Journal of Antimicrobial Chemotherapy Advance Access published March 25, 2015
J Antimicrob Chemother doi:10.1093/jac/dkv076
Activity of ceftaroline and comparator agents tested against Staphylococcus aureus from patients with bloodstream infections in US medical centres (2009–13) Helio S. Sader*, David J. Farrell, Robert K. Flamm and Ronald N. Jones JMI Laboratories, North Liberty, IA, USA *Corresponding author. Tel: +1-319-665-3370; Fax: +1-319-665-3371; E-mail: [email protected]
Received 17 November 2014; returned 13 February 2015; revised 25 February 2015; accepted 3 March 2015
Methods: A total of 4426 S. aureus isolates from patients with BSI were collected in 150 medical centres in the USA in 2009–13 and tested for susceptibility to ceftaroline and comparators by the CLSI broth microdilution method. Results: Overall, 45.5% of isolates were MRSA. Ceftaroline (MIC50/90, 0.25/1 mg/L) was active against 97.9% of S. aureus isolates at ≤1 mg/L (highest MIC, 2 mg/L). Daptomycin (MIC50/90, 0.25/0.5 mg/L), linezolid (MIC50/90, 1/2 mg/L) and vancomycin (MIC50/90, 1/1 mg/L) were active against ≥99.8% of isolates at the respective susceptible breakpoints. Susceptibility rates for clindamycin (MIC50/90, ≤0.25/.2 mg/L) and levofloxacin (MIC50/90, ≤0.5/.4 mg/L) were 80.8% and 59.2%, respectively. Against MSSA, ceftaroline (MIC50/90, 0.25/0.25 mg/L; 100.0% susceptible) was 16-, 4–8- and 4-fold more active in vitro (based on MIC50/90) than ceftriaxone (MIC50/90, 4/4 mg/L), linezolid (MIC50/90, 1/2 mg/L) and vancomycin (MIC50/90, 1/1 mg/L), respectively, and slightly more potent than daptomycin (MIC50/90, 0.25/0.5 mg/L). When tested against MRSA, ceftaroline was active against 95.4% and 100.0% of isolates at ≤1 and ≤2 mg/L, respectively. Moreover, ceftaroline retained significant activity against S. aureus with reduced susceptibility to vancomycin, daptomycin, clindamycin, levofloxacin and trimethoprim/sulfamethoxazole. Conclusions: Ceftaroline demonstrated potent in vitro activity when tested against a large collection of contemporary (2009–13) S. aureus isolates causing BSI in US hospitals. Keywords: MRSA, bacteraemia, antimicrobial resistance, surveillance
Introduction Staphylococcus aureus is a leading cause of bloodstream infection (BSI) and the management of such infections continues to present a number of significant challenges to treating physicians. Among infections caused by S. aureus, BSI is associated with high morbidity and mortality. S. aureus bacteraemia can lead to severe complications such as infective endocarditis, vertebral osteomyelitis and epidural abscess etc. Complications of S. aureus bacteraemia can lead to a poor prognosis because of difficulties regarding the anatomical site of infection or in reaching a timely diagnosis. The most difficult cases are those that persist despite antimicrobial therapy and without an easily identified and removable focus.1 Ceftaroline fosamil is a cephalosporin with anti-MRSA activity that was approved for clinical use in the USA (in 2010; Teflarow)2 and Europe (in 2012; Zinforow).3 Ceftaroline fosamil was approved based on two Phase 3 randomized, double-blind clinical trials for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections (ABSSSIs), which
demonstrated non-inferiority to comparator agents.4,5 Ceftaroline fosamil has not been evaluated in randomized clinical trials for the treatment of MRSA BSI and is not approved by the US FDA for this indication. However, its use has been reported in patients with MRSA bacteraemia and endocarditis, especially as salvage therapy in combination with other antimicrobials.6 – 17 We evaluated the in vitro activity of ceftaroline tested against a large collection of S. aureus isolated from patients with BSI in US hospitals.
Methods The Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance programme was designed to establish the baseline and monitor post-approval activity of ceftaroline and comparator agents in the USA. Participating centres submit clinical bacterial organisms (one per infection episode) that are consecutively collected according to a common protocol, which established the number of isolates for each bacterial species/genus, the target infection types and the period of time the isolates should be collected.18 Between 2009 and 2013, a total of 4426 S. aureus isolates collected through the AWARE programme were derived from patients
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Objectives: The objective of this study was to evaluate the in vitro antimicrobial activity of ceftaroline and comparator agents tested against Staphylococcus aureus isolates causing bloodstream infection (BSI).
