International Journal of Antimicrobial Agents 43 (2014) 284–286

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Short Communication

Ceftaroline activity tested against uncommonly isolated Gram-positive pathogens: report from the SENTRY Antimicrobial Surveillance Program (2008–2011) Helio S. Sader ∗ , Ronald N. Jones, Matthew G. Stilwell, Robert K. Flamm JMI Laboratories, 345 Beaver Kreek Center, Ste A, North Liberty, IA 52317, USA

a r t i c l e

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Article history: Received 24 May 2013 Accepted 4 October 2013 Keywords: Coagulase-negative staphylococci ␤-Haemolytic streptococci Viridans group streptococci

a b s t r a c t Ceftaroline was tested against 1859 clinically significant Gram-positive organisms from uncommonly isolated species. The organisms (31 species/groups) were collected from 133 medical centres worldwide over a 4-year period (2008–2011). Coagulase-negative staphylococci were generally susceptible to ceftaroline, with MIC50 values (minimum inhibitory concentration required to inhibit 50% of the isolates) of 0.06–0.5 mg/L. Ceftaroline was active against Micrococcus spp. [minimum inhibitory concentration required to inhibit 90% of the isolates (MIC90 ) = 0.06 mg/L], but showed more limited potency versus some Corynebacterium spp. and Listeria monocytogenes isolates. Ceftaroline was active against all ␤-haemolytic streptococci and viridans group streptococcal species/groups listed, with MIC50 and MIC90 values ranging from ≤0.015 mg/L to 0.03 mg/L and from ≤0.015 mg/L to 0.5 mg/L, respectively. Based on these in vitro findings, ceftaroline may have a potential role in the treatment of infections caused by these rarer species as guided by reference MIC test results. © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

1. Introduction Ceftaroline fosamil, the prodrug of ceftaroline, is a broadspectrum parenteral cephalosporin that was approved by the US Food and Drug Administration (FDA) for the treatment of acute bacterial skin and skin-structure infections and community-acquired bacterial pneumonia [1,2] and by the European Medicines Agency (EMA) for the treatment of complicated skin and soft-tissue infections (cSSTIs) and community-acquired pneumonia [3]. Ceftaroline has demonstrated potent in vitro bactericidal activity against resistant Gram-positive organisms, including meticillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae, as well as against common Gram-negative organisms [4,5]. Regulatory agencies and the Clinical and Laboratory Standards Institute (CLSI) have established ceftaroline breakpoint interpretive criteria for indicated staphylococcal and streptococcal species [2,6,7]. These criteria are very helpful for clinical laboratories in guiding therapy for serious Gram-positive infections; however, infections by less commonly encountered Gram-positive pathogens for which susceptibility data are not reported could also potentially benefit from ceftaroline as a treatment option when

∗ Corresponding author. Tel.: +1 319 665 3370; fax: +1 319 665 3371. E-mail address: [email protected] (H.S. Sader).

there is resistance or intolerance to other agents. To address this therapeutic possibility, here we present additional microbiological data on the spectrum of activity of ceftaroline by studying the compound against 31 Gram-positive species/groups that are clinically significant but less commonly isolated from contemporary clinical infections.

2. Material and methods A total of 1859 Gram-positive isolates was collected over a 4year period (2008–2011). The collection included 1273 streptococci [␤-haemolytic streptococci and viridans group streptococci (VGS)], 512 coagulase-negative staphylococci (CoNS) and 74 isolates from other Gram-positive species. The organisms were obtained from the SENTRY Antimicrobial Surveillance Program from infections cultured in 133 medical centres located worldwide as part of the AWARE (Assessing Worldwide Antimicrobial Resistance Evaluation) ceftaroline surveillance programme. The majority of isolates were from 79 US medical centres, whereas nine less common species isolates were obtained from worldwide hospital locations, including Corynebacterium spp., Listeria spp., Staphylococcus cohnii, Staphylococcus intermedius, Staphylococcus sciuri, Staphylococcus simulans, Staphylococcus xylosus, Streptococcus equisimilis and Streptococcus mutans. Isolates were primarily recovered from patients with bacteraemia (55%) and SSTIs (20%). Isolates were submitted to a reference monitoring laboratory where species

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H.S. Sader et al. / International Journal of Antimicrobial Agents 43 (2014) 284–286

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Table 1 Uncommonly isolated staphylococcal species and other Gram-positive pathogens (n = 586) tested by reference Clinical and Laboratory Standards Institute methods against ceftaroline. Organism (no. tested)

