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

doi:10.21203/rs.3.rs-31962/v3

Background:This study reports the global trends of antimicrobial susceptibility toceftaroline and ceftazidime-avibactam using data from the Antimicrobial Testing Leadership And Surveillance (ATLAS)programbetween2012and2016.

Methods: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. Theminimum inhibitory concentrations (MICs) andin vitro susceptibilities toceftarolineandceftazidime-avibactam were assessed using the Clinical andLaboratory Standards Institute (CLSI) 2019and European Committee on Antimicrobial Susceptibility Testing (EUCAST) 2019 guidelines.

Results:Between 2012 and 2016, 176,345 isolates were collectedfrom around the globeand included in theanalysis.Regarding Gram-negative bacteria, ceftazidime-avibactam demonstrated high susceptibility (>90%) against EnterobacteriaceaeandPseudomonas aeruginosa, with increasedantimicrobial activity observed from the addition of avibactam (4 mg/L) to ceftazidime.Regarding Gram-positive bacteria, ceftaroline showed >90% susceptibility againstStaphylococcus aureus, Streptococcus pneumoniae, α-and β-hemolytic Streptococcus.The antimicrobial susceptibilitiestoceftaroline and ceftazidime-avibactam were mostly stable from 2012 to 2016, but the susceptibilitiestoceftazidime-avibactam to carbapenem-resistant (CR)Klebsiella pneumoniae(88.4% to 81.6%) and to CR-Pseudomonas aeruginosa(89.6% to 72.7%) decreased over time. In terms of regional difference, the susceptibilities of methicillin-resistant Staphylococcus aureusto ceftaroline in Asia and of CR-Klebsiella pneumoniaeto ceftazidime-avibactam in Asia/Africa-Middle East were lowercompared with other regions,while the susceptibility of CR-Pseudomonas aeruginosa to ceftazidime-avibactam in North America was higher.

Conclusion: The addition of avibactam improves the activity of ceftazidime against EnterobacteriaceaeandPseudomonas 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 andCR-Pseudomonas aeruginosa toceftazidime-avibactam was observed.

Infectious Diseases

General Biochemistry

ceftaroline

ceftazidime-avibactam

antibiotics

surveillance

antimicrobial resistance

The rapidly increasing and global spreading of the resistance of bacteriato antibiotics in recent years is a serious challenge for clinicians and a global health crisis.¹Multi-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-Pseudomonasaeruginosa,and CR-Acinetobacterbaumannii are of particular concern since they are associated with tremendously increased mortality and morbidityrates.³^,⁴Recently, the World Health Organization has rated CR-Enterobacteriaceae,CR-Pseudomonas aeruginosa, and CR-Acinetobacter baumannii as top critical-priority resistant bacteria, outweighing methicillin-resistantStaphylococcus aureus.⁵Consequently, updated epidemiological data on antibiotic resistance is needed to adapt the treatment strategies to the reality, which changes at an alarming rate.⁴^,^6-8

Ceftaroline is a fifth-generation broad-spectrum cephalosporin.It ismainly active against methicillin-resistant Staphylococcus aureus and Gram-positive bacteria,but also against Gram-negative bacteria.⁹Ceftarolineis indicated for community-acquired pneumonia and complicated skin infections.^10-13Avibactam 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)enzymesby covalentacylation of the active-site serine residue.¹⁴ Ceftazidime-avibactam 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, 205medical 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, intra-abdominal infection, urinary tract infection, lower respiratory tract infection, and blood infection). The pathogens were isolated and identified by each participating center, storedin tryptic soy broth with glycerol at -70°C, and shippedtoInternational Health Management Associates, Inc. (IHMA; Schaumburg, IL, USA) forsusceptibilitytesting.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 infectiousevent 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 Staphylococcus aureus is defined in this study as Staphylococcus aureus resistant to oxacillin.

Antimicrobial susceptibility testing

IHMA (Schaumburg, IL, USA) carried out all antimicrobial susceptibility tests using the broth microdilution method.The minimum inhibitory concentrations (MICs) were interpreted using theClinical and Laboratory Standards Institute (CLSI) 2019 and the European Committee on Antimicrobial Susceptibility Testing (EUCAST)2019 breakpoints.¹⁶^,¹⁷Tigecycline was interpreted using the Food and Drug Administration and EUCAST 2019 interpretative breakpoints.Ceftaroline, ceftazidime-avibactam (avibactam at a fixed concentration of 4 mg/L), and the following comparator agents were tested:ceftazidime, cefepime, penicillin, ampicillin, piperacillin-tazobactam,doripenem, imipenem, meropenem, levofloxacin, moxifloxacin, clindamycin, erythromycin, vancomycin, teicoplanin, linezolid, daptomycin, gentamicin, tigecycline, minocycline, trimethoprim-sulfamethoxazole,amikacin, colistin, aztreonam, quinupristin-dalfopristin, andoxacillin.In the present study, the data were analyzed for Escherichia coli, Klebsiella pneumoniae, Enterobactercloacae, Citrobacter freundii, Proteus mirabilis, Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus, Streptococcus pneumoniae,α- and β-hemolytic Streptococcus, coagulase-negative Staphylococcus, Enterococcus faecalis, and Enterococcus faecium, as well as resistant species includingCR-Escherichia coli, CR-Klebsiella pneumoniae, CR-Enterobacter cloacae, CR-Pseudomonas aeruginosa,CR-Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus, and penicillin-resistant Streptococcus pneumoniae. All tests included quality control strains from the American Type Culture Collection (ATCC; Manassas, VA, USA).Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 700603, Pseudomonas aeruginosa ATCC 27853, Staphylococcusaureus ATCC 29213, and Streptococcus pneumoniae ATCC 49619 were used for quality control according to the CLSI 2019 guidelines. All quality control results were within the published ranges.

Sample retrieval

A total of 176,345isolates were collected between 2012 and 2016. The numbers of isolates of each species group tested are listed in Tables 1 and 2. The largest number of isolates were collected from patients >60 years (82,518, 46.8%) and 31-60 years (59,428, 33.7%), followed by patients <18 years (19,446, 11.0%) and 19-30 years (13,350, 7.6%). Regarding the infection types, 64,032 (36.3%) isolates were collected from skin and skin structure infections, 52,077 (29.5%) from lower respiratory tract infections, 26,868 (15.2%) from urinary tract infections, 12,847 (7.3%) from intra-abdominal infections, and 11,930 (6.8%) from the 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 from patients in the general medical wards, general surgical wards, emergency rooms, medical intensive care unit (ICUs), surgical ICUs, and general pediatric wards,respectively.