2 of 4
LVX-NS, levofloxacin non-susceptible (MIC, ≥2 mg/L); CLI-NS, clindamycin non-susceptible (MIC, ≥1 mg/L); VAN ≥2, includes isolates with vancomycin MICs of 2 mg/L (122) or 4 mg/L (1); SXT-NS, trimethoprim/sulfamethoxazole non-susceptible (MIC, ≥4 mg/L); DAP-NS, daptomycin non-susceptible (MIC, ≥2 mg/L). Susceptibility defined according to CLSI breakpoint criteria.20 b According to CLSI, US FDA and EUCAST breakpoint criteria.2,20,21
a
1 0.25 1 1 1 1 1 — 0.25 0.25 0.5 0.5 1 0.5 0.5 0.5 1 (,0.1) 1 (,0.1) — — — — — — S. aureus (4426) MSSA (2413) MRSA (2013) LVX-NS (1806) CLI-NS (847) VAN ≥2 (123) SXT-NS (88) DAP-NS (7)
12 (0.3) 12 (0.5) — 3 (0.2) — 2 (1.6) 1 (1.1) —
222 (5.3) 221 (9.7) 1 (,0.1) 21 (1.3) 13 (1.5) 5 (5.7) 2 (3.4) —
2105 (52.9) 2067 (95.4) 38 (1.9) 243 (14.8) 110 (14.5) 29 (29.3) 24 (30.7) —
1113 (78.0) 111 (.99.9) 1002 (51.7) 710 (54.1) 247 (43.7) 29 (52.8) 22 (55.7) 5 (71.4)
880 (97.9) 1 (100.0) 879 (95.4) 737 (94.9) 396 (90.4) 47 (91.1) 33 (93.2) 2 (100.0)
93 (100.0) — 93 (100.0) 92 (100.0) 81 (100.0) 11 (100.0) 6 (100.0) —
MIC90 1 0.5 0.25 0.12 0.06 0.03 Organisma (no.)
No. of isolates (cumulative percentage) inhibited at a ceftaroline MIC (mg/L) of
Table 1. Summary of ceftaroline activity tested against 4426 S. aureus isolates from bacteraemia (USA, 2009 –13)
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Overall, 97.9% of S. aureus isolates were susceptible (MIC, ≤1 mg/L) to ceftaroline (MIC50, 0.25 mg/L and MIC90, 1 mg/L) and the highest ceftaroline MIC value was only 2 mg/L (Table 1). The percentage of ceftaroline-non-susceptible isolates varied slightly during the study period as follows: 1.8% in 2009, 1.1% in 2010, 2.1% in 2011, 2.5% in 2012 and 2.0% in 2013. Oxacillin was active against 54.5% of isolates (45.5% MRSA), whereas daptomycin (MIC50, 0.25 mg/L and MIC90, 0.5 mg/L), linezolid (MIC50, 1 mg/L and MIC90, 2 mg/L) and vancomycin (MIC50 and MIC90, 1 mg/L) were active against ≥99.8% of S. aureus isolates (Table 2). Susceptibility rates according to CLSI breakpoints for erythromycin (MIC50 and MIC90, .16 mg/L), clindamycin (MIC50, ≤0.25 mg/L and MIC90, .2 mg/L) and levofloxacin (MIC50, ≤0.5 mg/L and MIC90, .4 mg/L) were 42.5%, 80.8% and 59.2%, respectively (Table 2). Against MSSA, ceftaroline (MIC 50 and MIC90, 0.25 mg/L; 100.0% susceptible) was 16-, 4 – 8- and 4-fold more active in vitro (based on MIC50 and MIC90 values) than ceftriaxone (MIC50 and MIC90, 4 mg/L), linezolid (MIC50, 1 mg/L and MIC90, 2 mg/L) and vancomycin (MIC50 and MIC90, 1 mg/L), respectively, and slightly more potent than daptomycin (MIC50, 0.25 mg/L and MIC90, 0.5 mg/L; Table 2). Ceftaroline was active against 95.4% of MRSA isolates at ≤1 mg/L (MIC50, 0.5 mg/L; MIC90 , 1 mg/L; and highest MIC, 2 mg/L; Table 1). Susceptibility rates (CLSI) for clindamycin and levofloxacin when testing MRSA isolates were 63.9% and 22.9%, respectively, while ≥99.7% of MRSA isolates were susceptible to daptomycin (MIC50, 0.25 mg/L and MIC90 , 0.5 mg/L), linezolid (MIC50, 1 mg/L and MIC90, 2 mg/L) and vancomycin (MIC50 and MIC90, 1 mg/L; Table 2). Ceftaroline also demonstrated potent in vitro activity against other resistant subsets. When tested against S. aureus isolates with decreased susceptibility to vancomycin (MIC, ≥2 mg/L; n ¼ 123), ceftaroline was active against 91.1% and 100.0% of isolates at MICs of ≤1 and ≤2 mg/L, respectively (MIC50, 0.5 mg/L and MIC90, 1 mg/L; Table 1). Ceftaroline was also active against S. aureus isolates non-susceptible to daptomycin [n ¼ 7; MIC50, 0.5 mg/L; all isolates (7/7) susceptible], clindamycin (n ¼ 847; MIC50 and MIC90 , 1 mg/L; 90.4% susceptible), levofloxacin (n¼ 1806; MIC50, 0.5 mg/L and MIC90, 1 mg/L; 94.8% susceptible) or trimethoprim/sulfamethoxazole (n ¼ 88; MIC50, 0.5 mg/L and MIC90, 1 mg/L; 93.2% susceptible; Table 1). Only one isolate, an MRSA, was non-susceptible to linezolid (MIC, .8 mg/L; Table 2) and exhibited a ceftaroline MIC of 0.5 mg/L.
