Antimicrobial Susceptibility Trends Among Staphylococcus aureus from United States Hospitals:

AAC Accepted Manuscript Posted Online 19 June 2017 Antimicrob. Agents Chemother. doi:10.1128/aac.01043-17 Copyright 2017 American Society for Microbiology. All Rights Reserved. 1 2 Antimicrobial Susceptibility Trends Among Staphylococcus aureus from United States Hospitals: Results from 7 Years of the Ceftaroline (AWARE) Surveillance Program (2010 2016) 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Running title: Antimicrobial susceptibility of S. aureus in the U.S. Helio S. Sader, Rodrigo E. Mendes, Jennifer M. Streit, Robert K. Flamm JMI Laboratories, North Liberty, Iowa, USA Key words: Methicillin-resistant Staphylococcus aureus, MRSA, skin and skin structure infection, ceftaroline, cephalosporin Contact Information: Helio S. Sader, M.D., Ph.D. JMI Laboratories 345 Beaver Kreek Centre, Suite A North Liberty, IA 52317 Phone: (319) 665-3370 Fax: (319) 665-3371 Email: helio-sader@jmilabs.com 1

32 33 34 35 36 37 38 39 40 41 Abstract We evaluated trends in Staphylococcus aureus antimicrobial susceptibility in United States hospitals in the 2010-2016 period. A total of 21,056 clinical isolates from 42 medical centers were tested for susceptibility by broth microdilution methods. MRSA rates decreased from 50.0% (2010) to 42.2% (2016). Susceptibility to erythromycin, levofloxacin, and clindamycin increased slightly, whereas susceptibility to ceftaroline, trimethoprim-sulfamethoxazole, and tetracycline remained stable. Ceftaroline retained potent activity against MSSA and MRSA (97.2% susceptible) with no marked variations. Count: 74 words. Downloaded from http://aac.asm.org/ on September 2, 2018 by guest 2

42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 Staphylococcus aureus and Escherichia coli represent the most common pathogens causing infection in hospitalized patients in the United States (U.S.) (1), and infections caused by antimicrobial-resistant S. aureus, especially methicillin-resistant (MRSA) strains, often occur in epidemic waves initiated by 1 or a few successful clones. These "epidemic waves" are not uniformly spread around the globe, but tend to be delimited somewhat by continent or smaller world regions (2, 3). Thus, the epidemiology of MRSA in U.S. hospitals is constantly changing, requiring continuous monitoring of its antimicrobial resistance profile (4). Ceftaroline fosamil (Teflaro ), prodrug of ceftaroline, was approved in 2010 by the U.S. Food and Drug Administration (FDA) for the treatment of acute bacterial skin and skin structure infections (ABSSSI) due to susceptible isolates of S. aureus (including methicillin-susceptible [MSSA] and MRSA isolates), Streptococcus pyogenes, Streptococcus agalactiae, E. coli, Klebsiella pneumoniae, and Klebsiella oxytoca. Ceftaroline fosamil was also approved for community-acquired bacterial pneumonia (CABP) due to Streptococcus pneumoniae (including cases with concurrent bacteremia), S. aureus (MSSA only), Haemophilus influenzae, K. pneumoniae, K. oxytoca, and E. coli (5, 6). The antimicrobial resistance surveillance program Assessing Worldwide Antimicrobial Resistance and Evaluation (AWARE) was designed to monitor the activity of ceftaroline and comparator agents and provides contemporary and longitudinal information on the activity of this agent against relevant pathogens. Previous reports from the AWARE program have provided analyses of ceftaroline activity against bacterial isolates recovered from indicated sites of infections, specific patient populations, and selected organism groups and resistant subsets, as well as yearly variation on its in vitro activity and potency (7-10). In this investigation we evaluated trends in S. aureus susceptibility rates to ceftaroline and comparators in the 2010-2016 period. Clinically significant bacterial isolates were consecutively collected (1/patient) from various infection types and all S. aureus isolates (n=21,056) were from patients hospitalized in medical centers that participated in the AWARE Program. Isolates were from 42 medical centers located in 30 states (from all 9 census divisions), including (number of medical centers): Alaska (1), Alabama (1), Arkansas (1), Colorado (1), Illinois (1), Indiana (1), Iowa (1), Kentucky (2), Louisiana (1), Maine (1), Massachusetts (1), Michigan (2), Minnesota (2), Missouri (1), Nebraska (1), New Jersey (2), New Mexico (1), New York (3), North Carolina (1), North Dakota (1), Ohio (3), Oregon (1), Pennsylvania (1), Tennessee (1), Texas (3), Utah (1), Vermont (1), Virginia (1), Washington (2), and Wisconsin (2). Forty of these 42 medical centers participated in the AWARE Program 3