Table 1:In vitro susceptibilities of Gram-negative strains obtained from the ATLAS program, 2012-2016.

Organism/Antibiotic	No. of isolates	MIC₅₀	MIC₉₀	MIC Range	CLSI†			EUCAST
Organism/Antibiotic	No. of isolates	MIC₅₀	MIC₉₀	MIC Range	S%	I%	R%	S%	I%	R%
*Escherichia coli*
Ceftaroline	21903	0.12	256	0.015-256	66.5	2.6	30.9	66.5	0	33.5
Ceftazidime-avibactam	21903	0.12	0.25	0.015-256	99.8	0	0.2	99.8	0	0.2
Ceftazidime	21903	0.25	32	0.015-256	79.2	3.0	17.8	74.0	5.1	20.8
Cefepime	21903	0.12	32	0.12-32	76.2	4.7	19.1	74.6	3.6	21.8
Pip-taz	21903	2	16	0.25-256	90.3	4.6	5.1	84.8	5.4	9.8
Doripenem	21903	0.03	0.06	0.008-16	99.6	0.1	0.3	99.6	0.1	0.3
Imipenem	21903	0.25	0.25	0.03-16	99.1	0.4	0.5	99.5	0.4	0.2
Meropenem	21903	0.03	0.06	0.004-16	99.5	0.1	0.4	99.6	0.2	0.2
Levofloxacin	21903	0.25	16	0.004-16	62.3	1.7	36.0	58.8	2.8	38.4
Tigecycline	21903	0.25	0.5	0.015-16	99.8	0.2	0	99.0	0.8	0.2
Amikacin	21903	2	8	0.25-64	98.2	0.9	0.9	94.5	3.7	1.8
Colistin	13964	0.5	1	0.06-16	NA	NA	NA	99.5	0	0.5
Aztreonam	21903	0.12	64	0.015-256	76.0	3.1	20.9	72.3	3.7	24.0
*Klebsiella pneumoniae*
Ceftaroline	18114	0.25	256	0.015-256	57.5	2.0	40.5	57.5	0	42.5
Ceftazidime-avibactam	18114	0.12	1	0.015-256	98.8	0	1.2	98.8	0	1.2
Ceftazidime	18114	0.25	128	0.015-256	64.3	1.9	33.8	61.6	2.7	35.7
Cefepime	18114	0.12	32	0.12-32	65.1	6.0	28.9	63.7	3.2	33.1
Pip/taz	18114	4	256	0.25-256	73.0	7.8	19.2	64.4	8.6	27.0
Doripenem	18114	0.06	0.5	0.008-16	91.6	1.0	7.4	91.6	1.0	7.4
Imipenem	18114	0.25	1	0.03-16	90.3	1.9	7.8	92.2	2.4	5.5
Meropenem	18114	0.06	0.5	0.004-16	91.1	1.1	7.9	92.1	2.0	5.9
Levofloxacin	18114	0.12	8	0.004-16	73.2	3.1	23.7	61.8	9.1	29.1
Tigecycline	18114	0.5	2	0.015-16	96.4	3.1	0.5	88.2	8.2	3.6
Amikacin	18114	1	8	0.25-64	93.6	3.0	3.4	91.0	2.6	6.4
Colistin	12884	0.5	1	0.06-16	NA	NA	NA	96.3	0	3.7
Aztreonam	18114	0.12	256	0.015-256	64.2	1.0	34.8	62.4	1.8	35.8
*Enterobacter cloacae*
Ceftaroline	4330	0.5	256	0.015-256	60.0	3.1	37.0	60.0	0.0	40.1
Ceftazidime-avibactam	4330	0.25	1	0.015-256	97.8	0.0	2.2	97.8	0.0	2.2
Ceftazidime	4330	0.5	128	0.015-256	67.3	1.4	31.3	64.0	3.3	32.7
Cefepime	4330	0.12	32	0.12-32	78.5	8.8	12.7	73.3	10.8	15.9
Pip-taz	4330	4	256	0.25-256	75.3	8.0	16.7	69.9	5.4	24.7
Doripenem	4330	0.06	0.25	0.008-16	96.8	0.4	2.9	96.8	0.4	2.9
Imipenem	4330	0.5	1	0.03-16	93.1	3.5	3.4	96.6	2.0	1.5
Meropenem	4330	0.06	0.12	0.004-16	96.8	0.6	2.6	97.4	1.3	1.3
Levofloxacin	4330	0.06	4	0.004-16	88.8	2.8	8.4	80.8	5.7	13.5
Tigecycline	4330	0.5	1	0.015-16	96.3	3.2	0.5	90.1	6.2	3.7
Amikacin	4330	2	4	0.25-64	97.6	0.9	1.6	96.0	1.6	2.4
Colistin	2889	0.5	1	0.12-16	NA	NA	NA	93.7	0.0	6.3
Aztreonam	4330	0.12	64	0.015-256	68.2	1.4	30.4	65.8	2.4	31.8
*Citrobacter freundii*
Ceftaroline	2327	0.25	128	0.015-256	61.9	2.1	36.0	61.9	0	38.1
Ceftazidime-avibactam	2327	0.12	0.5	0.015-256	98.5	0	1.5	98.5	0	1.5
Ceftazidime	2327	0.5	128	0.015-256	68.0	1.9	30.1	64.3	3.8	32.0
Cefepime	2327	0.12	4	0.12-32	89.8	3.6	6.7	84.4	7.3	8.4
Pip-taz	2327	4	128	0.25-256	77.1	12.0	11.0	70.5	6.6	23.0
Doripenem	2327	0.06	0.12	0.008-16	97.9	0.3	1.8	97.9	0.3	1.8
Imipenem	2327	0.5	2	0.03-16	88.9	8.5	2.6	97.4	2.1	0.5
Meropenem	2327	0.03	0.06	0.004-16	97.7	0.5	1.8	98.2	1.2	0.6
Levofloxacin	2327	0.12	4	0.008-16	87.0	4.0	9.0	76.5	6.2	17.3
Tigecycline	2327	0.5	1	0.015-8	98.9	1.1	0	94.9	4.0	1.1
Amikacin	2327	2	4	0.25-64	98.4	0.4	1.2	97.1	1.3	1.6
Colistin	1593	0.5	1	0.06-16	NA	NA	NA	99.6	0	0.4
Aztreonam	2327	0.25	64	0.015-256	69.2	2.4	28.4	66.2	3.1	30.8
*Proteus mirabilis*
Ceftaroline	3950	0.12	128	0.015-256	79.4	2.0	18.6	79.4	0	20.6
Ceftazidime-avibactam	3950	0.03	0.06	0.015-256	99.7	0	0.3	99.7	0	0.3
Ceftazidime	3950	0.06	1	0.015-256	95.2	1.7	3.1	91.1	4.1	4.8
Cefepime	3950	0.12	8	0.12-32	88.2	3.4	8.5	86.9	2.9	10.3
Pip-taz	3950	0.5	1	0.25-256	98.5	0.9	0.6	97.7	0.8	1.5
Doripenem	3950	0.25	0.5	0.008-16	98.4	1.0	0.6	98.4	1.0	0.6
Imipenem	3950	2	4	0.03-16	25.8	45.9	28.3	71.7	27.7	0.6
Meropenem	3950	0.06	0.12	0.004-16	99.6	0.2	0.3	99.8	0.2	0.1
Levofloxacin	3950	0.12	8	0.015-16	76.6	5.5	17.9	64.9	4.5	30.6
Tigecycline	3950	2	8	0.03-16	52.2	37.3	10.5	20.9	31.3	47.8
Amikacin	3950	4	8	0.25-64	95.6	1.1	3.4	91.5	4.1	4.4
Colistin	2412	16	16	0.25-16	NA	NA	NA	0.5	0	99.5
Aztreonam	3950	0.015	0.5	0.015-256	95.9	0.8	3.3	93.1	2.9	4.1
*Pseudomonas aeruginosa*
Ceftaroline	16014	16	256	0.015-256	NA	NA	NA	NA	NA	NA
Ceftazidime-avibactam	16014	2	8	0.015-256	91.9	0	8.1	91.9	0	8.1
Ceftazidime	16014	4	64	0.06-256	76.7	4.6	18.8	76.7	0	23.4
Cefepime	16014	4	32	0.12-32	78.4	11.2	10.5	78.4	0	21.6
Pip-taz	16014	8	256	0.25-256	68.9	13.8	17.3	68.9	0	31.2
Doripenem	16013	0.5	8	0.008-16	74.3	7.6	18.2	67	7.2	25.8
Imipenem	16014	2	16	0.03-16	63.4	8.2	28.4	71.6	4.5	23.9
Meropenem	16014	0.5	16	0.008-16	72.5	6.0	21.5	72.5	11.9	15.6
Levofloxacin	16014	1	8	0.004-16	70.4	6.8	22.9	61.7	0	38.3
Amikacin	16014	4	16	0.25-64	90.4	2.7	6.9	85.9	4.5	9.6
Colistin	12449	1	2	0.06-16	96.6	0	3.4	96.6	0	3.4
Aztreonam	16014	8	32	0.015-256	NA	NA	NA	3.9	73.4	22.8
*Acinetobacter baumannii*
Ceftaroline	3567	256	256	0.015-256	NA	NA	NA	NA	NA	NA
Ceftazidime-avibactam	3567	32	128	0.03-256	NA	NA	NA	NA	NA	NA
Ceftazidime	3567	64	256	0.015-256	30.1	2.4	67.5	NA	NA	NA
Cefepime	3567	32	32	0.12-32	29.9	10.4	59.7	NA	NA	NA
Pip-taz	3567	256	256	0.25-256	25.4	3.7	70.9	NA	NA	NA
Doripenem	3567	8	16	0.015-16	33.2	1.4	65.4	30.4	2.8	66.8
Imipenem	3567	16	16	0.03-16	33.8	1.2	65.0	33.8	2.7	63.5
Meropenem	3567	16	16	0.015-16	32.8	1.6	65.6	32.8	3.5	63.7
Levofloxacin	3567	8	16	0.03-16	29	9.6	61.4	26.1	1.0	73
Tigecycline	3567	1	2	0.015-16	NA	NA	NA	NA	NA	NA
Amikacin	3567	64	64	0.25-64	42.5	5.8	51.7	40.2	2.3	57.5
Colistin	2404	1	2	0.06-16	94.3	0	5.7	94.3	0	5.7
Aztreonam	3567	64	256	0.015-256	NA	NA	NA	NA	NA	NA

