PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of aacPermissionsJournals.ASM.orgJournalAAC ArticleJournal InfoAuthorsReviewers
 
Antimicrob Agents Chemother. 2016 January; 60(1): 343–347.
Published online 2015 December 31. Prepublished online 2015 October 26. doi:  10.1128/AAC.01867-15
PMCID: PMC4704164

In Vitro Activity of Ceftaroline against Staphylococcus aureus Isolated in 2012 from Asia-Pacific Countries as Part of the AWARE Surveillance Program

Abstract

Ceftaroline, the active metabolite of the prodrug ceftaroline-fosamil, is an advanced-generation cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA). This investigation provides in vitro susceptibility data for ceftaroline against 1,971 S. aureus isolates collected in 2012 from seven countries (26 centers) in the Asia-Pacific region as part of the Assessing Worldwide Antimicrobial Resistance and Evaluation (AWARE) program. Broth microdilution as recommended by the CLSI was used to determine susceptibility. In all, 62% of the isolates studied were MRSA, and the ceftaroline MIC90 for all S. aureus isolates was 2 μg/ml (interpretive criteria: susceptible, ≤1 μg/ml). The overall ceftaroline susceptibility rate for S. aureus was 86.9%, with 100% of methicillin-sensitive S. aureus isolates and 78.8% of MRSA isolates susceptible to this agent. The highest percentages of ceftaroline-nonsusceptible MRSA isolates came from China (47.6%), all of which showed intermediate susceptibility, and Thailand (37.1%), where over half (52.8%) of isolates were resistant to ceftaroline (MIC, 4 μg/ml). Thirty-eight ceftaroline-nonsusceptible isolates (MIC values of 2 to 4 μg/ml) were selected for molecular characterization. Among the isolates analyzed, sequence type 5 (ST-5) was the most common sequence type encountered; however, all isolates analyzed from Thailand were ST-228. Penicillin-binding protein 2a (PBP2a) substitution patterns varied by country, but all isolates from Thailand had the Glu239Lys substitution, and 12 of these also carried an additional Glu447Lys substitution. Ceftaroline-fosamil is a useful addition to the antimicrobial agents that can be used to treat S. aureus infections. However, with the capability of this species to develop resistance to new agents, it is important to recognize and monitor regional differences in trends as they emerge.

INTRODUCTION

The challenges of multidrug-resistant (MDR) Staphylococcus aureus are problematic in many geographic regions. Asia has one of the highest prevalence rates of methicillin-resistant S. aureus (MRSA), including MDR isolates, in the world (1). The relative paucity of therapeutic options has led to significant morbidity and mortality in this region (2). There are antimicrobial agents available for treating infections caused by MDR MRSA infections (e.g., daptomycin, linezolid). However, safety concerns have been raised for some of these compounds, and resistance against these agents has been described, albeit rarely (3,6). The recently approved agent ceftaroline-fosamil has a good safety profile and is approved by the U.S. Food and Drug Administration (in 2010) and the European Medicines Agency (in 2012) for the treatment of infections caused by S. aureus (7,10). Current clinical indications include community-acquired pneumonia (CAP) and complicated skin and skin structure infections (cSSSI), with MRSA included among the target pathogens for cSSSI (11,20). In addition to inhibiting essential penicillin-binding proteins (PBPs), ceftaroline also has a high affinity for PBP2a, which confers resistance to an array of other beta-lactams characteristic of MRSA (21). Ceftaroline's special attribute of having activity against MRSA is key to this drug's contribution as a therapeutic option for treating serious infections caused by S. aureus (22,26).

With the clinical availability of ceftaroline in some Asia-Pacific countries, it is important to establish a baseline of in vitro activity from the outset and to use this baseline to evaluate trends in resistance should they occur. This study evaluated the in vitro activity of ceftaroline and comparator agents against S. aureus recovered from patients hospitalized in Asia-Pacific countries. In addition, molecular analysis of a subset of ceftaroline-nonsusceptible isolates was performed to determine their PBP2a substitutions and the sequence types associated with this group of isolates.

