Antimicrobial activity of ceftaroline tested against bacterial isolates causing respiratory tract and skin and skin structure infections in US medical centers in 2013

Diagnostic Microbiology and Infectious Disease 82 (2015) 78–84

Contents lists available at ScienceDirect

Diagnostic Microbiology and Infectious Disease journal homepage: www.elsevier.com/locate/diagmicrobio

Antimicrobial activity of ceftaroline tested against bacterial isolates causing respiratory tract and skin and skin structure infections in US medical centers in 2013 Helio S. Sader ⁎, David J. Farrell, Rodrigo E. Mendes, Robert K. Flamm, Mariana Castanheira, Ronald N. Jones JMI Laboratories, North Liberty, IA, USA

a r t i c l e

i n f o

Article history: Received 19 December 2014 Received in revised form 27 January 2015 Accepted 30 January 2015 Available online 10 February 2015 Keywords: Streptococcus pneumoniae Staphylococcus aureus MRSA Cephalosporin

a b s t r a c t A total of 4533 isolates from community-acquired respiratory tract infections (CARTIs) and 8446 from skin and skin structure infections (SSSIs) were consecutively collected in 149 US medical centers in 2013. Strains were susceptibility tested by broth microdilution method against ceftaroline and numerous comparators. Ceftaroline (MIC50/90, ≤0.015/0.12 μg/mL) was more potent than ceftriaxone (MIC50/90, ≤0.06/1 μg/mL) against Streptococcus pneumoniae and highly active against ceftriaxone-nonsusceptible strains (n = 201; MIC90, 0.25 μg/mL). Ceftaroline was also very active against Haemophilus influenzae (MIC50/90, 0.008/0.015 μg/mL), methicillinsusceptible (MIC50/90, 0.25/0.25 μg/mL) and methicillin-resistant Staphylococcus aureus (MIC50/90, 1/1 μg/mL), and β-hemolytic streptococci (highest MIC, 0.03 μg/mL). Ceftaroline exhibited good activity against non– extended-spectrum β-lactamase (ESBL) phenotype isolates of Klebsiella spp. and Escherichia coli (96.7% susceptible and MIC90 of 0.25 μg/mL for both) but limited activity against ESBL phenotype isolates. In summary, ceftaroline exhibited potent in vitro activity against a large collection of bacterial isolates causing CARTI and SSSI in US medical centers. © 2015 Elsevier Inc. All rights reserved.

1. Introduction Community-acquired respiratory tract infections (CARTIs) may be caused by bacteria resistant to some or many available therapies, and the choice of the appropriate initial empiric therapy is important to minimize morbidity and mortality (File, 2006; File and Marrie, 2010; Kollef et al., 2005). In spite of the increasing concern over the emergence of antimicrobial resistance, there have been relatively few new antibacterial agents licensed for the treatment of CARTI in the United States and/or Europe (File and Marrie, 2010). Skin and skin structure infection (SSSI) encompasses a wide range of clinical presentations, from mild cases of cellulitis and subcutaneous tissue infections to complicated deep-seated infections with systemic signs of sepsis and the presence of complicating comorbidities, such as neutropenia, ischemia, and/or tissue necrosis. The vast majority of SSSIs are caused by Staphylococcus aureus followed by β-hemolytic streptococci, usually Lancefield groups A, C, and G, with group B being more common in diabetics and the elderly (Dryden, 2010; Stevens et al., 2005). Ceftaroline is a cephalosporin with broad-spectrum in vitro bactericidal activity against Gram-positive and common Gram-negative pathogens causing CARTI and SSSI, including oxacillin (methicillin)– susceptible (MSSA) and methicillin-resistant S. aureus (MRSA), multidrug-resistant Streptococcus pneumoniae, β-lactamase–producing ⁎ Corresponding author. Tel.: +1-319-665-3370; fax: +1-319-665-3371. E-mail address: [email protected] (H.S. Sader). http://dx.doi.org/10.1016/j.diagmicrobio.2015.01.015 0732-8893/© 2015 Elsevier Inc. All rights reserved.

Haemophilus influenzae, and common Gram-negative organisms, including non–extended-spectrum β-lactamase (ESBL) phenotype Enterobacteriaceae (Frampton, 2013; Jones et al., 2011; Lodise and Low, 2012). The prodrug, ceftaroline fosamil, was approved by the US Food and Drug Administration (FDA) for the treatment of communityacquired bacterial pneumonia and acute bacterial SSSIs in 2010 (Teflaro™, 2012). The activity of ceftaroline against pathogens causing community-acquired and health care–associated infections in US medical centers has been continuously monitored by the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) program since 2008 (Flamm et al., 2014b; Pfaller et al., 2014), and as part of this program, we evaluated the potency and spectrum of ceftaroline and several comparators tested against CARTI and SSSI pathogens collected from US medical centers in 2013. 2. Materials and methods 2.1. Organism collection A total of 4533 isolates from patients with CARTI and 8446 from patients with SSSI were collected in 149 US medical centers in 2013. The collection of isolates from CARTI included 3099 S. pneumoniae (6.5% ceftriaxone nonsusceptible), 931 Haemophilus influenzae (23.8% β-lactamase positive), 99 Haemophilus parainfluenzae, and 404 Moraxella catarrhalis, whereas the isolates from SSSI comprised 6100 Gram positives (5182 S. aureus, 746 β-hemolytic streptococci, and 172 viridans group streptococci) and 2346 Enterobacteriaceae. Escherichia

