Carbapenem resistant organisms: A 9-year surveillance and trends at Saint George University Medical Center

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Carbapenem resistant organisms: A 9-year surveillance and trends at Saint George University Medical Center夽 Amanda Chamieh 1 , Gerard El-Hajj 1 , Claude Afif 1 , Eid Azar ∗,1 Saint George Hospital University Medical Center, Faculty of Medicine and Medical Sciences, University of Balamand, P.O. Box 166 378, Achrafieh, Beirut 11 00 2807, Lebanon

a r t i c l e

i n f o

Article history: Received 11 January 2019 Received in revised form 14 February 2019 Accepted 16 February 2019 Keywords: Carbapenem resistant enterobacteriaceae Carbapenem resistant organisms CRE epidemiology

a b s t r a c t Introduction: Carbapenem resistant organisms (CRO) constitute a large group of bacteria with different mechanisms of resistance and recently increasing global incidence. This rise has ambiguous dynamics and essential local epidemiologic data is lacking. Materials and methods: In this retrospective study at the 400-bed Saint George Hospital (SGH) in Beirut, Lebanon, we retrieved electronic laboratory records of all intrinsic and acquired CRO isolates from January 1, 2010 until June 30, 2018. Isolation density was calculated as: number of isolates/1000PD. Analysis carried out using WHOnet with a trend time series analysis. Results: During the study period, a total of 2150 non-duplicate CRO were isolated. While Acinetobacter baumanii (AB), Pseudomonas aeruginosa (CRPa), and Stenotrophomonas maltophilia (Sm) constituted 85% of total CRO in the study period, the carbapenem resistant enterobacteriaceae (CRE) rose from few sporadic cases before 2016 to a solid 32% of total CRO in 2018. Our most concrete trends were as follows. The rate of AB bacteremia was at an average of 0.114/1000 PD from 2011 to 2014. In 2015, a sudden doubling of AB bacteremia to 0.23/1000 PD. In 2017, there was a significant decrease to 0.113/1,000PD (p < 0.0001) to reach 0.097/1000PD in 2018 with a continuously declining trend. The peak of Sm bacteremia was in 2016 at 0.121/1000PD after which it significantly decreased by 21% in 2017 to disappear in 2018 (p < 0.0001). There were no significant trends observed in the isolation density of the CRPa group from 2010 until June 2018. Klebsiella pneumonia (CRKp) bacteremia was isolated first in 2013, then in 2016 and continued to rise (p = 0.028). In 2017, carbapenem resistant KP bacteremia rate doubled to 0.05/1,000PD from 0.024/1000 (p = 0.0139). Conclusion: In conclusion, this 9-year study at SGH depicts the major trends and dynamics of local CRO isolation, mainly A. baumanii, P. aeruginosa and CRKp. Further efforts are warranted both locally and internationally for a richer understanding of this trend. Bearing in mind that understanding antimicrobial resistance is a complex, multifaceted process that is only feasible when all its aspects are combined: molecular, phenotypic and clinical. © 2019 Published by Elsevier Limited on behalf of King Saud Bin Abdulaziz University for Health Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Introduction The effective global dissemination of carbapenem resistant organisms (CRO) [1] is an emergent threat that has nowadays become endemic in some settings [2,3].

夽 This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. ∗ Corresponding author. E-mail address: [email protected] (E. Azar). 1 All authors equally contributed to the preparation of this manuscript.

In 2015, the Center for Disease Control (CDC) redefined carbapenem resistance as resistance to imipenem, meropenem, doripenem, and ertapenem or a documentation that the isolate possesses a carbapenemase. Under this umbrella, carbapenem resistance can be phenotypic or genotypic. This enables us to further categorize CRO into carbapenemase producers (CP-CRO) that hydrolyze carbapenems and non-carbapenemase producers (NCPCRO) that alter the bacterial cell membrane with resulting porin mutations [2,4]. A major contributor to the rapid worldwide distribution of CRO is their highly transmissible plasmids carrying carbapenemase genes [5,6]. The so far known mechanisms of CP-CRO include NDM, OXA, VIM, IMP, KPC genes. These are found on plasmids

https://doi.org/10.1016/j.jiph.2019.02.019 1876-0341/© 2019 Published by Elsevier Limited on behalf of King Saud Bin Abdulaziz University for Health Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: Chamieh A, et al. Carbapenem resistant organisms: A 9-year surveillance and trends at Saint George University Medical Center. J Infect Public Health (2019), https://doi.org/10.1016/j.jiph.2019.02.019