MATERIALS AND METHODS

A total of 1,971 clinical isolates of S. aureus were collected in 2012 from 26 medical centers in Asia-Pacific as part of the Assessing Worldwide Antimicrobial Resistance and Evaluation (AWARE) program. Countries and the number of medical centers included Australia (3), China (9), Japan (3), Philippines (3), South Korea (2), Taiwan (3), and Thailand (3). The majority of isolates were collected from skin and skin structure (1,004 isolates) and respiratory tract (755) specimens. The remainder were from other specimen sources. MICs were determined and interpreted according to Clinical and Laboratory Standards Institute (CLSI) guidelines (27, 28). Quality-control isolates were tested concurrently, and all values were within recommended CLSI quality-control ranges (28).

A random sample of 38 isolates with a ceftaroline MIC value of 2 or 4 μg/ml, i.e., intermediate or resistant, respectively, was selected from China (9 isolates), Japan (6), Philippines (1), South Korea (4), Taiwan (4), and Thailand (14) for molecular characterization. Whole-genome sequencing was performed to enable determination of sequence types (ST), staphylococcal cassette chromosome mec element (SCCmec) types, and PBP2a substitutions as previously described (29). Seven reference isolates with ceftaroline MIC values of 1 or 2 μg/ml were included for comparisons and quality assurance.

RESULTS

The overall profile of the S. aureus population analysis based on ceftaroline and comparator activities is provided in Table 1. Of the 1,971 isolates 1,220 (61.9%) were MRSA. Resistance to erythromycin, clindamycin, and levofloxacin was 51.9%, 35.7%, and 41.2%, respectively. Resistance to any of the other drugs tested was uncommon. Against this total population of Asian isolates, the ceftaroline MIC90 value was 2 μg/ml. Ceftaroline maintained an overall susceptibility level of 86.9% against these isolates. All ceftaroline-nonsusceptible isolates were MRSA, and the 13.1% nonsusceptible isolates were comprised of 11.6% with MIC values in the intermediate category (MIC of 2 μg/ml) and 1.5% with a ceftaroline MIC of 4 μg/ml, which is the resistant breakpoint.

TABLE 1
Activities of ceftaroline and comparator agents against 1,971 isolates of S. aureus from Asia-Pacific countries

The cumulative frequency MIC distributions of ceftaroline according to methicillin susceptibility status and country of origin are shown in Table 2. For MSSA isolates, the ceftaroline MIC50 and MIC90 values (0.25 μg/ml) were identical across all countries. By-country variability for ceftaroline MIC90s was observed among the MRSA isolates and ranged from 1 μg/ml (Australia) to 4 μg/ml (Thailand). Of the 30 ceftaroline-resistant isolates (all with an MIC of 4 μg/ml), 28 (93.3%) were from Thailand; the remaining 2 were from Japan and South Korea. Within Thailand, the 28 resistant isolates came from two of the three study sites (one site collected 12 resistant isolates, and the other collected 16 isolates). It was not determined if these 28 isolates were clonally related. The highest percentage of ceftaroline-nonsusceptible isolates (MIC of 2 μg/ml) came from China (162 of 340 [47.6%]). In contrast, 100% of the isolates from Australia were susceptible to ceftaroline.

TABLE 2
Distribution of ceftaroline MIC values for S. aureus isolates from Asia-Pacific countries

Analyses of ceftaroline activity against S. aureus samples isolated from the source of infection with the approved indications demonstrated that the overall ceftaroline nonsusceptibility percentage was higher among MRSA isolates from respiratory specimens (32.2%) than those from skin and skin structure specimens (9.1%) (data not shown). Among respiratory specimen isolates, the highest rates of nonsusceptibility were 48.5%, 38.8%, and 36.4% among isolates from China, Thailand, and South Korea, respectively. This same hierarchy of nonsusceptibility was observed among skin and skin structure specimens.

Among the 38 ceftaroline-nonsusceptible isolates selected for molecular characterization, the most common sequence types were ST-5, ST-238, and ST-239 (Table 3). All ceftaroline-nonsusceptible isolates (MICs of 2 and 4 μg/ml) selected for analysis from Thailand were ST-228. Six isolates from three countries had wild-type sequence PBP2a substitutions (defined as that found in S. aureus USA300). The remainder of the isolates analyzed had PBP2a substitutions that varied considerably among countries of origin. All of the molecularly characterized isolates from Thailand (11 isolates inhibited by 4 μg/ml ceftaroline and 3 isolates inhibited by 2 μg/ml) had a Glu239Lys substitution, and all but 2 isolates also had an additional Glu447Lys substitution.