2
Results and discussion
MIC50
Percentage susceptibilityb
with BSI. Isolates were collected from 150 medical centres distributed through all nine US Census regions. Isolates were identified at the participating medical centre and sent to the coordinator laboratory (JMI Laboratories, North Liberty, IA, USA) for reference susceptibility testing. Species identification was performed at the coordinator laboratory by MALDI-TOF using the Bruker Daltonics MALDI Biotyper (Billerica, MA, USA) on isolates that were not identified to species level by the participating centre. Isolates were tested for susceptibility to ceftaroline and multiple comparator agents by reference broth microdilution methods as described by CLSI M07-A919 and CLSI interpretations were based on CLSI (M100-S24)20 and EUCAST21 breakpoint criteria. Validated MIC panels were manufactured by ThermoFisher Scientific (Cleveland, OH, USA). Isolates were tested in CAMHB. Concurrent testing of quality control strains assured proper test conditions.
97.9 100.0 95.4 94.8 90.4 91.1 93.2 100.0
Sader et al.
JAC
Ceftaroline activity against S. aureus causing bacteraemia
Table 2. Antimicrobial activity of ceftaroline and comparator agents when tested against S. aureus isolates from bacteraemia (USA, 2009 –13) MIC (mg/L) Antimicrobial agent (no. tested)
50%
90%
range
CLSIa
EUCASTa
0.25 4 1 .16 ≤0.25 ≤0.5 ≤0.5 ≤2 1 1 0.25
1 .8 .2 .16 .2 .4 ≤0.5 ≤2 2 1 0.5
0.03– 2 0.5 to .8 ≤0.25 to .2 ≤0.25 to .16 ≤0.25 to .2 ≤0.5 to .4 ≤0.5 to .2 ≤2 to .8 ≤0.12 to .8 0.25– 4 ≤0.06 –2
97.9/2.1/0.0 54.5/0.0/45.5 54.5/0.0/45.5 42.5/1.9/55.6 80.8/0.3/18.9 59.2/1.1/39.7 98.0/0.0/2.0 95.5/0.7/3.8 .99.9/0.0/,0.1 .99.9/,0.1/0.0 99.8/—/—
97.9/0.0/2.1 54.5/0.0/45.5 54.5/0.0/45.5 42.8/0.5/56.7 80.4/0.4/19.2 59.2/1.1/39.7 98.0/0.2/1.8 93.2/1.4/5.4 .99.9/0.0/,0.1 .99.9/0.0/,0.1 99.8/0.0/0.2
0.25 4 .16 ≤0.25 2 ≤0.5 ≤2 2 1 0.5
0.03– 1 0.5 to .8 ≤0.25 to .16 ≤0.25 to .2 ≤0.5 to .4 ≤0.5 to .2 ≤2 to .8 ≤0.12 –2 0.25– 2 0.12– 1
100.0/0.0/0.0 100.0/0.0/0.0 69.9/2.4/27.7 95.0/0.2/4.8 89.5/0.6/9.9 98.8/0.0/1.2 96.4/0.7/2.9 100.0/0.0/0.0 100.0/0.0/0.0 100.0/—/—
100.0/0.0/0.0 100.0/0.0/0.0 70.3/0.8/28.9 94.8/0.2/5.0 89.5/0.6/9.9 98.8/0.1/1.1 95.4/0.3/4.3 100.0/0.0/0.0 100.0/0.0/0.0 100.0/0.0/0.0
1 .8 .16 .2 .4 ≤0.5 ≤2 2 1 0.5
0.12– 2 2 to .8 ≤0.25 to .16 ≤0.25 to .2 ≤0.5 to .4 ≤0.5 to .2 ≤2 to .8 0.25 to .8 0.5–4 ≤0.06 –2
95.4/4.6/0.0 0.0/0.0/100.0 9.6/1.3/89.1 63.9/0.3/35.8 22.9/1.7/75.4 97.0/0.0/3.0 94.3/0.9/4.8 .99.9/0.0/,0.1 .99.9/,0.1/0.0 99.7/—/—
95.4/0.0/4.6 0.0/0.0/100.0 9.8/0.3/89.9 63.1/0.8/36.1 22.9/1.7/75.4 97.0/0.3/2.7 90.6/2.7/6.7 .99.9/0.0/,0.1 .99.9/0.0/,0.1 99.7/0.0/0.3
MSSA (2413) ceftaroline ceftriaxone erythromycin clindamycin levofloxacin SXT tetracycline linezolid vancomycin daptomycin
0.25 4 ≤0.25 ≤0.25 ≤0.5 ≤0.5 ≤2 1 1 0.25
MRSA (2013) ceftaroline ceftriaxone erythromycin clindamycin levofloxacin SXT tetracycline linezolid vancomycin daptomycin
0.5 .8 .16 ≤0.25 .4 ≤0.5 ≤2 1 1 0.25
SXT, trimethoprim/sulfamethoxazole. a Criteria as published by the CLSI20 and EUCAST.21
It is important to note that although 93 isolates (all MRSA) were above the ceftaroline susceptible breakpoint of 1 mg/L, all of them were only one doubling dilution higher (i.e. 2 mg/L). An increase in the ceftaroline MIC value has been correlated with decreased binding affinity for PBP2a, and a Glu239Lys mutation in the non-penicillin-binding domain has been reported in MRSA isolates with ceftaroline MICs of 2 mg/L from Spain (clone ST228-I) and Thailand (clone ST764-II).22 Analyses of genome sequences of clonal isolates with ceftaroline MICs of 2 and 8 mg/L suggested that a single substitution at key residues in the non-penicillin-binding domain of PBP2a could be sufficient to give a slight increase in the ceftaroline MIC and that an additional substitution in the penicillin-binding domain gives rise to a further elevation in the ceftaroline MIC value. 22 Moreover,
Monte Carlo simulations, using ceftaroline pharmacokinetic and pharmacodynamic properties, have indicated that target attainment rates (stasis or 1 log10 cfu/g bacterial cell kill) remained .95% up to an MIC of 2 mg/L (.MIC99) suggesting clinical efficacy in treating ABSSSIs caused by S. aureus isolates with ceftaroline MICs up to 2 mg/L.23 In summary, major changes in the epidemiology and susceptibility patterns of S. aureus have been observed in recent years.24 Since initial antimicrobial therapy is usually selected empirically, results of large multicentre surveillance programmes, such as the AWARE programme, are valuable to guide appropriate selection of empirical antimicrobial treatment. The results of this investigation demonstrate the potent in vitro activity of ceftaroline when tested against a large collection of contemporary (2009 – 13)
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S. aureus (4426) ceftaroline ceftriaxone oxacillin erythromycin clindamycin levofloxacin SXT tetracycline linezolid vancomycin daptomycin
Percentage susceptible/intermediate/resistant
Sader et al.