†Cefepime CLSI susceptibility for Enterobacteriaceae adopted the susceptible, susceptible-dose-dependent, and resistant categories.

CLSI＝Clinical Laboratory and Standards Institute; EUCAST= European Committee on Antimicrobial Susceptibility Testing; NA=not applicable.

Table 2: In vitro susceptibilities of Gram-positive strains obtained from the ATLAS program, 2012-2016.

Organism/Antibiotic	No. of isolates	MIC₅₀	MIC₉₀	MIC Range	CLSI			EUCAST
Organism/Antibiotic	No. of isolates	MIC₅₀	MIC₉₀	MIC Range	S%	I%	R%	S%	I%	R%
*Staphylococcus aureus*
Ceftaroline	50525	0.5	1	0.015-64	93.4	6.2	0.4	93.4	6.2	0.4
Ceftazidime-avibactam	50525	32	64	0.015-64	NA	NA	NA	NA	NA	NA
Ceftazidime	50525	32	64	0.015-64	NA	NA	NA	NA	NA	NA
Pip-taz	50525	8	32	0.12-32	NA	NA	NA	NA	NA	NA
Levofloxacin	50525	0.5	8	0.015-8	56.9	0.4	42.7	56.9	0	43.1
Moxifloxacin	50525	0.12	4	0.008-8	57.1	2.7	40.1	56.8	0	43.2
Tigecycline	50525	0.12	0.25	0.015-4	98.9	1.1	0	98.9	0	1.1
Minocycline	50525	0.12	1	0.12-16	93.2	3.4	3.4	89.4	1.4	9.2
Gentamicin	31019	0.5	64	0.06-64	85	0.7	14.3	56.1	0	43.9
Daptomycin	50525	0.5	1	0.06-4	99.8	0.2	0	99.8	0	0.2
Trimethoprim sulfa	31019	0.25	1	0.25-8	96.8	0	3.3	96.8	0.7	2.6
Teicoplanin	50525	0.5	1	0.12-32	100	0	0	98.1	0	1.9
Vancomycin	50525	1	2	0.25-4	100	0	0	100	0	0
Clindamycin	50525	0.12	4	0.03-8	74.8	0.3	24.9	74.2	0.6	25.2
Erythromycin	50525	1	16	0.12-16	48	3.4	48.6	50.6	0.3	49.1
Linezolid	50525	2	2	0.5-16	100	0	0	100	0	0
Oxacillin	50525	4	8	0.06-8	40.4	0	59.6	NA	NA	NA
*Streptococcus pneumoniae*
Ceftaroline	11005	0.008	0.12	0.004-32	99.7	0.3	0	98.7	0	1.3
Ceftazidime-avibactam	11005	0.25	16	0.015-128	NA	NA	NA	NA	NA	NA
Ceftazidime	11005	0.25	16	0.015-128	NA	NA	NA	NA	NA	NA
Doripenem	11005	0.015	1	0.015-8	98	2	0	98	0	2
Meropenem	11005	0.015	1	0.008-2	78	9.2	12.8	100	0	0
Levofloxacin	11005	1	1	0.12-16	98.5	0.2	1.3	98.5	0	1.5
Moxifloxacin	11005	0.12	0.25	0.03-8	98.5	0.5	1.1	98.4	0	1.6
Tigecycline	11005	0.03	0.03	0.008-2	99.9	0.1	0	NA	NA	NA
Minocycline	11005	0.12	4	0.015-4	71.3	5.1	23.6	69.6	1.7	28.7
Daptomycin	11005	0.25	0.5	0.03-8	NA	NA	NA	NA	NA	NA
Vancomycin	11005	0.25	0.5	0.008-2	100	0	0	100	0	0
Clindamycin	11005	0.06	2	0.008-2	74.8	0.4	24.8	75.2	0	24.8
Erythromycin	11005	0.06	2	0.008-2	64.3	0.3	35.4	64.3	0.3	35.4
Linezolid	11005	1	2	0.06-4	100	0	0	100	0	0
Penicillin	11005	0.03	2	0.015-16	61.8	20.7	17.5	61.8	28.9	9.3
*α-hemolytic Streptococcus*
Ceftaroline	12138	0.008	0.12	0.004-32	99.7	0.3	0	98.7	0	1.3
Ceftazidime-avibactam	12138	0.25	16	0.015-128	NA	NA	NA	NA	NA	NA
Ceftazidime	12138	0.25	16	0.015-128	NA	NA	NA	NA	NA	NA
Penicillin	12138	0.03	2	0.015-16	NA	NA	NA	NA	NA	NA
Doripenem	12138	0.015	1	0.015-8	NA	NA	NA	98	0	2
Meropenem	12138	0.015	1	0.008-2	NA	NA	NA	100	0	0
Levofloxacin	12138	1	2	0.12-16	98.3	0.3	1.4	98.5	0	1.5
Moxifloxacin	12138	0.12	0.25	0.03-8	98.5	0.5	1.1	98.4	0	1.6
Minocycline	12138	0.12	4	0.015-4	NA	NA	NA	69.6	1.7	28.7
Tigecycline	12138	0.03	0.03	0.008-2	NA	NA	NA	100	0	0
Clindamycin	12138	0.06	2	0.008-2	75.6	0.4	24.1	75.9	0	24.1
Erythromycin	12138	0.06	2	0.008-2	64.8	0.3	34.9	64.3	0.3	35.4
Vancomycin	12138	0.5	0.5	0.008-2	100	0	0	100	0	0
Linezolid	12138	1	2	0.06-8	100	0	0	100	0	0