No. (cumulative %) inhibited at ceftaroline MIC in mg/L ≤0.015

Coagulase-negative staphylococci (512) S. auricularis (17) – S. capitis (65) 4 (6.2) – S. cohnii (15) – S. haemolyticus (66) – S. hominis (119) – S. lugdunensis (87) – S. saprophyticus (26) S. sciuri (18) – S. simulans (24) – – S. warneri (38) – S. xylosus (37) Other species (74) 1 (5.3) Corynebacterium spp. (19) a – Listeria monocytogenes (39) 1 (6.3) Micrococcus spp. (16)

MIC (mg/L)

0.03

0.06

0.12

0.25

0.5

1

2

1 (5.9) 11 (23.1) – – 2 (1.7) – – – 1 (4.2) 1 (2.6) 3 (8.1)

5 (35.3) 31 (70.8) 1 (6.7) 1 (1.5) 6 (6.7) 1 (1.1) 2 (7.7) – 4 (20.8) 10 (28.9) 3 (16.2)

6 (70.6) 6 (80.0) 7 (53.3) 9 (15.2) 22 (25.2) 21 (25.3) 2 (15.4) 3 (16.7) 11 (66.7) 12 (60.5) 4 (27.0)

4 (94.1) 4 (86.2) 5 (86.7) 13 (34.8) 31 (51.3) 57 (90.8) 16 (76.9) 9 (66.7) 6 (91.7) 5 (73.7) 21 (83.8)

0 (94.1) 9 (100.0) 2 (100.0) 19 (63.6) 40 (84.9) 8 (100.0) 6 (100.0) 2 (77.8) 2 (100.0) 9 (97.4) 6 (100.0)

1 (100.0) – – 10 (78.8) 18 (100.0) – – 3 (94.4) – 1 (100.0) –

– – – 14 (100.0) – – – 1 (100.0) – – –

1 (10.5) – 2 (18.8)

2 (21.1) – 12 (93.8)

5 (73.7) – –

0 (73.7) 1 (2.6) –

1 (78.9) 4 (12.8) –

2 (31.6) – 1 (100.0)

3 (47.4) – –

≥4 – – – – – – – – – – – 4 (100.0) 34 (100.0) –

MIC50

MIC90

0.12 0.06 0.12 0.5 0.25 0.25 0.25 0.25 0.12 0.12 0.25

0.25 0.5 0.5 2 1 0.25 0.5 1 0.25 0.5 0.5

0.5 4 0.06

>32 4 0.06

MIC, minimum inhibitory concentration; MIC50/90 , MIC required to inhibit 50% and 90% of the isolates, respectively. a Corynebacterium amycolatum (n = 6), C. aurimucosum (n = 1), C. jeikeium (n = 3), C. pseudodiptheriticum (n = 1) and C. striatum (n = 8).

identification was confirmed using matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF/MS) (Bruker Daltonik GmbH, Bremen, Germany), when necessary. Isolates were stored in trypticase soy broth with 15% glycerol in temperature-monitored −80 ◦ C freezers. Minimum inhibitory concentration (MIC) testing and susceptibility determination for ceftaroline and comparators used reference CLSI methods with concurrent quality control [8]. Cation-adjusted Mueller–Hinton broth (Thermo Fisher Scientific, Cleveland, OH) was supplemented with 2.5–5% lysed horse blood (Thermo Fisher Scientific) when testing fastidious streptococcal species. All quality control results were within published ranges for ceftaroline when testing S. aureus ATCC 29213 and S. pneumoniae ATCC 49619 [6,8].