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which also encode genes of resistance to a multitude of other antimicrobials, thus rendering such isolates pan-drug resistant. This abundant genetic diversity leads to an ongoing discovery of novel mechanisms of carbapenem resistance with almost every newly encountered CRO isolate [7,8]. CRO belonging to the Enterobacteriaceae family of organisms have claimed their own classification as carbapenem resistant enterobacteriaceae (CRE), namely lactose fermenting organisms. In 2017, CDC added CRE to the list of the three urgent threats to human health and has since suggested protocols and resources as an attempt for global containment [9]. Accordingly, in the US, CRE was found to be implicated in 9000 infections and around 600 deaths per year. The Surveillance of antimicrobial resistance in Europe report of 2017 stated as well a rising incidence of CRE, exceeding 10% in some countries [10]. In Lebanon and other areas of the world, reliable data concerning carbapenem resistance epidemiology is missing [11]. In 2016 only 10 out of 21 countries forming the Eastern Mediterranean Region (EMR) participated in the global antimicrobial resistance surveillance system (GLASS), an initiative by WHO exploring the status of antimicrobial resistance monitoring (AMR) surveillance systems globally [12]. The report published in January 2018 revealed a striking discrepancy between population size, surveillance sites and presence of national AMR action plans in participating countries. For example, Bahrain has an active national AMR since 2016 that covers 80% of its 1.37 million inhabitants and has 32 surveillance sites reporting back to WHO. On the other hand, Egypt has only 15 surveillance sites and an early phase national AMR for a massive population of 93.77 million. Interestingly, Saudi Arabia, the largest Arab country with 31.55 million inhabitants has only 12 sites of surveillance and no national AMR. Lebanon has only 2 surveillance sites for a population of 5.85 million; which highlights the deficit in AMR surveillance and reporting [13]. As an opportunity to better understand the dynamics of the CRO epidemic in an area known for high resistance patterns in gramnegative infections, we aim to analyze the various trends of CRO isolation at Saint George Hospital (SGH) by a thorough determination of the isolation density and species repartition over the last 9 years.

Fig. 1. Distribution of carbapenem resistant isolates.

(ICRE) refers to Proteus mirabilis, Proteus vulgaris, Morganella morganii, and Serratia marrescens. Carbapenem resistant A. baumannii (CRAB) and Pseudomonas aeruginosa (CRPa) were defined as isolates resistant to imipenem or meropenem as per CLSI [14]. XDR-AB refers to an A. baumannii isolate susceptible only to tigecycline, colistin, and aminoglycosides. Lactose non-fermenters (NF) refer to CRPa, CRAB, and the intrinsically carbapenem resistant S. maltophilia (Sm). CRO refers to all the above-mentioned organisms. Only the first isolated carbapenem resistant bacterium was included per patient. If a patient had 2 different CRO, each was counted as a different isolate. The isolation density is expressed as number of isolates per 1000 PD.

Materials and methods Statistical analysis Study design and data collection This is a retrospective study conducted at SGH, a 400-bed tertiary care center in Beirut, Lebanon. Electronic laboratory records for all clinical microbiology isolates were recovered for a time period spanning from January 1, 2010 until June 30, 2018 from our Antimicrobial Stewardship Program (ASP) database. No medical records were accessed for the sake of this study, so we obtained a waiver for informed consent and IRB approval at our institution. The number of patient days (PD) was obtained from the electronic database as well. All microbiology cultures were uploaded to the WHOnet software. Our analysis only included carbapenem resistant Gramnegative blood, sputum, urine and other (wound, fluid) cultures. Definitions and variables We define Carbapenem resistance, being intrinsic or acquired, according to the 2015 CDC definitions. CRE include Escherichia coli (CREc), Klebsiella pneumonia (CRKp), Enterobacter cloacae, Enterobacter aerogenes, Enterobacter species, and Citrobacter fruendii, Proteus mirabilis, Proteus vulgaris, Morganella morganii, and Serratia marrescens. Intrinsic Colistin Resistant Enterobacteriaceae

The Mann–Kendall trend test and homogeneity test [95% confidence interval (CI); p < 0.05] were applied on isolation densities of CRO both expressed per 1000 patient days to analyze the progression over time. All analyses were performed using Microsoft Excel 2016 with XLSTAT 2014 add-on [15].