S. aureus isolates causing BSI in US hospitals. Furthermore, ceftaroline retained significant activity against S. aureus with reduced susceptibility to vancomycin, daptomycin, clindamycin, levofloxacin and trimethoprim/sulfamethoxazole. These in vitro data support the further clinical development of ceftaroline for treatment of BSIs, especially those caused by S. aureus, including MRSA.
Acknowledgements This study was presented in part at IDWeek 2014, Philadelphia, PA, USA (Poster # 729). We would like to thank all AWARE participants for providing bacterial isolates for this surveillance programme.
Funding
Transparency declarations This study was supported by Cerexa, Inc., a wholly owned subsidiary of Forest Laboratories, LLC. Forest Laboratories, Inc. was involved in the design and decision to present these results. Forest Laboratories, Inc. had no involvement in the collection, analysis and interpretation of data. JMI Laboratories, Inc. has also received research and educational grants in 2012–14 from Achaogen, Actelion, Affinium, American Proficiency Institute (API), 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, Wockhardt and Waterloo. Some JMI employees are advisors/consultants for Astellas, Cubist, Pfizer, Cempra, Cerexa-Forest and Theravance. With regard to speakers’ bureaus and stock options: none to declare.
References 1 Keynan Y, Rubinstein E. Staphylococcus aureus bacteremia, risk factors, complications, and management. Crit Care Clin 2013; 29: 547–62. 2 Teflarow. http://www.frx.com/pi/Teflaro_pi.pdf. 3 Zinforow Package Insert. http://www.ema.europa.eu/docs/en_ GB/document_library/EPAR_-_Product_Information/human/002252/ WC500132586.pdf. 4 Corey GR, Wilcox M, Talbot GH et al. Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection. Clin Infect Dis 2010; 51: 641–50. 5 File TM Jr, Low DE, Eckburg PB et al. Integrated analysis of FOCUS 1 and FOCUS 2: randomized, doubled-blinded, multicenter phase 3 trials of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in patients with community-acquired pneumonia. Clin Infect Dis 2010; 51: 1395– 405. 6 Beydoun K, Wenzel R. Left ventricular assist device endocarditis caused by vancomycin-intermediate Staphylococcus aureus successfully treated with ceftaroline: a review of the clinical case and overview of vancomycin resistance in Staphylococcus aureus. Clin Microbiol Newsl 2013; 35: 171– 6. 7 Ho TT, Cadena J, Childs LM et al. Methicillin-resistant Staphylococcus aureus bacteraemia and endocarditis treated with ceftaroline salvage therapy. J Antimicrob Chemother 2012; 67: 1267– 70.