H.S. Sader et al. / Diagnostic Microbiology and Infectious Disease 82 (2015) 78–84

coli, Klebsiella spp., and Proteus mirabilis isolates were grouped as “ESBL phenotype” based on the Clinical and Laboratory Standards Institute (CLSI) screening criteria for ESBL production, i.e., MIC of ≥2 μg/mL for ceftazidime or ceftriaxone or aztreonam (CLSI, 2014). All medical centers collected the strains following a common protocol, and only isolates determined to be significant by local criteria as the reported probable cause of the infection were included in this investigation. Species identification was performed at the participant medical center and confirmed at the monitoring laboratory (JMI Laboratories, North Liberty, IA, USA) using the Vitek 2 System (bioMerieux, Hazelwood, MO, USA) or MALDI-TOF (Bruker Daltonics, Bremen, Germany), when necessary. 2.2. Susceptibility methods Broth microdilution tests conducted according to the CLSI documents determined antimicrobial susceptibility of ceftaroline and numerous comparator antimicrobials used to treat CARTI and SSSI (CLSI, 2012). Validated MIC panels were manufactured by Thermo Fisher Scientific® (Cleveland, OH, USA). M. catarrhalis strains were tested in cation-adjusted Mueller–Hinton broth (CA-MHB), Streptococcus spp. isolates were tested in CA-MHB supplemented with 2.5–5% lysed horse blood, and Haemophilus spp. isolates were tested in Haemophilus Test Medium according to CLSI document M07-A9 (CLSI, 2012). Quality control (QC) strains included S. aureus ATCC 29213, E. coli ATCC 25922 and 35218, S. pneumoniae ATCC 49619, and H. influenzae ATCC 49247. Susceptibility percentages and validation of QC results were based on the CLSI guidelines (CLSI, 2014). Colony counts are performed in all QC strains and in 5% (randomly selected) of the testing isolates. 3. Results Ceftaroline was very active against all bacterial isolates from CARTI. Ceftaroline (MIC50/90, ≤0.015/0.12 μg/mL; 100.0% susceptible) was more potent (MIC90 value 8-fold lower) than ceftriaxone (MIC50/90, ≤0.06/ 1 μg/mL; 93.5% susceptible; Tables 1 and 2) when tested against S. pneumoniae, and highly active against ceftriaxone-nonsusceptible S. pneumoniae strains (n = 201; MIC50/90, 0.12/0.25 μg/mL; highest MIC, 0.5 μg/mL; Table 1). Ceftaroline was also active against penicillinnonsusceptible S. pneumoniae (penicillin MIC of N2 μg/mL) isolates (n = 222), with MIC50 of 0.12 μg/mL and MIC90 of 0.25 μg/mL (100.0% susceptible), whereas only 22.5% (50/222) of these isolates were susceptible to ceftriaxone (Fig. 1). Susceptibility rates (CLSI criteria) for S. pneumoniae were 92.8% for penicillin (MIC, ≤2 μg/mL), 88.5% for amoxicillin/clavulanate, 81.6% for meropenem, 56.0% for erythromycin, 77.0% for tetracycline, and 98.8% for levofloxacin (Table 2). Ceftaroline exhibited potent activity against H. influenzae (MIC50/90, 0.008/0.015 μg/mL; 100.0% susceptible; Tables 1 and 2). The highest ceftaroline MIC value among H. influenzae was 0.25 μg/mL (1 isolate, 0.1%), and 99.7% of isolates were inhibited at ≤0.06 μg/mL of ceftaroline (Table 1). Among H. influenzae, 23.8% of isolates (222/931) were β-

