A total of 176,345isolates were collected between 2012 and 2016. The numbers of isolates of each species group tested are listed in Table 1 and 2. The largest number of isolates were collected from patients of over 60 years (82,518, 46.8%) and of 31-60 years (59,428, 33.7%), followed by patients of under 18 years (19,446, 11.0%) and of 19-30 years (13,350, 7.6%). Regarding infection type, 64,032 (36.3%) isolates were collected from SSSI, 52,077 (29.5%) from LRTI, 26,868 (15.2%) from UTI, 12,847 (7.3%) from IAI and 11,930 (6.8%) from blood. In regard to hospital location, 74,554 (42.3%), 32,430 (18.4%), 17,024 (9.7%), 16,339(9.3%), 10,130(5.7%) and 8,200 (4.6%) isolates were received from patients in the general medical wards, general surgical wards, emergency rooms, medical intensive care unit (ICUs), surgical ICUs and general pediatric wards,respectively.
In vitro activities of ceftaroline and ceftazidime-avibactamagainstGram-negativebacteria from 2012 to 2016
Tables 1 (Gram-negative) and 2 (Gram-positive) show the in vitro activities of ceftaroline, ceftazidime-avibactam and comparator antibiotics against key bacterial species.
Ceftazidime-avibactam demonstrated high activities against all tested Gram-negative species (CLSI/EUCAST susceptibility, 91.9%-99.8%), exceptfor Acinetobacter baumannii(MIC50/MIC90, 32/128 mg/L). The addition of avibactam drastically increased the activity of ceftazidime against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundiiand Pseudomonas aeruginosa (CLSI susceptibilities of ceftazidime alone, 64.3%-79.2%) whereas a trend of decreased MIC was observed for Acinetobacter baumannii, as indicated by a 2-fold reduction in MIC90(ceftazidime, MIC50/MIC90, 64/256 mg/L).Regarding comparator agents, the susceptibility of Enterobacteriaceae was in general high to carbapenems and tigecycline (>90%). For Acinetobacter baumannii,the most potent antibiotics were colistin and tigecycline (MIC50/MIC90, 1/2 mg/L), with a MIC50 of ≥8 and a MIC90 of ≥16 mg/L observed for all other tested agents.
As to resistantGram-negative strains, theactivities of ceftazidime-avibactam were moderatefor CRECO (MIC50/MIC90, 0.5/256 mg/L), CRKPN (MIC50/MIC90, 1/256 mg/L) and CRPAE (MIC50/MIC90, 4/64 mg/L) and low for CRECL and CRABA (MIC50/MIC90, 64-128/256 mg/L) (Table 3).Regarding comparator agents, the susceptibilities to CRECO, CRKPN, CRECL, CRPAE and CRABA were low for the vast majority of tested antibiotics. Good potency was observed for tigecycline against all tested Enterobacteriaceae (MIC50/MIC90, 0.25-1/1-4 mg/L), and for colistin against CRECO, CRECL, CRPAE and CRABA (MIC50/MIC90, 0.5-1/1-2 mg/L).
The susceptibilities of various antibiotic agents against Gram-negative bacteria (total, regardless of drug resistance) were in general comparable using CLSI and EUCAST breakpoints, with the exception of imipenem and tigecycline againstProteus mirabilis (Table 1). Nevertheless, the susceptibilities of a number of resistant species was lower using the EUCAST breakpoints as compared with the CLSI breakpoints. For example, the susceptibilities of CRECO (72.3% vs. 40.5%) and CRECL (42.3% vs. 21.9%) to ceftazidime-avibactam, and the susceptibilities ofCRECO, CRKPN, CRECL and CRPAE to levofloxacin, tigecycline, amikacin (all with a >10% difference) were noticeably lower when EUCAST breakpoints were applied (Table 3).
In vitro activities of ceftaroline and ceftazidime-avibactam againstGram-positivebacteria from 2012 to 2016
In the Gram-positivestrains, ceftaroline showed more than 90% susceptibility rates for Staphylococcus aureus,Streptococcus pneumoniae, α-hemolytic Streptococcus, and β-hemolytic Streptococcus (CLSI). TheMIC50/MIC90 of ceftarolinefor CoNS and Enterococcus faecalis were 0.25/1 mg/L and 1/16 mg/L, respectively. Ceftaroline demonstrated low activity against Enterococcus faecium (MIC50/MIC90,64/64 mg/L)(Table 2). Ceftazidime-avibactam showed low activity against CoNS, Staphylococcus aureus, Enterococcus faecalis, and Enterococcus faecium (MIC50/MIC90: 16-64/64 mg/L),moderate activity against Streptococcus pneumoniaeand α-hemolytic Streptococcus(MIC50/MIC90, 0.25/16 mg/L) and high activity against β-hemolytic Streptococcus(MIC50/MIC90, 0.025/0.5 mg/L).The addition of avibactam to ceftazidime was not associated with improved activities against the tested gram-positive strains. For all tested Staphylococcus, Streptococcus and Enterococcus, high susceptibility (>90%) to linezolid, tigecycline, daptomycin and vancomycin were observed (with the exception ofEnterococcus faecium to vancomycin). High activities (susceptibility, >90%) of levofloxacin and moxifloxacin were also observed for Streptococcus.
