Global trends of antimicrobial susceptibility to ceftaroline and ceftazidime–avibactam: a surveillance study from the ATLAS program (2012–2016)

This study reports the global trends of antimicrobial susceptibility to ceftaroline and ceftazidime–avibactam using data from the Antimicrobial Testing Leadership and Surveillance (ATLAS) program between 2012 and 2016. For the 2012–2016 ATLAS program, 205 medical centers located in Africa-Middle East (n = 12), Asia–Pacific (n = 32), Europe (n = 94), Latin America (n = 26), North America (n = 31), and Oceania (n = 10) consecutively collected the clinical isolates. The minimum inhibitory concentrations (MICs) and in vitro susceptibilities to ceftaroline and ceftazidime–avibactam were assessed using the Clinical and Laboratory Standards Institute (CLSI) 2019and European Committee on Antimicrobial Susceptibility Testing (EUCAST) 2019 guidelines. Between 2012 and 2016, 176,345 isolates were collected from around the globe and included in the analysis. Regarding Gram-negative bacteria, ceftazidime–avibactam demonstrated high susceptibility (> 90%) against Enterobacteriaceae and Pseudomonas aeruginosa, with increased antimicrobial activity observed from the addition of avibactam (4 mg/L) to ceftazidime. Regarding Gram-positive bacteria, ceftaroline showed > 90% susceptibility against Staphylococcus aureus, Streptococcus pneumoniae, α-and β-hemolytic Streptococcus. The antimicrobial susceptibilities to ceftaroline and ceftazidime–avibactam were mostly stable from 2012 to 2016, but the susceptibilities to ceftazidime–avibactam to carbapenem-resistant (CR) Klebsiella pneumonia (88.4–81.6%) and to CR-P. aeruginosa (89.6–72.7%) decreased over time. In terms of regional difference, the susceptibilities of methicillin-resistant S. aureus to ceftaroline in Asia and of CR-K. pneumonia to ceftazidime–avibactam in Asia/Africa-Middle East were lower compared with other regions, while the susceptibility of CR-P. aeruginosa to ceftazidime–avibactam in North America was higher. The addition of avibactam improves the activity of ceftazidime against Enterobacteriaceae and P. aeruginosa. The global antimicrobial susceptibilities to ceftaroline and ceftazidime–avibactam were, in general, stable from 2012 to 2016, but a marked reduction in the susceptibilities of specific species and CR-P. aeruginosa to ceftazidime–avibactam was observed.


Introduction
The rapidly increasing and global spreading of the resistance of bacteria to antibiotics in recent years is a serious challenge for clinicians and a global health crisis [1]. Multi-drug resistance in both Gram-negative and -positive bacteria often leads to untreatable infections using conventional antibiotics, and even last-resort antibiotics are losing their power [2]. The increases in the occurrence of infections caused by third-generation cephalosporin-and carbapenem-resistant (CR)-Enterobacteriaceae, CR-Pseudomonas aeruginosa, and CR-Acinetobacter baumannii are of particular concern since they are associated with tremendously increased mortality and morbidityrates [3,4]. Recently, the World Health Organization has rated CR-Enterobacteriaceae, CR-P. aeruginosa, and CR-A. baumannii as top critical-priority resistant bacteria, outweighing methicillin-resistant Staphylococcus aureus [5]. Consequently, updated epidemiological data on antibiotic resistance is needed to adapt the treatment strategies to the reality, which changes at an alarming rate [4,[6][7][8].
Ceftaroline is a fifth-generation broad-spectrum cephalosporin. It is mainly active against methicillin-resistant S. aureus and Gram-positive bacteria, but also against Gram-negative bacteria [9]. Ceftarolineis indicated for community-acquired pneumonia and complicated skin infections [10][11][12][13]. Avibactam is a diazabicyclooctane derivative antibiotic that can reversibly inhibit β-lactamase enzymes, including Ambler class A (ESBL and KPC), class C, and partial class D (including OXA-1, OXA-10, and OXA-48-like) enzymes by covalent acylation of the active-site serine residue [14]. Ceftazidimeavibactam is a novel β-lactam/β-lactamase inhibitor combination that has shown potency against a wide variety of CR-Enterobacteriaceae. Ceftazidime-avibactam has been approved for the management of complicated urinary tract infections, complicated intra-abdominal infections, hospital-acquired pneumonia, and infections from aerobic Gram-negative bacteria with limited treatment options [15].
Ceftaroline and ceftazidime-avibactam are relatively novel antibiotics that show promises in the control of antibiotic-resistant pathogens. They are readily available around the globe. The patterns of resistance to ceftaroline and ceftazidime-avibactam around the globe remain to be defined exactly and represent crucial data for monitoring global health threats. Therefore, this study aimed to: (1) examine the in vitro activities of ceftaroline, ceftazidime-avibactam, and various comparative agents from 2012 to 2016 using the data from a global antibiotic surveillance program, the Antimicrobial Testing Leadership And Surveillance (ATLAS) program; and (2) compare the susceptibility profile of various pathogen species over time and across different regions of the world, with an emphasis on antibiotic-resistant pathogens.

