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Geographic patterns of Acinetobacter baumannii and carbapenem resistance in the Asia-Pacific Region: results from the Antimicrobial Testing Leadership and Surveillance (ATLAS) program, 2012-2019
Department of Internal Medicine, Changhua Christian Hospital, Changhua, TaiwanInstitute of Genomics and Bioinformatics, National Chung-Hsing University, Taichung City, Taiwan
Departments of Laboratory Medicine and Internal Medicine, China Medical University Hospital, Taichung, TaiwanSchool of Medicine, China Medical University, Taichung, TaiwanDepartments of Laboratory Medicine and Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
The prevalence of carbapenem-resistant Acinetobacter baumannii (CR-AB) varied among countries.
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Of 232 CR-AB isolates, 224 (96.6%) harbored at least one carbapenemase gene.
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Of the 226 carbapenemase genes detected, blaOXA-23 was the most dominant (94.7%).
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CR-AB showed varied resistance rates for minocycline, colistin, and tigecycline.
ABSTRACT
Objectives
This study aimed to investigate the geographic distribution of carbapenem-resistant Acinetobacter baumannii (CR-AB) isolates in the Asia-Pacific region.
Methods
We collected A. baumannii isolates using the Antimicrobial Testing Leadership and Surveillance program from 2012 to 2019. The minimum inhibitory concentrations (MICs) of the isolates were determined using the broth microdilution method. The major carbapenemase genes were identified using multiplex polymerase chain reaction assays for the isolates collected between 2012 and 2014. CR-AB was defined as isolates with meropenem MICs ≥8 mg/l.
Results
In total, 2674 A. baumannii isolates were collected from 13 countries, of which 1918 (71.7%) were CR-AB. The carbapenem resistance rates among A. baumannii isolates were as low as 2.8% and 6.5% in Japan and Australia, respectively, but as high as 88% and 87.2% in South Korea and India, respectively. Of the 232 CR-AB isolates that underwent carbapenemase gene screening, 224 (96.6%) harbored at least one carbapenemase gene. A total of 226 carbapenemase genes were detected, with blaOXA-23 (94.7%, 214/226) being the most dominant, followed by blaOXA-72 (2.7%, 6/226), blaOXA-58 (2.2%, 5/226), and blaNDM-1 (0.4%, 1/226). CR-AB isolates had >80% resistance to amikacin, ampicillin/sulbactam, cefepime, ceftazidime, ciprofloxacin, levofloxacin, and piperacillin/tazobactam. The rates of CR-AB resistance to minocycline and colistin were 7.2% (31/429) and 1.7% (23/1368). For cefoperazone/sulbactam and tigecycline, 50.2% (527/1049) and 93.3% (1789/1918) of CR-AB isolates had an MIC ≤16 mg/l and ≤2 mg/l, respectively.
Conclusion
The prevalence of carbapenem resistance in A. baumannii showed significant differences among countries in the Asia-Pacific region, and the treatment options were limited.
Acinetobacter baumannii is an aerobic, pleomorphic, and nonmotile, nonfermenting gram-negative coccobacillus that serves as an opportunistic pathogen in nosocomial infections [
Multicenter surveillance of antimicrobial susceptibilities and resistance mechanisms among Enterobacterales species and non-fermenting gram-negative bacteria from different infection sources in Taiwan from 2016 to 2018.
In vitro activity of cefiderocol, cefepime/enmetazobactam, cefepime/zidebactam, eravacycline, omadacycline, and other comparative agents against carbapenem-non-susceptible Pseudomonas aeruginosa and Acinetobacter baumannii isolates associated from bloodstream infection in Taiwan between 2018-2020.
]. A. baumannii is usually associated with substantial morbidity and mortality among patients who are immunocompromised in the intensive care unit (ICU), especially those requiring mechanical ventilation [
]. In the late 1970s, A. baumannii was still susceptible to the most commonly used antimicrobials; however, the rapid emergence of multidrug resistance, especially carbapenem resistance, has made it a troublesome hospital pathogen due to the easy contamination of the hospital environment and few effective antibiotic therapies [
Mechanisms protecting Acinetobacter baumannii against multiple stresses triggered by the host immune response, antibiotics and outside-host environment.