79

lactamase producers, and ceftaroline was very active against these strains (MIC50/90, 0.015/0.03 μg/mL; Table 1). Susceptibility rates for clarithromycin (MIC50 and MIC90, 8 μg/mL), azithromycin (MIC50/90, 1/ 2 μg/mL), and levofloxacin (MIC50 and MIC90, ≤0.12 μg/mL) among H. influenzae were 90.3%, 99.1%, and 99.8%, respectively (Table 2). Ceftaroline was also very active against H. parainfluenzae (MIC50/90, 0.008/0.03 μg/mL) and M. catarrhalis (MIC50/90, 0.06/0.12 μg/mL; Tables 1 and 2). When tested against bacterial isolates from SSSI, ceftaroline inhibited 99.4% of S. aureus strains at ≤1 μg/mL (Table 3), which is the susceptible breakpoint established by the CLSI, US-FDA, and EUCAST. All S. aureus isolates nonsusceptible to ceftaroline (31 of 3182; 0.6%) were MRSA. S. aureus susceptibility rates for other antimicrobial agents tested are shown in Fig. 2. Ceftaroline demonstrated potent activity against MSSA (MIC50 and MIC90, 0.25 μg/mL) and MRSA (MIC50 and MIC90, 1 μg/mL) isolates (Table 3). Against MSSA, ceftaroline was 16-, 4-, and 4-fold more active than ceftriaxone (MIC50 and MIC90, 4 μg/mL), linezolid (MIC50 and MIC90, 1 μg/mL), and vancomycin (MIC50 and MIC90, 1 μg/mL), respectively (data not shown). Furthermore, 17.2% of MSSA were clindamycin resistant, with 5.0% showing constitutive resistance and 12.2% showing inducible resistance (data not shown). Ceftaroline was one of the most active agents tested against S. aureus from SSSI (MIC50 and MIC50/90, 0.5/1 μg/mL; 99.4% susceptible; Tables 3 and 4), with potency and spectrum similar to that of vancomycin (MIC50 and MIC90, 1 μg/mL; 100% susceptible), linezolid (MIC50 and MIC90, 1 μg/mL; N99.9% susceptible), and daptomycin (MIC50/90, 0.25/ 0.5 μg/mL; 100.0% susceptible; Table 4). Overall, 51.0% of S. aureus isolates were MRSA (Tables 3 and 4 and Fig. 2). Furthermore, S. aureus showed high resistance rates to levofloxacin (38.1%; Table 4) and clindamycin (20.4% [Table 4]; 11.6% constitutive and 8.8% inducible resistance). Against β-hemolytic streptococci isolates from SSSI, ceftaroline demonstrated activity (MIC50 and MIC90, ≤0.015 μg/mL; highest MIC, 0.03 μg/mL; Table 3) comparable to that of penicillin (MIC50 and MIC90, ≤0.06 μg/mL), and it was at least 32-fold greater than linezolid (MIC50/90, 0.5/1 μg/mL) and 32-fold greater than vancomycin (MIC50/ 90, 0.25/0.5 μg/mL; Table 4). Viridans group streptococci, including strains resistant to penicillin and ceftriaxone, were very susceptible to ceftaroline (MIC50/90, 0.03/0.06 μg/mL; highest MIC, 0.5 μg/mL; Table 3), while 93.0 and 98.8% of strains were susceptible to penicillin (MIC50/90, ≤0.06/0.25 μg/mL) and ceftriaxone (MIC50/90, 0.25/ 0.5 μg/mL), respectively (data not shown). Ceftaroline inhibited 81.8% of Enterobacteriaceae at ≤0.5 μg/mL (Table 3), which is the susceptible breakpoint established by CLSI, USFDA, and EUCAST. Ceftaroline exhibited good activity against non-ESBL phenotype strains of Klebsiella spp., E. coli, and P. mirabilis (MIC90, 0.25 μg/mL for all 3 pathogens), but limited activity against ESBL phenotype and/or ceftriaxone-resistant strains (Table 3 and Fig. 3). Ceftaroline activity against E. coli (MIC50/90, 0.12/2 μg/mL and 87.2% susceptible) and Klebsiella spp. (MIC50/90, 0.12/16 μg/mL and 84.2% susceptible)

Table 1 Summary of ceftaroline activity when tested against bacterial isolates from CARTI (USA, 2013). No. of isolates (cumulative %) inhibited at ceftaroline MIC (μg/mL) of Organism (no. tested) S. pneumoniae (3099) Ceftriaxone non-Sb (201) Penicillin non-Sc (222) H. influenzae (931) β-lactamase positive (222) H. parainfluenzae (99) M. catarrhalis (404) a b c

≤0.004

0.008

0.015 1938 (62.5)

116 (12.5) 10 (4.5) 19 (22.2)

465 (62.4) 82 (41.4) 36 (58.6) 17 (4.2)

Lowest dilution tested for S. pneumoniae. Ceftriaxone MIC values of N1 μg/mL (CLSI, 2014). Penicillin MIC values of N2 μg/mL (CLSI, 2014).

