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Ceftaroline activity tested against contemporary Latin American bacterial pathogens (2011)

A total of 2484 target bacterial pathogens were collected (one per patient episode) from patients in 16 Latin American medical centers located in seven nations during 2011. Isolate identity was confirmed at a coordinating laboratory and susceptibility testing was performed for ceftaroline and comparator agents according to reference broth microdilution methods. A total of 30.0% of isolates were from respiratory tract, 29.4% from skin and skin structure, 21.4% from blood stream, 7.9% from urinary tract and 11.3% from other sites. Ceftaroline was active against Staphylococcus aureus (42.8% MRSA) with 83.6% of the isolates at ≤1 mg/L and all isolates at ≤2 mg/L (MIC5090, 0.25/2 mg/L). National MRSA rates ranged from a low of 28.8% in Colombia to a high of 68.1% in Chile. All Streptococcus pyogenes and Streptococcus agalactiae were susceptible to ceftaroline (MIC50/90 values were at ≤0.015/≤0.015 mg/L for both). All Streptococcus pneumoniae were susceptible to ceftaroline, linezolid, tigecycline and vancomycin. Susceptibility to ceftriaxone was at 88.4% (CLSI non-meningitis interpretive criteria) and 73.9% (CLSI meningitis interpretive criteria) for all S. pneumoniae. Ceftriaxone susceptibility was only at 33.3% (CLSI non-meningitis interpretive criteria) and 0.0% (CLSI meningitis interpretive criteria) for penicillin-intermediate (penicillin MIC, 4 mg/L) strains. All Haemophilus influenzae (29.4% β-lactamase-positive) isolates were susceptible to ceftaroline, amoxicillin–clavulanate, ceftriaxone, and levofloxacin. For the Latin American region, the ESBL-phenotype rate was 37.6% for Escherichia coli and 53.3% for Klebsiella pneumoniae. Ceftaroline was not active against ESBL-phenotype strains but was active against >90.0% of the non-ESBL-phenotype. The spectrum of activity of ceftaroline against pathogens from Latin America indicates that it merits further study for its potential use in the Latin American region.


Introduction
Ceftaroline fosamil (the prodrug of the active metabolite ceftaroline) is a new cephalosporin approved in the USA in 2010 for acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia and in Europe in Enterobacteriaceae. [7][8][9][10][11][12][13] Ceftaroline exhibits a level of binding affinity for PBPs in S. aureus including PBP2a in MRSA and in S. pneumoniae including PBP2B and 2X. 7,8 Ceftaroline and comparator agent activities against pathogens have been monitored since 2008 in the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) Program. [10][11][12][13] The program provides continuing longitudinal data on antimicrobial activity in order to provide contemporary information. In this report, we present the results of the Latin American regional surveillance program for 2484 target pathogens from 16 medical centers from seven countries collected during 2011 from SENTRY as part of the AWARE program.

Susceptibility testing
Bacterial isolates were tested for susceptibility to ceftaroline and comparator agents according to the reference broth microdilution methods of the Clinical and Laboratory Standards Institute (CLSI). 14 Susceptibility interpretations were based on CLSI (M100-S23) or EUCAST (2013) criteria; in the case of tigecycline the USA-FDA drug package insert criteria were used in lieu of CLSI criteria, as no CLSI interpretive criteria for tigecycline exist. [15][16][17] CLSI interpretive criteria for S. aureus for ceftaroline are susceptible, ≤1 mg/L; intermediate, 2 mg/L; resistant, ≥4 mg/L while EUCAST interpretive criteria are susceptible, ≤1 mg/L and resistant, >1 mg/L. Discussions on susceptibility presented in this report are based on CLSI interpretations unless otherwise specified. Cation-adjusted Mueller-Hinton broth (CA-MHB), supplemented with 2.5-5% lysed horse blood for streptococci, was used for susceptibility testing. For Haemophilus spp., Haemophilus Test Medium was used. 14 E. coli and Klebsiella spp. isolates were grouped as "ESBL-phenotype" based on the CLSI screening criteria for ESBL production, i.e. MIC of ≥2 mg/L for ceftazidime or ceftriaxone or aztreonam. 15