70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 during the entire period of this investigation (2010-2016), and the remaining 2 centers contributed isolates from 2010-2015. Isolates were tested for susceptibility to ceftaroline and multiple comparator agents by reference broth microdilution methods as described by Clinical and Laboratory Standard Institute (CLSI) M07-A10, and susceptibility interpretations were based on CLSI (M100-S27) and/or U.S. FDA, as well as EUCAST breakpoint criteria (6, 11-14). A susceptible breakpoint of 1 μg/ml was applied for ceftaroline as indicated by CLSI and EUCAST and based on ceftaroline fosamil 600 mg q12h dosage (6). MIC panels were manufactured at JMI Laboratories (2015-2016) (North Liberty, Iowa, USA) or purchased from Thermo Fisher Scientific (2010-2014) (Cleveland, Ohio, USA). Organisms were tested in cationadjusted Mueller-Hinton broth (Thermo Fisher Scientific). Ceftaroline and comparator agents were tested simultaneously using the same bacterial inoculum and testing reagents. Concurrent testing of quality control (QC) strains assured proper test conditions. All QC results were within CLSI published ranges (12). Yearly variation of susceptibility rates was evaluated by using CLSI susceptible breakpoints (M100-S27) (12) and applying Chi-square test for trend with the EpiInfo TM 7 software. S. aureus isolates evaluated in this investigation were collected from patients with skin and skin structure infections (52.0%), pneumonia (23.9%), bloodstream infections (16.8%), and other infection types (7.3%). Ceftaroline inhibited all S. aureus strains at 2 µg/ml, except for 1 isolate collected in 2016 from a patient with complicated urinary tract infection with a ceftaroline MIC of 4 μg/ml. Furthermore, ceftaroline susceptibility rates remained stable during the study period, with a high of 99.4% in 2010 and a low of 98.1% in 2014; 98.7% overall (Tables 1 and 2). MRSA rates showed a clear decrease during the investigation, varying from 50.0% in 2010 to a low of 42.2% in 2016 (p<0.01; 46.0% overall; Tables 1 and 2). Susceptibility (per CLSI) to levofloxacin oscillated from a low of 61.5% in 2011 and 2013 to a high of 64.0% in 2012 and 2014. Susceptibility (per CLSI) to erythromycin varied from a low of 38.5% in 2013 to a high of 44.1% in 2016, with a strong trend toward higher susceptibility rates during the last 4 years of the investigation (2013-2016; p<0.01); whereas susceptibility (per CLSI) to clindamycin remained practically stable during the period of the investigation, varying from 83.7% in 2010 to 85.0% in 2016 (Table 2). Susceptibility (per CLSI) to tetracycline and trimethoprim-sulfamethoxazole (TMP- SMX) also remained stable during the period of the study (Table 2). 4