3. Results Table 1 shows the ceftaroline MIC distributions and MIC50 and MIC90 values (MICs required to inhibit 50% and 90% of the isolates, respectively) from testing 512 CoNS isolates and 74 isolates from other Gram-positive species. CoNS species were generally very susceptible to ceftaroline, with a MIC50 of 0.06–0.5 mg/L. The most ceftaroline-susceptible species was Staphylococcus capitis (MIC50/90 = 0.06/0.5 mg/L), whereas higher ceftaroline MICs were observed among Staphylococcus haemolyticus (MIC50/90 = 0.5/2 mg/L) compared with other CoNS species. Ceftaroline was generally 2- to 16-fold more potent than vancomycin (MIC50/90 = 1/1–2 mg/L) when tested against CoNS (data not shown). Susceptibility to meticillin (oxacillin) varied broadly among CoNS species. The highest oxacillin susceptibility rate was observed for the Staphylococcus lugdunensis (95.4%), since this is the only CoNS species for which a higher susceptible breakpoint of ≤2 mg/L should be applied [6]. Oxacillin susceptibility was also relatively high for S. capitis (75.4%), whilst the lowest oxacillin susceptibility rates were observed among S. sciuri (5.7%), S. cohnii (6.7%), Staphylococcus saprophyticus (7.7%) and S. xylosus (18.9%). Oxacillin susceptibility rates for the remaining CoNS species were as follows: Staphylococcus auricularis, 47.9%; S. haemolyticus, 31.8%; Staphylococcus hominis, 30.3%; S. simulans, 45.8%; and Staphylococcus warneri, 47.4%. Ceftaroline was very active against Micrococcus spp. (MIC50/90 = 0.06/0.06 mg/L) but showed more limited activity versus some isolates of Corynebacterium spp.

(MIC50/90 = 0.5/ > 32 mg/L) and Listeria monocytogenes (MIC50/90 = 4/4 mg/L) (Table 1). Ceftaroline was highly active against all ␤-haemolytic streptococci (non-serogroups A and B) and VGS species/groups tested, with MIC50 and MIC90 values ranging from ≤0.015 mg/L to 0.03 mg/L and from ≤0.015 mg/L to 0.5 mg/L, respectively (Table 2). When tested against streptococci, the most ceftaroline-susceptible organisms were serogroup G, Streptococcus bovis group, Streptococcus dysgalactiae and Streptococcus gordonii (MIC90 ≤ 0.015 mg/L). In contrast, the highest ceftaroline MIC values (1 mg/L) were observed among Streptococcus oralis (MIC50/90 = 0.03/0.5 mg/L), Streptococcus mitis (MIC50/90 = 0.03/0.25 mg/L) and Streptococcus parasanguinis (MIC50/90 = 0.03/0.12 mg/L) (Table 2). The streptococcal species/groups less susceptible to penicillin were S. parasanguinis (MIC90 = 4 mg/L; 34.3% susceptible), Streptococcus salivarius/Streptococcus vestibularis (MIC90 = 0.5 mg/L; 42.9% susceptible), Streptococcus sanguinis (MIC90 = 1 mg/L; 62.9% susceptible), S. mitis (MIC90 = 2 mg/L; 65.5% susceptible) and S. oralis (MIC90 = 1 mg/L; 72.0% susceptible) (data not shown).

4. Discussion Ceftaroline has demonstrated potent in vitro activity against many common staphylococci and streptococci, such as S. aureus (including MRSA; MIC90 = 1 mg/L), CoNS (mainly Staphylococcus epidermidis; MIC90 = 0.5 mg/L), S. pneumoniae (MIC90 = 0.12 mg/L), ␤-haemolytic streptococci (MIC90 ≤ 0.03 mg/L) and VGS (MIC90 = 0.12 mg/L) in numerous investigations [4,5,9]. However, very limited information exists on the activity of ceftaroline tested against less frequently isolated Gram-positive species. CoNS represent an important cause of bacteraemia related to indwelling devices and most of these infections are hospitalacquired. Other important infections caused by CoNS include central nervous system shunt infections, native or prosthetic valve endocarditis, urinary tract infections and endophthalmitis [10]. CoNS species associated with human infections are usually resistant to oxacillin and other antimicrobials commonly used for the treatment of staphylococcal infections, leading to the frequent use of glycopeptides [11,12]. Serogroups C, F and G ␤-haemolytic streptococci can cause a wide array of infections, including upper respiratory tract infections, SSTIs, necrotising fasciitis, bacteraemia and endocarditis [13,14], whereas VGS represent a major cause of endocarditis as well as life-threatening bacteraemia with

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Table 2 Uncommon streptococcal species (n = 1273) tested against ceftaroline. Group/organism (no. tested)

Serogroup C (207) Serogroup F (56) Serogroup G (335) S. anginosus group S. anginosus (124) S. constellatus (44) S. intermedius (22) S. bovis group (47) a S. dysgalactiae group S. dysgalactiae (32) S. equisimilis (18) S. mitis group S. mitis (197) S. gordonii (13) S. oralis (25) S. parasanguinis (35) S. sanguinis (35) S. mutans group S. mutans (20) S. salivarius/S. vestibularis group (49) S. milleri group (14) b