Daptomycin	12138	0.25	0.5	0.03-8	99.3	0.7	0	100	0	0
*β-hemolytic Streptococcus*
Ceftaroline	9019	0.004	0.015	0.004-1	100	0	0	NA	NA	NA
Ceftazidime-avibactam	9019	0.12	0.5	0.015-128	NA	NA	NA	NA	NA	NA
Ceftazidime	9019	0.12	0.5	0.015-128	NA	NA	NA	NA	NA	NA
Penicillin	9019	0.015	0.06	0.015-8	NA	NA	NA	NA	NA	NA
Doripenem	9019	0.015	0.03	0.015-8	NA	NA	NA	100	0	0
Meropenem	9019	0.015	0.06	0.008-2	99.9	0.1	0	100	0	0
Levofloxacin	9019	0.5	1	0.12-16	98.3	0.2	1.5	98.2	0	1.9
Moxifloxacin	9019	0.12	0.25	0.03-8	NA	NA	NA	98.1	0	1.9
Minocycline	9019	0.12	4	0.015-4	69.9	30.1	0	65.6	0.9	33.4
Tigecycline	9019	0.03	0.06	0.008-2	100	0	0	100	0	0
Clindamycin	9019	0.06	0.12	0.008-2	90.6	0.3	9	91	0	9
Erythromycin	9019	0.06	2	0.008-2	83.4	0.7	15.8	84.4	0.6	15
Vancomycin	9019	0.5	0.5	0.008-1	100	0	0	100	0	0
Linezolid	9019	1	2	0.06-8	100	0	0	100	0	0
Daptomycin	9019	0.12	0.5	0.03-8	100	0	0	100	0	0
CoNS
Ceftaroline	8490	0.25	1	0.015-64	NA	NA	NA	NA	NA	NA
Ceftazidime-avibactam	8490	16	64	0.015-64	NA	NA	NA	NA	NA	NA
Ceftazidime	8490	16	64	0.015-64	NA	NA	NA	NA	NA	NA
Pip-taz	8490	2	32	0.12-32	NA	NA	NA	NA	NA	NA
Levofloxacin	8490	4	8	0.015-8	46.9	1.8	51.4	46.9	0	53.1
Moxifloxacin	8490	1	4	0.008-8	NA	NA	NA	NA	NA	NA
Minocycline	8490	0.25	0.5	0.12-16	48.9	14.6	36.5	46.5	0	53.5
Tigecycline	8490	0.25	0.5	0.015-4	98.7	1.3	0	98.7	0	1.3
Clindamycin	8490	0.12	8	0.03-8	65.5	2.1	32.4	63.7	1.9	34.5
Erythromycin	8490	8	16	0.12-16	33.1	1.1	65.8	33.4	0.3	66.3
Vancomycin	8490	1	2	0.25-8	99.9	0.1	0	99.9	0	0.1
Teicoplanin	8490	2	8	0.12-64	98	1.7	0.3	85	0	15
Linezolid	8490	1	2	0.5-16	99.4	0	0.6	99.4	0	0.6
Daptomycin	8490	0.5	1	0.06-4	99.6	0.4	0	99.6	0	0.4
Gentamicin	5336	2	64	0.06-64	54.7	5.5	39.8	33.8	0	66.3
Trimethoprim sulfa	5336	1	8	0.25-8	61	0	39	61	10	28.9
Oxacillin	8490	4	8	0.06-8	25.7	0	74.3	NA	NA	NA
*Enterococcus faecalis*
Ceftaroline	3194	1	16	0.015-64	NA	NA	NA	NA	NA	NA
Ceftazidime-avibactam	3194	64	64	1-64	NA	NA	NA	NA	NA	NA
Ceftazidime	3194	64	64	1-64	NA	NA	NA	NA	NA	NA
Levofloxacin	3194	1	16	0.06-16	68	1.1	30.8	NA	NA	NA
Tigecycline	3194	0.12	0.25	0.015-4	94.1	5.9	0	94.1	3.9	2
Minocycline	3194	16	16	0.06-16	25.8	13.7	60.5	NA	NA	NA
Daptomycin	3194	2	4	0.06-8	99.8	0.2	0	NA	NA	NA
Teicoplanin	3194	0.5	0.5	0.12-64	98.3	0.1	1.7	97.8	0	2.2
Vancomycin	3194	1	2	0.12-64	94.3	3.8	1.9	94.3	0	5.7
Erythromycin	3194	16	16	0.06-16	14.6	27.4	58	NA	NA	NA
Linezolid	3194	1	2	0.06-8	99.3	0.6	0.2	99.8	0	0.2
Quinupristin dalfopristin	2014	8	16	0.25-16	1	7.7	91.3	NA	NA	NA
*Enterococcus faecium*
Ceftaroline	2546	64	64	0.03-64	NA	NA	NA	NA	NA	NA
Ceftazidime-avibactam	2546	64	64	0.12-64	NA	NA	NA	NA	NA	NA
Ceftazidime	2546	64	64	0.12-64	NA	NA	NA	NA	NA	NA
Levofloxacin	2546	16	16	0.06-16	12.2	3.9	83.9	NA	NA	NA
Tigecycline	2546	0.12	0.25	0.015-8	95.5	4.5	0	95.5	3	1.5
Minocycline	2546	2	16	0.06-16	55.4	12.4	32.2	NA	NA	NA
Daptomycin	2546	4	4	0.06-16	98	2	0	NA	NA	NA
Teicoplanin	2546	1	64	0.12-64	76	1	23	75.2	0	24.8
Vancomycin	2546	1	64	0.12-64	69.2	5	25.8	69.2	0	30.8
Erythromycin	2546	16	16	0.06-16	3.6	11.2	85.2	NA	NA	NA
Linezolid	2546	1	2	0.06-16	97.4	2.5	0.2	99.8	0	0.2
Quinupristin dalfopristin	1577	1	4	0.06-16	73.2	13.9	12.9	NA	NA	NA

