Advertisement

Ceftaroline activity against Staphylococcus aureus isolated from patients with infective endocarditis, worldwide (2010–2019)

Open AccessPublished:November 15, 2020DOI:https://doi.org/10.1016/j.ijid.2020.11.130

      Highlights

      • 23,833 S. aureus isolates were collected from patients with bloodstream infection.
      • The samples included 396 isolates from patients with infective endocarditis (IE).
      • Isolates were collected from 340 medical centers worldwide, from 2010 to 2019.
      • Oxacillin resistance was 29.0% among IE isolates, and was highest in North America.
      • Ceftaroline was active against 95.2% of IE isolates (MIC50/90, 0.25/1 mg/L).

      Abstract

      Objective

      To evaluate the antimicrobial activity of ceftaroline against Staphylococcus aureus isolated from patients with infective endocarditis (IE).

      Methods

      23,833 S. aureus isolates were collected consecutively from patients with bloodstream infections (BSI) from 2010 to 2019, via the SENTRY Antimicrobial Surveillance Program, including 396 isolates from patients with a diagnosis of IE. Isolates were collected from 340 medical centers worldwide and susceptibility tested by reference broth microdilution in a monitoring laboratory.

      Results

      The oxacillin resistance (MRSA) rate was 29.0% among IE isolates, and was higher in North America (40.3%) than in Europe (25.4%) or the Latin America/Asia-Pacific region (LATAM-APAC; 18.6%). Ceftaroline was active against 95.2% of IE isolates (MIC50/90, 0.25/1 mg/L), with ceftaroline susceptibility higher in North America (99.2%) and LATAM-APAC (98.3%) than in Europe (92.0%). Among MRSA isolates from IE (n = 115; MIC50/90, 1/2 mg/L), ceftaroline susceptibility was 98.0% in North America, 90.9% in LATAM-APAC, and 68.5% in Europe. Among BSI isolates, MRSA rates were 43.6% in North America and 25.6% in Europe, while ceftaroline susceptibility rates were 98.1% in North America and 95.4% in Europe.

      Conclusions

      Ceftaroline demonstrated potent in vitro activity against a large collection of S. aureus isolates recovered from patients with BSI, including IE.

      Keywords

      Introduction

      Infective endocarditis (IE) is a disease with high morbidity and mortality that affects 1.5–11.6 people per 100,000 per year (
      • Harky A.
      • Zaim S.
      • Mallya A.
      • George J.J.
      Optimizing outcomes in infective endocarditis: a comprehensive literature review.
      ). While Streptococcus viridans was initially reported as the most common cause of IE, Staphylococcus aureus, which is most often associated with invasive procedures and healthcare contact, has now overtaken streptococci as the most common cause of IE (
      • Fowler Jr., V.G.
      • Miro J.M.
      • Hoen B.
      • Cabell C.H.
      • Abrutyn E.
      • Rubinstein E.
      • et al.
      Staphylococcus aureus endocarditis: a consequence of medical progress.
      ). This change is a cause for concern, since S. aureus has a more acute presentation with worse prognosis. Prosthetic valve IE and staphylococcal IE are associated with an increased risk of in-hospital death, while viridans streptococcal IE is associated with a decreased risk (
      • Murdoch D.R.
      • Corey G.R.
      • Hoen B.
      • Miro J.M.
      • Fowler Jr., V.G.
      • Bayer A.S.
      • et al.
      Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study.
      ).
      Ceftaroline fosamil is an advanced-generation cephalosporin active against methicillin-susceptible (MSSA) and methicillin-resistant S. aureus (MRSA). It was approved in October 2010 by the United States Food and Drug Administration (US FDA) for the treatment of adults with community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections (ABSSSI). In 2015, the US FDA approved a label expansion to include clinical data from patients with S. aureus bacteremia. In 2016, ceftaroline fosamil was approved for pediatric use with the same indications (
      • Pani A.
      • Colombo F.
      • Agnelli F.
      • Frantellizzi V.
      • Baratta F.
      • Pastori D.
      • et al.
      Off-label use of ceftaroline fosamil: a systematic review.
      ).
      Many reports have shown that ceftaroline is also effective in treating patients with bloodstream infections (BSI) and IE (
      • Casapao A.M.
      • Davis S.L.
      • Barr V.O.
      • Klinker K.P.
      • Goff D.A.
      • Barber K.E.
      • et al.
      Large retrospective evaluation of the effectiveness and safety of ceftaroline fosamil therapy.
      ,
      • Destache C.J.
      • Guervil D.J.
      • Kaye K.S.
      Ceftaroline fosamil for the treatment of Gram-positive endocarditis: CAPTURE study experience.
      ,
      • Ho T.T.
      • Cadena J.
      • Childs L.M.
      • Gonzalez-Velez M.
      • Lewis 2nd, J.S.
      Methicillin-resistant Staphylococcus aureus bacteraemia and endocarditis treated with ceftaroline salvage therapy.
      ,
      • Lin J.C.
      • Aung G.
      • Thomas A.
      • Jahng M.
      • Johns S.
      • Fierer J.
      The use of ceftaroline fosamil in methicillin-resistant Staphylococcus aureus endocarditis and deep-seated MRSA infections: a retrospective case series of 10 patients.
      ,
      • Polenakovik H.M.
      • Pleiman C.M.
      Ceftaroline for meticillin-resistant Staphylococcus aureus bacteraemia: case series and review of the literature.
      ,
      • Tattevin P.
      • Boutoille D.
      • Vitrat V.
      • Van Grunderbeeck N.
      • Revest M.
      • Dupont M.
      • et al.
      Salvage treatment of methicillin-resistant staphylococcal endocarditis with ceftaroline: a multicentre observational study.
      ,
      • White B.P.
      • Barber K.E.
      • Stover K.R.
      Ceftaroline for the treatment of methicillin-resistant Staphylococcus aureus bacteremia.
      ). The CAPTURE retrospective study reported an overall clinical success rate of 70.9% among 55 patients with Gram-positive endocarditis treated with ceftaroline. Interestingly, patients treated with ceftaroline as first-line therapy had a high success rate (75.0%), as did patients who had right-sided endocarditis (80.8%) and patients with MRSA infection (77.3%) (
      • Destache C.J.
      • Guervil D.J.
      • Kaye K.S.
      Ceftaroline fosamil for the treatment of Gram-positive endocarditis: CAPTURE study experience.
      ). Tattevin et al. reported a series of eight consecutive observations of ceftaroline use as salvage treatment for methicillin-resistant staphylococcal endocarditis in France. Results showed a positive outcome for five patients, and immediate clearance of blood cultures after ceftaroline initiation in seven of the eight patients (
      • Tattevin P.
      • Boutoille D.
      • Vitrat V.
      • Van Grunderbeeck N.
      • Revest M.
      • Dupont M.
      • et al.
      Salvage treatment of methicillin-resistant staphylococcal endocarditis with ceftaroline: a multicentre observational study.
      ). Our study evaluated the in vitro activity of ceftaroline against a large collection of S. aureus isolates recovered from patients hospitalized with IE worldwide. We also compared the antimicrobial susceptibility of the S. aureus from IE with the entire collection of S. aureus from BSI.

