype ESBL screen–positive phenotype Meropenem-susceptible (MIC, ≤1 mg/L) Meropenem-non-susceptible (MIC, ≥2 μg/mL) K. oxytoca Enterobacter spp. Citrobacter spp. P. mirabilis M. morganii S. marcescens

8422 4089 4333 622 1523 706 671 146 411 923 805 118 922 1

No. of isolates (cumulative %) inhibited at ceftaroline-avibactam MIC (μg/mL): ≤0.03

0.06

0.12

0.25

0.5

1

2

4

MIC50

MIC90

5 (0.1) 5 (0.1) – 52 (8.4) 1,512 (99.3) 706 (100.0) 669 (99.7) 137 (93.8) 353 (85.9) 687 (74.4) 635 (78.9) 52 (44.1) 687 (74.5)

35 (0.5) 35 (1.0) – 133 (29.7) 11 (100.0) – 2 (100.0) 9 (100.0) 37 (94.9) 201 (96.2) 160 (98.8) 41 (78.8) 200 (96.2)

622 (7.9) 620 (16.1) 2 (0.0) 101 (46.0) – – –

3438 (48.7) 3328 (97.5) 110 (2.6) 252 (86.5) – – –

3431 (89.4) 101 (100.0) 3330 (79.4) 77 (98.9) – – –

843 (99.4) – 843 (98.9) 6 (99.8) – – –

48 (100.0) – 48 (100.0) 1 (100.0) – – –

– – –

6 (97.8) 3 (99.6) – 3 (96.6) 3 (99.6)

6 (99.3) 4 (100.0) – 4 (100.0) 4 (100.0)

1 0.25 1 0.5 ≤0.03 ≤0.03 ≤0.03 ≤0.03 0.06 0.06 0.06 0.12 0.06

–

641 543 98 598

146 (22.8) 139 (25.6) 7 (7.1) 145 (24.2)

43

1 (2.3)

281 599 208 413 239 222

149 (53.0) 65 (10.9) 59 (28.4) 49 (11.9) 137 (57.3) 1 (0.5)

1 (100.0) 319 (72.5) 305 (81.8) 14 (21.4) 319 (77.6) 0 (2.3) 99 (88.3) 172 (39.6) 107 (79.8) 244 (70.9) 66 (84.9) 1 (0.9)

6 (96.4) 28 (99.2) 10 (100.0) 18 (94.1) 28 (99.2) – 94 65 29 86

– – – – –

– – – – –

–

–

–

–

–

26 (98.4) 8 (100.0) 18 (89.8) 13 (100.0)

6 (99.4) – 6 (95.9) –

2 (99.7) – 2 (98.0) –

2 (100.0) – 2 (100.0) –

0.06 0.06 0.12 0.06

0.25 0.12 1 0.12

11 (46.5)

13 (76.7)

6 (90.7)

2 (95.3)

2 (100.0)

0.5

1

6 (98.2) 79 (92.3) 7 (99.0) 14 (99.0) 11 (98.3) 62 (41.0)

4 (99.6) 36 (98.3) 1 (99.5) 2 (99.5) 3 (99.6) 96 (84.2)

1 (100.0) 10 (100.0) 1 (100.0) 2 (100.0) 1 (100.0) 32 (98.6)

– – – – – 1 (99.1)

– – – – – 2 (100.0)

≤0.03 0.12 0.06 0.06 ≤0.03 0.5

– (87.2) (93.7) (51.0) (92.0)

8 (20.9) 22 237 33 102 21 27

3 (100.0) – – – –

0.5 0.25 0.5 0.25 ≤0.03 ≤0.03 ≤0.03 ≤0.03 ≤0.03 ≤0.03 ≤0.03 0.06 ≤ 0.03

(96.1) (79.1) (95.7) (95.6) (93.7) (13.1)

46 26 20 35

– (94.4) (98.5) (71.4) (97.8)

– – –

0.12 0.25 0.12 0.12 0.12 1

Please cite this article as: Flamm RK, et al, Antimicrobial activity of ceftaroline combined with avibactam tested against bacterial organisms isolated from acute bacterial ski..., Diagn Microbiol Infect Dis (2014), http://dx.doi.org/10.1016/j.diagmicrobio.2014.01.003