CLSI＝Clinical Laboratory and Standards Institute; EUCAST= European Committee on Antimicrobial Susceptibility Testing; NA=not applicable; CoNS=coagulase-negative staphylococci.

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 comparatorsagainst the selectedbacteria. Ceftazidime-avibactam demonstrated high activities against all tested Gram-negative bacteria(CLSI/EUCAST 2019 susceptibility, 91.9%-99.8%). The susceptibility ofAcinetobacter baumanniiwas not calculated because of the absence of a breakpoint, but the MICs of this antibiotic werehigher for Acinetobacter baumanniithan for the other bacteria(MIC₅₀/MIC_90,32/128 mg/L). The addition of avibactam drastically increased the activity of ceftazidime against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii, and Pseudomonas aeruginosa (CLSI 2019 susceptibilities toceftazidime 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/MIC_90,64/256 mg/L).Regarding the comparator agents, the susceptibility of Enterobacteriaceae was, in general, high forcarbapenems and tigecycline (>90%). For Acinetobacter baumannii,the most potent antibiotics were colistin and tigecycline (MIC₅₀/MIC₉₀, 1/2 mg/L), with aMIC₅₀ of ≥8 and aMIC₉₀ of ≥16 mg/L observed for all other tested agents.

Regarding resistantGram-negative strains, theactivities of ceftazidime-avibactam were moderatefor CR-Escherichia coli (MIC₅₀/MIC₉₀, 0.5/256 mg/L), CR-Klebsiella pneumoniae (MIC₅₀/MIC₉₀, 1/256 mg/L),and CR-Pseudomonas aeruginosa (MIC₅₀/MIC₉₀, 4/64 mg/L) and low for CR-Enterobacter cloacae and CR-Acinetobacter baumannii (MIC₅₀/MIC_90,64-128/256 mg/L) (Table 3).Regarding the comparator agents, the susceptibilities ofCR-Escherichia coli, CR-Klebsiella pneumoniae, CR-Enterobacter cloacae, CR-Pseudomonas aeruginosa, and CR-Acinetobacter baumannii were low for the vast majority ofthe tested antibiotics. Good potency was observed for tigecycline against all tested Enterobacteriaceae (MIC₅₀/MIC_90,0.25-1/1-4 mg/L), and for colistin againstCR-Escherichia coli, CR-Enterobacter cloacae, CR-Pseudomonas aeruginosa, and CR-Acinetobacter baumannii (MIC₅₀/MIC_90, 0.5-1/1-2 mg/L).

Table 3: In vitro susceptibilities of multi-drug resistant strains obtained from the ATLAS program, 2012-2016.

