In this study, we assessed epidemiological trends of invasive carbapenem-non-susceptible Acinetobacter spp. isolates from hospital patients in the European Union and the European Economic Area (EAA) using data from EARS-Net. Similar to the conclusions reached previously by the ECDC , our study demonstrated the persisting challenge of CNA in Europe as the country-population weighted mean proportion of non-susceptible isolates exceeds 30% for the period between 2013 and 2017. The CNA proportion observed in our study is similar to the CNA proportion (35%) reported in a recently published nationwide survey done in the United States among hospitalized patients . A recent global study showed that carbapenem-non-susceptibility in Acinetobacter baumannii complex isolates from both invasive and non-invasive infections was considerably higher in the Asia-Pacific region (~ 79%), Latin America (~ 85%) and North America (~ 45%) compared to the mean CNA proportion in Europe described in our study . Importantly, in Europe the Southern-Eastern to Northern-Western gradient persists. In the Southern and Eastern regions, more than 70% of all Acinetobacter spp. isolates from invasive infections were carbapenem-non-susceptible, while in the North and the West, CNA proportions of less than 10% were observed. This gradient seen in the non-susceptibility of invasive Acinetobacter spp. to carbapenems was also observed for other pathogens in Europe, including Pseudomonas aeruginosa and Klebsiella pneumoniae , suggesting a systematic higher burden of invasive infections with drug-resistant Gram-negative pathogens in Southern and Eastern European regions. High CNA proportions in the Southern and Eastern regions is of great clinical concern, particularly in light of growing resistance against other antimicrobial drugs used as alternative therapeutic options to treat CNAs infections, such as fluoroquinolones and aminoglycoside antibiotics. Our analyses show that on average, > 70% of CNA are also non-susceptible to ciprofloxacin or gentamicin in Southern and Eastern Europe.
Differences in antimicrobial use, infection control and health care utilisation practices between the countries are possible reasons for the variation in the reported proportion of drug-resistant Acinetobacter spp. isolates . Previous studies have shown limited organizational support and practice of infection control measures like standard precautions among health workers that work in the medical ward as well as in critical areas like the ICU in Eastern (e.g. Poland) and Southern European (e.g. Greece) countries [21,22,23]. The 2017 ESAC-Net report showed an increasing trend of carbapenem consumption between 2013 and 2017 in many of the Southern and Eastern region countries, including Latvia, Lithuania, Romania, Poland and Hungary . This might partly explain the surge in carbapenem-non-susceptibility seen in these regions. In fact, an association between hospital carbapenem consumption and carbapenem-resistance rates of Acinetobacter have been described by multiples studies [25,26,27,28,29]. Beside antibiotic usage, other possible explanations for the observed gradient in CNA proportion have been suggested, such as differences in climate and socio-economic conditions across these European regions [30, 31].
In addition to regional differences in CNA proportions in Europe, this study identified factors that are associated with a higher likelihood of acquisition of carbapenem-non-susceptible Acinetobacter spp. Adult patients (> 20 years) show markedly higher CNA proportions than both babies and infants (< 1 years) and children and adolescents between 1 and 20 years. Importantly, the differences in non-susceptibility proportion between adults and babies/adolescents is also observed in regional analyses in Western, Southern and Eastern European regions, suggesting that the higher proportion of CNA in adult patients is a common feature in invasive Acinetobacter spp. infections, independent of inter-regional differences in CNA proportions. This finding is consistent with other studies that found children and adolescents are less susceptible to several infections with drug-resistant bacteria, including carbapenem-non-susceptible Klebsiella pneumoniae , Pseudomonas aeruginosa , as well as methicillin-resistant Staphylococcus aureus  and vancomycin-resistant Enterococcus faecium [35, 36]. Several factors may explain these age differences. It has been shown that elderly patients are more likely to be colonised with drug-resistant pathogens due to more frequent exposure to antibiotics throughout their lives. Moreover, elderly patients have more comorbidities than younger patients and are more likely to reside in nursing homes or other healthcare facilities, both factors that have been shown to be associated with increased AMR . This study also shows that male patients are associated with an increased likelihood of CNA compared to female patients. Male gender is also associated with higher proportions of other carbapenem-non-susceptible pathogens, including of Klebsiella pneumoniae and other Gram-negative rods [32, 38].
Unsurprisingly, most of the isolates in this study are from the ICUs, which is a known hotbed for nosocomial transmission of Acinetobacter spp. [11, 39]. This study shows that the proportion of CNA is highest among isolates collected in the ICU where many patients tend to have severe comorbidities and are exposed to antibiotics and devices that enable the transmission of pathogens [40,41,42]. Studies have also reported that admission to the ICU is a risk factor for the acquisition and isolation of CNA infections in other regions of the world, such as Northern Africa [43, 44].
Strengths and limitations
To our knowledge, this study is the largest and most comprehensive analysis of CNA infections in Europe, with more than 18,000 clinical isolates from 30 countries in the EU/EAA. EARS-Net data are based on routine clinical antimicrobial susceptibility data from national surveillance programmes. The accuracy and validity of the AMR data has been assured through annual external quality assessments on all laboratories from all countries, which showed they all performed generally well . However, it is important to consider the limitations of EARS-Net data. Firstly, participating national laboratories and hospitals might not be representative of an individual country, although according to the EARS-Net report 2017 , many countries across all regions reached a high isolate sample representativeness in their national surveillance systems. Secondly, population coverage varied among reporting countries. To address this issue, all statistical analyses used weightings based on the population sizes of the individual countries similar to that done in the EARS-Net reports. Thirdly, Acinetobacter spp. are not identified to the species level in the EARS-Net database. This is important in terms of carbapenem resistance, as A. baumannii isolates are more frequently carbapenem-resistant that other Acinetobacter species. Therefore, the differential proportion of A. baumannii among all Acinetobacter species across countries and regions might impact the CNA proportions recorded in EARS-Net. Last, different sampling routines in different healthcare settings such as due to limited resources can result in biased estimates of CNA proportions across European regions. However, due its clinical significance, inclusion of only invasive clinical specimen limits the bias that may result from some of the inconsistencies in sampling, although frequency of blood sampling varies between hospitals and countries.