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Groups 1, 2, 8+25, and 9, TEM wild-type (WT) and ESBL, SHV WT and ESBL, ACC, ACT/MIR, CMYII, DHA, FOX, KPC, and NDM-1. 3. Results 3.1. Ceftaroline-avibactam activity tested against Gram-positive isolates from ABSSSI When tested against 8422 S. aureus, ceftaroline-avibactam was very active with an MIC50 and MIC90 at 0.5 and 1 μg/mL, respectively; 99.4% susceptible at ≤1μg/mL (clinical susceptible breakpoint established by CLSI, EUCAST, and the USA-FDA for ceftaroline alone) (CLSI, 2013; EUCAST, 2013; Teflaro® Package Insert, 2012; Zinforo TM Package Insert, 2012) (Tables 1 and 2). Against 4089 methicillinsusceptible S. aureus (MSSA) isolates, the ceftaroline-avibactam MIC50/90 was 0.25/0.25 μg/mL, 4-fold more active than linezolid and vancomycin (MIC50/90, 1/1 μg/mL) and 16-fold more active than ceftriaxone (MIC50/90, 4/4 μg/mL). The highest ceftaroline-avibactam MIC value among MSSA strains was only 0.5 μg/mL, and 97.5% of strains were inhibited at a ceftaroline-avibactam MIC of ≤0.25 μg/mL (Tables 1 and 2). The MIC50/90 for ceftaroline and ceftarolineavibactam for the staphylococci were identical; avibactam provides no added activity for ceftaroline when tested against these Grampositive organisms. The overall percentage of MRSA across the 3 years was 51.4 (Tables 1 and 2). The ceftaroline-avibactam MIC50 and MIC90 were 0.5 and 1 μg/mL. All MRSA isolates were inhibited at a ceftarolineavibactam MIC of ≤2 μg/mL, and 98.9% of isolates were inhibited at a MIC of ≤1 μg/mL (Table 1). The activity of ceftaroline-avibactam against MRSA was comparable to that of linezolid (MIC50/90, 1/1 μg/ mL; N99.9% susceptible) and vancomycin (MIC50/90, 1/1 μg/mL; 100.0% susceptible; Table 2). MRSA strains exhibited high levels of resistance to erythromycin at 88.0 and 88.6% (CLSI and EUCAST breakpoint criteria, respectively), clindamycin (17.9 and 18.1%), and levofloxacin (57.5%; Table 2). Coagulase-negative staphylococci (CoNS) strains were susceptible to ceftaroline (MIC50/90, 0.25/0.5 μg/mL; Tables 2). A total of 99.8% of isolates were inhibited at a ceftaroline-avibactam MIC of ≤1 μg/mL with the highest ceftaroline MIC value among CoNS strains at only 2 μg/mL (1 isolate; Tables 1 and 2). Ceftarolineavibactam activity against CoNS was comparable to that of daptomycin (MIC50/90, 0.25/0.5μg/mL) and 2-fold more potent than linezolid (MIC50/90, 0.5/1 μg/mL) and 4-fold more potent than vancomycin (MIC50/90, 1/2 μg/mL; Table 2). Ceftaroline-avibactam showed activity comparable to ceftaroline against β-hemolytic streptococci and was similar in activity to penicillin (MIC50/90, ≤0.06/≤0.06 μg/mL), ceftriaxone (MIC50/90, ≤0.06/0.12 μg/mL), and tigecycline (MIC50/90, ≤0.03/≤0.03 μg/mL; Table 2). Decreased susceptibility was observed for tetracycline (51.2 and 50.4% susceptible according to CLSI and EUCAST breakpoint criteria, respectively), erythromycin (68.3% susceptible), and clindamycin (82.3 and 82.7% susceptible; Table 2). Ceftaroline-avibactam and ceftaroline (MIC50/90, ≤0.03/0.06 μg/mL) and tigecycline (MIC50/ 90, ≤0.03/≤0.03 μg/mL) were the most active agents tested against the viridans group streptococci (Table 2). Ceftaroline-avibactam was 16fold more potent than linezolid and vancomycin (MIC90, 1 μg/mL for both) and 8-fold more potent than daptomycin (MIC90, 0.5 μg/mL) against the viridans streptococci (Table 2). 3.2. Ceftaroline-avibactam activity tested against Gram-negative isolates from ABSSSI The overall ESBL screen–positive phenotype for USA E. coli isolates from ABSSSI was 12.8% (Table 1). Ceftaroline-avibactam was active against ESBL screen–positive and ESBL screen–negative phenotype E. coli. The MIC50/90 for ESBL screen–negative strains was ≤0.03/0.06 μg/

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mL and for ESBL screen–positive strains 0.06/0.12 μg/mL (Table 1). All E. coli MIC values for ceftaroline-avibactam were ≤0.5 μg/mL, the susceptible breakpoint for ceftaroline alone published by CLSI (2013), EUCAST (2013) and USA-FDA interpretive criteria. Resistance was high for other cephalosporins against ESBL screen–positive E. coli (ceftriaxone, 94.9/94.9 [CLSI/EUCAST]; ceftazidime, 61.0/72.9); resistance to ceftaroline alone was 96.6/96.6% (CLSI/EUCAST). Additionally, high levels of resistance occurred for ampicillin/sulbactam [69.5% (CLSI, 2013), 86.4% (EUCAST, 2013)], levofloxacin (66.9% [CLSI], 70.3 [EUCAST]), and gentamicin [30.1% (CLSI, 2013; EUCAST, 2013]; see Table 2. There was 1 meropenem-non-susceptible E. coli (meropenem MIC, 8 μg/mL), which exhibited a ceftaroline-avibactam MIC value of 0.06 μg/mL. That isolate was resistant to all other β-lactams tested but was susceptible to fluoroquinolones, tetracycline, and tigecycline and was shown to contain a KPC-3-type gene. For K. pneumoniae, the overall ESBL screen–positive phenotype for USA isolates from ABSSSI was 15.3% (Table 1). Ceftaroline-avibactam was active against ESBL screen–positive and ESBL screen–negative K. pneumoniae strains. The MIC50/90 values for ESBL-positive strains were 0.12/1 μg/mL and for ESBL screen–negative strains were at 0.06/0.12 μg/mL (Table 1). A total of 89.8% of ESBL-screen positive strains were inhibited at ≤0.5 μg/mL, the susceptible breakpoint for ceftaroline alone (CLSI/EUCAST; Table 1). All ESBL screen–negative K. pneumoniae strains exhibited ceftaroline-avibactam MIC values at ≤0.5 μg/mL (Table 1). For ESBL-positive screen K. pneumoniae resistances (CLSI/ EUCAST criteria) to ceftriaxone (85.7/85.7%), ceftazidime (79.6/ 88.8%), ceftaroline (98.0/99.0%), ampicillin/sulbactam (88.8/98.0%), piperacillin/tazobactam (71.4/79.6%), levofloxacin (72.4/75.5%), and gentamicin (34.7/46.9%) were also high (Table 2). Tigecycline susceptibility was high (97.9/88.7% [CLSI/EUCAST]), whereas meropenem was only active against 56.1/58.2% (CLSI/EUCAST) of ESBL screen–positive strains of K. pneumoniae (Table 2). There were 43 meropenem-non-susceptible K. pneumoniae isolates, 88.4% of which were fluoroquinolone resistant and 55.8% were susceptible to gentamicin. All 43 isolates were susceptible to tigecycline. The reduced activity of meropenem in K. pneumoniae was likely due primarily to the increasing occurrence of serine carbapanemases (KPCs) in the USA. Gram-negative isolates collected during 2012, which were ESBL screen positive, were subjected to microarray-based analysis to characterize the broad spectrum β-lactamases present. Greater than 60% of isolates analyzed (E. coli and K. pneumoniae) contained ≥2 βlactamases detectable by the microarray analysis. For 81 E. coli, the most common ESBLs present were CTX-M-15-like (58.0%; 1 isolate in addition to a CTX-M-15-like enzyme also contained an SHV-type ESBL) and CTX-M-14-like (18.5%; no other ESBLs noted in these isolates). CMY-2-like β-lactamases were found in 18.5% of ESBL screen–positive isolates, 2 of which also contained a CTX-M-15 like βlactamase. One E. coli isolate contained KPC-3 (ceftaroline-avibactam MIC, 0.06 μg/mL, and meropenem MIC, 8 μg/mL). For 65 K. pneumoniae, the most common ESBLs present were CTX-M-15-like (30.8%; 3 isolates of which also contained a KPC type and 1 contained a CTX-M-14-like β-lactamase). KPC was found in 46.2% of ESBL screen–positive isolates (nearly 2/3 were KPC-2-type). For Enterobacter spp., the fluoroquinolones, meropenem, gentamicin, and tigecycline all showed a high level of susceptibility (≥92.8%, CLSI/EUCAST; Table 2). However, piperacillin-tazobactam (86.1/82.9% susceptible; CLSI/EUCAST), ceftriaxone (79.3/79.3%), ceftaroline (77.3/77.3%), ceftazidime (83.0/80.8%), and ampicillinsulbactam (35.6/35.6%) showed diminished susceptibility (Table 2). All ceftaroline-avibactam MIC values for Enterobacter spp. were at ≤1 μg/mL with 98.3% at ≤0.5 μg/mL. Ceftaroline-avibactam was also highly potent against Proteus mirabilis (99.5% at ≤0.5 μg/mL), Morganella morganii (99.6% at ≤0.5 μg/mL), and Citrobacter spp. (99.5% at ≤0.5 μg/mL). Against Serratia marcescens, the MIC50/90 was 0.5/1 μg/mL, and 84.2% of isolates were inhibited at ≤0.5 μg/mL.