TABLE 3
Molecular analysis of 38 ceftaroline-nonsusceptible S. aureus isolates from Asia-Pacific countries

DISCUSSION

In this study, ceftaroline exhibited potent in vitro activity against clinical isolates of S. aureus from Asia-Pacific countries, with MRSA isolates from the seven countries that were monitored showing varied activity. The overall ceftaroline susceptibility percentage of this 2012 Asia-Pacific collection was 86.9%. This susceptibility rate was slightly lower than that observed in a previous surveillance study done in this region, in which susceptibility was 93.4% (30). However, differences in the medical centers and countries that provided isolates for analysis in these two separate surveillance studies preclude the ability to evaluate any changes in ceftaroline susceptibility trends over time. In comparison to other geographic areas studied, the Asia-Pacific region ceftaroline susceptibility rate found in this study was slightly higher than the 83.6% susceptibility found among isolates collected in Latin America during 2011 (31, 32). In contrast, the 98% ceftaroline susceptibility rate found in previous U.S. surveillance studies, in which the MRSA rate was approximately 50%, was substantially higher than the susceptibility rate found in the current Asia-Pacific study (32,34). The current Asia-Pacific S. aureus data also demonstrated ceftaroline activity against MRSA (MIC50, 1 μg/ml) similar to that observed in Europe, Turkey, and Israel (35). Based on these findings, it is evident that the level of in vitro activity of ceftaroline against MRSA can vary notably from one geographic region to another.

However, the interpretation of relative ceftaroline activity across regions, or patient types, or any other parameter based on percent susceptibility alone should be viewed with caution. As shown in Table 2, the MIC distributions were very similar across countries, and the nonsusceptible populations were entirely comprised of strains with ceftaroline MICs only 1 or 2 dilutions above the susceptible breakpoint of 1 μg/ml. These slight differences in MIC distributions more likely reflect differences in PBP2a substitutions associated with certain lineages than they do the acquisition of any overt resistance mechanism. Several recent studies in which the documented mechanism among isolates with higher ceftaroline MICs involved substitutions in PBP2a support this likelihood (21, 36, 37, 38). The most common substitutions appear to be located in the non-penicillin-binding domain that produces low-level (intermediate) resistance, and molecular analysis for selected isolates demonstrated that most, but not all, isolates with ceftaroline MICs of 2 μg/ml carried such substitutions (37). This association was confirmed in the current study. Additional substitutions in the penicillin-binding region have resulted in MIC values of >2 μg/ml, which was observed for isolates from Japan, South Korea, Thailand, Spain, Switzerland, and Greece (36,38). In the present study, the majority of isolates with an MIC value of 4 μg/ml were from Thailand, and all of those that were analyzed had a Glu447Lys substitution in the penicillin-binding region. This substitution was not seen in any of the other ceftaroline-nonsusceptible isolates characterized in this study. However, the association of these substitutions with higher ceftaroline MICs has been described previously (21, 22, 36). These findings suggest a clonal relationship among the isolates from Thailand, with MICs of 4 μg/ml, but further studies would be needed to establish this relationship. It is of interest that in the countries with the highest ceftaroline nonsusceptibility rates (China and Thailand), ceftaroline had not been approved at the time of the study. While at least one in vitro study suggested that certain beta-lactams (e.g., ceftobiprole) could select for mutants with higher ceftaroline MICs, there are no reports of this happening in the clinical environment (22). In any case, without the availability of usage data and with insufficient year-to-year data for each region, it is difficult to conclude the reasons for differences in regional ceftaroline susceptibility rates and whether there have been any changes over time. The different susceptibility rates may very well be a reflection of the most common PBP2a substitution “clones” most prevalent in a given area pre-ceftaroline usage. Certain substitutions, such as those found in isolates from Thailand, would result in reduced affinity for ceftaroline and thus higher MICs relative to other PBP2a substitutions that have a lesser impact on ceftaroline activity. Ongoing surveillance and further molecular characterization of such isolates will be important to help understand what trends may or may not be emerging.

In consideration of the underlying mechanisms behind higher ceftaroline MICs, the clustering and proximity of ceftaroline MICs between susceptible and nonsusceptible populations may be more a reflection of where the interpretive breakpoints are set than of any emerging resistance (38). Discerning the true clinical relevance between a strain that is susceptible to ceftaroline with an MIC of 1 μg/ml and one that is intermediate (MIC, 2 μg/ml) or resistant (MIC, 4 μg/ml) could be quite difficult. Nonetheless, the in vitro data provided in this study indicate that ceftaroline-fosamil provides a strong treatment option for infections caused by S. aureus, including MRSA. However, because S. aureus has a proven propensity to develop resistance to many antimicrobial agents, including beta-lactams, ongoing regional and global surveillance initiatives are needed to monitor any changes in susceptibility trends over the time that ceftaroline clinical use expands.