Bacterial isolates
For the 2012-2016 ATLAS program, 205 medical centers located in Africa-Middle East (n = 12), Asia-Pacific (n = 32), Europe (n = 94), Latin America (n = 26), North America (n = 31), and Oceania (n = 10) contributed to the consecutive collection of clinical isolates. The specimens were obtained from inpatients with specific types of infections (skin and skin structure infection, intraabdominal infection, urinary tract infection, lower respiratory tract infection, and blood infection). The pathogens were isolated and identified by each participating center, stored in tryptic soy broth with glycerol at − 70 °C, and shipped to International Health Management Associates, Inc. (IHMA; Schaumburg, IL, USA) for susceptibility testing. The present study only included the isolates considered to be the potential pathogen of the patient's infection. If multiple samples were taken from the same patient during an infectious event, only the first positive sample for this infectious event was included in the ATLAS program. The pathogen identification was confirmed by MALDI-TOF at IHMA (Schaumburg, IL, USA) prior to susceptibility testing. Methicillin-resistant S. aureus is defined in this study as S. aureus resistant to oxacillin.
The susceptibilities to the various antibiotics against Gram-negative bacteria (total, regardless of drug resistance) were in general comparable using CLSI 2019 and EUCAST 2019 breakpoints, except for imipenem and tigecycline against P. mirabilis (Table 1). Nevertheless, the susceptibilities of many resistant species were lower using the EUCAST 2019 breakpoints compared with the CLSI 2019 breakpoints. For example, the susceptibilities of CR-E. coli (72.3% vs. 40.5%) and CR-E. cloacae (42.3% vs. 21.9%) to ceftazidime-avibactam, and the susceptibilities of CR-E. coli, CR-K. pneumoniae, CR-E. cloacae, and CR-P. aeruginosa to levofloxacin, tigecycline, and amikacin (all with a > 10% difference) were noticeably lower when the EUCAST 2019 breakpoints were applied (Table 3).
The susceptibilities of Gram-positive bacteria (regardless of drug resistance) were similar between the CLSI 2019 and EUCAST 2019 breakpoints, except for the susceptibility of coagulase-negative Staphylococcus to teicoplanin and gentamicin. In terms of resistant strains, noticeably lower susceptibility of penicillin-resistant S. pneumoniae to ceftaroline (98.2% vs. 86.8%) and meropenem (3.4% vs. 100%) was observed using ECUAST breakpoints as compared with CLSI 2019 breakpoints.      (Fig. 3a).  (Fig. 3b). The susceptibility rates in Asia and Africa-Middle East were, in general, lower than in the other regions during the study period.
The proportion of CR-P. aeruginosa among all P. aeruginosa remained relatively stable over time The overall global susceptibility of CR-P. aeruginosa to ceftazidime-avibactam decreased from 89.6% in 2012 to 72.7% in 2016, with a marked decrease observed for all regions (Fig. 3). The susceptibility rate in North America (2012/2016: 93.2%/86.0%) was, in general, higher than in other regions.