Please cite this article as: Flamm RK, et al, Antimicrobial activity of ceftaroline combined with avibactam tested against bacterial organisms isolated from acute bacterial ski..., Diagn Microbiol Infect Dis (2014), http://dx.doi.org/10.1016/j.diagmicrobio.2014.01.003

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Table 2 Activity of ceftaroline-avibactam and comparator antimicrobial agents when tested bacterial isolates from patients with acute bacterial skin and skin structure infections from the USA (2010–2012). Organism (no. of isolates) antimicrobial agent S. aureus (8422) Ceftaroline-avibactam Ceftaroline Oxacillin Ceftriaxonea Cefepimea Erythromycin Clindamycin Levofloxacin Trimethoprim/sulfamethoxazole Tetracycline Tigecyclineb Linezolid Vancomycin Daptomycin MSSA (4089) Ceftaroline-avibactam Ceftaroline Ceftriaxonea Cefepimea Erythromycin Clindamycin Levofloxacin Trimethoprim/sulfamethoxazole Tetracycline Tigecyclineb Linezolid Vancomycin Daptomycin MRSA (4333) Ceftaroline-avibactam Ceftaroline Erythromycin Clindamycin Levofloxacin Trimethoprim/sulfamethoxazole Tetracycline Tigecyclineb Linezolid Vancomycin Daptomycin CoNSc (622) Ceftaroline-avibactam Ceftaroline Ceftriaxonea Cefepimea Erythromycin Clindamycin Levofloxacin Trimethoprim/sulfamethoxazole Tetracycline Tigecyclineb Linezolid Vancomycin Daptomycin β-hemolytic streptococcid (1523) Ceftaroline-avibactam Ceftarolinea Ceftriaxonea Penicillin Erythromycin Clindamycin Levofloxacin Linezolid Tetracycline Tigecyclineb Trimethoprim/sulfamethoxazole Vancomycin Daptomycin Viridans group streptococcie (411) Ceftaroline-avibactam Ceftaroline Ceftriaxone Penicillin

MIC90 (μg/mL)

MIC range (μg/mL)

CLSIa %S/%I/%R

EUCASTa %S/%I/%R

0.5 0.5 N2 N8 4 N4 ≤0.25 ≤0.5 ≤0.5 ≤0.25 0.06 1 1 0.25

1 1 N2 N8 N16 N4 N2 N4 ≤0.5 ≤0.25 0.12 1 1 0.5

≤0.03–2 ≤0.015–2 ≤0.25 to N2 ≤0.06 to N8 ≤0.5 to N16 ≤0.25 to N4 ≤0.25 to N2 ≤0.5 to N4 ≤0.5 to N4 ≤0.25 to N8 ≤0.03–0.5 ≤0.12–8 0.25–2 ≤0.06–2

-/-/99.4/0.6/48.6/0.0/51.4 48.6/0.0/51.4 48.6/0.0/51.4 36.1/2.1/61.8 88.5/0.1/11.4 63.3/1.6/35.1 98.8/0.0/1.2 95.7/0.3/3.9 100.0/-/N99.9/0.0/b0.1 100.0/0.0/0.0 N99.9/-/-

-/-/99.4/0.0/0.6 48.6/0.0/51.4 48.6/0.0/51.4 48.6/0.0/51.4 36.4/0.8/62.8 88.1/0.4/11.5 63.3/1.6/35.1 98.8/0.2/1.0 94.6/0.7/4.8 100.0/0.0/0.0 N99.9/0.0/b0.1 100.0/0.0/0.0 N99.9/0.0/b0.1

0.25 0.25 4 2 ≤0.25 ≤0.25 ≤0.5 ≤0.5 ≤0.25 0.06 1 1 0.25

0.25 0.25 4 4 N4 ≤0.25 4 ≤0.5 ≤0.25 0.12 1 1 0.5

≤0.03–0.5 ≤0.015–0.5 ≤0.06 to N8 ≤0.5–8 ≤0.25 to N4 ≤0.25 to N2 ≤0.5 to N4 ≤0.5 to N4 ≤0.25 to N8 ≤0.03–0.5 ≤0.12–2 0.25–2 ≤0.06–1

-/-/100.0/-/100.0/0.2/0.0 100.0/0.0/0.0 63.0/3.1/33.9 95.4/0.1/4.5 87.7/1.0/11.3 99.5/0.0/0.5 96.0/0.7/3.3 100.0/-/100.0/0.0/0.0 100.0/0.0/0.0 100.0/-/-

-/-/100.0/0.0/0.0 100.0/0.0/0.0 100.0/0.0/0.0 63.4/1.1/35.5 95.1/0.3/4.6 87.7/1.0/11.3 99.5/0.2/0.3 95.1/0.2/4.8 100.0/0.0/0.0 100.0/0.0/0.0 100.0/0.0/0.0 100.0/0.0/0.0