ACKNOWLEDGMENTS

We gratefully acknowledge the contributions of the clinical trial investigators, laboratory personnel, and all members of the AWARE program.

This study at International Health Management Associates, Inc. (IHMA) was supported by AstraZeneca Pharmaceuticals L.P., which also included compensation fees for services in relation to preparing the manuscript. None of the IHMA authors (D.J.B., D.F.S., D.J.H., and S.K.B.) has a personal financial interest in the sponsor of this paper (AstraZeneca Pharmaceuticals).

All authors provided analysis input and have read and approved the final manuscript.

Funding Statement

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

REFERENCES

1. Chen CJ, Huang YC 2014. New epidemiology of Staphylococcus aureus infection in Asia. Clin Microbiol Infect 20:605–623. doi:.10.1111/1469-0691.12705 [PubMed] [Cross Ref]
2. Su CH, Chang SC, Yan JJ, Tseng SH, Chien LJ, Fang CT 2013. Excess mortality and long-term disability from healthcare-associated Staphylococcus aureus infections: a population-based matched cohort study. PLoS One 8:e71055. doi:.10.1371/journal.pone.0071055 [PMC free article] [PubMed] [Cross Ref]
3. Kollipara R, Downing C, Lee M, Guidry J, Curis S, Tyring S 2014. Current and emerging drugs for acute bacterial skin and skin structure infections: an update. Expert Opin Emerg Drugs 19:431–440. doi:.10.1517/14728214.2014.955015 [PubMed] [Cross Ref]
4. Gould IM, David MZ, Esposito S, Garau J, Lina G, Mazzei T, Peters G 2012. New insights into methicillin-resistant Staphylococcus aureus (MRSA) pathogenesis, treatment and resistance. Int J Antimicrob Agents 39:96–104. doi:.10.1016/j.ijantimicag.2011.09.028 [PubMed] [Cross Ref]
5. Rincon S, Panesso D, Diaz L, Carvajal LP, Reyes J, Munita JM, Arias CA 2014. Resistance to “last resort” antibiotics in Gram-positive cocci: the post-vancomycin era. Biomedica 34(Suppl 1):191–208. doi:.10.7705/biomedica.v34i0.2210 [PMC free article] [PubMed] [Cross Ref]
6. Rodvold KA, McConeghy KW 2014. Methicillin-resistant Staphylococcus aureus therapy: past, present, and future. Clin Infect Dis 58(Suppl 1):S20–S27. doi:.10.1093/cid/cit614 [PubMed] [Cross Ref]
7. Casapao AM, Steed ME, Levine DP, Rybak MJ 2012. Ceftaroline fosamil for community-acquired bacterial pneumonia and acute bacterial skin and skin structure infection. Expert Opin Pharmacother 13:1177–1186. doi:.10.1517/14656566.2012.685718 [PubMed] [Cross Ref]
8. Shirley DT, Heil EL, Johnson JK 2013. Ceftaroline fosamil: a brief clinical review. Infect Dis Ther 2:95–110. doi:.10.1007/s40121-013-0010-x [PMC free article] [PubMed] [Cross Ref]
9. Forest Laboratories.2012. Teflaro™ (ceftaroline fosamil) prescribing information (10/2012). Forest Laboratories, New York, NY: http://www.frx.com/pi/teflaro_pi.pdf.
10. Electronic Medicines Compendium. Zinforo 600 mg powder for concentration for solution for infusion. Summary of product characteristics. Datapharm Communications, Leatherhead, Surrey, United Kingdom. http://www.medicines.org.uk/emc/searchresults.aspx?term=Zinforo&searchtype=QuickSearch.
11. Arshad S, Hartman P, Zervos MJ 2014. A novel treatment option for MRSA pneumonia: ceftaroline fosamil-yielding new hope in the fight against a persistent infection. Expert Rev Anti Infect Ther 12:727–729. doi:.10.1586/14787210.2014.908118 [PubMed] [Cross Ref]
12. Bally M, Dendukuri N, Sinclair A, Ahern SP, Poisson M, Brophy J 2012. A network meta-analysis of antibiotics for treatment of hospitalised patients with suspected or proven methicillin-resistant Staphylococcus aureus infection. Int J Antimicrob Agents 40:479–495. doi:.10.1016/j.ijantimicag.2012.08.004 [PubMed] [Cross Ref]