Results
The following numbers of organisms were collected from the 16 (Tables 1 and 2). Ceftaroline was 16-fold more active than ceftriaxone against MSSA (data not shown). By definition all MRSA are resistant to ceftriaxone and all other ␤-lactams except for the anti-MRSA cephalosporin ceftaroline. 15,16 National MRSA rates ranged from a low of 28.8% in Colombia to a high of 68.1% in Chile (Table 3). All S. aureus were susceptible to daptomycin, linezolid, tigecycline, and vancomycin ( Table 2).
The overall susceptibility of S. aureus to ceftaroline was 83.6% (Table 2). For MSSA, susceptibility to ceftaroline was 100.0% and for MRSA it was 61.6% ( Table 2). All ceftaroline non-susceptible S. aureus isolates (16.4% of all S. aureus) were MRSA and exhibited a MIC value of 2 mg/L (intermediate by CLSI criteria, resistant by EUCAST criteria) ( Table 1). MRSA with a ceftaroline MIC at 2 mg/L were found in all sampled countries and rates varied from country to country. The percent of MRSA isolates which exhibited a MIC of 2 mg/L are listed for each country in rank order: Columbia (6.7%), Mexico (15.5%), Argentina (35.5%), Brazil (39.8%), Venezuela (41.9%), Panama (47.8%) and Chile (83.9%) (data not shown). Isolates with a ceftaroline MIC at 2 mg/L were found in respiratory, skin and soft tissue, bloodstream, and other infection types.
All S. pyogenes and S. agalactiae were susceptible to ceftaroline and MIC 50/90 values were at ≤0.015/≤0.015 mg/L (Tables 1 and 2). S. pyogenes was highly susceptible to many other agents including ceftriaxone, penicillin, daptomycin, tigecycline, vancomycin and linezolid, each at 100.0% susceptibility (Table 2). However, susceptibility to tetracycline was only at 81.8% and erythromycin at 90.9% (Table 2). All isolates were susceptible to levofloxacin based on CLSI criteria; however, 7.6% of isolates were non-susceptible to levofloxacin based on EUCAST criteria ( Table 2). All S. agalactiae were susceptible to all tested ␤-lactams, as well as daptomycin, linezolid, tigecycline and vancomycin ( Table 2).
For the Latin American region, the ESBL-phenotype rate for 518 E. coli was 37.6% (Table 1). Only two nations ESBL-phenotype defined as MIC of ≥2 mg/L for ceftazidime or ceftriaxone or aztreonam (CLSI, 2013). for gentamicin (Table 4). Susceptibilities were decreased further for the ESBL-phenotype strains of E. coli, where for example, levofloxacin susceptibility was at 14.4% (Table 4). For K. pneumoniae, tigecycline was the only agent tested which exhibited greater than 90% susceptibility (97.9%; 94.7% by EUCAST criteria; Table 4). As was noted for E. coli, the ESBL-phenotype strains of K. pneumoniae showed much higher resistance rates for most other agents; the exception was tigecycline, which still showed susceptibility at 97.5% (92.6% by EUCAST criteria; Table 4). Ceftaroline was not active against ESBL-phenotype strains of E. coli and K. pneumoniae; however 90.7% of non-ESBL-phenotype E. coli and 95.5% of non-ESBL-phenotype K. pneumoniae were susceptible to ceftaroline (Table 4).

Discussion
Previous AWARE surveillance studies in the USA indicated that for S. aureus including MRSA the MIC 90 for ceftaroline was at 1 mg/L and the highest MIC values occurred in MRSA at 2 mg/L. 10 in North America. This may be due to differences in circulating MRSA clones and would be reflected in the regional and local susceptibility patterns. [20][21][22] For example, the highest percentage of MRSA with ceftaroline MIC of 2 mg/L in our study was observed in Chile (83.9%) where previous studies had shown that the Cordobes/Chilean clone predominates. 22 This clone displays the staphylococcal cassette chromosome mec (SCCmec) type I which was shown to have a modal value for ceftaroline-avibactam of 2 mg/L compared to 1 mg/L for SCCmec types II and III and 0.5 mg/L for SCCmec type IV. 21 Overall ␤-streptococci were highly susceptible to ceftaroline and other commonly used agents. However, S. pneumoniae exhibited decreased susceptibility to a number of agents. For example, the overall rate of penicillin-non-susceptibility for S. pneumoniae (penicillin, MIC, ≥4 mg/L) in the Latin American region was at 13.7% and varied on a national basis, up to 66.7% in Venezuela. Further, susceptibility of S. pneumoniae to ceftriaxone was at 88.4% (CLSI non-meningitis interpretive criteria) or 73.9% (CLSI meningitis interpretive criteria) for all S. pneumoniae (Table 2). Ceftriaxone susceptibility was decreased even more for penicillin-non-susceptible strains. Ceftaroline, which exhibited 100.0% susceptibility to all S. pneumoniae, may provide a potential alternative when penicillin or ceftriaxone non-susceptible isolates are a concern.
Ceftaroline was active against non-ESBL-phenotype Enterobacteriaceae; however as for third generation cephalosporins, it was not active against ESBL-phenotype strains. As the ESBL-phenotype occurred frequently in the Latin American region and varied among individual nations the likelihood of encountering a ESBL-phenotype strain will need to be considered in determining the potential role for ceftaroline. Examples of variation in national rates in this study included ESBL-phenotype E. coli isolates ranging from 10.0% (Venezuela) to 70.7% (Mexico) and for ESBL-phenotype K. pneumoniae national rates from 40.0% in Panama to 58.8% in Chile.
In summary, ceftaroline was shown to have in vitro activity against Gram-positive and selected Gram-negative pathogens isolated from patients in the Latin American region during 2011. The spectrum of activity for ceftaroline included key pathogens, which are found in a variety of infections including community-acquired pneumonia and skin and soft tissue infections. This included potent activity against non-ESBL producing E. coli and K. pneumoniae but a lack of activity against MDR Gram-negative bacteria such as ESBL-producing E. coli and K. pneumonia, which occurred frequently in the Latin American region. The spectrum of activity of ceftaroline against pathogens isolated from patients in Latin American medical centers indicates that it merits further study for its potential use in the region.

Funding
This study was funded by AstraZeneca, and JMI Laboratories received compensation fees for services in relation to preparing the manuscript, which was funded by AstraZeneca.