98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 When tested against MSSA, ceftaroline (MIC 50/90, 0.25/0.25 μg/ml; 100.0% susceptible) was 16-fold more active than ceftriaxone (MIC 50/90, 4/4 μg/ml; 100.0% susceptible; Table 1). MSSA susceptibility rates (per CLSI) remained stable for clindamycin (94.1/95.8% in 2010/2016), levofloxacin (88.6/89.3% in 2010/2016), and tetracycline (95.3/96.9% in 2010/2016), and oscillated from a low of 63.2% in 2012 to a high of 68.3% in 2010 for erythromycin (68.3/67.7% in 2010/2016), with no clear trend in any direction during the investigation (Table 2). Ceftaroline was very active against MRSA (MIC 50/90, 0.5/1 µg/ml; 97.2% susceptible overall; Table 1) with susceptibility rates varying from 98.8% in 2010 to 96.7% in 2016. The highest susceptibility rate (98.8%) was observed in 2010 and the lowest (95.6%) in 2014 (Table 2). MRSA susceptibility rates (per CLSI) for clindamycin and levofloxacin showed a decreasing trend from 2010 to 2016 to a low of 70.3% for clindamycin (p=0.01) and 28.6% for levofloxacin (p<0.01; Table 2). Daptomycin (MIC 50/90, 0.25/0.5 μg/ml; 99.9% susceptible), linezolid (MIC 50/90, 1/1 μg/ml; >99.9% susceptible), tigecycline (MIC 50/90, 0.06/0.12 μg/ml; >99.9% susceptible), vancomycin (MIC 50/90, 1/1 μg/ml; >99.9% susceptible), and TMP-SMX (MIC 50/90, 0.5/ 0.5 μg/ml; 97.7% susceptible) were also very active against MRSA overall (Table 1) with no marked variation during the study period (yearly data for TMP-SMX are presented in Table 2). Tetracycline also showed good and stable in vitro activity against MRSA over the years with susceptibility rates (per CLSI) varying from a low of 92.8% in 2015 to a high of 95.7% in 2016 (Table 2). MRSA epidemiology in the U.S. changed considerably as community-acquired MRSA (CA-MRSA) emerged and rapidly disseminated in the late 1990s (15). CA-MRSA was first noted as a genotypically distinct clone of MRSA (identified as USA300 by pulsed-field gel electrophoresis) that emerged as an important cause of SSSI as well as severe invasive syndromes in patients with no known exposure to a health care environment (3). The susceptibility pattern of USA300 was initially described as being susceptible to TMP-SMX, clindamycin, and tetracycline, but resistant to erythromycin and variably susceptible to the fluoroquinolones (16, 17); however, local spread of multidrug-resistant USA300 clones has been reported (18-20). Although USA300 is still the main S. aureus clone causing community-acquired and health careassociated infections in many parts of the U.S., its prevalence seems to be decreasing in some areas (4, 21). Chambers and DeLeo (2) have shown that the epidemiology of S. aureus is continually changing, with strains containing different antimicrobial susceptibility patterns replacing each other as the dominant clone. Thus, a 5

126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 decrease in the USA300 prevalence may result in changes in the antimicrobial resistance profiles of S. aureus, emphasizing the importance of monitoring this organism through large resistance surveillance programs. These investigation results clearly showed a continued decrease in MRSA rates between 2010 and 2016 in the hospitals participating in the AWARE program. Susceptibility to other agents, such as levofloxacin, clindamycin, and erythromycin, also showed some increase during the same period, whereas susceptibility to ceftaroline, TMP-SMX, and tetracycline remained stable. Furthermore, ceftaroline retained potent in vitro activity against MRSA (97.2% susceptible) and MSSA (100.0% susceptible) with no marked variations or trends (MIC creep) during the study period. It is also important to note that during this investigation, resistance to daptomycin, linezolid, vancomycin, or tigecycline remained extremely rare among S. aureus with no sign of increasing (data not shown). The absence of data on the incidence of S. aureus and MRSA infections in the medical centers that provided bacterial isolates represents a limitation of the study. Without incidence data it is not possible to evaluate if the decreased MRSA rates observed in this investigation were caused by a real decrease in the incidence of MRSA infections or by a proportional increase in the occurrence of MSSA infections. Another limitation of the study is the restricted number of medical centers included in the investigation. Despite these limitations, the results presented provide valuable information on the evolving S. aureus antimicrobial susceptibility patterns in the U.S. medical centers that participate in the AWARE program. 6