      Materials and methods

      Bacterial isolates

      The SENTRY Antimicrobial Surveillance Program collected 23,833 S. aureus isolates from patients with bloodstream infections in medical centers located in North America (11,900 isolates from 176 medical centers in the US and Canada), Europe (7772 isolates from 83 centers in 24 countries), and Latin America and the Asia-Pacific region (LATM-APAC; 4161 isolates from 81 medical centers in 26 countries). The isolates were collected consecutively between January 2010 and December 2019. Only one isolate per infection episode was included in the program. Isolates were determined to be clinically significant based on local guidelines, and were submitted to a central monitoring laboratory (JMI Laboratories, North Liberty, Iowa, USA) along with limited demographic information, which included the source of BSI. Among those 23,833 isolates, 396 were recovered from patients with a diagnosis of IE, including 124 isolates from North America (19 US medical centers), 213 isolates from Europe (34 medical centers in 16 countries), and 59 isolates from LATAM-APAC (22 centers in 11 countries). Each participating laboratory initially identified the isolates, which were confirmed by the reference monitoring laboratory through standard algorithms, supported by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (Bruker Daltonics, Bremen, Germany).

      Antimicrobial susceptibility testing

      Isolates were susceptibility tested by broth microdilution at JMI Laboratories, following guidelines in the CLSI M07 (
      • CLSI
      M07Ed11. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard: Eleventh Edition.
      ) and using 96-well reference panels manufactured by JMI Laboratories (2015–19) or acquired from Thermo Fisher (Cleveland, Ohio, USA; 2010–14). All isolates were tested at JMI Laboratories. Quality assurance was performed by concurrently testing CLSI-recommended quality control (QC) reference strains, S. aureus ATCC 29213 and Enterococcus faecalis ATCC 29212. All QC results were within published acceptable ranges. US FDA and CLSI breakpoints were applied for ceftaroline (susceptible at ≤1 mg/L) and comparator agents (
      • CLSI
      M100Ed30. Performance Standards for Antimcirobial Susceptibility Testing: 30th Informational Supplement.
      ).