Results General observed trend of fermenters vs. non-fermenters, CRO vs. CRE Throughout the study period, a total of 2150 CRO were isolated (Fig. 1) with a total of 656,810 PD. It is notable that starting 2016, a general trend of increased imipenem resistance among this group of organisms was observed (p = 0.098) (Fig. 2). In 2010–2011, the ratio of lactose fermenters (F) to NF was 0.029 and started to increase after 2012 to reach in 2017 average of 0.15. In 2018, there is a significant increase by almost four-fold of this ratio. As for the percentage of CRE out of all CRO, in 2010–2011, it was 3% and increased to stabilize at average of 8% until 2017. In 2018, CRE quadruples to 32% of CRO (Fig. 3).

Please cite this article in press as: Chamieh A, et al. Carbapenem resistant organisms: A 9-year surveillance and trends at Saint George University Medical Center. J Infect Public Health (2019), https://doi.org/10.1016/j.jiph.2019.02.019

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Fig. 2. Isolation density of all carbapenem resistant isolates/1000PD per year.

Fig. 3. Ratio of lactose fermenter(F) to non-fermenter(NF) and carbapenem resistant enterobacteriacea (CRE)/carbapenem resistant organisms (CRO) ratio.

Fig. 4. Carbapenem resistant A. baumanii (CRAB) and S. maltophilia (Sm) bacteremia/1000PD.

Distribution of carbapenem resistant isolates by species Acinetobacter baumanii The greatest proportion of carbapenem resistant isolates belonged to CRAB, constituting 42.3% of all isolates and totaling 910 CRAB isolates throughout the study period. The rate of XDR-AB bacteremia was at an average of 0.114/1000 PD from 2011 to 2014. In 2015, a sudden doubling of XDR-AB bacteremia to 0.23/1000 PD observed. In 2017, there was a significant decrease to 0.113/1000 PD (p < 0.0001) to reach 0.097/1000 PD in 2018 with a continuously declining trend (Fig. 4). Sputum isolation density of CRAB decreased by 50% from 0.96 to 0.48/1000 PD (p < 0.0001). Urine cultures decreased after 2015 (p = 0.03) by 52% from 0.18 to 0.093/1000 PD. Other cultures such as wound and fluid had a decreasing trend after 2016 with no statistical significance. Stenotrophomonas maltophilia The total number of Sm isolates was 433 throughout the study period, constituting 20.3% of all carbapenem resistant isolates. Sm rate was at a yearly average of 0.017/1000 PD from 2010 until 2014,

where it began increasing. The peak of Sm bacteremia was in 2016 at 0.121/1000 PD after which it significantly decreased by 21% in 2017 to disappear in 2018 (p < 0.0001) (Fig. 4). No trends were noted in sputum, wound or fluid cultures of Sm. No urinary isolates were obtained in 2010, 2014, 2015, and 2018. Pseudomonas aeruginosa CRPa isolates constituted 23% of carbapenem resistant isolates, totaling 496 throughout the study period. There were no significant trends observed in the isolation density of CRPa group from 2010 until June 2018. Rates of bacteremia were at an average of 0.028/1000 PD per year except one value of 0.082/1000 PD in 2014. CRPa in sputum was at an average of 0.4/1000 PD per year while in urine, wound and fluid averaged 0.2/1000 PD per year (Fig. 5). Escherichia coli CREc isolates form 5.7% of carbapenem resistant enterobacteriaceae. The total number of isolated was 123 throughout the study period. CREc bacteremia was noted in 2013, 2014 and 2016 at 0.048/1000PD (p = 0.037). In 2018, the average rate of CREc bac-

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Fig. 5. Isolation density of carbapenem resistant pseudomonas /1000 PD.