]. In general, OXA-type enzymes show weak cephalosporin- and carbapenem-hydrolyzing activities; however, the overexpression of these genes through the insertion of sequence (IS) elements that provide additional promoters increases carbapenem resistance [
]. This is mostly the case with the OXAs, which use ISAba1 (OXA-51, OXA-23, OXA-235) or ISAba3 (OXA-58); however, OXA-40 and OXA-143 do not have IS element promoters [
Trends of major antimicrobial resistance phenotypes in Enterobacterales and Gram-negative non-fermenters from ATLAS and EARS-net surveillance systems: Italian vs. European and global data, 2008–2018.
]. A recent worldwide investigation of multidrug-resistant A. baumannii revealed that pooled imipenem resistance rates increased significantly from 23.8% and 51.6% to 73.9% during 2000-2005, 2006-2010, and 2011-2016, respectively, among Organization for Economic Cooperation and Development countries. A cross-sectional comparison also demonstrated heterogeneous carbapenem resistance rates, ranging from 7% to 100% for A. baumannii in different countries [
Trends of major antimicrobial resistance phenotypes in Enterobacterales and Gram-negative non-fermenters from ATLAS and EARS-net surveillance systems: Italian vs. European and global data, 2008–2018.
]. Geographic data on antibiotic resistance in A. baumannii from different countries might be beneficial for appropriate antimicrobial treatment, especially for those used as empirical therapies. The Antimicrobial Testing Leadership and Surveillance (ATLAS) program evaluates the longitudinal in vitro activity of the various antimicrobials against clinical isolates collected worldwide [
]. We used the ATLAS database and selected A. baumannii isolates to evaluate in vitro antimicrobial susceptibility, as correlated with resistance genes, from 2012 to 2019 across countries in the Asia-Pacific region.
Materials and methods
Bacterial isolates and identification
The ATLAS program evaluates the longitudinal in vitro activity of various antimicrobials belonging to cephalosporin, glycylcycline, polymyxin, monobactam, carbapenem, aminoglycoside, tetracycline, macrolide, and antifolate classes against unique clinical isolates collected worldwide. The different drugs belonging to various antimicrobial classes are added or removed from the antimicrobial panels listed on the website and can vary annually [
]. A. baumannii isolates were collected from 12 countries in the Asian region (China, Hong Kong, India, Japan, South Korea, Malaysia, Pakistan, Singapore, Taiwan, Thailand, and Vietnam) and one country in the Pacific region (Australia). In the ATLAS program, all participant countries contributed to the A. baumannii isolates throughout the 8 years, except for India, Malaysia, Pakistan, Singapore, Vietnam, and Australia, which did not contribute data in some years (Supplementary Table 1). The data on patient characteristics, including outpatient/inpatient, ward/ICU, cultural sources, and age, were collected. Only the first isolate from a single patient was included in the study. The matrix-assisted laser desorption ionization time-of-flight mass spectrometry (Biotyper, Bruker Daltonics, Billerica, MA, USA) at the International Health Management Associates (Schaumburg, IL, USA) was used to confirm the identification of all isolates before antimicrobial susceptibility testing [
In vitro activity of ceftazidime-avibactam against Enterobacterales and Pseudomonas aeruginosa isolates collected in Latin America as part of the ATLAS global surveillance program, 2017–2019.
Antimicrobial susceptibility testing of aerobic bacterial isolates was performed according to the Clinical and Laboratory Standards Institute (CLSI) standard method using custom 96-well broth microdilution panels [
]. Most susceptibility and minimum inhibitory concentrations (MICs) results were interpreted using the CLSI interpretive criteria. The cefoperazone/sulbactam interpretive break points used were based on the package insert, in that isolates with MICs ≤16 mg/l were considered susceptible, and those with MICs ≥64 mg/l were resistant, as previously reported [
]. For colistin, A. baumannii with an MIC ≤ of 2 mg/l was defined as intermediate, and ≥4 mg/l was defined as resistant, according to the CLSI criteria [
]. In addition, there are currently no available break points for aztreonam, ceftaroline, ceftazidime/avibactam, and tigecycline in the CLSI guidelines. In this study, an A. baumannii isolate with an MIC ≤2 mg/l to tigecycline was considered susceptible according to the interpretive criteria approved by the US Food and Drug Administration for Enterobacterales, as previously reported [
]. The details of the antimicrobial agents tested according to the year and country are listed in Supplementary Table 2.