      Results and discussion

      Ceftaroline was active against 95.2% of IE isolates (MIC50/90, 0.25/1 mg/L). Ceftaroline susceptibility was higher in North America (MIC50/90, 0.25/1 mg/L; 99.2% susceptible) and LATAM-APAC (MIC50/90, 0.25/0.5 mg/L; 98.3% susceptible) than in Europe (MIC50/90, 0.25/1 mg/L; 92.0% susceptible) (Table 1, Table 2). The overall oxacillin resistance (MRSA) rate among IE isolates was 29.0%, with MRSA rate higher in North America (40.3%) than in Europe (25.4%) and LATAM-APAC (18.6%) (Table 2).
      Table 1Summary of ceftaroline activity tested against S. aureus isolates from infective endocarditis and bloodstream infections (2010–2019).
      Organism/infectionNo. of isolates (cumulative %)
      Values in bold indicate susceptible percentage.
      inhibited at a ceftaroline MIC (mg/L) of:
      MIC (mg/L)
      type (no. tested)0.060.120.250.5124850%90%
      Infective endocarditis (396)5 (1.3)35 (10.1)230 (68.2)64 (84.3)43 (95.2)19 (100.0)0.251
      MSSA (281)5 (1.8)35 (14.2)226 (94.7)15 (100.0)0.250.25
      MRSA (115)4 (3.5)49 (46.1)43 (83.5)19 (100.0)12
       North America (124)1(0.8)10 (8.9)59 (56.5)32 (82.3)21 (99.2)1 (100.0)0.251
      MSSA (74)1 (1.4)10 (14.9)57 (91.9)6 (100.0)0.250.25
      MRSA (50)2 (4.0)26 (56.0)21 (98.0)1 (100.0)0.51
       Europe (213)4 (1.9)21 (11.7)127 (71.4)25 (83.1)19 (92.0)17 (100.0)0.251
      MSSA (159)4 (2.5)21 (15.7)125 (94.3)9 (100.0)0.250.25
      MRSA (54)2 (3.7)16 (33.3)19 (68.5)17 (100.0)12
       LATAM-APAC (59)0 (0.0)4 (6.8)44 (81.4)7 (93.2)3 (98.3)1 (100.0)0.250.5
      MSSA (48)4 (8.3)44 (100.0)0.250.25
      MRSA (11)7 (63.6)3 (90.9)1 (100.0)0.51
      Bloodstream infections (23,833)123 (0.5)1913 (8.5)12 848 (62.4)4233 (80.2)3768 (96.0)928 (99.9)15 (>99.9)5 (100.0)0.251
      MSSA (15 188)122 (0.8)1907 (13.4)12 669 (96.8)488 (>99.9)2 (100.0)0.250.25
      MRSA (8645)1 (<0.1)6 (0.1)179 (2.2)3745 (45.5)3766 (89.0)928 (99.8)15 (99.9)5 (100.0)12
       North America (11 900)52 (0.4)882 (7.8)5681 (55.6)2827 (79.3)2232 (98.1)225 (>99.9)1 (100.0)0.251
      MSSA (6712))51 (0.8)878 (13.8)5564 (96.7)219 (100.0)0.250.25
      MRSA (5188)1 (<0.1)4 (0.1)117 (2.4)2608 (52.6)2232 (95.6)225 (>99.9)10.51
       Europe (7772)66 (0.8)792 (11.0)4791 (72.7)812 (83.1)957 (95.4)350 (99.9)3 (>99.9)1 (100.0)0.251
      MSSA (5781)66 (1.1)790 (14.8)4748 (96.9)176 (>99.9)1 (100.0)0.250.25
      MRSA (1991)2 (0.1)43 (2.3)636 (34.2)956 (82.2)350 (99.8)3 (99.9)1 (100.0)12
       LATAM-APAC (4161)5 (0.1)239 (5.9)2376 (63.0)594 (77.2)579 (91.1)353 (99.6)11 (99.9)4 (100.0)0.251
      MSSA (2695)5 (0.2)239 (9.1)2357 (96.5)93 (>99.9)1 (100.0)
      MRSA (1466)19 (1.3)501 (35.5)578 (74.9)353 (99.0)11 (99.7)4 (100.0)12
      Abbreviations: MSSA, methicillin-susceptible S. aureus; MRSA, methicillin-resistant S. aureus; LATAM-APAC, Latin America and Asia-Pacific region.
      a Values in bold indicate susceptible percentage.
      Table 2Antimicrobial activity of ceftaroline and comparator agents tested against S. aureus from infective endocarditis and bloodstream infections (2010–2019).
      Antimicrobial agent/ infection typeMIC in mg/L% susceptible by region (no. of isolates)
      Criteria as published by CLSI (2020).
      MIC50MIC90NAEURLATAM-APACAll regions
      Infective endocarditis(124)(213)(59)(396)
       Ceftaroline0.25199.292.098.395.2
       Oxacillin0.5>259.774.681.471.0
       Clindamycin≤0.25>283.791.593.289.4
       Dalbavancin≤0.030.06100.0100.0100.0100.0
       Daptomycin0.250.5100.0100.0100.0100.0
       Doxycycline≤0.060.2598.499.596.698.7
       Erythromycin≤0.25>445.274.684.766.9
       Levofloxacin≤0.5>471.873.791.575.8
       Linezolid12100.0100.0100.0100.0
       Minocycline≤0.060.1298.6100.0100.099.5
       Teicoplanin≤2≤2100.0100.0100.0100.0
       Tetracycline≤0.5≤0.594.494.883.192.9
       Trimethoprim-sulfamethoxazole≤0.5≤0.599.2100.094.999.0
       Vancomycin11100.0100.0100.0100.0
      Bloodstream infections(11 900)(7772)(4161)(23,833)
       Ceftaroline0.25198.195.491.196.0
       Oxacillin0.5>256.474.464.863.7
       Clindamycin≤0.25>282.991.178.784.9
       Dalbavancin≤0.030.06>99.9100.0>99.9>99.9
       Daptomycin0.250.599.9>99.9>99.999.9
       Doxycycline0.120.2598.598.195.297.8
       Erythromycin≤0.25>443.472.661.356.0
       Levofloxacin≤0.5>461.374.874.167.9
       Linezolid12100.0100.0100.0100.0
       Minocycline≤0.060.1298.999.597.598.9
       Teicoplanin≤2≤2100.0>99.9100.0>99.9
       Tetracycline≤0.5195.692.485.192.7
       TMP-SMX≤0.5≤0.597.999.496.398.1