0.5 0.5 N4 ≤0.25 4 ≤0.5 ≤0.25 0.06 1 1 0.25

1 1 N4 N2 N4 ≤0.5 ≤0.25 0.12 1 1 0.5

0.12–2 0.12–2 ≤0.25 to N4 ≤0.25 to N2 ≤0.5 to N4 ≤0.5 to N4 ≤0.25 to N8 ≤0.03–0.5 ≤0.12–8 0.25–2 0.12–2

-/-/98.8/1.2/10.8/1.2/88.0 81.9/0.2/17.9 40.3/2.2/57.5 98.2/0.0/1.8 95.4/0.1/4.5 100.0/-/N99.9/0.0/b0.1 100.0/0.0/0.0 N99.9/-/-

-/-/98.8/0.0/1.2 11.0/0.4/88.6 81.6/0.3/18.1 40.3/2.2/57.5 98.2/0.2/1.6 94.1/1.2/4.8 100.0/0.0/0.0 N99.9/0.0/b0.1 100.0/0.0/0.0 N99.9/0.0/b0.1

0.25 0.25 4 2 N4 ≤0.25 ≤0.5 ≤0.5 ≤0.25 0.06 0.5 1 0.25

0.5 0.5 N8 8 N4 N2 N4 N4 N8 0.12 1 2 0.5

≤0.015–2 ≤0.015–2 0.5 to N8 ≤0.5 to N16 ≤0.25 to N4 ≤0.25 to N2 ≤0.5 to N4 ≤0.5 to N4 ≤0.25 to N8 ≤0.03–0.5 0.25 to N8 ≤0.12–4 ≤0.06–1

-/-/-/-/37.0/0.0/63.0 37.0/0.0/63.0 43.9/2.4/53.7 74.7/1.6/23.7 69.9/1.3/28.8 74.3/0.0/25.7 87.6/1.2/11.3 -/-/99.4/0.0/0.6 100.0/0.0/0.0 100.0/-/-

-/-/-/-/37.0/0.0/63.0 37.0/0.0/63.0 44.7/0.6/54.7 73.1/1.7/25.3 69.9/1.3/28.8 74.3/10.9/14.8 80.4/6.8/12.7 100.0/0.0/0.0 99.4/0.0/0.6 100.0/0.0/0.0 100.0/0.0/0.0

≤0.03 ≤0.015 ≤0.06 ≤0.06 ≤0.25 ≤0.25 ≤0.5 1 1 ≤0.03 ≤0.5 0.5 0.12

≤0.03 ≤0.015 0.12 ≤0.06 N4 N2 1 1 N8 ≤0.03 ≤0.5 0.5 0.25

≤0.03–0.06 ≤0.015–0.06 ≤0.06–0.5 ≤0.06–0.12 ≤0.25 to N4 ≤0.25 to N2 ≤0.5 to N4 ≤0.12–1 ≤0.25 to N8 ≤0.03–0.12 ≤0.5 to N4 ≤0.12–1 ≤0.06–0.5

-/-/100.0/-/100.0/-/100.0/-/68.3/0.9/30.8 82.3/0.4/17.3 99.3/0.2/0.5 100.0/-/51.2/0.8/48.0 100.0/-/-/-/100.0/-/100.0/-/-

-/-/100.0/-/100.0/0.0/0.0 100.0/0.0/0.0 68.3/0.9/30.8 82.7/0.0/17.3 95.7/3.6/0.7 100.0/0.0/0.0 50.4/0.8/48.8 100.0/0.0/0.0 98.0/0.6/1.4 100.0/0.0/0.0 100.0/0.0/0.0

≤0.03 0.03 0.25 ≤0.06

0.06 0.06 0.5 0.25

≤0.03–1 ≤0.015–1 ≤0.06–8 ≤0.06 to N4

-/-/-/-/96.8/1.7/1.5 86.4/11.8/1.7

-/-/-/-/93.9/0.0/6.1 92.5/5.8/1.7

MIC50 (μg/mL)

Please cite this article as: Flamm RK, et al, Antimicrobial activity of ceftaroline combined with avibactam tested against bacterial organisms isolated from acute bacterial ski..., Diagn Microbiol Infect Dis (2014), http://dx.doi.org/10.1016/j.diagmicrobio.2014.01.003

R.K. Flamm et al. / Diagnostic Microbiology and Infectious Disease xxx (2014) xxx–xxx

5

Table 2 (continued) Organism (no. of isolates) antimicrobial agent Erythromycin Clindamycin Levofloxacin Linezolid Tetracycline Tigecyclineb Vancomycin Daptomycin E. coli (923) Ceftaroline-avibactam Ceftaroline Ceftriaxone Ceftazidime Ampicillin/sulbactam Piperacillin/tazobactam Meropenem Levofloxacin Gentamicin Tigecyclineb ESBL screen–positive phenotype (118) Ceftaroline-avibactam Ceftaroline Ceftriaxone Ceftazidime Ampicillin/sulbactam Piperacillin/tazobactam Meropenem Ciprofloxacin Levofloxacin Gentamicin Tigecyclineb K. pneumoniae (641) Ceftaroline-avibactam Ceftaroline Ceftriaxone Ceftazidime Ampicillin/sulbactam Piperacillin/tazobactam Meropenem Ciprofloxacin Levofloxacin Gentamicin Tigecyclineb ESBL screen–positive phenotype (98) Ceftaroline-avibactam Ceftaroline Ceftriaxone Ceftazidime Ampicillin/sulbactam Piperacillin/tazobactam Meropenem Ciprofloxacin Levofloxacin Gentamicin Tigecyclineb K. oxytoca (281) Ceftaroline-avibactam Ceftaroline Ceftriaxone Ceftazidime Ampicillin/sulbactam Piperacillin/tazobactam Meropenem Ciprofloxacin Levofloxacin Gentamicin Tigecyclineb Enterobacter spp.f (599) Ceftaroline-avibactam Ceftaroline Ceftriaxone Ceftazidime Ampicillin/sulbactam Piperacillin/tazobactam Meropenem Ciprofloxacin

MIC50 (μg/mL)

MIC90 (μg/mL)

MIC range (μg/mL)

CLSIa %S/%I/%R

EUCASTa %S/%I/%R

≤0.25 to N4 ≤0.25 to N2 ≤0.5 to N4 ≤0.12–2 ≤0.25 to N8 ≤0.03–0.25 ≤0.12–1 ≤0.06–4