Detection of β-lactamase genes
Although A. baumannii isolates were collected between 2012 and 2019, a program to detect β-lactamase genes was conducted between 2012 and 2014. In addition, only the A. baumannii isolates from China in 2012 and 2013 were included because the isolates from 2014 were not available when the screening program was performed. A single colony grown on an overnight blood agar plate (Thermo Fisher Scientific, Waltham, MA, USA) at 35°C was collected for genomic DNA extraction. The genome was extracted using the QIAamp DNA Mini Kit (QIAGEN, Valencia, CA, USA) and the QIAcube instrument (QIAGEN) according to the manufacturer's instructions. Multiplex polymerase chain reaction assays were performed to screen for the presence of currently known acquired OXA genes in A. baumannii (blaOXA-23-like, blaOXA-24/40-like, blaOXA-58-like, blaOXA-143-like, and blaOXA-235-like), metallo-β-lactamases (blaGIM, blaIMI, blaIMP, blaNDM, and blaVIM), and carbapenemase genes (blaGES and blaKPC), as previously described [
In vitro activity of ceftazidime-avibactam against Enterobacterales and Pseudomonas aeruginosa isolates collected in Latin America as part of the ATLAS global surveillance program, 2017–2019.
MedCalc software version 20.110 (MedCalc Software Ltd, Los Angeles, CA, USA) was used for the statistical analyses. Categorical variables were compared using chi-square or Fisher's exact tests. All tests were two-tailed, and a P-value <0.05 was considered significant.
Ethics
The institutional review board of each participating hospital approved the ATLAS program, including that of the National Taiwan University Hospital (Taipei, Taiwan) (NTUH 201211047RSC). Written informed consent was waived owing to the need for a bacterial collection study, with a minimal risk design for patients.
Results
Characteristics of A. baumannii isolates
In total, 2674 A. baumannii isolates were collected from 13 counties using the ATLAS program between 2012 and 2019. The demographics of the patients and the culture sources of the isolates are summarized in Table 1. A total of 13 countries, including 12 Asian countries and one Pacific country, participated in the ATLAS program during the study period. Among those, seven countries, including China, Hong Kong, Japan, South Korea, Philippines, Taiwan, and Thailand, participated in the ATLAS program for the entire 8 years, and other counties had data interruptions in some years. Although the number of isolates increased from 2012 to 2019, we were unable to conclude an increasing prevalence of A. baumannii because the participating countries and the number of sites were not uniform throughout the study period (Supplementary Table 1). Even for each country, the number of patients was not completely representative of its prevalence because of the variation of the participating sites. For example, the number of participating sites in China increased from eight in 2012 to 17 in 2019, and the number of isolates submitted increased from 31 in 2012 to 340 in 2019.
Table 1Patient demographics and culture sources for Acinetobacter baumannii isolates collected in the Asia-Pacific region as part of the antimicrobial testing leadership and surveillance (ATLAS) study, 2012 to 2019.
Most of the isolates were collected from hospitalized patients, and only 6.5% were collected from clinics (0.5%, n = 13) or emergency rooms (6.0%, n = 160). One-third of the patients were admitted to the ICU (38.0%, n = 1016) and half were from wards (49.2%, n = 1316). For both the ICU and wards, more A. baumannii isolates were collected from patients in medical departments than from those in surgical departments. Most infected patients were adults, and 50.9% (n = 1362) were aged >60 years. The most common source of infection was respiratory tract infections (57.0%, n = 1523), followed by bloodstream infections (12.8%, n = 341) and skin/musculoskeletal infections (11.6%, n = 310). Although there were different numbers of participating countries in the ATLAS program from 2012 to 2019, we still noted an increasing number of A. baumannii isolates collected from the seven countries involved in the program, from 89 isolates in 2012 to 693 isolates in 2019. The proportion of isolates collected from respiratory samples, blood samples, patients in the ICU, and patients aged 61 years and older in each county is summarized in Supplement Table 3.