       Vancomycin11100.0100.0100.0100.0
      Abbreviations: TMP-SMX, Trimethoprim-sulfamethoxazole; NA, North America; EUR, Europe; LATAM-APAC, Latin America and Asia-Pacific regions.
      a Criteria as published by
      • CLSI
      M100Ed30. Performance Standards for Antimcirobial Susceptibility Testing: 30th Informational Supplement.
      ).
      All ceftaroline nonsusceptible MRSA isolates from patients with IE (n = 19) had a ceftaroline MIC of 2 mg/L. Thus, it is important to note that the results from a phase 3 randomized, controlled, non-inferiority trial showed that ceftaroline fosamil 600 mg administered every 8 h with 2-h infusions was effective and well tolerated in the treatment of patients with complicated skin and skin structure infections, and could provide adequate exposure against S. aureus with ceftaroline MIC values of ≤4 mg/L (
      • Das S.
      • Li J.
      • Iaconis J.
      • Zhou D.
      • Stone G.G.
      • Yan J.L.
      • et al.
      Ceftaroline fosamil doses and breakpoints for Staphylococcus aureus in complicated skin and soft tissue infections.
      ). Based on the results of this trial, both CLSI and EUCAST have changed ceftaroline breakpoints to include an intermediate of 2 mg/L (EUCAST) or a susceptible dose-dependent range of 2–4 mg/L (CLSI) (
      • Sader H.S.
      • Jones R.N.
      Impact of EUCAST, CLSI and USCAST ceftaroline breakpoint changes on the susceptibility of methicillin-resistant Staphylococcus aureus isolates collected from US medical centres (2015–2018).
      ,
      • Urban E.
      • Stone G.G.
      Impact of EUCAST ceftaroline breakpoint change on the susceptibility of methicillin-resistant Staphylococcus aureus isolates collected from patients with complicated skin and soft-tissue infections.
      ).
      The highest ceftaroline MIC value among MSSA isolates from IE was 0.5 mg/L (n = 281; MIC50/90, 0.25/0.25 mg/L; 100.0% susceptible). Among MRSA isolates from IE, ceftaroline MIC values were lower in North America (n = 50; MIC50/90, 0.5/1 mg/L; 98.0% susceptible) and LATAM-APAC (n = 11; MIC50/90, 0.5/1 mg/L; 90.9% susceptible) compared with Europe (n = 54; MIC50/90, 1/2 mg/L; 68.5% susceptible) (Table 1). In general, most MRSA isolates had ceftaroline MIC values of 0.5 mg/L or 1 mg/L (n = 115; MIC50/90, 1/2 mg/L; 83.5% susceptible overall) (Table 1).
      Dalbavancin (MIC50/90, ≤0.03/0.06 mg/L), daptomycin (MIC50/90, 0.25/0.5 mg/L), linezolid (MIC50/90, 1/2 mg/L), teicoplanin (MIC50/90, ≤2/≤2 mg/L), and vancomycin (MIC50/90, 1/1 mg/L) exhibited complete activity (100.0% susceptible) against S. aureus from IE (Table 2).
      Isolates from all BSI combined (n = 23,833; MIC50/90, 0.25/1 mg/L; 96.0% susceptible) exhibited ceftaroline susceptibility similar to isolates from IE (Table 1). All MSSA isolates from BSI (n = 15,188; MIC50/90, 0.25/0.25 mg/L) were susceptible to ceftaroline, whereas for MRSA isolates, ceferoline susceptibility rates were 95.6% in North America (MIC50/90, 0.5/1 mg/L), 82.2% in Europe (MIC50/90, 1/2 mg/L), and 74.9% in LATAM-APAC (MIC50/90, 1/2 mg/L) (Table 1). Only 20 of the 23,833 BSI isolates (<0.1%) exhibited ceftaroline MICs >2 mg/L (Table 1); 15 isolates had ceftaroline MICs of 4 mg/L (one from the US, three from Italy, and 11 from LATAM-APAC, including Hong Kong [one], Japan [two], Peru [two], South Korea [four], and Thailand [two]), and five isolates displayed ceftaroline MICs of 8 mg/L (one from Spain, one from South Korea, and three from Thailand; data not shown).
      Although susceptibility to ceftaroline among IE isolates was higher in North America (99.2%) compared with Europe (92.0%) and LATAM-APAC (98.3%), susceptibility to other drugs, such as oxacillin, clindamycin, erythromycin, and levofloxacin, were lower in North America compared with Europe and LATAM-APAC (Table 2). Oxacillin susceptibility rates among IE/BSI isolates were 59.7%/56.4% in North America, 74.6%/74.4% in Europe, and 81.4%/64.8% in LATAM-APAC (Table 2). Dalbavancin (MIC50/90, ≤0.03/0.06 mg/L), daptomycin (MIC50/90, 0.25/0.5 mg/L), linezolid (MIC50/90, 1/2 mg/L), teicoplanin (MIC50/90, ≤2/≤2 mg/L), and vancomycin (MIC50/90, 1/1 mg/L) were active against ≥99.9% of S. aureus from BSI (Table 2).