Fig. 6. Isolation density of carbapenem resistant E. coli (CREc) and carbapenem resistant K. pneumonia (CRKP) / 1000PD.

teremia doubled to 0.097/1000 PD (p < 0.0001). A rising trend was also observed among sputum cultures starting 2013 (p = 0.0127), from 0.027/1000PD to 0.07/1000PD in 2016 at which remained high till 2018. As for urinary isolates that started to appear in 2012, no significant trend was noted; the rate of CREc in urine is at around 0.72/1000PD. Wound and fluid culture isolation density has been on the rise since 2013 (p < 0.0001) from 0.027 to 0.102/1000PD (Fig. 6). Klebsiella pneumoniae CRKp are almost equivalent to CREc at 5.35% of carbapenem resistant isolates, a total of 115 throughout the study duration. There is a generally increasing trend, significant as of 2016 (p < 0.028). CRKp bacteremia was isolated once in 2013, then in 2016 and continues to rise (p = 0.028) (Fig. 4). In 2017, CRKp bacteremia rate doubled to 0.05/1000PD (p = 0.0153) from 0.024/1000 (p = 0.0139). Sputum isolates were at a steady rate of 0.052/1000PD from 2010 till 2017, after which there is a significant increase to 0.29/1000 PD (0.0058). Urinary isolates of CRKp significantly increased after 2016, from average of 0.02 to 0.184/100 PD (p = 0.034). Wound and fluid cultures witnessed two significantly increasing trends, in 2013 (0.016–0.03/1000PD) and 2018 (0.037–0.29/1000PD) (p < 0.0001) (Fig. 6). Other Enterobacteriaceae Enterobacteriaceae other than CREc and CRKp summed up to 73 isolates that include Enterobacter sp. and Citrobacter sp., and carbapenem resistant ICRE (CR-ICRE). Non-ICRE bacteremias only appear in 2014, 2016 and 2017, at average of 0.008/1000PD, although they consistently appeared in sputum, urinary, wound and fluid cultures. On the other hand, CR-ICRE was only isolated in the urine in 2018 at rate of 0.048/1000PD (Table 1). These trends were all statistically insignificant.

Discussion Our study is the first 9-year epidemiologic work that describes and analyzes the trends of all isolated CRO and their isolation density at a tertiary university medical center in Lebanon. Our results enabled us to detect an increasing trend of CRE:CRO, increasing from 3% in 2010 to 32% in 2018. In other words, we observed an epidemiologic shift from a non-lactose fermenter dominance to lactose fermenter dominance in carbapenem resistant organisms. According to a systematic review describing antimicrobial resistance in Arab countries published in December 2018 [16], the prevalence of CRE ranges from 1%–28%,1%–28%, CRPa 3%–93%, CRAB 36%–93% of total isolates. In Lebanon, CRE is 1% of 18,713 total isolates, with CRKp at 3% while CREc 1%, CRPa 28% of 3920 isolates, CRAB 82% of 3552. This is comparable to our study that showed an increasing number of CRKp as compared to CREc in the last 2 years, raising the question of a newly circulating CRKp in our country. However, while this systematic review is more comprehensive than the GLASS report, it is still based on individual scientific publications and not comprehensive national surveillance data and with no trend analysis. In our study, the main CRE representatives, E.coli and K. pneumonia, followed two different epidemiologic patterns. CREc appears since 2010 and starts to increase steadily since 2012 to reach 0.435/1000PD in 2018. On the other hand, CRKp is at a stable average of 0.15/1000PD until a dramatic increase by 4-fold in 2018. In November 2017, we observed in our ICU a clonal outbreak of carbapenem and colistin resistant ST 383 K. pneumonia (XDR-KP) co-harboring NDM-5 and OXA-48. The index cases were 2 healthy young community patients that were eventually discharged home. This deserves further investigation and collaboration with other Lebanese centers.

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Table 1 Isolation density of CRO according to specimen type. Year