Antimicrobial susceptibility
The MICs and antimicrobial susceptibility rates are listed in Table 2. For all A. baumannii isolates, most of the tested antibiotics had susceptibility rates of less than 40%, except for 77.5% (n = 440/568) of the A. baumannii isolates that were susceptible to minocycline. The resistance rate of A. baumannii to colistin was 1.8%, but the remaining isolates (98.2%, n = 1846/1880) with MICs ≤2 mg/l were categorized as intermediate according to the CLSI guidelines. There are currently no available CLSI break points for the MICs of aztreonam, cefoperazone/sulbactam, ceftaroline, ceftazidime/avibactam, and tigecycline for A. baumannii. The susceptibility rate of A. baumannii to cefoperazone/sulbactam in our study was 36.4% (n = 506/1390), according to the criteria from the product pack insert. For ceftaroline, 93.9% (n = 1977/2106) of the A. baumannii isolates had an MIC >1 mg/l, and these were considered resistant based on the interpretive criteria for Enterobacterales. The combination of a new β-lactamase inhibitor, avibactam, with ceftazidime did not obviously influence the MIC distribution compared with ceftazidime alone. Regarding tigecycline, 94.8% (n = 2534/2674) of the A. baumannii isolates had an MIC ≤2 mg/l, and these were considered susceptible according to the interpretive criteria approved by the US Food and Drug Administration for Enterobacterales.
Table 2Antimicrobial susceptibility of Acinetobacter baumannii in the Asia-Pacific regions of the antimicrobial testing leadership and surveillance (ATLAS) program, 2012-2019.
Using the susceptibility to meropenem as a reference, the number of CR-AB was 1918 (71.7%), and the susceptibility rates were significantly reduced for almost all antimicrobial agents compared with those for carbapenem-susceptible A. baumannii (CS-AB), including amikacin (16.1% [309/1918] vs 97.2% [722/743], P <0.05), ampicillin/sulbactam (3.7% [39/1049] vs 94.6% [317/335], P <0.05), cefepime (0.7% [13/1918] vs 93.8% [697/743], P <0.05), cefoperazone/sulbactam (17.0% [178/1049] vs 96.7% [324/335], P <0.05), ciprofloxacin (1.6% [17/1049] vs 90.4% [303/335], P <0.05), minocycline (71.1% [305/429] vs 99.2% [131/132], P <0.05), piperacillin/tazobactam (0.5% [9/1918] vs 92.2% [685/743], P <0.05), and trimethoprim/sulfamethoxazole (19.8% [208/1049] vs 91.9% [308/335], P <0.05). The colistin resistance rate of CR-AB was similar to that of all A. baumannii strains (1.7% [23/1368] vs 1.8% [11/506], P-value = 0.61). A comparison of the cumulative percentage of isolates with different MICs between CS-AB and CR-AB for ampicillin/sulbactam, cefoperazone/sulbactam, minocycline, and tigecycline is illustrated in Figure 1. A right shift in the MIC distribution was noted for all four antibiotics, and the CS-AB isolates were generally associated with lower MIC50 values than CR-AB isolates. For tigecycline, the rates of isolates with MICs ≤2 mg/l were 93.3% (1789/1918) and 98.5% (732/743), and the MIC50 were 1 and 0.12 mg/l for CR-AB and CS-AB, respectively. In addition, we selected data from China, Taiwan, South Korea, Philippines, and Thailand to investigate whether there was a change in carbapenem resistance among A. baumannii isolates over time because those countries had participated in the ATLAS study consistently through 2012 to 2019. The trends of resistance to meropenem, minocycline, colistin, and tigecycline are illustrated in Supplemental Figure S1. The susceptibility of A. baumannii to meropenem declined gradually, but the resistance rates to colistin and the MIC distribution of tigecycline showed no significant change over time. In contrast, the susceptibility to minocycline increased between 2014 and 2017. Unfortunately, the susceptibility of minocycline was not performed since 2017.
Figure 1Cumulative percentages of CR-AB and CS-AB for different MICs (mg/l) of ampicillin/sulbactam (a), cefoperazone/sulbactam (b), minocycline (c), and tigecycline (d). Red dash line indicates Clinical and Laboratory Standards Institute susceptible breakpoints for ampicillin/sulbactam and minocycline, and cutoff values for cefoperazone/sulbactam (MIC ≤16 mg/l) and tigecycline (MIC ≤2 mg/l).