Organism/Antibiotic	No. of isolates	MIC₅₀	MIC₉₀	MIC Range	CLSI†			EUCAST
Organism/Antibiotic	No. of isolates	MIC₅₀	MIC₉₀	MIC Range	S%	I%	R%	S%	I%	R%
CRECO
Ceftaroline	119	256	256	0.015-256	10.9	1.7	87.4	9.5	0	90.5
Ceftazidime-avibactam	119	0.5	256	0.03-256	72.3	0	27.7	40.5	0	59.5
Ceftazidime	119	64	256	0.12-256	22.7	4.2	73.1	11.9	2.4	85.7
Cefepime	119	32	32	0.12-32	8.4	16	75.6	0	2.4	97.6
Pip-taz	119	256	256	0.5-256	21.9	5.9	72.3	19.1	2.4	78.6
Doripenem	119	4	16	0.03-16	32.8	11.8	55.5	19.1	2.4	78.6
Imipenem	119	8	16	4-16	0	0	100	0	0	100
Meropenem	119	8	16	0.015-16	26.1	6.7	67.2	19.1	7.1	73.8
Levofloxacin	119	8	16	0.015-16	24.4	3.4	72.3	7.1	2.4	90.5
Tigecycline	119	0.25	1	0.03-4	98.3	1.7	0	88.1	7.1	4.8
Amikacin	119	8	64	1-64	78.2	5	16.8	59.5	7.1	33.3
Colistin	79	0.5	1	0.12-16	NA	NA	NA	96.3	0	3.7
Aztreonam	119	64	256	0.015-256	23.5	0.8	75.6	16.7	2.4	81
CRKPN
Ceftaroline	1418	256	256	0.06-256	0.6	0	99.4	0	0	100
Ceftazidime-avibactam	1418	1	256	0.015-256	85.6	0	14.4	83.6	0	16.4
Ceftazidime	1418	256	256	0.12-256	4	2.5	93.5	0.6	0.7	98.7
Cefepime	1418	32	32	0.12-32	3.5	8	88.6	0.4	0.6	99
Pip-taz	1418	256	256	2-256	1.5	1.1	97.4	0.3	0.1	99.6
Doripenem	1418	8	16	0.03-16	4.2	5.4	90.4	0.7	0.4	98.9
Imipenem	1418	16	16	4-16	0	0	100	0	0	100
Meropenem	1418	16	16	0.015-16	2.9	4	93.1	0.8	3.9	95.3
Levofloxacin	1418	8	16	0.03-16	12.7	3.5	83.9	3.1	1.6	95.2
Tigecycline	1418	1	2	0.06-16	92.6	6.3	1.1	74.7	17.1	8.2
Amikacin	1418	16	64	0.25-64	52.1	28.1	19.8	30.3	13.2	56.6
Colistin	1046	1	16	0.06-16	NA	NA	NA	74.2	0	25.8
Aztreonam	1418	256	256	0.03-256	4.4	0.4	95.1	2.7	0.2	97.1
CRECL
Ceftaroline	149	256	256	0.06-256	4.7	0.7	94.6	1.6	0	98.4
Ceftazidime-avibactam	149	128	256	0.06-256	42.3	0	57.7	21.9	0	78.1
Ceftazidime	149	256	256	0.12-256	8.7	1.3	89.9	1.6	1.6	96.9
Cefepime	149	32	32	0.12-32	14.8	10.7	74.5	4.7	0	95.3
Pip-taz	149	256	256	2-256	10.1	5.4	84.6	1.6	1.6	96.9
Doripenem	149	8	16	0.06-16	14.1	6.7	79.2	0	0	100
Imipenem	149	8	16	4-16	0	0	100	0	0	100
Meropenem	149	8	16	0.03-16	14.1	12.1	73.8	1.6	17.2	81.3
Levofloxacin	149	4	16	0.03-16	43.6	7.4	49	17.2	4.7	78.1
Tigecycline	149	1	4	0.12-8	83.9	14.1	2	59.4	15.6	25
Amikacin	149	4	64	0.5-64	80.5	5.4	14.1	60.9	7.8	31.3
Colistin	118	0.5	1	0.12-16	NA	NA	NA	93.8	0	6.3
Aztreonam	149	64	256	0.06-256	24.2	2	73.8	18.8	6.3	75
CRPAE
Ceftaroline	4546	128	256	0.015-256	NA	NA	NA	NA	NA	NA
Ceftazidime-avibactam	4546	4	64	0.015-256	74.5	0	25.5	70.6	0	29.4
Ceftazidime	4546	16	128	0.12-256	46.6	8.2	45.3	41.4	0	58.6
Cefepime	4546	16	32	0.25-32	47.2	23.2	29.6	41.5	0	58.6
Pip-taz	4546	64	256	0.25-256	34.7	24.8	40.5	29.4	0	70.7
Doripenem	4545	8	16	0.03-16	15.1	22.8	62.1	1.8	5.9	92.3
Imipenem	4546	16	16	8-16	0	0	100	0	0	100
Meropenem	4546	16	16	0.06-16	11.7	15.4	72.9	4.9	33.5	61.7
Levofloxacin	4546	8	16	0.015-16	36	10	54	22.1	0	77.9
Tigecycline	4546	16	16	0.03-16	NA	NA	NA	NA	NA	NA
Amikacin	4546	8	64	0.25-64	72.8	7.3	19.9	60.5	9.2	30.4
Colistin	3521	1	2	0.06-16	96.4	0	3.6	96.6	0	3.4
Aztreonam	4546	16	128	0.06-256	30.7	21	48.3	1.1	46.6	52.4
CRABA
Ceftaroline	2318	256	256	2-256	NA	NA	NA	NA	NA	NA
Ceftazidime-avibactam	2318	64	256	0.06-256	NA	NA	NA	NA	NA	NA
Ceftazidime	2318	128	256	1-256	5.1	2.3	92.7	NA	NA	NA
Cefepime	2318	32	32	0.25-32	3.6	10.7	85.7	NA	NA	NA
Pip-taz	2318	256	256	4-256	0.4	0.7	99	NA	NA	NA
Doripenem	2318	8	16	0.5-16	0.2	0.4	99.4	0	0	100
Imipenem	2318	16	16	8-16	0	0	100	0	0	100
Meropenem	2318	16	16	1-16	0.1	0.5	99.4	0	1.9	98.1
Levofloxacin	2318	8	16	0.06-16	3.8	11.4	84.9	1.4	0.6	98
Tigecycline	2318	1	4	0.03-16	NA	NA	NA	NA	NA	NA
Amikacin	2318	64	64	0.25-64	19.3	7.8	73	16.4	2.7	80.9
Colistin	1552	1	2	0.12-16	92.1	0	7.9	92	0	8
Aztreonam	2318	64	256	2-256	NA	NA	NA	NA	NA	NA
MRSA
Ceftaroline	30100	0.5	2	0.03-64	89.0	10.3	0.7	NA	NA	NA
Ceftazidime-avibactam	30100	64	64	2-64	NA	NA	NA	NA	NA	NA
Ceftazidime	30100	64	64	1-64	NA	NA	NA	NA	NA	NA
Pip-taz	30100	32	32	0.12-32	NA	NA	NA	NA	NA	NA
Doripenem	30100	2	8	0.008-8	NA	NA	NA	NA	NA	NA
Meropenem	30100	4	16	0.015-16	NA	NA	NA	NA	NA	NA
Levofloxacin	30100	4	8	0.015-8	32.4	0.5	67.1	NA	NA	NA
Moxifloxacin	30100	2	4	0.008-8	32.6	3.9	63.5	NA	NA	NA
Minocycline	30100	0.12	8	0.12-16	89.4	5.3	5.4	NA	NA	NA
Tigecycline	30100	0.12	0.5	0.015-4	98.5	1.5	0	NA	NA	NA
Clindamycin	30100	0.12	8	0.03-8	61	0.3	38.7	NA	NA	NA
Erythromycin	30100	8	16	0.12-16	29.7	2.5	67.8	NA	NA	NA
Vancomycin	30100	1	2	0.25-4	100	0	0	NA	NA	NA
Teicoplanin	30100	1	2	0.12-32	100	0	0	NA	NA	NA
Linezolid	30100	2	2	0.5-16	100	0	0	NA	NA	NA
Daptomycin	30100	0.5	1	0.06-4	99.7	0.3	0	NA	NA	NA
Gentamicin	18616	1	64	0.06-64	78.2	0.9	21	NA	NA	NA
Trimethoprim sulfa	18616	0.25	1	0.25-8	95.6	0	4.4	NA	NA	NA
Oxacillin	30100	4	8	4-8	0	0	100	NA	NA	NA
PRSP
Ceftaroline	1925	0.12	0.25	0.008-32	98.2	1.8	0	86.8	0	13.2
Ceftazidime-avibactam	1925	16	64	1-128	NA	NA	NA	NA	NA	NA
Ceftazidime	1925	16	64	1-128	NA	NA	NA	NA	NA	NA
Penicillin	1925	4	8	2-16	0	0	100	0	0	100
Doripenem	1925	1	2	0.015-8	89.4	10.6	0	81.1	0	18.9
Meropenem	1925	1	2	0.008-2	3.4	32.3	64.3	100	0	0
Levofloxacin	1925	1	2	0.12-16	95.3	0.5	4.2	94.1	0	6
Moxifloxacin	1925	0.12	0.25	0.03-8	95.7	1.5	2.8	94.6	0	5.4
Minocycline	1925	4	4	0.03-4	28.5	13.2	58.3	18.8	3	78.2
Tigecycline	1925	0.03	0.03	0.008-2	99.8	0.2	0	NA	NA	NA
Clindamycin	1925	2	2	0.008-2	32.6	0.3	67.2	24.3	0	75.7
Erythromycin	1925	2	2	0.008-2	13.9	0.2	86	10.9	0.1	89
Vancomycin	1925	0.5	0.5	0.015-2	99.9	0.1	0	100	0	0
Linezolid	1925	1	1	0.06-2	100	0	0	100	0	0