Culture Type

A. baumannii

S. maltophilia

P. aeruginosa

E.coli

K. pneumoniae

Other Enterobacteriacea

2010

Blood Other Sputum Urine

0 0 0.322 0.038

0.019 0.095 0.702 0

0.019 0.152 0.398 0.171

0 0 0.019 0

0 0 0.019 0.019

0.000 0.000 0.000 0.000

2011

Blood Other Sputum Urine

0.126 0.440 0.770 0.016

0.016 0.141 0.660 0.031

0.016 0.157 0.330 0.063

0 0.016 0 0

0 0.016 0.047 0

0.000 0.016 0.031 0.000

2012

Blood Other Sputum Urine

0.065 0.425 1.211 0.327

0.016 0.131 0.573 0.033

0.049 0.295 0.475 0.295

0 0.049 0.033 0.033

0 0.033 0.082 0.033

0.000 0.033 0.033 0.016

2013

Blood Other Sputum Urine

0.168 0.365 1.081 0.289

0.015 0.107 0.442 0.015

0.015 0.137 0.442 0.198

0.015 0.015 0.015 0.061

0.015 0.030 0.076 0

0.000 0.076 0.122 0.046

2014

Blood Other Sputum Urine

0.096 0.574 1.422 0.232

0.109 0.055 0.602 0

0.082 0.205 0.369 0.246

0.041 0.082 0.068 0.068

0 0.096 0.096 0.027

0.014 0.041 0.027 0.014

2015

Blood Other Sputum Urine

0.229 0.494 1.206 0.193

0.060 0.109 0.711 0.000

0.012 0.169 0.531 0.157

0 0.121 0.024 0.109

0 0.036 0.048 0.048

0.000 0.084 0.060 0.012

2016

Blood Other Sputum Urine

0.193 0.229 0.713 0.145

0.121 0.145 0.350 0.048

0.012 0.181 0.374 0.217

0.048 0.109 0.072 0.145

0.024 0.048 0.024 0.012

0.012 0.072 0.024 0.012

2017

Blood Other Sputum Urine

0.113 0.214 0.427 0.063

0.025 0.038 0.402 0.013

0.038 0.214 0.251 0.151

0.013 0.075 0.075 0.063

0.050 0.038 0.025 0.151

0.013 0.038 0.013 0.063

2018

Blood Other Sputum Urine

0.097 0.242 0.532 0.072

0.000 0.145 0.580 0

0.048 0.362 0.435 0.266

0.097 0.121 0.072 0.145

0.048 0.290 0.290 0.217

0.000 0.072 0.048 0.097

As for the crescendo-decrescendo pattern of CRAB and Sm, the ASP at our institution reported a strong correlation between rates of CRAB bacteremia and high carbapenem consumption. Another microbiologic work showed the appearance of a more sensitive ST25 A.baumannii clone. The ASP first detected an XDRAB mainly in the intensive care unit (ICU) in early 2015, reaching 0.47/1000 PD that was accompanied by the steadily increasing rate of carbapenem consumption of 130DDD. This led to investigating the rationale behind carbapenem-colistin combination therapy in CRAB infections. An institutional study of 100 consecutive nonduplicate XDR-AB isolates by the checkerboard technique found no synergy between carbapenem and colistin [17]. As of July 2016, colistin monotherapy protocol was adapted for any CRAB infection at SGH, and ICU carbapenem consumption was not to exceed threshold of 2 out of 10 ICU patients. This resulted in a tremendous curb in carbapenem consumption by almost 70% and near elimination of XDR-AB ST2 from our ICU [18]. This may allow us to conclude that carbapenem pressure played a significant role in the rise of this group of CRO, whereby selective pressure probably led to the outbreak of intrinsic carbapenem resistant Sm and persistence of CRAB. On the other hand, the complexity of CRPa was emphasized by the series of mini outbreaks that averaged at 0.8/1000 PD. However, these findings are not sufficient reason to establish causality for the endemicity of CRPa at our institution. Last but not least, CRE is undoubtedly on the rise [1], creating a very complex situation since they are mainly fecally carried [19].

In addition, CRE may be isolated from critical patients as well as a simple colonization of the outpatient. This highlights an important limitation encountered in our retrospective work: the isolation of carbapenem resistant organism is not equivalent to an infection. As we learned from our XDR-KP experience, an outbreak may have no direct clinical value. This means that reporting the isolation density of carbapenem resistant E. coli and K. pneumonia as on the rise may be misleading and is incomplete without relating it to the development of a clinical syndrome. Moreover, reporting of antimicrobial resistance and the underlying mechanisms is incomplete without molecular characterization and genotyping of isolates. This was a limitation in the analysis of our results. Conclusion In conclusion, this study mainly demonstrated that CRO is a diverse and dynamic group, and we are facing this global epidemic with very little knowledge and imperfect tools. CRO has an independent pattern of isolation probably as a result of the individual interplay between carbapenem resistance mechanisms and external factors, which are both beyond the scope of our study. More work is needed to demonstrate whether this epidemiologic rise of CRO has yet started to have a clinical impact. In such cases, the interdependence of microbiology and its novel, rapid technologies, epidemiologic surveillance of hospital associated infections, and strategies for infection control and antimicrobial stewardship are all needed at a national level to thoroughly address CRO.

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