No. (cumulative %) inhibited at ceftaroline MIC in mg/L ≤0.015

0.03

154 (74.4) 17 (30.4) 328 (97.9)

49 (98.1) 30 (83.9) 6 (99.7)

4 (100.0) 9 (100.0) 1 (100.0)

68 (94.4) 20 (75.0) 2 (95.5) –

7 (100.0) 10 (97.7) 1 (100.0) –

49 (39.5) 13 (29.5) 19 (86.4) 47 (100.0) 32 (100.0) 16 (88.9)

– 2 (100.0)

0.06

0.12

– –

89 (45.2) 12 (92.3) 7 (28.0) 17 (48.6) 24 (68.6)

50 (70.6) 1 (100.0) 11 (72.0) 6 (65.7) 6 (85.7)

26 (83.8) – 2 (80.0) 6 (82.9) 2 (91.4)

16 (80.0) 27 (55.1) 6 (42.9)

0 (80.0) 16 (87.8) 8 (100.0)

2 (90.0) 5 (98.0) –

MIC (mg/L) 0.25

0.5

1

MIC50

MIC90

– – –

– – –

– – –

– – –

≤0.015 0.03 ≤0.015

0.03 0.06 ≤0.015

– 0 (97.7) – –

– 1 (100.0) – –

– – – –

– – – –

0.03 0.03 ≤0.015 ≤0.015

0.03 0.06 0.03 ≤0.015

– –

– –

– –

– –

≤0.015 ≤0.015

≤0.015 0.03

2 (90.9) – 2 (88.0) 0 (91.4) 1 (100.0)

9 (95.4) – 2 (96.0) 0 (91.4) –

9 (100.0) – 1 (100.0) 3 (100.0) –

0.03 ≤0.015 0.03 0.03 ≤0.015

0.25 ≤0.015 0.5 0.12 0.06

– – –

– – –

– – –

≤0.015 ≤0.015 0.03

0.06 0.06 0.03

12 (89.8) – 0 (80.0) 3 (91.4) 2 (97.1) 2 (100.0) 1 (100.0) –

MIC, minimum inhibitory concentration; MIC50/90 , MIC required to inhibit 50% and 90% of the isolates, respectively. a Includes S. bovis group NOS (n = 31), S. gallolyticus (n = 13) and S. infantarius (n = 3). b Taxonomy unclear but most closely related to S. anginosus group.

septic shock in neutropenic patients. Furthermore, the management of severe VGS infections can be challenging due to increasing rates of penicillin resistance and the potential for in vivo development of resistance to glycopeptides [15]. The in vitro ceftaroline susceptibility results presented here document the wide potential clinical application to uncommonly isolated Gram-positive species. Ceftaroline exhibited potent in vitro activity against many rare Gram-positive pathogens for which susceptibility information is currently less available to guide therapy. Based on these findings, ceftaroline may have a potential role in the treatment of infections caused by these species as guided by reference MIC test results or published literature. Funding: This study was funded by educational/research grants from Cerexa, Inc. (Oakland, CA), a wholly owned subsidiary of Forest Laboratories, Inc. (New York, NY). Cerexa, Inc. was involved in the study design and decision to present the results. Cerexa, Inc. had no involvement in the collection, analysis or interpretation of data. Competing interests: JMI Laboratories, Inc. has received research and educational grants in 2010–2012 from Achaogen, Aires, American Proficiency Institute (API), Anacor, Astellas, AstraZeneca, bioMérieux, Cempra, Cerexa, ContraFect, Cubist, Dipexium, Enanta, Furiex, GlaxoSmithKline, Johnson & Johnson, LegoChem Biosciences Inc., Meiji Seika Kaisha, Nabriva, Novartis, Pfizer, PPD Therapeutics, Premier Research Group, Rempex, Rib-X Pharmaceuticals, Seachaid, Shionogi, The Medicines Co., Theravance, Thermo Fisher and some other corporations. Some JMI employees are advisors/consultants for Astellas, Cubist, Pfizer, Cempra, Cerexa-Forest and Theravance. Ethical approval: Not required. References [1] File Jr TM, Wilcox MH, Stein GE. Summary of ceftaroline fosamil clinical trial studies and clinical safety. Clin Infect Dis 2012;55(Suppl 3):S173–80. [2] Teflaro® prescribing information. Forest Laboratories, Inc.; 2012. http://www.frx.com/pi/Teflaro pi.pdf [accessed January 2013].

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