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9 Pagani L, Bonnin P, Janssen C et al. Ceftaroline for the treatment of prosthetic valve endocarditis due to methicillin-resistant Staphylococcus aureus. J Heart Valve Dis 2014; 23: 219– 21. 10 Polenakovik HM, Pleiman CM. Ceftaroline for meticillin-resistant Staphylococcus aureus bacteraemia: case series and review of the literature. Int J Antimicrob Agents 2013; 42: 450–5. 11 Sakoulas G, Moise PA, Casapao AM et al. Antimicrobial salvage therapy for persistent staphylococcal bacteremia using daptomycin plus ceftaroline. Clin Ther 2014; 36: 1317 –33. 12 Rose WE, Schulz LT, Andes D et al. Addition of ceftaroline to daptomycin after emergence of daptomycin-nonsusceptible Staphylococcus aureus during therapy improves antibacterial activity. Antimicrob Agents Chemother 2012; 56: 5296– 302. 13 Tattevin P, Boutoille D, Vitrat V et al. Salvage treatment of methicillinresistant staphylococcal endocarditis with ceftaroline: a multicentre observational study. J Antimicrob Chemother 2014; 69: 2010 –3. 14 Vazquez JA, Maggiore CR, Cole P et al. Ceftaroline fosamil for the treatment of Staphylococcus aureus bacteremia secondary to acute bacterial skin and skin structure infections or community-acquired bacterial pneumonia. Infect Dis Clin Pract (Baltim Md) 2015; 23: 39 –43. 15 Espedido BA, Jensen SO, van Hal SJ. Ceftaroline fosamil salvage therapy: an option for reduced-vancomycin-susceptible MRSA bacteraemia. J Antimicrob Chemother 2015; 70: 797–801. 16 Paladino JA, Jacobs DM, Shields RK et al. Use of ceftaroline after glycopeptide failure to eradicate meticillin-resistant Staphylococcus aureus bacteraemia with elevated vancomycin minimum inhibitory concentrations. Int J Antimicrob Agents 2014; 44: 557–63. 17 Barber KE, Rybak MJ, Sakoulas G. Vancomycin plus ceftaroline shows potent in vitro synergy and was successfully utilized to clear persistent daptomycin-non-susceptible MRSA bacteraemia. J Antimicrob Chemother 2015; 70: 311–3. 18 Sader HS, Flamm RK, Farrell DJ et al. Activity analyses of staphylococcal isolates from pediatric, adult and elderly patients; AWARE ceftaroline surveillance program. Clin Infect Dis 2012; 55 Suppl 3: S181–6. 19 Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically— Ninth Edition: Approved Standard M07-A9. CLSI, Wayne, PA, USA, 2012. 20 Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Twenty-fourth Informational Supplement M100-S24. CLSI, Wayne, PA, USA, 2014. 21 EUCAST. Breakpoint Tables for Interpretation of MICs and Zone Diameters, Version 4.0, January 2014. http://www.eucast.org/clinical_breakpoints/. 22 Alm RA, McLaughlin RE, Kos VN et al. Analysis of Staphylococcus aureus clinical isolates with reduced susceptibility to ceftaroline: an epidemiological and structural perspective. J Antimicrob Chemother 2014; 69: 2065– 75. 23 Drusano GL. Pharmacodynamics of ceftaroline fosamil for complicated skin and skin structure infection: rationale for improved anti-methicillinresistant Staphylococcus aureus activity. J Antimicrob Chemother 2010; 65 Suppl 4: iv33–9. 24 Chua K, Laurent F, Coombs G et al. Antimicrobial resistance: not community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA)! A clinician’s guide to community MRSA—its evolving antimicrobial resistance and implications for therapy. Clin Infect Dis 2011; 52: 99–114.
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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.
8 Jongsma K, Joson J, Heidari A. Ceftaroline in the treatment of concomitant methicillin-resistant and daptomycin-non-susceptible Staphylococcus aureus infective endocarditis and osteomyelitis: case report. J Antimicrob Chemother 2013; 68: 1444–5.
J Antimicrob Chemother doi:10.1093/jac/dkv076
Activity of ceftaroline and comparator agents tested against Staphylococcus aureus from patients with bloodstream infections in US medical centres (2009–13) Helio S. Sader*, David J. Farrell, Robert K. Flamm and Ronald N. Jones JMI Laboratories, North Liberty, IA, USA *Corresponding author. Tel: +1-319-665-3370; Fax: +1-319-665-3371; E-mail: [email protected]
Received 17 November 2014; returned 13 February 2015; revised 25 February 2015; accepted 3 March 2015
Methods: A total of 4426 S. aureus isolates from patients with BSI were collected in 150 medical centres in the USA in 2009–13 and tested for susceptibility to ceftaroline and comparators by the CLSI broth microdilution method. Results: Overall, 45.5% of isolates were MRSA. Ceftaroline (MIC50/90, 0.25/1 mg/L) was active against 97.9% of S. aureus isolates at ≤1 mg/L (highest MIC, 2 mg/L). Daptomycin (MIC50/90, 0.25/0.5 mg/L), linezolid (MIC50/90, 1/2 mg/L) and vancomycin (MIC50/90, 1/1 mg/L) were active against ≥99.8% of isolates at the respective susceptible breakpoints. Susceptibility rates for clindamycin (MIC50/90, ≤0.25/.2 mg/L) and levofloxacin (MIC50/90, ≤0.5/.4 mg/L) were 80.8% and 59.2%, respectively. Against MSSA, ceftaroline (MIC50/90, 0.25/0.25 mg/L; 100.0% susceptible) was 16-, 4–8- and 4-fold more active in vitro (based on MIC50/90) than ceftriaxone (MIC50/90, 4/4 mg/L), linezolid (MIC50/90, 1/2 mg/L) and vancomycin (MIC50/90, 1/1 mg/L), respectively, and slightly more potent than daptomycin (MIC50/90, 0.25/0.5 mg/L). When tested against MRSA, ceftaroline was active against 95.4% and 100.0% of isolates at ≤1 and ≤2 mg/L, respectively. Moreover, ceftaroline retained significant activity against S. aureus with reduced susceptibility to vancomycin, daptomycin, clindamycin, levofloxacin and trimethoprim/sulfamethoxazole. Conclusions: Ceftaroline demonstrated potent in vitro activity when tested against a large collection of contemporary (2009–13) S. aureus isolates causing BSI in US hospitals. Keywords: MRSA, bacteraemia, antimicrobial resistance, surveillance
Introduction Staphylococcus aureus is a leading cause of bloodstream infection (BSI) and the management of such infections continues to present a number of significant challenges to treating physicians. Among infections caused by S. aureus, BSI is associated with high morbidity and mortality. S. aureus bacteraemia can lead to severe complications such as infective endocarditis, vertebral osteomyelitis and epidural abscess etc. Complications of S. aureus bacteraemia can lead to a poor prognosis because of difficulties regarding the anatomical site of infection or in reaching a timely diagnosis. The most difficult cases are those that persist despite antimicrobial therapy and without an easily identified and removable focus.1 Ceftaroline fosamil is a cephalosporin with anti-MRSA activity that was approved for clinical use in the USA (in 2010; Teflarow)2 and Europe (in 2012; Zinforow).3 Ceftaroline fosamil was approved based on two Phase 3 randomized, double-blind clinical trials for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections (ABSSSIs), which
demonstrated non-inferiority to comparator agents.4,5 Ceftaroline fosamil has not been evaluated in randomized clinical trials for the treatment of MRSA BSI and is not approved by the US FDA for this indication. However, its use has been reported in patients with MRSA bacteraemia and endocarditis, especially as salvage therapy in combination with other antimicrobials.6 – 17 We evaluated the in vitro activity of ceftaroline tested against a large collection of S. aureus isolated from patients with BSI in US hospitals.