† Cefepime CLSI susceptibility for Enterobacteriaceae adopted the susceptible, susceptible-dose-dependent, and resistant categories.

CLSI＝Clinical Laboratory and Standards Institute; EUCAST= European Committee on Antimicrobial Susceptibility Testing; CRECO=Carbapenem-resistant Escherichia coli; CRKPN=Carbapenem-resistant Klebsiella pneumoniae; CRECL=Carbapenem-resistant Enterobacter cloacae; CRPAE=Carbapenem-resistant Pseudomonas aeruginosa; CRABA=Carbapenem-resistant Acinetobacter baumannii; MRSA=Methicillin-resistant Staphylococcus aureus; PRSP=Penicillin-resistant Streptococcus pneumoniae; NA=not applicable.

The susceptibilities tothe various antibioticsagainst Gram-negative bacteria (total, regardless of drug resistance) were in general comparable using CLSI 2019 and EUCAST 2019 breakpoints, except for imipenem and tigecycline againstProteus 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 ofCR-Escherichia coli(72.3% vs. 40.5%) and CR-Enterobacter cloacae(42.3% vs. 21.9%) to ceftazidime-avibactam, and the susceptibilities ofCR-Escherichia coli, CR-Klebsiella pneumoniae, CR-Enterobacter cloacae, and CR-Pseudomonas aeruginosa to levofloxacin, tigecycline, and amikacin (all with a >10% difference) were noticeably lower when the EUCAST 2019breakpoints 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 ofStaphylococcus aureus,Streptococcus pneumoniae, α-hemolytic Streptococcus, and β-hemolytic Streptococcus (CLSI 2019). TheMIC₅₀/MIC₉₀ of ceftarolinefor coagulase-negative Staphylococcus 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 coagulase-negative Staphylococcus, 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 (excepted forEnterococcus faecium to vancomycin). High activities (susceptibility, >90%) of levofloxacin and moxifloxacin were observed for Streptococcus.

Regarding the resistant Gram-positive strains, ceftaroline demonstrated high activities against methicillin-resistant Staphylococcus aureus (CLSI 2019susceptibility, 89.0%) and penicillin-resistant Streptococcus pneumoniae (CLSI 2019susceptibility, 98.2%), whereas ceftazidime-avibactam demonstrated limited activities (MIC₅₀/MIC₉₀: 16-64/64 mg/L) (Table 3).For comparator agents, potent activity(CLSI 2019 susceptibility, >95%) against methicillin-resistant Staphylococcus aureuswas observed for linezolid, tigecycline, vancomycin, teicoplanin, daptomycin, and trimethoprim sulfa, whereas the susceptibility of penicillin-resistant Streptococcus pneumoniae(CLSI 2019 susceptibility, >95%) was high to linezolid, tigecycline, vancomycin, levofloxacin, and moxifloxacin (Table 3).

Thesusceptibilities ofGram-positive bacteria (regardless of drug resistance) were similar between the CLSI 2019 and EUCAST 2019 breakpoints, except for the susceptibility of coagulase-negative Staphylococcus toteicoplaninand gentamicin. In terms of resistant strains, noticeably lower susceptibility of penicillin-resistant Streptococcus 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.

Global trend of the susceptibilities of pathogens against ceftaroline and ceftazidime-avibactam from 2012 to 2016

Figure 1 presents the trends of susceptibilities to ceftaroline against key bacterial species over time in different regions using the CLSI 2019 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, but some decreases were observed in specific areas of the world. For Escherichia coli,the susceptibilities were consistently higher in North America(77.1%-82.0%) and lower in Asia (45.1%-53.0%). Higher susceptibilities in North Americawere also observed for Klebsiella pneumoniae and Proteus mirabilis,and lower susceptibilities in Asia were observed for Staphylococcus aureus.For Enterobacter cloacae, 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 2019 breakpoint. The susceptibility of Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis to ceftazidime-avibactam remained high (>95%) and relatively stable over time, but with some decreases were observed in specific regions. The susceptibilities of Enterobacter cloacaeand Citrobacter freundiito ceftazidime-avibactam remained relatively stable over time in all regions, but the susceptibilities in Asia (2013/2016: 94.6%/94.6% and 94.9%/94.7%) decreased in 2013 and wereconsistently lower than the global ratesthereafter (2013/2016: 98.3%/97.4% and 99.7%/97.6%). The global susceptibilities of Pseudomonas aeruginosa to ceftazidime-avibactam globally decreased from 2012 to 2016 (2012/2016: 97.1%/92.0%), with lower rates observed in Latin America (2012/2016: 92.7%/86.6%), and higher rates observed in North America (2012/2016: 97.9%/96.6%).