Detection of carbapenemase genes in A. baumannii isolates
Among the 480 A. baumannii isolates collected during 2012-2014, 402 were subjected to carbapenemase gene screening because 78 isolates from China in 2014 were not included. Among the 402 A. baumannii isolates, 232 were CR-AB. Only one isolate from China with blaOXA-23 was susceptible to meropenem (MIC = 1 mg/l), and 226 carbapenemase genes were detected in the CR-AB strains. Of the 232 CR-AB isolates, 224 (96.6%) harbored at least one carbapenemase gene. The 226 carbapenemase genes detected in 224 CR-AB strains included blaOXA-23 (94.7%, 214/226), blaOXA-72 (2.7%, 6/226), blaOXA-58 (2.2%, 5/226), and blaNDM-1 (0.4%, 1/226). Two isolates from the Philippines harbored both blaOXA-23 and blaOXA-58. In our study, no class A carbapenemase but one class B carbapenemase (blaNDM-1)-related genes were detected.
Geographic differences in A. baumannii antimicrobial resistance
The antimicrobial resistance of A. baumannii varied significantly between countries in the Asia-Pacific region in the ATLAS surveillance program from 2012 to 2019 (Figure 2). The carbapenem resistance rates ranged from the lowest in Japan (2.8%) to the highest in South Korea (88%). Among the carbapenemase genes, blaOXA-23 was the most prevalent and was found in CR-AB in all nine countries enrolled in the carbapenemase gene screening. Furthermore, blaOXA-58 was detected in the Philippines, Taiwan, and Thailand, whereas blaOXA-72 was detected in Taiwan. Class B carbapenemases were few, and only one blaNDM-1 gene was found in South Korea. Almost every CR-AB isolate contained at least one carbapenemase gene (96.6%; 224/232). CR-AB without a carbapenemase gene was detected in three from China, two from South Korea, one from Malaysia, one from the Philippines, and one from Taiwan (Table 3).
Figure 2Proportion of resistant phenotypes and distribution of CR Acinetobacter baumannii in each of the 12 countries that participated in the antimicrobial testing leadership and surveillance (ATLAS) program, from 2012 to 2019 (Vietnam was not included in the figure because fewer than 30 isolates were available). The color in this figure indicates the prevalence of CR A. baumannii.
Table 3Distribution of CR and multidrug-resistant Acinetobacter baumannii and β-lactamase genes in different countries in the Asia-Pacific region of the antimicrobial testing leadership and surveillance (ATLAS) program, 2012-2014.
Countries
n
CR A. baumannii, n (%)
Isolates of CR A. baumannii with detected β-lactamase gene, n (%)
Multidrug-resistant A. baumannii has been increasingly reported to cause various infections associated with high morbidity and mortality rates worldwide [
]. The increasing prevalence of carbapenem resistance among A. baumannii strains has led the World Health Organization to designate CR-AB as one of the three most important pathogens that threaten human health. However, the distribution of multidrug-resistant A. baumannii is not equal across regions worldwide because of different selective environmental pressures, differences in hospital infection control practices, or endemics in the participating hospitals. In this study, 71.7% (1918/2674) of isolates were identified as CR-AB. In addition, a significant geographic difference was noted in the carbapenem resistance rates, ranging from 2.8% in Japan to 88% in South Korea. Carbapenemase genes were found in a high percentage of the CR-AB isolates (96.6%, 224/232), and blaOXA-23 was the most prevalent in the Asia-Pacific region based on the ATLAS program.
In 2001, the emergence of carbapenem resistance in A. baumannii was deemed a great threat to human health, which urgently required surveillance programs and implementation of infection control interventions [
Trends of major antimicrobial resistance phenotypes in Enterobacterales and Gram-negative non-fermenters from ATLAS and EARS-net surveillance systems: Italian vs. European and global data, 2008–2018.
]. The Global Antimicrobial Resistance and Use Surveillance System, with 109 countries and territories worldwide, reported that 64% of Acinetobacter spp. isolated from bloodstream infections were carbapenem-resistant, with a wide spectrum of variability ranging from 18.4% to 78% worldwide [
]. For the isolates from the Asia-Pacific region in the current study, most countries had CR-AB proportions similar to or higher than the global median of the Global Antimicrobial Resistance and Use Surveillance System program. The two exceptional counties were Japan and Australia, and their carbapenem-resistant rates for A. baumannii were all less than 10%. A recently published national report on antimicrobial use and resistance in human health demonstrated low resistance rates to meropenem among the A. baumannii isolates in Australia (2.4% and 3.1% in 2018 and 2019, respectively) [
] investigated the molecular characteristics of 645 isolates of A. baumannii from 2012 to 2013, and the results revealed that most isolates belonging to A. baumannii international clone II were carbapenem-susceptible in Japan and did not emerge as carbapenem-resistant clones that had spread worldwide. Noninternational clone II A. baumannii isolates from Japan have diverse domestic sequence types and are associated with a low prevalence of acquired carbapenemase genes. The success of carbapenem resistance in A. baumannii in Japan deserves global attention to overcome the CR-AB epidemics [
Trends and correlation between antibacterial consumption and carbapenem resistance in gram-negative bacteria in a tertiary hospital in China from 2012 to 2019.