      Ceftaroline and oxacillin susceptibility rates among BSI isolates from North America oscillated with no significant yearly changes or clear trend during the 10-year study period (Table 3). The highest ceftaroline susceptibility rate was observed in 2010 (99.5%) and the lowest in 2018 (96.1%, which increased to 98.1% in 2019). Oxacillin susceptibility in North America ranged from a low of 54.4% in 2011 to a high of 60.6% in 2017 (Table 3). Ceftaroline susceptibility rates showed more variability in Europe and LATAM-APAC than in North America. Ceftaroline susceptibility was particularly low in 2014 in Europe (91.8%) and, in the remaining years (excluding 2014), ranged from a low of 93.5% in 2017 to a high of 97.2% in 2019 (Table 3). The low ceftaroline susceptibility rate observed in Europe in 2014 was driven by high numbers of ceftaroline nonsusceptible isolates reported from Italy, Portugal, and Romania. Ceftaroline susceptibility rates were 78.7% in Italy, 55.0% in Portugal, and 69.2% in Romania, and elsewhere ranged from 94.1% (Russia) to 100.0% (Belgium, Czech Republic, France, Greece, Hungary, Slovenia, Sweden, UK, and Ukraine) in Europe in 2014 (data not shown). Susceptibility to oxacillin in Europe was lowest in 2011 (71.4%) and highest in 2019 (77.6%) (Table 3).
      Table 3Yearly susceptibility rates for ceftaroline (CPT) and oxacillin (OXA) stratified by region.
      Year (no. for all regions)% susceptible
      Criteria as published by CLSI (2020).
      North AmericaEuropeLATAM-APAC
      Includes isolates from 26 countries located in Latin America and the Asia-Pacific region.
      CPTOXACPTOXACPTOXA
      2019 (1614)98.158.397.277.694.870.6
      2018 (1644)96.156.994.875.996.871.8
      2017 (1960)97.060.693.575.695.070.1
      2016 (2339)98.058.297.172.893.472.3
      2015 (2167)97.755.795.874.194.269.9
      2014 (1629)97.654.991.8
      Low susceptibility in Europe in 2014 was mainly due to low rates in Italy, Portugal, and Romania.
      72.5
      Isolates from bloodstream infections were not collected in these regions in 2014.
      Isolates from bloodstream infections were not collected in these regions in 2014.
      2013 (2438)98.258.695.578.288.960.6
      2012 (2119)96.956.294.572.689.065.7
      2011 (2934)99.054.495.271.488.159.7
      2010 (4989)99.554.696.974.290.159.5
      Abbreviations: CPT, ceftaroline; OXA, oxacillin.
      a Criteria as published by
      • CLSI
      M100Ed30. Performance Standards for Antimcirobial Susceptibility Testing: 30th Informational Supplement.
      ).
      b Includes isolates from 26 countries located in Latin America and the Asia-Pacific region.
      c Low susceptibility in Europe in 2014 was mainly due to low rates in Italy, Portugal, and Romania.
      d Isolates from bloodstream infections were not collected in these regions in 2014.
      Among the BSI isolates from LATAM-APAC, susceptibility rates to ceftaroline and oxacillin were much lower in the first four years of the investigation (2010–2013) compared with the last five years (2015–2019; isolates from BSI were not collected from these regions in 2014). The occurrence of lower susceptibility rates in the first four years was due to the fact that some countries with very high rates of resistance in general, such as China, India, and Indonesia, contributed isolates only between 2010 and 2013. Susceptibility rates ranged from 93.4% (2016) to 96.8% (2018) for ceftaroline, and from 69.3% (2015) to 72.3% (2016) for oxacillin in LATAM-APAC in 2015–2019 (Table 3).
      In summary, ceftaroline demonstrated potent in vitro activity against a large collection of S. aureus isolates recovered from patients with BSI, including IE. Ceftaroline in particular was active against MRSA from North American medical centers. Our results corroborated those of other investigations. Zhang et al. evaluated ceftaroline in vitro activity against 61,045 S. aureus isolates, including 35,837 MRSA, collected in 2012–2017 from medical centers located in the US, Europe, South America, APAC, and the Africa/West Asia region as part of the ATLAS program (
      • Zhang Z.
      • Chen M.
      • Yu Y.
      • Liu B.
      • Liu Y.
      In vitro activity of ceftaroline and comparators against Staphylococcus aureus isolates: results from 6 years of The ATLAS Program (2012 to 2017).
      ). Overall, 90.3% of MRSA isolates were susceptible to ceftaroline (MIC50/90, 0.5/2 mg/L), and ceftaroline susceptibility rates were highest in the US (99.5%), followed by Europe (94.0%), Africa-West Asia (92.3%), South America (84.4%), and APAC (75.9%) (
      • Zhang Z.
      • Chen M.
      • Yu Y.
      • Liu B.
      • Liu Y.
      In vitro activity of ceftaroline and comparators against Staphylococcus aureus isolates: results from 6 years of The ATLAS Program (2012 to 2017).