13. Casapao AM, Davis SL, Barr VO, Klinker KP, Goff DA, Barber KE, Kaye KS, Mynatt RP, Molloy LM, Pogue JM, Rybak MJ 2014. Large retrospective evaluation of the effectiveness and safety of ceftaroline fosamil therapy. Antimicrob Agents Chemother 58:2541–2546. doi:.10.1128/AAC.02371-13 [PMC free article] [PubMed] [Cross Ref]
14. Critchley IA, Eckburg PB, Jandourek A, Biek D, Friedland HD, Thye DA 2011. Review of ceftaroline fosamil microbiology: integrated FOCUS studies. J Antimicrob Chemother 66(Suppl 3):iii45–iii51. doi:.10.1093/jac/dkr098 [PubMed] [Cross Ref]
15. File TM Jr, Wilcox MH, Stein GE 2012. Summary of ceftaroline fosamil clinical trial studies and clinical safety. Clin Infect Dis 55(Suppl 3):S173–S180. doi:.10.1093/cid/cis559 [PubMed] [Cross Ref]
16. Frampton JE. 2013. Ceftaroline fosamil: a review of its use in the treatment of complicated skin and soft tissue infections and community-acquired pneumonia. Drugs 73:1067–1094. doi:.10.1007/s40265-013-0075-6 [PubMed] [Cross Ref]
17. Goodman JJ, Martin SI 2012. Critical appraisal of ceftaroline in the management of community-acquired bacterial pneumonia and skin infections. Ther Clin Risk Manag 8:149–156. doi:.10.2147/TCRM.S17413 [PMC free article] [PubMed] [Cross Ref]
18. Lodise TP, Low DE 2012. Ceftaroline fosamil in the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. Drugs 72:1473–1493. doi:.10.2165/11635660-000000000-00000 [PubMed] [Cross Ref]
19. Pasquale TR, Tan MJ, Trienski TL, File TM Jr 2015. Methicillin-resistant Staphylococcus aureus nosocomial pneumonia patients treated with ceftaroline: retrospective case series of 10 patients. J Chemother 27:29–34. doi:.10.1179/1973947813Y.0000000156 [PubMed] [Cross Ref]
20. Santos PD, Davis A, Jandourek A, Smith A, David Friedland H 2013. Ceftaroline fosamil and treatment of acute bacterial skin and skin structure infections: CAPTURE study experience. J Chemother 25:341–346. doi:.10.1179/1973947813Y.0000000144 [PMC free article] [PubMed] [Cross Ref]
21. Long SW, Olsen RJ, Mehta SC, Palzkill TG, Cernoch PL, Perez KK, Musick WL, Rosato AE, Musser JM 2014. PBP2a mutations causing high-level ceftaroline resistance in clinical methicillin-resistant Staphylococcus aureus isolates. Antimicrob Agents Chemother 58:6668–6674. doi:.10.1128/AAC.03622-14 [PMC free article] [PubMed] [Cross Ref]
22. Chan LC, Basuino L, Diep B, Hamilton S, Chatterjee SS, Chambers HF 2015. Ceftobiprole- and ceftaroline-resistant methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 59:2960–2963. doi:.10.1128/AAC.05004-14 [PMC free article] [PubMed] [Cross Ref]
23. Klevens RM, Morrison MA, Nadle J, Petit S, Gershman K, Ray S, Harrison LH, Lynfield R, Dumyati G, Townes JM, Craif AS, Zell ER, Fosheim GE, McDougal LK, Carey RB, Fridkin SK, Active Bacterial Core surveillance (ABCs) MRSA Investigators. 2007. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 298:1763–1771. doi:.10.1001/jama.298.15.1763 [PubMed] [Cross Ref]
24. Ray GT, Suaya JA, Baxter R 2012. Trends and characteristic of culture-confirmed Staphylococcus aureus infections in a large U.S. integrated health care organization. J Clin Microbiol 50:1950–1957. doi:.10.1128/JCM.00134-12 [PMC free article] [PubMed] [Cross Ref]
25. Rubinstein E, Kollef MH, Nathwani D 2008. Pneumonia caused by methicillin-resistant Staphylococcus aureus. Clin Infect Dis 46(Suppl 5):S378–S385. doi:.10.1086/533594 [PubMed] [Cross Ref]