259 (90.2) 80 (77.5) 19 (87.9) 24 (10.1)

a

MIC (μg/mL)

0.03

0.06

0.12

0.25

0.5

50%

90%

303 (72.3) 1 (0.5)

303 (82.1) 1 (1) 2 (0.9) 13 (99.7) 9 (98.6) 2 (97.0) 132 (66.3)

443 (96.4) 101 (51.2) 124 (56.8) 2 (99.9) 2 (99.5) 2 (99.0) 101 (91.3)

100 (99.6) 86 (94.0) 84 (94.6) 1 (100.0) 1 (100.0) 0 (99.0) 32 (99.3)

12 (100.0) 12 (100.0) 12 (100.0)

≤0.015 0.12 0.12 0.008 0.015 0.008 0.06

0.12 0.25 0.25 0.015 0.03 0.03 0.12

75 (98.3) 38 (94.6) 7 (94.9) 95 (33.7)

1 (100.0) 3 (100.0)

80

H.S. Sader et al. / Diagnostic Microbiology and Infectious Disease 82 (2015) 78–84

Table 2 Activity of ceftaroline and comparator antimicrobial agents when tested against isolates of S. pneumoniae and H. influenzae from CARTI (USA, 2013). %S/I/R (CLSI)a

Antimicrobial agent

MIC (μg/mL)

Organism (no. tested)

MIC50

MIC90

Range

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

0.12 1 2 2 4 0.5 N16 N2 1 1 32 N4 0.5

≤0.015–0.5 ≤0.06–8 ≤0.06–8 ≤0.06–8 ≤1 to N8 ≤0.06–2 ≤0.12 to N16 ≤0.25 to N2 ≤0.12 to N4 ≤0.12–2 ≤0.03 to N32 ≤0.5 to N4 ≤0.12–0.5

100.0/-/93.5/6.0/0.5 92.8/6.8/0.4 60.7/24.9/14.5 88.5/3.7/7.8 81.6/11.2/7.2 56.0/0.8/43.2 83.6/0.5/15.9 98.8/0.3/0.9 100.0/-/77.0/0.2/22.8 70.1/12.5/17.4 100.0/-/-

0.008 ≤0.06 ≤0.25 ≤1 ≤0.5 ≤0.06 0.5 ≤0.5 1 8 ≤0.12

0.015 ≤0.06 N8 2 ≤0.5 0.12 0.5 N4 2 8 ≤0.12

≤0.001–0.25 ≤0.06–0.12 ≤0.25 to N8 ≤1–4 ≤0.5 ≤0.06–0.25 ≤0.12 to N16 ≤0.5 to N4 ≤0.03 to N4 ≤0.12 to N16 ≤0.12 to N4

100.0/-/100.0/-/75.8/1.1/23.1 100.0/0.0/0.0 100.0/0.0/0.0 100.0/-/99.1/0.2/0.8 67.7/4.1/28.2 99.1/-/90.3/8.4/1.3 99.8/-/-

S. pneumoniae (3,099) Ceftarolineb Ceftriaxone Penicillinc Penicillind Amoxicillin/clavulanate Meropenem Erythromycin Clindamycin Levofloxacin Linezolid Tetracycline TMP/SMX Vancomycin H. influenzae (931) Ceftarolineb Ceftriaxone Ampicillin Amoxicillin/clavulanate Piperacillin/tazobactam Meropenem Tetracycline TMP/SMX Azithromycin Clarithromycin Levofloxacin

TMP/SMX = trimethoprim/sulfamethoxazole. a Criteria as published by the CLSI (2014). b US-FDA breakpoints were applied when available (Teflaro™, 2012). c Criteria as published by the CLSI (CLSI, 2012) for “Penicillin parenteral non-meningitis” (S ≤2, I = 4, R ≥8 μg/mL). d Criteria as published by the CLSI (CLSI, 2012) for “Penicillin oral penicillin V” (S ≤0.06, I = 0.12–1, R ≥2 μg/mL).

were similar to that of ceftriaxone (MIC50/90, ≤0.06/1 μg/mL and 90.1% susceptible for E. coli and MIC50/90, ≤0.06/8 μg/mL and 88.2% susceptible for Klebsiella spp.; Table 4). When tested against Enterobacter cloacae, ceftaroline (MIC50/90, 0.25/ N32 μg/mL; Table 3) demonstrated similar activity compared to that of ceftriaxone (MIC50/90, 0.25/N8 μg/mL) and ceftazidime (MIC50/90, 0.25/ 32 μg/mL; data not shown). Overall, 82.5% and 85.6% of E. cloacae strains