      ).
      Our results also showed a considerable geographical variation in ceftaroline activity against MRSA, with higher susceptibility rates in North America compared with Europe and LATAM-APAC. Similar geographical variations have been reported previously, likely related to MRSA clonality. Ceftaroline potency (MIC value) against MRSA varies according to the SCCmec type, and is highest (lowest MIC values) against isolates carrying SCCmec type IV, followed by types II, III, and I (
      • Lahiri S.D.
      • McLaughlin R.E.
      • Whiteaker J.D.
      • Ambler J.E.
      • Alm R.A.
      Molecular characterization of MRSA isolates bracketing the current EUCAST ceftaroline-susceptible breakpoint for Staphylococcus aureus: the role of PBP2a in the activity of ceftaroline.
      ,
      • Sader H.S.
      • Rhomberg P.R.
      • Doyle T.B.
      • Flamm R.K.
      • Mendes R.E.
      Evaluation of the revised ceftaroline disk diffusion breakpoints when testing a challenge collection of methicillin-resistant Staphylococcus aureus isolates.
      ). Since a relatively small number of pandemic MRSA clones have caused a majority of MRSA infections worldwide, and a few specific clones tend to disseminate and predominate in a geographical region, the in vitro activity of ceftaroline varies by geographical region based on the SCCmec types of clone that predominate in that particular region (
      • Robinson D.A.
      • Enright M.C.
      Evolutionary models of the emergence of methicillin-resistant Staphylococcus aureus.
      ,
      • Sader H.S.
      • Rhomberg P.R.
      • Doyle T.B.
      • Flamm R.K.
      • Mendes R.E.
      Evaluation of the revised ceftaroline disk diffusion breakpoints when testing a challenge collection of methicillin-resistant Staphylococcus aureus isolates.
      ).
      The surveillance data we present in this report do have limitations. During the 10-year period of the SENTRY Program evaluated here, some medical centres, or some countries, did not participate every year. This inconsistency may have caused a slight skew in the data analysis. As participating centers leave the program, additional centers from that region are added, with the goal of maintaining a robust and broadly representative sample from as many countries and regions as possible. Another limitation of this investigation was the fact that the criteria used to categorize a bacterial isolate as ‘clinically significant’ was not defined in the study protocol; instead, this definition was based on local infectious disease algorithms, which may have varied among participating medical centres. Despite the study limitations, these results provide invaluable information about the antimicrobial susceptibility of S. aureus causing BSI and IE in global medical centers.
      Due to their bactericidal activity and a safety profile that allows the use of high doses, the β-lactams are the first-line agents for the treatment of IE (
      • Baddour L.M.
      • Wilson W.R.
      • Bayer A.S.
      • Fowler Jr, V.G.
      • Tleyjeh I.M.
      • Rybak M.J.
      • et al.
      Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association.
      ). However, a β-lactam effective against MRSA was not available until the approval of ceftaroline. The use of anti-MRSA agents recommended for IE, such as vancomycin and daptomycin, can be limited by poor tolerance, elevated MICs, clinical failures, and/or the emergence of resistance (
      • Tattevin P.
      • Boutoille D.
      • Vitrat V.
      • Van Grunderbeeck N.
      • Revest M.
      • Dupont M.
      • et al.
      Salvage treatment of methicillin-resistant staphylococcal endocarditis with ceftaroline: a multicentre observational study.
      ). Ceftaroline has demonstrated clinical success as an alternative to these agents in the treatment of serious infections due to MRSA, including BSI and IE, as well as S. aureus strains with reduced susceptibility to vancomycin/or daptomycin (
      • Arshad S.
      • Huang V.
      • Hartman P.
      • Perri M.B.
      • Moreno D.
      • Zervos M.J.
      Ceftaroline fosamil monotherapy for methicillin-resistant Staphylococcus aureus bacteremia: a comparative clinical outcomes study.
      ). The results of this investigation, coupled with reports of favorable clinical outcomes, support further investigations. Large, prospective, randomized controlled trials are needed to assess the efficacy and safety of ceftaroline in treating BSI and IE.