], another quasi-experimental ecological study demonstrated a reduction in carbapenem use and the prevalence of CR-AB through a multifaceted, educational interview-based antimicrobial steward program [
Do specific antimicrobial stewardship interventions have an impact on carbapenem resistance in Gram-negative bacilli? a multicentre quasi-experimental ecological study: time-trend analysis and characterization of carbapenemases.
The phenotype of carbapenem resistance in A. baumannii is mainly due to carbapenem-hydrolyzing class D β-lactamase genes, including blaOXA-51-like, blaOXA-23-like, blaOXA-24/40-like, and blaOXA-58-like. The blaOXA-51-like gene is located on the chromosome and is intrinsic to most A. baumannii isolates [
]. blaOXA-23-, blaOXA-24/40-, and blaOXA-58-like genes are the three major classes responsible for worldwide CR-AB epidemics and can be found on chromosomes or plasmids [
]. The blaOXA-23 gene is the most widely spread gene and has been detected in isolates from multiple countries in Asia, South America, and Europe. Moreover, blaOXA-58 has been reported in China, India, and Thailand, whereas blaOXA-24/40-like has been reported in Indonesia and Iran [
]. The results of carbapenemase gene screening in our study are consistent with previous geographic prevalence data. Here, blaOXA-23 was the most frequently detected in the three major classes among the CR-AB isolates in the Asia-Pacific region. For the other class of carbapenemases, only one isolate from South Korea tested positive for the blaNDM-1 gene. Klebsiella pneumoniae carbapenemase, which is disseminated worldwide in the Enterobacterales, is rarely found in A. baumannii. To date, only some isolates in Puerto Rico have been identified to carry blaKPC [
In our study, the options for CR-AB treatment were limited. Antibiotics with relatively lower MICs than other comparator antibiotics included minocycline, tigecycline, and colistin. A recent treatment guideline published by the Infectious Diseases Society of America recommends tetracycline derivatives as monotherapy or combination therapies for CR-AB infections [
Infectious Diseases Society of America guidance on the treatment of AmpC β-lactamase-producing Enterobacterales, carbapenem-resistant Acinetobacter baumannii, and Stenotrophomonas maltophilia infections.
Infectious Diseases Society of America guidance on the treatment of AmpC β-lactamase-producing Enterobacterales, carbapenem-resistant Acinetobacter baumannii, and Stenotrophomonas maltophilia infections.
]. Otherwise, tigecycline is an alternative option and is recommended for prescription at a higher dose (200 mg loading dose, followed by 100 mg every 12 hours) than usual to overcome the higher mortality than that with comparators in some randomized trials to treat CR-AB with the usual dose [
]. Colistin has reliable in vitro activity against CR-AB isolates but is suggested to be a component of combination therapy for moderate-to-severe CR-AB infection owing to its narrow therapeutic window [
]. Regarding the β-lactam and β-lactamase inhibitor combinations used in our study, the in vitro efficacy of ceftazidime against CR-AB was not enhanced by the addition of avibactam, and the results were similar to those of many previous studies [
In vitro activity of imipenem/relebactam, meropenem/vaborbactam, ceftazidime/avibactam, cefepime/zidebactam and other novel antibiotics against imipenem-non-susceptible gram-negative bacilli from Taiwan.
Synergistic Effect of ceftazidime-avibactam with meropenem against panresistant, carbapenemase-harboring Acinetobacter baumannii and Serratia marcescens investigated using time-kill and disk approximation assays.
] showed in vitro synergistic activities by combining ceftazidime/avibactam with colistin, tobramycin, and tigecycline at 1 × MIC concentrations. The activity of cefoperazone/sulbactam against CR-AB depends on the mechanism of carbapenem resistance [
]. Most of the CR-AB isolates harbored carbapenemase genes, and a low susceptibility rate to cefoperazone/sulbactam was observed in the current study.