62.0/3.9/34.1 88.8/1.0/10.2 96.6/1.0/2.4 100.0/-/63.5/4.4/32.1 100.0/-/100.0/-/99.8/-/-

-/-/89.8/0.0/10.2 -/-/-/-/-/-/-/-/100.0/0.0/0.0 -/-/-

≤0.25 ≤0.25 ≤0.5 1 0.5 ≤0.03 0.5 0.25

N4 1 2 1 N8 ≤0.03 1 0.5

≤0.03 0.12 ≤0.06 0.12 8 2 ≤0.12 ≤0.5 ≤1 0.12

0.06 16 N8 4 N32 8 ≤0.12 N4 N8 0.12

≤0.03–0.5 ≤0.015 to N32 ≤0.06 to N8 0.03 to N32 0.5 to N32 ≤0.5 to N64 ≤0.12–8 ≤0.5 to N4 ≤1 to N8 ≤0.03–1

-/-/83.3/2.8/13.9 87.8/0.2/12.1 90.7/1.5/7.8 53.6/19.5/26.9 95.8/1.9/2.3 99.9/0.0/0.1 69.0/0.2/30.8 89.2/0.1/10.7 100.0/0.0/0.0

-/-/83.3/0.0/16.7 87.8/0.2/12.1 88.0/2.7/9.3 53.6/0.0/46.4 93.2/2.6/4.2 99.9/0.1/0.0 68.4/0.6/31.0 88.0/1.2/10.8 100.0/0.0/0.0

0.06 N32 N8 16 32 8 ≤0.12 N4 N4 2 0.12

0.12 N32 N8 N32 N32 64 ≤0.12 N4 N4 N8 0.25

≤0.03–0.5 0.12 to N32 0.25 to N8 0.5 to N32 2 to N32 1 to N64 ≤0.12–8 ≤0.5 to N4 ≤0.5 to N4 ≤1 to N8 0.06–0.25

-/-/3.4/0.0/96.6 4.2/0.9/94.9 27.1/11.9/61.0 13.6/16.9/69.5 78.0/11.8/10.2 99.2/0.0/0.8 28.8/0.9/70.3 29.7/3.4/66.9 69.9/0.0/30.1 100.0/0.0/0.0

-/-/3.4/0.0/96.6 84.2/0.9/94.9 6.8/20.3/72.9 13.6/0.0/86.4 64.4/13.6/22.0 99.2/0.8/0.0 26.3/2.5/71.2 28.0/1.7/70.3 68.3/1.6/30.1 100.0/0.0/0.0

0.06 0.12 ≤0.06 0.12 4 4 ≤0.12 ≤0.03 ≤0.5 ≤1 0.25

0.25 N32 N8 32 N32 N64 ≤0.12 N4 N4 2 0.5

≤0.03–4 ≤0.015 to N32 ≤0.06 to N8 0.03 to N32 0.5 to N32 ≤0.5 to N64 ≤0.12 to N8 ≤0.03 to N4 ≤0.5 to N4 ≤1 to N8 0.06–4

-/-/82.4/2.0/15.6 86.6/0.4/13.1 86.4/1.3/12.2 74.9/6.8/18.3 86.5/1.8/11.7 93.3/0.3/6.4 85.3/1.4/13.3 86.5/1.6/11.9 91.9/2.1/5.9 99.1/0.9/0.0

-/-/82.4/0.0/17.6 86.6/0.4/13.1 84.9/1.5/13.6 74.9/0.0/25.1 81.7/4.8/13.5 93.6/1.4/5.1 83.9/1.3/14.7 85.3/1.2/13.5 90.3/1.7/8.1 95.6/3.5/0.9

1 N32 N8 N32 N32 N64 N8 N4 N4 N8 2

≤0.03–4 0.5 to N32 0.12 to N8 1 to N32 8 to N32 1 to N64 ≤0.12 to N8 ≤0.03 to N4 ≤0.5 to N4 ≤1 to N8 0.12–4

-/-/1.0/1.0/98.0 12.2/2.1/85.7 11.2/9.2/79.6 2.0/9.2/88.8 20.4/8.2/71.4 56.1/2.1/41.8 19.4/4.1/76.5 24.5/3.1/72.4 53.1/12.2/34.7 97.9/2.1/0.0

-/-/1.0/0.0/99.0 12.2/2.1/85.7 1.0/10.2/88.8 2.0/0.0/98.0 16.3/4.1/79.6 58.2/8.1/33.7 15.3/4.1/80.6 20.4/4.1/75.5 43.9/9.2/46.9 88.7/9.2/2.1

≤0.03–1 0.03 to N32 ≤0.06 to N8 0.03 to N32 1 to N32 ≤0.5 to N64 ≤0.12–2 ≤0.03 to N4 ≤0.5 to N4 ≤1 to N8 0.06–2

-/-/88.3/2.2/9.6 90.4/1.3/8.2 96.1/0.3/3.6 65.8/25.3/8.9 92.5/0.7/6.8 99.6/0.4/0.0 96.8/1.4/1.8 97.9/0.6/1.4 97.9/1.0/1.1 100.0/0.0/0.0

-/-/88.3/0.0/11.7 90.4/1.3/8.2 95.4/0.6/3.9 65.8/0.0/34.2 90.4/2.1/7.5 100.0/0.0/0.0 96.1/0.7/3.2 96.8/1.2/2.1 97.2/0.7/2.1 99.3/0.7/0.0

≤0.015–1 ≤0.015 to N32 ≤0.06 to N8 0.03 to N32 1 to N32 ≤0.5 to N64 ≤0.06 to N8 ≤0.03 to N4

-/-/77.3/4.0/18.7 79.3/1.8/18.9 83.0/0.6/16.4 35.6/23.1/41.3 86.1/6.3/7.6 99.0/0.2/0.8 93.8/1.5/4.7

-/-/77.3/0.0/22.7 79.3/1.8/18.9 80.8/2.2/17.0 35.6/0.0/64.4 82.9/3.1/13.9 99.2/0.5/0.3 92.8/1.0/6.2

0.12 N32 N8 N32 N32 N64 ≤0.12 N4 N4 4 0.5 ≤0.03 0.25 ≤0.06 0.12 8 2 ≤0.12 ≤0.03 ≤0.5 ≤1 0.12

0.12 1 0.25 0.25 16 8 ≤0.12 0.06 ≤0.5 ≤1 0.25

0.12 0.25 0.25 0.25 16 2 ≤0.06 ≤0.03

0.25 N32 N8 32 N32 64 ≤0.06 0.25

(continued on next page)