were susceptible to ceftriaxone and ceftazidime, respectively (data not shown), and 82.3% were susceptible to ceftaroline (Table 3). Ceftaroline showed variable activity against Enterobacter aerogenes (MIC50/90, 0.12/32 μg/mL; 80.6% susceptible) and Morganella morganii (MIC50/90, 0.12/32 μg/mL; 73.7% susceptible; Table 3). Susceptibility rates of these 2 organisms for ceftriaxone were 80.6% and 88.4%, respectively (data not shown). Ceftaroline was slightly more active against Citrobacter koseri (MIC50/90, 0.12/0.5 μg/mL; 92.9% susceptible) compared to Citrobacter freundii (MIC50/90, 0.25/1 μg/mL; 89.7% susceptible; Table 3). Ceftaroline exhibited modest activity against Serratia marcescens (MIC50/90, 1/2 μg/mL; 43.2% susceptible), Proteus vulgaris (MIC50/90, 1/32 μg/mL; 39.3% susceptible), and Providencia spp. (MIC50/ 90, 0.5/8 μg/mL; 51.9% susceptible; Table 3). 4. Discussion This study evaluated the activity of ceftaroline and several comparator agents against a large collection of bacterial isolates from CARTI (n = 4533) and SSSI (n = 8446) collected in 2013 from 149 US medical centers distributed through all 9 Census regions. Overall, ceftaroline was the most active agent tested against the CARTI pathogens, and all S. pneumoniae and H. influenzae isolates were ceftaroline susceptible according to CLSI and US-FDA breakpoint criteria (no interpretive criteria are available for H. parainfluenzae or M. catarrhalis) (CLSI, 2012; Teflaro™, 2012). Ceftaroline MIC90 value for S. pneumoniae was 8-fold lower than those of ceftriaxone, levofloxacin, and linezolid and 16-fold lower than that of penicillin. Furthermore, ceftaroline retained activity against ceftriaxone-nonsusceptible S. pneumoniae. Our results are consistent with those reported by other investigators by showing that ceftaroline's spectrum of coverage for S. pneumoniae (at 100.0% susceptible) is similar to that of linezolid, tigecycline, and vancomycin (Critchley et al., 2011; Frampton, 2013). Moreover, ceftaroline was also highly active against H. influenzae (100.0% susceptible, MIC90, 0.03 μg/mL), H. parainfluenzae (MIC90, 0.03 μg/mL), and M. catarrhalis (MIC90, 0.12 μg/mL) (Flamm et al., 2014a; Pfaller et al., 2012). Ceftaroline demonstrated potent in vitro activity against the most common organisms isolated from patients with SSSI. Ceftaroline activity against S. aureus (MIC50/90, 0.25/1 μg/mL) was greater than that of vancomycin (MIC50/90, 1/1 μg/mL) and linezolid (MIC50/90, 1/2 μg/mL), whereas activity against β-hemolytic streptococci (MIC50/90, ≤0.008/ 0.015 μg/mL) was more similar to that of penicillin (MIC50/90, ≤0.03/ 0.06 μg/mL) and ceftriaxone (MIC50/90, ≤0.06/≤0.06 μg/mL). Ceftaroline was also very active against viridans group streptococci (MIC90,

Fig. 1. Ceftaroline and ceftriaxone MIC distributions when tested against penicillin-nonsusceptible (MIC, N2 μg/mL) S. pneumoniae (n = 222).

Table 3 Summary of ceftaroline activity tested against bacterial isolates collected from patients with SSSIs in US medical centers (AWARE Program USA, 2013). Organism/subgroup (no. of isolates)

a

0.03

0.06

MIC (μg/mL)

0.12

0.25

0.5

1

2

4

8

16

N16

50%

90%

2 (0.0)

1 (0.1)

5 (0.2)

186 (3.7)

2262 (47.4)

1369 (73.8)

1326 (99.4)

31 (100.0)

0.5

1

2 (0.1)

1 (0.1)

5 (0.3)

182 (7.5) 4 (0.2)

2225 (95.1) 37 (1.6)

125 (100.0) 1244 (48.6)

1326 (98.8)

31 (100.0)

0.25 1 ≤0.015

711 (95.3)

35 (100.0)

0.25 1 ≤0.015

318 (99.7)

1 (100.0)

≤0.015

≤0.015

314 (90.2)

34 (100.0)

≤0.015

≤0.015

≤0.015

≤0.015

0.03

0.06

79 (100.0) 69 (40.1)

75 (83.7)

26 (98.8)

1 (99.4)

0 (99.4)

8 (0.3)

87 (4.0)

579 (28.7)

677 (57.6)

360 (72.9)

209 (81.8)

126 (87.2)

40 (88.9)

28 (90.1)

25 (91.2)

28 (92.4)

179 (100.0)

0.12

4

6 (0.9)

53 (9.0)

222 (42.9)

182 (70.7)

66 (80.8)

42 (87.2)

13 (89.2)

6 (90.1)

6 (91.0)

6 (91.9)

5 (92.7)

48 (100.0)

0.12

2

6 (1.0)

53 (10.1)

222 (48.3)

182 (79.6)

63 (90.4)

37 (96.7)

13 (99.0)

5 (99.8)

1 (100.0)

0.12

0.25

3 (4.1)

5 (11.0)

0 (11.0)

1 (12.3)

5 (19.2)

6 (27.4)

5 (34.2)

48 (100.0)

N32

N32

89 (78.6) 89 (90.2)

27 (84.2) 27 (96.7)

14 (87.1) 11 (99.3)

5 (88.2) 2 (99.8)

3 (88.8) 0 (99.8)

5 (89.8) 0 (99.8)

7 (91.3) 0 (99.8)

42 (100.0) 1 (100.0)

0.12 0.12

16 0.25

3 (4.8)