Our study has several limitations. First, not all countries continuously contributed to the data in the ATLAS program. Some had data interruptions in certain years during the study period; therefore, a trend analysis of the Asia-Pacific region could not be performed. Second, carbapenemase genes were only tested in the first 3 years. The distribution of carbapenemase genes may be altered over time owing to the worldwide dissemination of CR-AB. Finally, although a high percentage of CR-AB had carbapenemase genes detected, some of the CR-AB isolates tested negative, and other resistance mechanisms, such as an overlooked enzyme, upstream modification of intrinsic OXA-51, porin change, or efflux pump upregulation, were not further investigated.
In conclusion, this study showed the detailed distribution of CR-AB in countries in the Asia-Pacific region through the ATLAS program. Although a high percentage of A. baumannii isolates were carbapenem-resistant, we noted that Japan and Australia had very low rates of CR-AB. Class D β-lactamases, particularly blaOXA-23, are highly prevalent in this region. There are limited options for treating CR-AB, and minocycline, tigecycline, and colistin have relatively lower MICs than the other comparator agents. Continuous monitoring of multidrug resistance helps implement timely infection control policies to prevent further dissemination.
Declaration of competing interest
The authors have no competing interests to declare.
Funding
This study was supported by Pfizer Pharmaceutical (NY, USA).
Ethical approval
The institutional review board of each participating hospital approved the ATLAS program, including that of the National Taiwan University Hospital (Taipei, Taiwan; NTUH 201211047RSC). Written informed consent was waived owing to the need for a bacterial collection study, with a minimal risk design for patients. This study followed the policies and guidelines from the ATLAS database managed by the International Health Management Associates and approved by Pfizer Pharmaceutical.
Acknowledgments
The authors thank all the investigators of the participating hospitals in the Asia-Pacific region for their cooperation and support in the Antimicrobial Testing Leadership and Surveillance (ATLAS) from 2012 to 2019.
Author contributions
YLL: conception and design of the study, acquisition of data, analysis and interpretation of the data, drafting the article (led), revising the article, and final approval of the version. WCK: data acquisition, revision of the article, and final approval of the manuscript. PRH: conception and design of the study, acquisition of data, analysis and interpretation of the data, revision of the article (led), and final approval of the version (led).
Multicenter surveillance of antimicrobial susceptibilities and resistance mechanisms among Enterobacterales species and non-fermenting gram-negative bacteria from different infection sources in Taiwan from 2016 to 2018.
In vitro activity of cefiderocol, cefepime/enmetazobactam, cefepime/zidebactam, eravacycline, omadacycline, and other comparative agents against carbapenem-non-susceptible Pseudomonas aeruginosa and Acinetobacter baumannii isolates associated from bloodstream infection in Taiwan between 2018-2020.
Mechanisms protecting Acinetobacter baumannii against multiple stresses triggered by the host immune response, antibiotics and outside-host environment.
Trends of major antimicrobial resistance phenotypes in Enterobacterales and Gram-negative non-fermenters from ATLAS and EARS-net surveillance systems: Italian vs. European and global data, 2008–2018.
In vitro activity of ceftazidime-avibactam against Enterobacterales and Pseudomonas aeruginosa isolates collected in Latin America as part of the ATLAS global surveillance program, 2017–2019.
Trends and correlation between antibacterial consumption and carbapenem resistance in gram-negative bacteria in a tertiary hospital in China from 2012 to 2019.
Do specific antimicrobial stewardship interventions have an impact on carbapenem resistance in Gram-negative bacilli? a multicentre quasi-experimental ecological study: time-trend analysis and characterization of carbapenemases.
Infectious Diseases Society of America guidance on the treatment of AmpC β-lactamase-producing Enterobacterales, carbapenem-resistant Acinetobacter baumannii, and Stenotrophomonas maltophilia infections.
In vitro activity of imipenem/relebactam, meropenem/vaborbactam, ceftazidime/avibactam, cefepime/zidebactam and other novel antibiotics against imipenem-non-susceptible gram-negative bacilli from Taiwan.
Synergistic Effect of ceftazidime-avibactam with meropenem against panresistant, carbapenemase-harboring Acinetobacter baumannii and Serratia marcescens investigated using time-kill and disk approximation assays.
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