Please cite this article as: Flamm RK, et al, Antimicrobial activity of ceftaroline combined with avibactam tested against bacterial organisms isolated from acute bacterial ski..., Diagn Microbiol Infect Dis (2014), http://dx.doi.org/10.1016/j.diagmicrobio.2014.01.003

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R.K. Flamm et al. / Diagnostic Microbiology and Infectious Disease xxx (2014) xxx–xxx

Table 2 (continued) Organism (no. of isolates) antimicrobial agent Levofloxacin Gentamicin Tigecyclineb P. mirabilis (413) Ceftaroline-avibactam Ceftaroline Ceftriaxone Ceftazidime Ampicillin/sulbactam Piperacillin/tazobactam Meropenem Ciprofloxacin Levofloxacin Gentamicin Tigecyclineb M. morganii (239) Ceftaroline-avibactam Ceftaroline Ceftriaxone Ceftazidime Ampicillin/sulbactam Piperacillin/tazobactam Meropenem Ciprofloxacin Levofloxacin Gentamicin Tigecyclineb Citrobacter spp.g (208) Ceftaroline-avibactam Ceftaroline Ceftriaxone Ceftazidime Ampicillin/sulbactam Piperacillin/tazobactam Meropenem Ciprofloxacin Levofloxacin Gentamicin Tigecyclineb S. marcescens (222) Ceftaroline-avibactam Ceftaroline Ceftriaxone Ceftazidime Ampicillin Ampicillin/sulbactam Piperacillin/tazobactam Meropenem Ciprofloxacin Levofloxacin Gentamicin Tigecyclineb

MIC50 (μg/mL)

MIC90 (μg/mL)

MIC range (μg/mL)

CLSIa %S/%I/%R

EUCASTa %S/%I/%R

≤0.12 ≤1 0.25

0.5 ≤1 0.5

≤0.12 to N4 ≤1 to N8 0.06–4

95.5/1.5/3.0 95.5/0.3/4.2 99.0/1.0/0.0

93.6/1.9/4.5 95.3/0.2/4.5 95.8/3.2/1.0

0.06 0.12 ≤0.06 0.06 1 ≤0.5 ≤0.06 ≤0.03 ≤0.12 ≤1 2

0.12 0.5 ≤0.06 0.06 16 1 ≤0.06 N4 N4 8 4

0.03–1 0.03 to N32 ≤0.06 to N8 0.03–8 0.5 to N32 ≤0.5 to N64 ≤0.06–0.5 ≤0.03 to N4 ≤0.12 to N4 ≤1 to N8 0.12–8

-/-/93.0/2.4/4.6 96.9/0.6/2.4 99.8/0.2/0.0 89.1/6.5/4.4 99.8/0.0/0.2 100.0/0.0/0.0 74.0/3.2/22.8 79.1/4.2/16.7 89.3/2.2/8.5 84.5/15.3/0.2

-/-/93.0/0.0/7.0 96.9/0.6/2.4 97.1/2.7/0.2 89.1/0.0/10.9 99.5/0.3/0.2 100.0/0.0/0.0 70.9/3.1/26.0 74.5/4.6/20.9 86.7/2.6/10.7 44.6/39.9/15.5

≤0.03 0.12 ≤0.06 0.12 16 ≤0.5 ≤0.12 ≤0.03 ≤0.5 ≤1 0.5

0.12 N32 2 8 32 2 ≤0.12 N4 N4 N8 2

≤0.03–1 ≤0.015 to N32 ≤0.06 to N8 0.03 to N32 1 to N32 ≤0.5 to N64 ≤0.12–0.25 ≤0.03 to N4 ≤0.5 to N4 ≤1 to N8 0.12 to N4

-/-/74.1/2.2/23.8 88.2/2.8/8.9 86.6/4.2/9.2 22.3/37.4/40.3 97.9/0.8/1.3 100.0/0.0/0.0 73.1/5.5/21.4 77.7/8.0/14.3 87.8/1.3/10.9 95.4/3.8/0.8

-/-/74.1/0.0/25.9 88.2/2.8/8.9 79.5/7.1/13.4 22.3/0.0/77.7 97.1/0.9/2.1 100.0/0.0/0.0 67.6/5.5/26.9 72.7/5.0/22.3 84.5/3.3/12.2 89.5/5.9/4.6

0.06 0.12 0.12 0.25 4 2 ≤0.06 ≤0.03 ≤0.12 ≤1 0.12

0.12 1 1 1 32 16 ≤0.06 0.12 0.5 ≤1 0.5

≤0.015–1 0.03 to N32 ≤0.06 to N8 0.03 to N32 1 to N32 ≤0.5 to N64 ≤0.06–4 ≤0.03 to N4 ≤0.12 to N4 ≤1 to N8 0.06–4

-/-/89.9/0.5/9.6 90.3/1.0/8.7 91.8/1.0/7.2 81.6/6.4/12.1 93.3/4.8/1.9 99.5/0.0/0.5 94.2/1.0/4.8 94.7/0.5/4.8 94.7/0.5/4.8 99.5/0.5/0.0

-/-/89.9/0.0/10.1 90.3/1.0/8.7 90.4/1.3/8.2 81.6/0.0/18.4 88.9/4.4/6.7 99.5/0.5/0.0 92.8/1.4/5.8 93.3/1.4/5.3 94.7/0.0/5.3 96.1/3.4/0.5

0.5 1 0.25 0.25 N8 32 2 ≤0.06 0.12 ≤0.12 ≤1 0.5

1 2 1 0.5 N8 N32 4 ≤0.06 1 1 ≤1 1

0.03–4 0.06 to N32 ≤0.06 to N8 0.06 to N32 4 to N8 1 to N32 ≤0.5 to N64 ≤0.06 to N8 ≤0.03 to N4 ≤0.12 to N4 ≤1 to N8 0.12–4

-/-/36.9/44.2/18.9 93.2/1.8/5.0 96.4/0.3/3.2 5.4/0.0/94.6 9.5/17.5/73.0 97.3/1.8/0.9 98.2/0.8/0.9 91.4/2.3/6.3 93.7/2.7/3.6 97.7/0.5/1.8 98.6/1.4/0.0