3 (9.7)

3 (14.5)

5 (22.6)

7 (33.9)

41 (100.0)

N32

N32

3 (96.2)

12 (100.0)

0.12

0.5

0.12

0.25

1 (0.2) 1 (0.2)

1 (1.1)

9 (2.1) 9 (2.4)

132 (29.5) 132 (33.8)

148 (60.2) 148 (69.0)

1 (100.0)

2 (0.6)

107 (34.9)

134 (77.9)

31 (87.8)

16 (92.9)

4 (94.2)

0 (94.2)

1 (94.6)

2 (95.2)

2 (0.7)

107 (36.9)

134 (82.4)

31 (92.9)

16 (98.3)

4 (99.7)

0 (99.7)

0 (99.7)

1 (100.0)

1 (5.9)

1 (11.8)

3 (29.4)

12 (100.0)

N32

N32

5 (1.5)

10 (4.5)

90 (31.5)

124 (68.8)

45 (82.3)

8 (84.7)

5 (86.2)

1 (86.5)

2 (87.1)

3 (88.0)

40 (100.0)

0.25

N32

2 (2.2)

34 (38.7)

34 (75.3)

4 (79.6)

1 (80.6)

3 (83.9)

0 (83.9)

3 (87.1)

0 (87.1)

2 (89.2)

10 (100.0)

0.12

32

8 (9.5)

34 (45.3)

17 (63.2)

5 (68.4)

5 (73.7)

6 (80.0)

1 (81.1)

3 (84.2)

2 (86.3)

3 (89.5)

10 (100.0)

0.12

32

26 (30.6)

44 (82.4)

3 (85.9)

6 (92.9)

5 (98.8)

0 (98.8)

0 (98.8)

0 (98.8)

0 (98.8)

1 (100.0)

0.12

0.5

3 (5.2)

21 (41.4)

22 (79.3)

6 (89.7)

1 (91.4)

0 (91.4)

0 (91.4)

0 (91.4)

1 (93.1)

4 (100.0)

0.25

1

5 (4.0)

49 (43.2)

51 (84.0)

12 (93.6)

3 (96.0)

3 (98.4)

1 (99.2)

1 (100.0)

1

2

2 (3.6)

1 (5.4)

1 (7.1)

8 (21.4)

10 (39.3)

10 (57.1)

6 (67.9)

5 (76.8)

4 (83.9)

1 (85.7)

8 (100.0)

1

32

6 (11.5)

10 (30.8)

6 (42.3)

3 (48.1)

2 (51.9)

11 (73.1)

5 (82.7)

3 (88.5)

1 (90.4)

2 (94.2)

3 (100.0)

0.5

8

H.S. Sader et al. / Diagnostic Microbiology and Infectious Disease 82 (2015) 78–84

Staphylococcus aureus (5182) MSSA (2540) MRSA (2642) β-Hemolytic streptococci (746) Streptococcus pyogenes (319 Streptococcus agalactiae (348) Streptococcus dysgalactiae (79) Viridans group streptococci (172) Enterobacteriaceae (2346) Escherichia coli (655) Non-ESBL phenotype (582) ESBL phenotypea (73) Klebsiella spp. (482) Non-ESBL phenotype (420) ESBL phenotypea (62) Proteus mirabilis (312) Non-ESBL phenotype (295) ESBL phenotypea (17) Enterobacter cloacae (333) Enterobacter aerogenes (93) Morganella morganii (95) Citrobacter koseri (85) Citrobacter freundii (58) Serratia marcescens (125) Proteus vulgaris (56) Providencia spp. (52)

No. of isolates (cumulative %) inhibited at ceftaroline MIC (μg/mL) of ≤0.015

Isolates with MIC of ≥2 μg/mL for ceftazidime or ceftriaxone or aztreonam (CLSI, 2014). 81

82

H.S. Sader et al. / Diagnostic Microbiology and Infectious Disease 82 (2015) 78–84

Fig. 2. Antimicrobial susceptibility of 5182 S. aureus isolates from patients with SSSI (AWARE Program USA, 2013).