Discussion
Ceftaroline and ceftazidime-avibactam are relatively recent antibiotics that are active against a variety of bacterial species, including some with innate antibiotic resistance [10][11][12][13]15]. The exact resistance patterns to those antibiotics still need to be defined exactly, and there is a crucial need for global surveillance of antibiotic resistance. This study reveals the patterns of the susceptibilities of different bacterial species to a variety of antibiotics, with a focus on ceftaroline and ceftazidime-avibactam, around the world, and over 5 years. The results indicate that the global resistance of CR-P. aeruginosa to ceftazidime-avibactam greatly increased over time, while the susceptibility profile of ceftaroline and ceftazidime-avibactam against other species were relatively stable.
The first objective of this study was to examine the overall in vitro activities of ceftaroline and ceftazidime-avibactam using data from the ATLAS program. The results showed that ceftaroline was highly potent (> 90% susceptibility) against Gram-positive strains, including S. aureus, S. pneumoniae, and Streptococcus. On the other hand, ceftazidime-avibactam showed susceptibility > 90% against Gram-negative bacteria, including Enterobacteriaceae, P. aeruginosa, and P. mirabilis, with overtly increased antimicrobial activity observed with the addition of avibactam to    States of America [20][21][22], and Europe [23], and with the AWARE surveillance program [24][25][26], but with some minute differences that could be due to the specimens' area of origin since the present study included specimens from all over the world. Another source of difference could be the tested period since bacterial susceptibility changes over time. Indeed, as shown by the results to the second objective of the present study, the patterns of resistance varied among species, among world regions, and over time.  The main differences were that the susceptibility rates of E. coli and S. aureus to ceftaroline in Asia were lower than the global rates, while those in Europe and North America were generally similar or higher than the global rates. Asia also showed lower susceptibility rates to ceftazidime-avibactam against C. freundii, E. cloacae, and P. mirabilis. A study examined the resistance patterns to ceftaroline, ceftazidime, and piperacillin-tazobactam and revealed similar patterns between Europe and the United States of America [20]. A study across different areas of the United States of America also reported good susceptibility profiles of ceftaroline against respiratory pathogens [27]. A recent report from the World Health Organization revealed high rates of antibiotic resistance all over the world [28,29]. Antibiotic resistance is a major concern worldwide, and significant differences in the resistance patterns can be observed. The World Health Organization highlighted that even if antibiotic resistance has increased all over the world, the increase was particularly alarming in Asia because of poor health and environment practices such as antibiotic over-prescription, poor infection control, poor waste management, overuse of antibiotics in farming, food security, and restricted access to the newest antibiotics [30][31][32]. Furthermore, the Asia-Pacific region is the most populous region in the world. Many of its countries are among the poorest, and poor health infrastructure is often encountered [33]. In addition, specific resistance mechanisms (e.g., the New Delhi metallo-β-lactamase-1) are also encountered in Asia [34]. The TEST study showed that Africa and Asia were the two regions of the world with the highest occurrence of S. aureus resistant to multiple antibiotics among blood-borne infections [35].
There is a plea for worldwide, automated, and comprehensive surveillance of antimicrobial resistance patterns [8,36,37]. Such surveillance could help optimize the worldwide use of antibiotics to improve infection control and minimize the occurrence of resistant strains [38]. In fact, surveillance and proper actions are necessary to avoid medical, social, and economic setbacks that could threaten the very fabric of the global community [38]. Even if the present study focused on ceftaroline and ceftazidime-avibactam, the ATLAS program provides the comprehensive global susceptibility profiles of many antibiotics against a large number of bacterial species. ATLAS receives data from all regions of the world and covers many years. Therefore, it helps provide certain help for the global surveillance of bacterial resistance.
This study has limitations. First, this was a retrospective study, with the inevitable confounding biases, such as the nature of the participating hospitals (mostly tertiary university-affiliated centers), the exact patient populations consulting at those hospitals, and the lack of many variables at the patient level. Second, this study is purely descriptive. Because of the large sample size, minute nonclinically significant differences in susceptibility could be statistically significant, which could be misleading [39,40]; therefore, statistical tests were not performed.

Conclusion
In summary, the present study showed that the addition of avibactam improved the activity of ceftazidime against Enterobacteriaceae and P. aeruginosa. The global antimicrobial susceptibilitiestoceftaroline and ceftazidime-avibactam were, in general, stable from 2012 to 2016, but a marked reduction in the susceptibilities of specific species and CR-P. aeruginosa for ceftazidime-avibactam was observed in specific regions of the world.