Regarding resistant Gram-positive strains, ceftaroline demonstrated high activities against MRSA (CLSIsusceptibility, 89.0%) and PRSP (CLSI susceptibility, 98.2%) whereas ceftazidime-avibactam demonstrated limited activities (MIC50/MIC90: 16-64/64 mg/L) (Table 3).For comparator agents, potent activity(CLSI susceptibility, >95%) against MRSA was observed for linezolid, tigecycline, vancomycin, teicoplanin, daptomycin and trimethoprim sulfa whereas the susceptibility of PRSP (CLSI susceptibility, >95%) was high to linezolid, tigecycline, vancomycin, levofloxacin and moxifloxacin (Table 3).
Thesusceptibilities ofGram-positive bacteria (regardless of drug resistance) were similar for CLSI and EUCAST breakpoints, expect for the susceptibility of CoNS toteicoplaninand gentamicin. In terms of resistant strains, noticeably lower susceptibility of PRSP to ceftaroline (98.2% vs. 86.8%) and meropenem (3.4% vs. 100%) was observed using ECUAST breakpoints as compared with CLSI breakpoints.
Global trend of susceptibility of pathogens against ceftaroline and ceftazidime-avibactam from 2012 to 2016
Figure 1 presents the trends of susceptibility to ceftaroline against key bacterial species over time in different regions using the CLSI breakpoints. For Escherichia coli (2012/2016:66.2%/66.5%), Klebsiella pneumoniae (2012/2016: 57.4%/60.4%), Proteus mirabilis(2012/2016: 78.7%/81.2%), Staphylococcus aureus(2012/2016:92.5%/95.1%) and Streptococcus pneumoniae(2012/2016:99.9%/99.7%),the overall global susceptibility to ceftaroline remained relatively stable in all regions from 2012 to 2016. For Escherichia coli,the susceptibility was consistently higher in NA (77.1%-82.0%) and lower in Asian (45.1%-53.0%). Higher susceptibilities in NA were also observed for Klebsiella pneumoniae and Proteus mirabilis and lower susceptibility in Asia was observed for Staphylococcus aureus.For Enterobacter clocae, the global susceptibility gradually increased from 56.2% in 2012 to 64.6% in 2016.ForCitrobacter freundii, the global susceptibility peaked at 69.1% in 2014, decreased slightly in 2015 and rebounded to 63.2% in 2016.
Figure 2 presents the trends of susceptibility to ceftazidime-avibactam against key bacterial species over time in different regions using the CLSI breakpoint. The susceptibility of Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis to ceftazidime-avibactam remained high (>95%) and relatively stable over time in all regions. The susceptibility of Enterobacter cloacaeand Citrobacter freundiito ceftazidime-avibactam remained relatively stable over time in all regions, but the susceptibility in Asia (2013/2016: 94.6%/94.6% and 94.9%/94.7%) decreased in 2013 and was consistently lower than the global ratesthereafter (2013/2016: 98.3%/97.4% and 99.7%/97.6%). The global susceptibility of Pseudomonas aeruginosa to ceftazidime-avibactam globally decreased from 2012 to 2016 (2012/2016: 97.1%/92.0%), with lower rates observed in LA (2012/2016: 92.7%/86.6%), and higher rates observed in NA (2012/2016: 97.9%/96.6%).
Global trend of susceptibility of ceftaroline and ceftazidime-avibactam against multidrug-resistant species
The proportion of MRSA among all Staphylococcus aureusremained stable from 2012 to 2016 (59.8% at both 2012 and 2016), with higher prevalence observed for NA (2012/2016: 66.5%/68.1%) and lower prevalence observed for LA (2012/2016: 55.9%/53.3%). The overall global susceptibility of MRSA to ceftarolineincreased slightly from 87.5% in 2012 to 91.7% in 2016, with marked increase observed in AM (2012/2016: 88.7%/97.8%), Europe (2012/2016: 89.8%/96.2%) and LA (2012/2016: 78.2%/88.2%) (Figure 3A). The susceptibility of MRSA to ceftaroline in Asia was consistently lower than all other regions (2012/2016: 75.2%/75.5%).
The proportion of CRKPN among all Klebsiella pneumoniaeslightly increased from 6.7% in 2012 to8.2% in 2016, with higher prevalence observed for LA (2012/2016: 9.2%/11.2%) and Europe (2012/2016: 9.3%/10.4%). Conversely, the overall global susceptibility of CRKPN to ceftazidime-avibactam decreased from 88.4% in 2012 to 81.6% in 2016, with marked decrease observed in AM (2012/2016: 100%/63.6%), Asia (2012/2016: 76.9%/68.2%), and LA (2012/2016: 100%/90%) (Figure 3B). The susceptibility rates in Asia and AM were in general lower than other regions during the study period.
The proportion of CRPAE among all Pseudomonas aeruginosaremained relatively stable over time (2012/2016: 26.5%/26.7%), with higher prevalence observed for LA (2012/2016: 36.3%/34.4%). The overall global susceptibility of CRPAE to ceftazidime-avibactam decreased from 89.6% in 2012 to 72.7% in 2016, with marked decrease observed for all regions (Figure 3). The susceptibility rate in NA (2012/2016: 93.2%/86.0%) was in general higher than other regions.