145 Acknowledgements 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 The authors would like to thank all participants of the Assessing Worldwide Antimicrobial Resistance and Evaluation (AWARE) Program for providing bacterial isolates. This study was supported by Allergan. Allergan was involved in the design and decision to present these results, and JMI Laboratories received compensation fees for services in relation to preparing this manuscript. Allergan was not involved in the collection, analysis, or interpretation of data. JMI Laboratories contracted to perform services in 2016 for Achaogen, Actelion, Allecra Therapeutics, Allergan, AmpliPhi Biosciences, API, Astellas Pharma, AstraZeneca, Basilea Pharmaceutica, Bayer AG, BD, Biomodels, Cardeas Pharma Corp., CEM-102 Pharma, Cempra, Cidara Therapeutics, Inc., CorMedix, CSA Biotech, Cutanea Life Sciences, Inc., Debiopharm Group, Dipexium Pharmaceuticals, Inc., Duke, Entasis Therapeutics, Inc., Fortress Biotech, Fox Chase Chemical Diversity Center, Inc., Geom Therapeutics, Inc., GSK, Laboratory Specialists, Inc., Medpace, Melinta Therapeutics, Inc., Merck & Co., Inc., Micromyx, MicuRx Pharmaceuticals, Inc., Motif Bio, N8 Medical, Inc., Nabriva Therapeutics, Inc., Nexcida Therapeutics, Inc., Novartis, Paratek Pharmaceuticals, Inc., Pfizer, Polyphor, Rempex, Scynexis, Shionogi, Spero Therapeutics, Symbal Therapeutics, Synlogic, TenNor Therapeutics, TGV Therapeutics, The Medicines Company, Theravance Biopharma, ThermoFisher Scientific, VenatoRx Pharmaceuticals, Inc., Wockhardt, Zavante Therapeutics, Inc. There are no speakers bureaus or stock options to declare. 7

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226 227 Table 1 Activity of ceftaroline and comparator antimicrobial agents when tested against 21,056 Staphylococcus aureus isolates (2010-2016) Organism / antimicrobial a CLSI agent (no. tested) MIC 50 MIC 90 S. aureus (21,056) EUCAST a %S %R %S %R Ceftaroline 0.25 1 98.7 <0.1 98.7 1.3 Ceftriaxone 4 >8 54.0 46.0 Oxacillin 1 >2 54.0 46.0 54.0 46.0 Erythromycin >4 >4 40.8 54.8 41.3 57.1 Clindamycin 0.25 >2 84.9 14.9 84.6 15.1 Levofloxacin 0.5 >4 63.1 35.5 63.1 36.9 TMP-SMX b 0.5 0.5 98.7 1.3 98.7 1.1 Tetracycline 0.5 0.5 95.4 3.9 93.8 5.3 Tigecycline 0.06 0.12 >99.9 c >99.9 <0.1 Linezolid 1 1 >99.9 <0.1 >99.9 <0.1 Vancomycin 1 1 >99.9 0.0 >99.9 <0.1 Daptomycin 0.25 0.5 99.9 99.9 0.1 MSSA (11,377) Ceftaroline 0.25 0.25 100.0 0.0 100.0 0.0 Ceftriaxone 4 4 Erythromycin 0.25 >4 66.0 28.4 66.5 31.2 Clindamycin 0.25 0.25 95.0 4.7 94.7 5.0 Levofloxacin 0.5 4 89.2 10.1 89.2 10.8 TMP-SMX b 0.5 0.5 99.5 0.5 99.5 0.4 Tetracycline 0.5 0.5 96.1 3.2 94.8 4.9 Tigecycline 0.06 0.12 100.0 c 100.0 0.0 Linezolid 1 1 >99.9 <0.1 >99.9 <0.1 Vancomycin 1 1 100.0 0.0 100.0 0.0 Daptomycin 0.25 0.5 >99.9 >99.9 <0.1 MRSA (9,679) Ceftaroline 0.5 1 97.2 <0.1 97.2 2.8 Erythromycin >4 >4 11.3 85.8 11.6 87.5 Clindamycin 0.25 >2 72.9 26.8 72.7 27.1 Levofloxacin 4 >4 32.6 65.3 32.6 67.4 TMP-SMX b 0.5 0.5 97.7 2.3 97.7 2.0 Tetracycline 0.5 1 94.6 4.8 92.5 5.9 11