26. Woods C, Colice G 2014. Methicillin-resistant Staphylococcus aureus pneumonia in adults. Expert Rev Respir Med 8:641–651. doi:.10.1586/17476348.2014.940323 [PubMed] [Cross Ref]
27. Clinical and Laboratory Standards Institute. 2012. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standards, 9th ed CLSI document M07-A9. Clinical and Laboratory Standards Institute, Wayne, PA.
28. Clinical and Laboratory Standards Institute. 2014. Performance standards for antimicrobial susceptibility testing; twenty-fourth informational supplement. CLSI document M100-S24. Clinical and Laboratory Standards Institute, Wayne, PA.
29. Alm RA, McLaughlin RE, Kos VN, Sader HS, Iaconis JP, Lahiri SD 2014. Analysis of Staphylococcus aureus clinical isolates with reduced susceptibility to ceftaroline: an epidemiological and structural perspective. J Antimicrob Chemother 69:2065–2075. doi:.10.1093/jac/dku114 [PubMed] [Cross Ref]
30. Sader HS, Flamm RK, Jones RN 2013. Antimicrobial activity of ceftaroline and comparator agents tested against bacterial isolates causing skin and soft tissue infections and community-acquired respiratory tract infections isolated from the Asia-Pacific region and South Africa (2010). Diagn Microbiol Infect Dis 76:61–68. doi:.10.1016/j.diagmicrobio.2013.01.005 [PubMed] [Cross Ref]
31. Flamm RK, Sader HS, Jones RN 2014. Ceftaroline activity tested against contemporary Latin American bacterial pathogens (2011). Braz J Infect Dis 18:187–195. doi:.10.1016/j.bjid.2013.11.005 [PubMed] [Cross Ref]
32. Farrell DJ, Castanheira M, Mendes RE, Sader HS, Jones RN 2012. In vitro activity of ceftaroline against multidrug-resistant Staphylococcus aureus and Streptococcus pneumoniae: a review of published studies and the AWARE Surveillance Program (2008-2010). Clin Infect Dis 55:S206–214. doi:.10.1093/cid/cis563 [PubMed] [Cross Ref]
33. Flamm RK, Sader HS, Jones RN 2014. Ceftaroline activity against organisms isolated from respiratory tract infections in USA hospitals: results from the AWARE program, 2009-2011. Diagn Microbiol Infect Dis 78:437–442. doi:.10.1016/j.diagmicrobio.2013.10.020 [PubMed] [Cross Ref]
34. Flamm RK, Sader HS, Farrell DJ, Jones RN 2012. Ceftaroline potency among 9 US census regions: report from the 2010 AWARE program. Clin Infect Dis 55(Suppl 3):S194–S205. doi:.10.1093/cid/cis562 [PubMed] [Cross Ref]
35. Castanheira M, Jones RN, Sader HS 2014. Activity of ceftaroline and comparator agents tested against contemporary Gram-positive and -negative (2011) isolates collected in Europe, Turkey, and Israel. J Chemother 26:202–210. doi:.10.1179/1973947813Y.0000000135 [PubMed] [Cross Ref]
36. Kelley WL, Jousselin A, Barras C, Lelong E, Renzoni A 2015. Missense mutations in PBP2A affecting ceftaroline susceptibility detected in epidemic hospital-acquired methicillin-resistant Staphylococcus aureus clonotypes ST228 and ST247 in western Switzerland archived since 1998. Antimicrob Agents Chemother 59:1922–1930. doi:.10.1128/AAC.04068-14 [PMC free article] [PubMed] [Cross Ref]
37. Mendes RE, Tsakris A, Sader HS, Jones RN 2012. Characterization of methicillin-resistant Staphylococcus aureus displaying increased MICs of ceftaroline. J Antimicrob Chemother 67:1321–1324. doi:.10.1093/jac/dks069 [PubMed] [Cross Ref]
38. Lahiri SD, McLaughlin RE, Whiteaker JD, Ambler JE, Alm RA 2015. 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 70:2488–2498. doi:.10.1093/jac/dkv131 [PubMed] [Cross Ref]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)