Methods The Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance programme was designed to establish the baseline and monitor post-approval activity of ceftaroline and comparator agents in the USA. Participating centres submit clinical bacterial organisms (one per infection episode) that are consecutively collected according to a common protocol, which established the number of isolates for each bacterial species/genus, the target infection types and the period of time the isolates should be collected.18 Between 2009 and 2013, a total of 4426 S. aureus isolates collected through the AWARE programme were derived from patients
# The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected]
1 of 4
Downloaded from http://jac.oxfordjournals.org/ at Seton Hall on April 4, 2015
Objectives: The objective of this study was to evaluate the in vitro antimicrobial activity of ceftaroline and comparator agents tested against Staphylococcus aureus isolates causing bloodstream infection (BSI).
2 of 4
LVX-NS, levofloxacin non-susceptible (MIC, ≥2 mg/L); CLI-NS, clindamycin non-susceptible (MIC, ≥1 mg/L); VAN ≥2, includes isolates with vancomycin MICs of 2 mg/L (122) or 4 mg/L (1); SXT-NS, trimethoprim/sulfamethoxazole non-susceptible (MIC, ≥4 mg/L); DAP-NS, daptomycin non-susceptible (MIC, ≥2 mg/L). Susceptibility defined according to CLSI breakpoint criteria.20 b According to CLSI, US FDA and EUCAST breakpoint criteria.2,20,21
a
1 0.25 1 1 1 1 1 — 0.25 0.25 0.5 0.5 1 0.5 0.5 0.5 1 (,0.1) 1 (,0.1) — — — — — — S. aureus (4426) MSSA (2413) MRSA (2013) LVX-NS (1806) CLI-NS (847) VAN ≥2 (123) SXT-NS (88) DAP-NS (7)
12 (0.3) 12 (0.5) — 3 (0.2) — 2 (1.6) 1 (1.1) —
222 (5.3) 221 (9.7) 1 (,0.1) 21 (1.3) 13 (1.5) 5 (5.7) 2 (3.4) —
2105 (52.9) 2067 (95.4) 38 (1.9) 243 (14.8) 110 (14.5) 29 (29.3) 24 (30.7) —
1113 (78.0) 111 (.99.9) 1002 (51.7) 710 (54.1) 247 (43.7) 29 (52.8) 22 (55.7) 5 (71.4)
880 (97.9) 1 (100.0) 879 (95.4) 737 (94.9) 396 (90.4) 47 (91.1) 33 (93.2) 2 (100.0)
93 (100.0) — 93 (100.0) 92 (100.0) 81 (100.0) 11 (100.0) 6 (100.0) —
MIC90 1 0.5 0.25 0.12 0.06 0.03 Organisma (no.)