228 229 230 231 232 Organism / antimicrobial a CLSI agent (no. tested) MIC 50 MIC 90 EUCAST a %S %R %S %R Tigecycline 0.06 0.12 >99.9 c >99.9 <0.1 Linezolid 1 1 >99.9 <0.1 >99.9 <0.1 Vancomycin 1 1 >99.9 0.0 >99.9 <0.1 Daptomycin 0.25 0.5 99.9 99.9 0.1 a Criteria as published by CLSI (12) and EUCAST (13) b TMP-SMX, trimethoprim-sulfamethoxazole c Breakpoints from US FDA Package Insert (14) Downloaded from http://aac.asm.org/ on September 2, 2018 by guest 12

233 Table 2. Staphylococcus aureus antimicrobial susceptibility stratified by year (2010-2016) 234 235 Organism/ % susceptible (CLSI) a year (no.) Ceftaroline Oxacillin Erythromycin Clindamycin Levofloxacin Tetracycline TMP-SMX b S. aureus 2010 (1,364) 99.4 50.0 40.2 83.7 62.0 95.3 98.5 2011 (1,370) 98.9 50.7 39.5 84.4 61.5 95.5 98.5 2012 (4,131) 98.9 53.6 38.7 85.3 64.0 95.2 98.8 2013 (4,123) 98.8 50.7 38.5 84.9 61.5 95.7 98.7 2014 (3,026) 98.1 55.3 42.8 84.9 64.0 94.9 98.9 2015 (3,506) 98.7 56.4 41.9 84.8 63.9 95.0 98.6 2016 (3,536) 98.6 57.8 44.1 85.0 63.7 96.4 98.5 MSSA 2010 (682) 100.0 100.0 68.3 94.1 88.6 95.3 99.3 2011 (695) 100.0 100.0 67.8 95.7 89.8 96.3 98.8 2012 (2,214) 100.0 100.0 63.2 94.4 89.2 95.6 99.5 2013 (2,092) 100.0 100.0 65.9 95.1 88.5 96.0 99.7 2014 (1,673) 100.0 100.0 67.9 95.1 89.8 95.7 99.4 2015 (1,978) 100.0 100.0 64.4 94.9 89.1 96.7 99.6 2016 (2,043) 100.0 100.0 67.7 95.8 89.3 96.9 99.7 MRSA 2010 (682) 98.8 0.0 12.0 73.2 35.3 95.3 97.8 2011 (675) 97.8 0.0 10.4 72.7 32.4 94.7 98.1 2012 (1,917) 97.7 0.0 10.3 74.8 34.9 94.7 98.0 2013 (2,031) 97.6 0.0 10.5 74.4 33.6 95.5 97.6 2014 (1,353) 95.6 0.0 11.8 72.3 32.2 93.8 98.3 2015 (1,528) 97.0 0.0 12.7 71.8 31.3 92.8 97.3 2016 (1,493) 96.7 0.0 11.9 70.3 28.6 95.7 96.9 a Criteria as published by CLSI (12) b TMP-SMX, trimethoprim-sulfamethoxazole 13