Global trend of the susceptibilitiestoceftaroline and ceftazidime-avibactam against multi-drug-resistant species

The proportion of methicillin-resistant Staphylococcus aureus among all Staphylococcus aureusremained stable from 2012 to 2016 (59.8% in 2012 and 2016), with higher prevalence observed inNorth America (2012/2016: 66.5%/68.1%) and lower prevalence observed inLatin America (2012/2016: 55.9%/53.3%). The overall global susceptibility of methicillin-resistant Staphylococcus aureus to ceftarolineincreased slightly from 87.5% in 2012 to 91.7% in 2016, with a marked increase observed in Africa-Middle East (2012/2016: 88.7%/97.8%), Europe (2012/2016: 89.8%/96.2%), and Latin America (2012/2016: 78.2%/88.2%) (Figure 3A). The susceptibility of methicillin-resistant Staphylococcus aureus to ceftaroline in Asia was consistently lower than in all other regions (2012/2016: 75.2%/75.5%).

The proportion of CR-Klebsiella pneumoniaeamong all Klebsiella pneumoniaelightly increased from 6.7% in 2012 to8.2% in 2016, with higher prevalence observed inLatin America(2012/2016: 9.2%/11.2%) and Europe (2012/2016: 9.3%/10.4%). Conversely, the overall global susceptibility of CR-Klebsiella pneumoniaeto ceftazidime-avibactam decreased from 88.4% in 2012 to 81.6% in 2016, with a marked decrease observed in Africa-Middle East (2012/2016: 100%/63.6%), Asia (2012/2016: 76.9%/68.2%), and Latin America (2012/2016: 100%/90%) (Figure 3B). The susceptibility rates in Asia and Africa-Middle Eastwere, in general, lower than in the other regions during the study period.

The proportion of CR-Pseudomonas aeruginosa among all Pseudomonas aeruginosaremained relatively stable over time (2012/2016: 26.5%/26.7%), with higher prevalence observed for Latin America (2012/2016: 36.3%/34.4%). The overall global susceptibility of CR-Pseudomonas aeruginosa to ceftazidime-avibactam decreased from 89.6% in 2012 to 72.7% in 2016, with a marked decrease observed for all regions (Figure 3). The susceptibility rate in North America (2012/2016: 93.2%/86.0%) was, in general, higher than in other regions.

Ceftaroline and ceftazidime-avibactam are relatively recent antibiotics that are active against a variety of bacterial species, including some with innate antibiotic resistance.^10-13^,¹⁵The 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 ofCR-Pseudomonas 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 overallin 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 Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus. On the other hand, ceftazidime-avibactam showed susceptibility >90% against Gram-negative bacteria, including Enterobacteriaceae, Pseudomonas aeruginosa, and Proteus mirabilis, with overtly increased antimicrobial activity observed with the addition of avibactam to ceftazidime.Further analysis of the data fromChina showed that similar to the global pattern, the susceptibilities ofEscherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosato ceftazidime-avibactam were high (92.9%-99.0%)in China. Those results are generally similar with those of surveillance studies in China,¹⁸ Asia,¹⁹the United States of America,^20-22 and Europe,²³and with the AWARE surveillance program,^24-26 but with some minute differences that could be due to the specimens' area of origin since the present study includedspecimens 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 variedamong species, among world regions, and over time. The main differences were that the susceptibility rates ofEscherichia coli and Staphylococcus aureusto 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 againstCitrobacter freundii, Enterobacter cloacae, and Proteus 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.²⁰A study across different areas of the United Statesof America also reported good susceptibility profiles of ceftaroline against respiratory pathogens.²⁷A recent report from the World Health Organization revealed high rates of antibiotic resistance all over the world.²⁸^,²⁹Antibiotic 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.^30-32Furthermore, 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.³³In 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 occurrenceof 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.³⁸Even if the present study focused on ceftaroline and ceftazidime-avibactam, the ATLAS program provides the comprehensive global susceptibility profiles of many antibiotics againsta large number of bacterial species. ATLAS receives datafrom all regions of the world and covers many years. Therefore, it helps provide certain help for the global surveillanceof bacterial resistance.

This study has limitations. First, this was a retrospective study, with the inevitableconfounding 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 non-clinically significant differences in susceptibility could be statistically significant, which could be misleading;³⁹^,⁴⁰ therefore, statistical tests were not performed.

In summary, the present study showed that the addition of avibactam improved the activity of ceftazidime against Enterobacteriaceae and Pseudomonas aeruginosa.The global antimicrobial susceptibilitiestoceftaroline and ceftazidime-avibactam were,in general, stablefrom 2012 to 2016, but a marked reduction in the susceptibilitiesof specific species andCR-Pseudomonas aeruginosa for ceftazidime-avibactam was observed in specificregions of the world.

Acknowledgments

We are grateful to IHMA laboratory staff for their work on the antimicrobialsusceptibility tests.

Conflict of interest

All authors declare that they have no conflict of interest and have submitted the ICMJE Form for disclosure of potential conflicts of interest. Conflicts that the editors consider relevant tothe content of the manuscript have been disclosed.

FUNDING

This study was supported byPfizer Inc.Further support was provided by the National Key Research and Development Program of China (2018YFC1200100, 2018YFC1200105) and CAMSInitiative for Innovative Medicine (grant no. 2016-I2M-3–014). The funders had no role in the study design, collection, and analysis of data,interpretation of results, or preparation of the manuscript.

AUTHOR CONTRIBUTION

H.Z., Y.C.X.,P.Y.J, and Q.W.Y.conceived and designed the study, performed the experiments, analyzed the data, and wrote the paper. Y.Z.,G.Z.,J.J.Z.,W.K.,S.M.D.,T.W.,R.J.,J.W.C., and Y.L.L. helped perform the experiments. All authors read and approved the final version of the manuscript.

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

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Abstract

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