No. of isolates (cumulative percentage) inhibited at a ceftaroline MIC (mg/L) of
Table 1. Summary of ceftaroline activity tested against 4426 S. aureus isolates from bacteraemia (USA, 2009 –13)
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Overall, 97.9% of S. aureus isolates were susceptible (MIC, ≤1 mg/L) to ceftaroline (MIC50, 0.25 mg/L and MIC90, 1 mg/L) and the highest ceftaroline MIC value was only 2 mg/L (Table 1). The percentage of ceftaroline-non-susceptible isolates varied slightly during the study period as follows: 1.8% in 2009, 1.1% in 2010, 2.1% in 2011, 2.5% in 2012 and 2.0% in 2013. Oxacillin was active against 54.5% of isolates (45.5% MRSA), whereas daptomycin (MIC50, 0.25 mg/L and MIC90, 0.5 mg/L), linezolid (MIC50, 1 mg/L and MIC90, 2 mg/L) and vancomycin (MIC50 and MIC90, 1 mg/L) were active against ≥99.8% of S. aureus isolates (Table 2). Susceptibility rates according to CLSI breakpoints for erythromycin (MIC50 and MIC90, .16 mg/L), clindamycin (MIC50, ≤0.25 mg/L and MIC90, .2 mg/L) and levofloxacin (MIC50, ≤0.5 mg/L and MIC90, .4 mg/L) were 42.5%, 80.8% and 59.2%, respectively (Table 2). Against MSSA, ceftaroline (MIC 50 and MIC90, 0.25 mg/L; 100.0% susceptible) was 16-, 4 – 8- and 4-fold more active in vitro (based on MIC50 and MIC90 values) than ceftriaxone (MIC50 and MIC90, 4 mg/L), linezolid (MIC50, 1 mg/L and MIC90, 2 mg/L) and vancomycin (MIC50 and MIC90, 1 mg/L), respectively, and slightly more potent than daptomycin (MIC50, 0.25 mg/L and MIC90, 0.5 mg/L; Table 2). Ceftaroline was active against 95.4% of MRSA isolates at ≤1 mg/L (MIC50, 0.5 mg/L; MIC90 , 1 mg/L; and highest MIC, 2 mg/L; Table 1). Susceptibility rates (CLSI) for clindamycin and levofloxacin when testing MRSA isolates were 63.9% and 22.9%, respectively, while ≥99.7% of MRSA isolates were susceptible to daptomycin (MIC50, 0.25 mg/L and MIC90 , 0.5 mg/L), linezolid (MIC50, 1 mg/L and MIC90, 2 mg/L) and vancomycin (MIC50 and MIC90, 1 mg/L; Table 2). Ceftaroline also demonstrated potent in vitro activity against other resistant subsets. When tested against S. aureus isolates with decreased susceptibility to vancomycin (MIC, ≥2 mg/L; n ¼ 123), ceftaroline was active against 91.1% and 100.0% of isolates at MICs of ≤1 and ≤2 mg/L, respectively (MIC50, 0.5 mg/L and MIC90, 1 mg/L; Table 1). Ceftaroline was also active against S. aureus isolates non-susceptible to daptomycin [n ¼ 7; MIC50, 0.5 mg/L; all isolates (7/7) susceptible], clindamycin (n ¼ 847; MIC50 and MIC90 , 1 mg/L; 90.4% susceptible), levofloxacin (n¼ 1806; MIC50, 0.5 mg/L and MIC90, 1 mg/L; 94.8% susceptible) or trimethoprim/sulfamethoxazole (n ¼ 88; MIC50, 0.5 mg/L and MIC90, 1 mg/L; 93.2% susceptible; Table 1). Only one isolate, an MRSA, was non-susceptible to linezolid (MIC, .8 mg/L; Table 2) and exhibited a ceftaroline MIC of 0.5 mg/L.
2
Results and discussion
MIC50
Percentage susceptibilityb
with BSI. Isolates were collected from 150 medical centres distributed through all nine US Census regions. Isolates were identified at the participating medical centre and sent to the coordinator laboratory (JMI Laboratories, North Liberty, IA, USA) for reference susceptibility testing. Species identification was performed at the coordinator laboratory by MALDI-TOF using the Bruker Daltonics MALDI Biotyper (Billerica, MA, USA) on isolates that were not identified to species level by the participating centre. Isolates were tested for susceptibility to ceftaroline and multiple comparator agents by reference broth microdilution methods as described by CLSI M07-A919 and CLSI interpretations were based on CLSI (M100-S24)20 and EUCAST21 breakpoint criteria. Validated MIC panels were manufactured by ThermoFisher Scientific (Cleveland, OH, USA). Isolates were tested in CAMHB. Concurrent testing of quality control strains assured proper test conditions.
97.9 100.0 95.4 94.8 90.4 91.1 93.2 100.0
Sader et al.
JAC
Ceftaroline activity against S. aureus causing bacteraemia
Table 2. Antimicrobial activity of ceftaroline and comparator agents when tested against S. aureus isolates from bacteraemia (USA, 2009 –13) MIC (mg/L) Antimicrobial agent (no. tested)
50%
90%
range
CLSIa
EUCASTa
0.25 4 1 .16 ≤0.25 ≤0.5 ≤0.5 ≤2 1 1 0.25
1 .8 .2 .16 .2 .4 ≤0.5 ≤2 2 1 0.5
0.03– 2 0.5 to .8 ≤0.25 to .2 ≤0.25 to .16 ≤0.25 to .2 ≤0.5 to .4 ≤0.5 to .2 ≤2 to .8 ≤0.12 to .8 0.25– 4 ≤0.06 –2
97.9/2.1/0.0 54.5/0.0/45.5 54.5/0.0/45.5 42.5/1.9/55.6 80.8/0.3/18.9 59.2/1.1/39.7 98.0/0.0/2.0 95.5/0.7/3.8 .99.9/0.0/,0.1 .99.9/,0.1/0.0 99.8/—/—
97.9/0.0/2.1 54.5/0.0/45.5 54.5/0.0/45.5 42.8/0.5/56.7 80.4/0.4/19.2 59.2/1.1/39.7 98.0/0.2/1.8 93.2/1.4/5.4 .99.9/0.0/,0.1 .99.9/0.0/,0.1 99.8/0.0/0.2