0.06 μg/mL), including penicillin-nonsusceptible strains with ceftriaxone MIC values of up to 8 μg/mL. When tested against E. coli, Klebsiella spp., and P. mirabilis isolates from SSSI, ceftaroline activity was similar to those of ceftriaxone and ceftazidime, as has been shown by other investigators (Karlowsky et al., 2013). Furthermore, the results presented here are similar to those of previous publications (Flamm et al., 2014b; Jones et al., 2011; Pfaller et al., 2012, 2014), indicating that ceftaroline in vitro activity remained stable against key bacterial species responsible for respiratory tract infection and SSSI since its approval for clinical use in the United States in 2010 (Teflaro™, 2012). In summary, the results of this investigation corroborate those of previous publications and indicate that ceftaroline continues to display potent in vitro activity against common bacterial pathogens from CARTI (100.0% susceptible) and SSSI isolated from US patients. Ceftaroline was particularly active against ceftriaxone-nonsusceptible S. pneumoniae and MRSA strains (0.0% resistance and 1.2% intermediate). Thus, ceftaroline continues to represent a valuable agent for treatment of CARTI and SSSI in the United States. Disclosures This study was supported by Cerexa, a wholly-owned subsidiary of Forest Laboratories. Forest Laboratories was involved in the design and decision to present these results. Forest Laboratories had no involvement in the collection, analysis, and interpretation of data. JMI Laboratories has also received research and educational grants in 2012–2014 from Achaogen, Actelion, Affinium, American Proficiency Institute, AmpliPhi Bio, Anacor, Astellas, AstraZeneca, Basilea, BioVersys, Cardeas, Cempra, Cubist, Daiichi, Dipexium, Durata, Fedora, Furiex, Genentech, GlaxoSmithKline, Janssen, Johnson & Johnson, Medpace, Meiji Seika Kaisha, Melinta, Merck, Methylgene, Nabriva, Nanosphere, Novartis, Pfizer, Polyphor, Rempex, Roche, Seachaid, Shionogi, Synthes, The Medicines Co., Theravance, ThermoFisher, Venatorx, Vertex, and Waterloo. Some JMI employees are advisors/consultants for Astellas, Cubist, Pfizer, Cempra, Cerexa-Forest, and Theravance. In regard to speakers bureaus and stock options—none to declare. Acknowledgments This study performed at JMI Laboratories was supported in part by an Educational/Research Grant from Forest/Cerexa, and JMI Laboratories received compensation fees for services in relation to preparing the manuscript, which was funded by the sponsor. The authors would

like to thank all AWARE participants for providing bacterial isolates for this surveillance program. References Clinical and Laboratory Standards Institute (CLSI). M07-A9. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard: ninth edition. Wayne, PA: CLSI; 2012. Clinical and Laboratory Standards Institute (CLSI). M100-S24. Performance standards for antimicrobial susceptibility testing: 24th informational supplement. Wayne, PA: CLSI; 2014. Critchley IA, Eckburg PB, Jandourek A, Biek D, Friedland HD, Thye DA. Review of ceftaroline fosamil microbiology: integrated FOCUS studies. J Antimicrob Chemother 2011;66(Suppl. 3):iii45–51. Dryden MS. Complicated skin and soft tissue infection. J Antimicrob Chemother 2010; 65(Suppl. 3):iii35–44. File Jr TM. Clinical implications and treatment of multiresistant Streptococcus pneumoniae pneumonia. Clin Microbiol Infect 2006;12(Suppl. 3):31–41. File Jr TM, Marrie TJ. Burden of community-acquired pneumonia in North American adults. Postgrad Med 2010;122:130–41. Flamm RK, Sader HS, Farrell DJ, Jones RN. Antimicrobial activity of ceftaroline tested against drug resistant subsets of Streptococcus pneumoniae from United States medical centers. Antimicrob Agents Chemother 2014a;58:2468–71. Flamm RK, Sader HS, Jones RN. Ceftaroline activity against organisms isolated from respiratory tract infections in USA hospitals: results from the AWARE Program, 2009–2011. Diagn Microbiol Infect Dis 2014b;78:437–42. Frampton JE. Ceftaroline fosamil: a review of its use in the treatment of complicated skin and soft tissue infections and community-acquired pneumonia. Drugs 2013;73: 1067–94. Jones RN, Farrell DJ, Mendes RE, Sader HS. Comparative ceftaroline activity tested against pathogens associated with community-acquired pneumonia: results from an international surveillance study. J Antimicrob Chemother 2011; 66(Suppl. 3):iii69–80. Karlowsky JA, Adam HJ, Baxter MR, Lagace-Wiens PR, Walkty AJ, Hoban DJ, et al. In vitro activity of ceftaroline-avibactam against gram-negative and grampositive pathogens isolated from patients in Canadian hospitals from 2010 to 2012: results from the CANWARD surveillance study. Antimicrob Agents Chemother 2013;57:5600–11. Kollef MH, Shorr A, Tabak YP, Gupta V, Liu LZ, Johannes RS. Epidemiology and outcomes of health-care–associated pneumonia: results from a large US database of culturepositive pneumonia. Chest 2005;128:3854–62. Lodise TP, Low DE. Ceftaroline fosamil in the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. Drugs 2012;72:1473–93. Pfaller MA, Farrell DJ, Sader HS, Jones RN. AWARE ceftaroline surveillance program (2008–2010); trends in resistance patterns among Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States. Clin Infect Dis 2012;55(Suppl. 3):S187–93. Pfaller MA, Flamm RK, Sader HS, Jones RN. Ceftaroline activity against bacterial organisms isolated from acute bacterial skin and skin structure infections in United States medical centers (2009–2011). Diagn Microbiol Infect Dis 2014;78:422–8. Stevens DL, Bisno AL, Chambers HF, Everett ED, Dellinger P, Goldstein EJ, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis 2005;41:1373–406. Teflaro™ Package Insert 2012. New York City, NY. Available at http://www.frx.com/pi/ Teflaro_pi.pdf. Accessed August 2013. Tygacil® Package Insert 2012. Wyeth Pharmaceuticals, Philadelphia, PA. Available at www.tygacil.com.