-/-/36.9/0.0/63.1 93.2/1.8/5.0 95.9/0.5/3.6 5.4/0.0/94.6 9.5/0.0/90.5 95.5/1.8/2.7 99.1/0.4/0.5 86.9/4.5/8.6 90.1/3.7/6.3 96.8/0.9/2.3 93.2/5.3/1.4

a Criteria as published by the CLSI (2013) and EUCAST (2013). For staphylococci, β-lactam susceptibility (other than ceftaroline) was directed by oxacillin results. For β-hemolytic streptococci, β-lactam susceptibility (EUCAST interpretive criteria) was directed by penicillin. b In the absence of CLSI breakpoint, USA-FDA breakpoints were applied when available (Tygacil® Package Insert, 2012). c Includes: Staphylococcus capitis (11 strains), S. caprae (6 strains), S. cohnii (4 strains), S. epidermidis (227 strains), S. haemolyticus (13 strains), S. hominis (14 strains), S. intermedius (3 strains), S. lugdunensis (87 strains), S. pasteuri (2 strains), S. pettenkoferi (3 strains), S. pseudintermedius (1 strain), S. saprophyticus (3 strains), S. schleiferi (3 strains), S. sciuri (1 strain), S. simulans (8 strains), S. warneri (8 strains), and unspeciated CoNS (228 strains). d Includes: Streptococcus dysgalactiae (7 strains), S. pyogenes (706 strains), S. agalactiae (671 strains), Group C Streptococcus (96 strains), Group F Streptococcus (8 strains), and Group G Streptococcus (35 strains). e Includes: Streptococcus anginosus (116 strains), S. bovis (2 strains), S. bovis group (1 strain), S. canis (1 strain), S. constellatus (34 strains), S. gallolyticus (6 strains), S. gordonii (4 strains), S. halichoeri (1 strain), S. infantarius (1 strain), S. intermedius (18 strains), S. massiliensis (2 strains), S. milleri (14 strains), S. mitis (28 strains), S. oralis (14 strains), S. parasanguinis (9 strains), S. pasteurianus (1 strain), S. salivarius (5 strains), S. sanguinis (7 strains), S. vestibularis (2 strains), unspeciated alpha-haemolytic streptococci (12 strains), and unspeciated viridans group streptococci (133 strains). f Includes: Enterobacter aerogenes (117 strains) and E. cloacae (482 strains). g Includes: Citrobacter freundii (107 strains) and C. koseri (101 strains).

3.3. Susceptibility trends for key ABSSSI pathogens for ceftarolineavibactam and select drugs The percentage of MRSA in the USA for 52 institutions, which participated in all 3 years (2010–2012), ranged from 48.7 to 53.6% for ABSSSI (Table 3). During this time, levofloxacin resistance ranged from 32.0 to 33.7% and clindamycin resistance from 10.3 to 13.6%

(Table 3). Although resistance to the above agents (methicillin/ oxacillin, clindamycin, and levofloxacin) remained high among S. aureus isolates, resistance to ceftaroline-avibactam was not detected over the 3-year study interval. However, there were 1.3% of all MRSA, which displayed a ceftaroline-avibactam MIC at 2 μg/mL, which is the CLSI intermediate category for ceftaroline (data not shown). In E. coli, ceftriaxone resistance, which was 10.5% overall, ranged yearly from

Please cite this article as: Flamm RK, et al, Antimicrobial activity of ceftaroline combined with avibactam tested against bacterial organisms isolated from acute bacterial ski..., Diagn Microbiol Infect Dis (2014), http://dx.doi.org/10.1016/j.diagmicrobio.2014.01.003

R.K. Flamm et al. / Diagnostic Microbiology and Infectious Disease xxx (2014) xxx–xxx Table 3 Antimicrobial susceptibility stratified by year of occurrence. Organism/ antimicrobial

Overall

S. aureus Ceftaroline-avibactam Ceftaroline Oxacillin Clindamycin Levofloxacin E. coli Ceftaroline-avibactam Ceftriaxone ESBL phenotypeb Meropenem Levofloxacin Gentamicin K. pneumoniae Ceftaroline-avibactam Ceftriaxone ESBL phenotypeb Meropenem Levofloxacin Gentamicin

(n = 4677) 0.0 0.0 50.4 11.4 32.6 (n = 676) 0.0 10.5 11.1 0.1 28.4 11.2 (n = 458) 0.0 15.7 17.9 8.5 14.4 6.3

% Resistant or ESBL phenotypea 2010

2011

2012

(n = 956) 0.0 0.0 52.3 13.6 33.7 (n = 61) 0.0 18.0 18.0 0.0 32.8 16.4 (n = 41) 0.0 9.8 12.2 4.9 0.1 4.9

(n = 952) 0.0 0.0 53.6 12.3 33.1 (n = 167) 0.0 11.4 11.4 0.0 26.9 12.6 (n = 122) 0.0 18.0 19.7 7.4 16.4 6.6

(n = 2769) 0.0 0.0 48.7 10.3 32.0 (n = 448) 0.0 9.2 10.0 0.2 28.3 10.0 (n = 295) 0.0 15.6 18.0 9.5 14.6 6.4

a Criteria as published by the CLSI (2013); for ceftaroline-avibactam, the CLSI interpretive criteria for ceftaroline alone were applied for comparison purposes. b Percentage of isolates with positive ESBL screening test, i.e., MIC of ≥2 μg/mL for ceftazidime or ceftriaxone or aztreonam (CLSI, 2013).