0.25 4 .16 ≤0.25 2 ≤0.5 ≤2 2 1 0.5
0.03– 1 0.5 to .8 ≤0.25 to .16 ≤0.25 to .2 ≤0.5 to .4 ≤0.5 to .2 ≤2 to .8 ≤0.12 –2 0.25– 2 0.12– 1
100.0/0.0/0.0 100.0/0.0/0.0 69.9/2.4/27.7 95.0/0.2/4.8 89.5/0.6/9.9 98.8/0.0/1.2 96.4/0.7/2.9 100.0/0.0/0.0 100.0/0.0/0.0 100.0/—/—
100.0/0.0/0.0 100.0/0.0/0.0 70.3/0.8/28.9 94.8/0.2/5.0 89.5/0.6/9.9 98.8/0.1/1.1 95.4/0.3/4.3 100.0/0.0/0.0 100.0/0.0/0.0 100.0/0.0/0.0
1 .8 .16 .2 .4 ≤0.5 ≤2 2 1 0.5
0.12– 2 2 to .8 ≤0.25 to .16 ≤0.25 to .2 ≤0.5 to .4 ≤0.5 to .2 ≤2 to .8 0.25 to .8 0.5–4 ≤0.06 –2
95.4/4.6/0.0 0.0/0.0/100.0 9.6/1.3/89.1 63.9/0.3/35.8 22.9/1.7/75.4 97.0/0.0/3.0 94.3/0.9/4.8 .99.9/0.0/,0.1 .99.9/,0.1/0.0 99.7/—/—
95.4/0.0/4.6 0.0/0.0/100.0 9.8/0.3/89.9 63.1/0.8/36.1 22.9/1.7/75.4 97.0/0.3/2.7 90.6/2.7/6.7 .99.9/0.0/,0.1 .99.9/0.0/,0.1 99.7/0.0/0.3
MSSA (2413) ceftaroline ceftriaxone erythromycin clindamycin levofloxacin SXT tetracycline linezolid vancomycin daptomycin
0.25 4 ≤0.25 ≤0.25 ≤0.5 ≤0.5 ≤2 1 1 0.25
MRSA (2013) ceftaroline ceftriaxone erythromycin clindamycin levofloxacin SXT tetracycline linezolid vancomycin daptomycin
0.5 .8 .16 ≤0.25 .4 ≤0.5 ≤2 1 1 0.25
SXT, trimethoprim/sulfamethoxazole. a Criteria as published by the CLSI20 and EUCAST.21
It is important to note that although 93 isolates (all MRSA) were above the ceftaroline susceptible breakpoint of 1 mg/L, all of them were only one doubling dilution higher (i.e. 2 mg/L). An increase in the ceftaroline MIC value has been correlated with decreased binding affinity for PBP2a, and a Glu239Lys mutation in the non-penicillin-binding domain has been reported in MRSA isolates with ceftaroline MICs of 2 mg/L from Spain (clone ST228-I) and Thailand (clone ST764-II).22 Analyses of genome sequences of clonal isolates with ceftaroline MICs of 2 and 8 mg/L suggested that a single substitution at key residues in the non-penicillin-binding domain of PBP2a could be sufficient to give a slight increase in the ceftaroline MIC and that an additional substitution in the penicillin-binding domain gives rise to a further elevation in the ceftaroline MIC value. 22 Moreover,
Monte Carlo simulations, using ceftaroline pharmacokinetic and pharmacodynamic properties, have indicated that target attainment rates (stasis or 1 log10 cfu/g bacterial cell kill) remained .95% up to an MIC of 2 mg/L (.MIC99) suggesting clinical efficacy in treating ABSSSIs caused by S. aureus isolates with ceftaroline MICs up to 2 mg/L.23 In summary, major changes in the epidemiology and susceptibility patterns of S. aureus have been observed in recent years.24 Since initial antimicrobial therapy is usually selected empirically, results of large multicentre surveillance programmes, such as the AWARE programme, are valuable to guide appropriate selection of empirical antimicrobial treatment. The results of this investigation demonstrate the potent in vitro activity of ceftaroline when tested against a large collection of contemporary (2009 – 13)
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S. aureus (4426) ceftaroline ceftriaxone oxacillin erythromycin clindamycin levofloxacin SXT tetracycline linezolid vancomycin daptomycin
Percentage susceptible/intermediate/resistant
Sader et al.
S. aureus isolates causing BSI in US hospitals. Furthermore, ceftaroline retained significant activity against S. aureus with reduced susceptibility to vancomycin, daptomycin, clindamycin, levofloxacin and trimethoprim/sulfamethoxazole. These in vitro data support the further clinical development of ceftaroline for treatment of BSIs, especially those caused by S. aureus, including MRSA.
Acknowledgements This study was presented in part at IDWeek 2014, Philadelphia, PA, USA (Poster # 729). We would like to thank all AWARE participants for providing bacterial isolates for this surveillance programme.
Funding
Transparency declarations This study was supported by Cerexa, Inc., a wholly owned subsidiary of Forest Laboratories, LLC. Forest Laboratories, Inc. was involved in the design and decision to present these results. Forest Laboratories, Inc. had no involvement in the collection, analysis and interpretation of data. JMI Laboratories, Inc. has also received research and educational grants in 2012–14 from Achaogen, Actelion, Affinium, American Proficiency Institute (API), 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, Wockhardt and Waterloo. Some JMI employees are advisors/consultants for Astellas, Cubist, Pfizer, Cempra, Cerexa-Forest and Theravance. With regard to speakers’ bureaus and stock options: none to declare.
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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.
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