H.S. Sader et al. / Diagnostic Microbiology and Infectious Disease 82 (2015) 78–84 Table 4 Activity of ceftaroline and comparator antimicrobial agents when tested against most commonly organisms isolated from skin and soft tissue infections (USA, 2013). Antimicrobial agent organism (no. tested) Ceftaroline Oxacillin Erythromycin Clindamycin Levofloxacin TMP/SMXc Tigecyclined Linezolid Daptomycin Vancomycin β-Hemolytic streptococci (746)e Ceftaroline Penicillin Ceftriaxone Erythromycin Clindamycin Levofloxacin Linezolid Tetracycline Tigecyclined Daptomycin Vancomycin Escherichia coli (655) Ceftarolineb Ceftriaxone Ceftazidime Ampicillin/sulbactam Piperacillin/tazobactam Meropenem Levofloxacin Gentamicin Tigecyclined Klebsiella spp. (482)f Ceftarolinec Ceftazidime Ceftriaxone Ampicillin/sulbactam Piperacillin/tazobactam Meropenem Levofloxacin Gentamicin Tigecyclined

MIC (μg/mL)

%S/I/R

MIC50

MIC90

Range

(CLSI)a

0.5 N2 N16 ≤0.25 0.25 ≤0.5 0.06 1 0.25 1

1 N2 N16 N2 N4 ≤0.5 0.06 1 0.5 1

≤0.015–2 ≤0.25 to N2 ≤0.12 to N16 ≤0.25 to N2 ≤0.12 to N4 ≤0.5 to N4 0.015–0.25 ≤0.12–8 ≤0.06–1 0.25–2

99.4/0.6/0.0 49.0/0.0/51.0 36.4/2.5/61.1 79.5/0.1/20.4b 62.7/2.1/35.2 98.8/0.0/1.2 100.0/-/N99.9/0.0/b0.1 100.0/-/100.0/0.0/0.0

≤0.015 ≤0.06 ≤0.06 ≤0.12 ≤0.25 0.5 0.5 8 0.03 0.12 0.25

≤0.015 ≤0.06 0.12 N16 N2 1 1 N32 0.03 0.25 0.5

≤0.015–0.03 ≤0.06–0.12 ≤0.06–0.12 ≤0.12 to N16 ≤0.25 to N2 ≤0.12 to N4 0.25–1 0.06 to N32 ≤0.008–0.12 ≤0.06–0.5 ≤0.12–0.5

100.0/-/100.0/-/100.0/-/64.8/0.8/34.4 81.4/0.2/18.4 99.1/0.2/0.7 100.0/-/47.5/1.4/51.1 100.0/-/100.0/-/100.0/-/-

0.12 ≤0.06 0.12 8 2 ≤0.06 ≤0.12 ≤1 0.12

2 1 1 32 8 ≤0.06 N4 N8 0.12

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

87.2/2.0/10.8 90.1/0.1/9.8 93.9/2.0/4.1 50.8/22.7/26.5 96.6/2.0/1.4 100.0/0.0/0.0 70.7/0.9/28.4 88.7/0.3/10.9 100.0/0.0/0.0

0.12 0.12 ≤0.06 8 2 ≤0.06 ≤0.12 ≤1 0.25

16 4 8 32 16 ≤0.06 1 ≤1 0.5

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

84.2/2.8/12.9 90.7/0.2/9.1 88.2/0.3/11.4 73.9/12.3/13.7 91.0/2.3/6.7 96.9/0.0/3.1 90.7/1.0/8.3 93.8/1.2/5.0 99.2/0.8/0.0

TMP/SMX = trimethoprim/sulfamethoxazole. a Criteria as published by the CLSI (2014). b Includes constitutive (11.6%) and inducible (8.8%) resistance. c US-FDA breakpoints were applied when available (Tygacil®, 2012). d Includes Streptococcus agalactiae (348 strains), S. dysgalactiae (79 strains), and S. pyogenes (319 strains). e Includes Klebsiella oxytoca (163 strains) and K. pneumoniae (319 strains).

83

84

H.S. Sader et al. / Diagnostic Microbiology and Infectious Disease 82 (2015) 78–84

Fig. 3. Ceftaroline MIC distributions for isolates of ESBL phenotype (n = 152) and non-ESBL phenotype (n = 1297) Enterobacteriaceae from patients with SSSI (AWARE Program USA, 2013). Includes E. coli (655), K. pneumoniae (319), K. oxytoca (163), and P. mirabilis (312).