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increasing occurrence in the USA of KPC-producing K. pneumoniae isolates, the relatively large number of meropenem-non-susceptible K. pneumoniae isolates (6.7%) in this study may have been due in large part to the presence of such strains, although molecular characterization of these strains would need to be done to confirm this. Analysis of the Gram-negative isolates from 2012 for the presence of broadspectrum β-lactamases indicated that 46.2% of the ESBL screen– positive K. pneumoniae contained the serine carbapenemase KPC (63.3%, KPC-2 type; 36.7%, KPC-3-type). The most common ESBLs present in ESBL screen–positive E. coli were CTX-M-15-like and CTXM-14-like. The data from this current study on isolates from ABSSSI demonstrated a similar spectrum and potency for ceftarolineavibactam activity against Gram-negative bacteria as shown previously (Sader et al., 2013b) and extend that work with the presentation of data solely from ABSSSI isolates. In summary, ceftaroline-avibactam (a cephalosporin combined with a novel non-β-lactam β-lactamase inhibitor) showed excellent activity against both Gram-positive and Gram-negative pathogens associated with ABSSSI against a collection of 14,504 isolates from patients in USA medical centers (2010–2012). The combination of ceftaroline-avibactam provides the Gram-positive spectrum of ceftaroline including MRSA and MDR S. pneumoniae and provides antiEnterobacteriaceae activity similar to tigecycline or meropenem. Acknowledgments

9.2 to 18.0%, nearly identical to the ESBL screen–positive phenotype (Table 3). Levofloxacin resistance in E. coli was high, ranging from 26.9 to 32.8% yearly (Table 3). For K. pneumoniae, ceftriaxone resistance ranged from 9.8 to 18.0% yearly with an ESBL screen–positive phenotype ranging from 12.2 to 19.7% (Table 3). Levofloxacin resistance in K. pneumoniae (0.1–16.4%) was lower than in E. coli (Table 3). Meropenem resistance in K. pneumoniae was at 8.5% overall, ranging from 4.9 to 9.5% from 2010 through 2012 (Table 3). 4. Discussion Ceftaroline-avibactam was demonstrated to be active in vitro against the most common pathogens associated with ABSSSI. During this large surveillance program conducted in the USA during 2010– 2012, ceftaroline-avibactam activity against Gram-positive pathogens was shown for S. aureus (MIC50/90, 0.5/1 μg/mL) to be comparable to vancomycin (MIC50/90, 1/1 μg/mL), linezolid (MIC50/90, 1/1 μg/mL), and daptomycin (MIC50/90, 0.251/0.5 μg/mL). Against β-hemolytic streptococci, ceftaroline-avibactam (MIC50/90, ≤0.03/≤0.03 μg/mL) had activity similar to penicillin (MIC50/90, ≤0.06/≤0.06 μg/mL) and ceftriaxone (MIC50/90, ≤0.06/0.12 μg/mL). The results of this study are similar to those reported by Sader et al. (2013b) who tested a large diverse collection of organisms from the USA collected from respiratory, bloodstream, urinary tract, skin structure, and other infections. In their study, S. aureus exhibited an MIC50/90 of 0.25/1 μg/ mL, and β-streptococci, a MIC50/90 of ≤0.03/≤0.03 μg/mL. In this current study, only ABSSSI isolates were tested, whereas in Sader et al. (2013b), less than 25% of isolates were from ABSSSI. Against Gram-negative bacteria that cause ABSSSI including MDR isolates and ESBL screen–positive bacteria, ceftaroline-avibactam was shown to have potent activity. Against all E. coli (MIC50/90, ≤0.03/0.06 μg/mL), the highest MIC value for ceftaroline-avibactam was 0.5 μg/ mL (Table 1). The activity of ceftaroline-avibactam was most similar to meropenem and tigecycline for E. coli, as well as K. oxytoca and K. pneumoniae. However, ceftaroline-avibactam (98.4% of all K. pneumoniae isolates ≤0.5 μg/mL) retained activity against many of the meropenem-non-susceptible strains. The “third generation” cephalosporins and ceftaroline alone were not active against ESBL screen– positive phenotype or meropenem-resistant isolates. Given the

This study was supported by Forest Laboratories, Inc. Forest Laboratories, Inc., was involved in the design and decision to present these results. Forest Laboratories, Inc., had no involvement in the collection, analysis, or interpretation of data; Scientific Therapeutics Information, Inc., provided editorial coordination, which was funded by Forest Research Institute, Inc. JMI Laboratories, Inc., also has received research and educational grants in 2009–2012 from American Proficiency Institute, Anacor, Astellas, AstraZeneca, Bayer, Cempra, Contrafect, Cubist, Daiichi, Dipexium, Enanta, Furiex, GlaxoSmithKline, Johnson & Johnson (Ortho McNeil), LegoChem Biosciences Inc., Meiji Seika Kaisha, Merck, Nabriva, Novartis, Pfizer (Wyeth), Rempex, Rib-X Pharmaceuticals, Seachaid, Shionogi, The Medicines Co., Theravance, ThermoFisher, and some other corporations. Some JMI employees are advisors/consultants for Astellas, Cubist, Pfizer, Cempra, Forest/ Cerexa, J&J, and Theravance. In regards to speakers bureaus and stock options—none to declare. We express our appreciation to S. Benning and M. Janechek in the preparation of this manuscript and to the JMI laboratory staff members for scientific assistance in performing the study. References Castanheira M, Sader HS, Farrell DJ, Mendes RE, Jones RN. Activity of ceftaroline-avibactam tested against gram-negative organism populations, including strains expressing one or more beta-lactamases and methicillin-resistant Staphylococcus aureus carrying various SCCmec types. Antimicrob Agents Chemother 2012;56:4779–85. Castanheira M, Farrell SE, Deshpande LM, Mendes RE, Jones RN. Prevalence of βlactamase encoding genes among Enterobacteriaceae bacteremia isolates collected in 26 USA hospitals: report from the SENTRY Antimicrobial Surveillance Program (2010). Antimicrob Agents Chemother 2013;57:3012–20. Castanheira M, Farrell SE, Krause KM, Jones RN, Sader HS. Contemporary diversity of βlactamases among Enterobacteriaceae in the nine United States census regions and ceftazidime-avibactam activity tested against isolates producing the most prevalent β-lactamase groups. Antimicrob Agents Chemother 2014. in press. Clinical and Laboratory Standards Institute (CLSI). Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard: ninth edition, M07-A9. Wayne, PA: CLSI; 2012. Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial susceptibility testing: 23rd informational supplement (M100-S23). Wayne, PA: CLSI; 2013. Dryden MS. Complicated skin and soft tissue infection. J Antimicrob Chemother 2010;65(Suppl 3):iii35–44. Ehmann DE, Jahic H, Ross PL, Gu RF, Hu J, Kern G, et al. Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor. Proc Natl Acad Sci U S A 2012;109:11663–8.

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Please cite this article as: Flamm RK, et al, Antimicrobial activity of ceftaroline combined with avibactam tested against bacterial organisms isolated from acute bacterial ski..., Diagn Microbiol Infect Dis (2014), http://dx.doi.org/10.1016/j.diagmicrobio.2014.01.003