      Funding

      This study was supported by Allergan (prior to its acquisition by AbbVie). Allergan (now AbbVie) was involved in the study design and decision to present these results, and JMI Laboratories received compensation fees for services in relation to preparing the manuscript. Allergan (now AbbVie) had no involvement in the collection, analysis, and interpretation of data.

      Author disclosure statement

      JMI Laboratories was contracted to perform services in 2019–2020 for: Achaogen, Inc., Albany College of Pharmacy and Health Sciences, Allecra Therapeutics, Allergan, AmpliPhi Biosciences Corp., Amicrobe Advanced Biomaterials, Amplyx, Antabio, American Proficiency Institute, Arietis Corp., Arixa Pharmaceuticals, Inc., Astellas Pharma Inc., Athelas, Basilea Pharmaceutica Ltd., Bayer AG, Becton, Dickinson and Company, bioMerieux SA, Boston Pharmaceuticals, Bugworks Research Inc., CEM-102 Pharmaceuticals, Cepheid, Cidara Therapeutics, Inc., CorMedix Inc., DePuy Synthes, Destiny Pharma, Discuva Ltd., Dr. Falk Pharma GmbH, Emery Pharma, Entasis Therapeutics, Eurofarma Laboratorios SA, US Food and Drug Administration, Fox Chase Chemical Diversity Center, Inc., Gateway Pharmaceutical LLC, GenePOC Inc., Geom Therapeutics, Inc., GlaxoSmithKline plc, Harvard University, Helperby, HiMedia Laboratories, F. Hoffmann-La Roche Ltd., ICON plc, Idorsia Pharmaceuticals Ltd., Iterum Therapeutics plc, Laboratory Specialists, Inc., Melinta Therapeutics, Inc., Merck & Co., Inc., Microchem Laboratory, Micromyx, MicuRx Pharmaceuticals, Inc., Mutabilis Co., Nabriva Therapeutics plc, NAEJA-RGM, Novartis AG, Oxoid Ltd., Paratek Pharmaceuticals, Inc., Pfizer, Inc., Polyphor Ltd., Pharmaceutical Product Development, LLC, Prokaryotics Inc., Qpex Biopharma, Inc., Roivant Sciences, Ltd., Safeguard Biosystems, Scynexis, Inc.,SeLux Diagnostics, Inc., Shionogi and Co., Ltd., SinSa Labs, Spero Therapeutics, Summit Pharmaceuticals International Corp., Synlogic, T2 Biosystems, Inc., Taisho Pharmaceutical Co., Ltd., TenNor Therapeutics Ltd., Tetraphase Pharmaceuticals, Theravance Biopharma, University of Colorado, University of Southern California-San Diego, University of North Texas Health Science Center, VenatoRx Pharmaceuticals, Inc., Viosera Therapeutics, Vyome Therapeutics Inc., Wockhardt, Yukon Pharmaceuticals, Inc., Zai Lab, Zavante Therapeutics, Inc. There are no speakers’ bureaus or stock options to declare.

      Conflicts of interest

      None of the authors has a conflict of interest.

      Ethical approval

      Not required.

      Acknowledgements

      The authors would like to thank all participants in the International Dalbavancin Evaluation of Activity (IDEA) Surveillance Program for providing bacterial isolates. The authors also would like to thank Amy Chen and Judy Oberholser for editorial assistance.

      References

        • Arshad S.
        • Huang V.
        • Hartman P.
        • Perri M.B.
        • Moreno D.
        • Zervos M.J.
        Ceftaroline fosamil monotherapy for methicillin-resistant Staphylococcus aureus bacteremia: a comparative clinical outcomes study.
        Int J Infect Dis. 2017; 57: 27-31
        • Baddour L.M.
        • Wilson W.R.
        • Bayer A.S.
        • Fowler Jr, V.G.
        • Tleyjeh I.M.
        • Rybak M.J.
        • et al.
        Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association.
        Circulation. 2015; 132: 1435-1486
        • Casapao A.M.
        • Davis S.L.
        • Barr V.O.
        • Klinker K.P.
        • Goff D.A.
        • Barber K.E.
        • et al.
        Large retrospective evaluation of the effectiveness and safety of ceftaroline fosamil therapy.
        Antimicrob Agents Chemother. 2014; 58: 2541-2546
        • CLSI
        M07Ed11. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard: Eleventh Edition.
        Clinical and Laboratory Standards Institute, Wayne, PA2018
        • CLSI
        M100Ed30. Performance Standards for Antimcirobial Susceptibility Testing: 30th Informational Supplement.
        Clinical and Laboratory Standards Institute, Wayne, PA2020
        • Das S.
        • Li J.
        • Iaconis J.
        • Zhou D.
        • Stone G.G.
        • Yan J.L.
        • et al.
        Ceftaroline fosamil doses and breakpoints for Staphylococcus aureus in complicated skin and soft tissue infections.
        J Antimicrob Chemother. 2019; 74: 425-431
        • Destache C.J.
        • Guervil D.J.
        • Kaye K.S.
        Ceftaroline fosamil for the treatment of Gram-positive endocarditis: CAPTURE study experience.
        Int J Antimicrob Agents. 2019; 53: 644-649
        • Fowler Jr., V.G.
        • Miro J.M.
        • Hoen B.
        • Cabell C.H.
        • Abrutyn E.
        • Rubinstein E.
        • et al.
        Staphylococcus aureus endocarditis: a consequence of medical progress.
        JAMA. 2005; 293: 3012-3021
        • Harky A.
        • Zaim S.
        • Mallya A.
        • George J.J.
        Optimizing outcomes in infective endocarditis: a comprehensive literature review.
        J Card Surg. 2020; 35: 1600-1608
        • Ho T.T.
        • Cadena J.
        • Childs L.M.
        • Gonzalez-Velez M.
        • Lewis 2nd, J.S.
        Methicillin-resistant Staphylococcus aureus bacteraemia and endocarditis treated with ceftaroline salvage therapy.
        J Antimicrob Chemother. 2012; 67: 1267-1270
        • Lahiri S.D.
        • McLaughlin R.E.
        • Whiteaker J.D.
        • Ambler J.E.
        • Alm R.A.
        Molecular characterization of MRSA isolates bracketing the current EUCAST ceftaroline-susceptible breakpoint for Staphylococcus aureus: the role of PBP2a in the activity of ceftaroline.
        J Antimicrob Chemother. 2015; 70: 2488-2498
        • Lin J.C.
        • Aung G.
        • Thomas A.
        • Jahng M.
        • Johns S.
        • Fierer J.
        The use of ceftaroline fosamil in methicillin-resistant Staphylococcus aureus endocarditis and deep-seated MRSA infections: a retrospective case series of 10 patients.
        J Infect Chemother. 2013; 19: 42-49
        • Murdoch D.R.
        • Corey G.R.
        • Hoen B.
        • Miro J.M.
        • Fowler Jr., V.G.
        • Bayer A.S.
        • et al.
        Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study.
        Arch Intern Med. 2009; 169: 463-473
        • Pani A.
        • Colombo F.
        • Agnelli F.
        • Frantellizzi V.
        • Baratta F.
        • Pastori D.
        • et al.
        Off-label use of ceftaroline fosamil: a systematic review.
        Int J Antimicrob Agents. 2019; 54: 562-571
        • Polenakovik H.M.
        • Pleiman C.M.
        Ceftaroline for meticillin-resistant Staphylococcus aureus bacteraemia: case series and review of the literature.
        Int J Antimicrob Agents. 2013; 42: 450-455
        • Robinson D.A.
        • Enright M.C.
        Evolutionary models of the emergence of methicillin-resistant Staphylococcus aureus.
        Antimicrob Agents Chemother. 2003; 47: 3926-3934
        • Sader H.S.
        • Jones R.N.
        Impact of EUCAST, CLSI and USCAST ceftaroline breakpoint changes on the susceptibility of methicillin-resistant Staphylococcus aureus isolates collected from US medical centres (2015–2018).
        Clin Microbiol Infect. 2020; 26: 658-659
        • Sader H.S.
        • Rhomberg P.R.
        • Doyle T.B.
        • Flamm R.K.
        • Mendes R.E.
        Evaluation of the revised ceftaroline disk diffusion breakpoints when testing a challenge collection of methicillin-resistant Staphylococcus aureus isolates.
        J Clin Microbiol. 2018; 56e00777
        • Tattevin P.
        • Boutoille D.
        • Vitrat V.
        • Van Grunderbeeck N.
        • Revest M.
        • Dupont M.
        • et al.
        Salvage treatment of methicillin-resistant staphylococcal endocarditis with ceftaroline: a multicentre observational study.
        J Antimicrob Chemother. 2014; 69: 2010-2013
        • Urban E.
        • Stone G.G.
        Impact of EUCAST ceftaroline breakpoint change on the susceptibility of methicillin-resistant Staphylococcus aureus isolates collected from patients with complicated skin and soft-tissue infections.
        Clin Microbiol Infect. 2019; 25 (1429 e1–e4)
        • White B.P.
        • Barber K.E.
        • Stover K.R.
        Ceftaroline for the treatment of methicillin-resistant Staphylococcus aureus bacteremia.
        Am J Health Syst Pharm. 2017; 74: 201-208
        • Zhang Z.
        • Chen M.
        • Yu Y.
        • Liu B.
        • Liu Y.
        In vitro activity of ceftaroline and comparators against Staphylococcus aureus isolates: results from 6 years of The ATLAS Program (2012 to 2017).
        Infect Drug Resist. 2019; 12: 3349-3358