Chapter 1: Introduction
1.7 Carbapenem Resistant Enterobacteriaceae in the Arabian
Table 6: Mechanisms of tigecycline resistance in Enterobacteriaceae (Pournaras et al., 2016)
expatriates also do the same, the latter group mostly for economic reasons. Countries most commonly targeted are Germany, the UK, USA, India and Thailand. At the same time the GCC countries also increasingly offer high level health care for visitors coming specifically for treatment and hospitalization (Hotelier, 2014). All these factors make the GCC countries highly exposed to bacteria carrying various resistance genes.
A characteristic controversy between the level of the curative segment of the local health care systems and that of antibiotic surveillance, and to some extent antimicrobial stewardship, exists in the region. Clinical medicine, particularly in large centers, is highly developed with state-of-art oncohematology, traumatology, intensive care etc, i.e. fields that are usually heavy users of broad spectrum antimicrobials.
However, over-the-counter purchase of medication is common. Although antibiotics are not among the most commonly purchased drugs (Yeboah and Yeboah, 2014;
Barakat-Haddad and Siddiqua, 2018) and there are strict laws requiring prescription for them, they are practically freely available at pharmacies. Prescription of antibiotics is much less coordinated in community settings than in hospitals. Regarding hospitals, there are considerable differences even within the same country and very little data are available in that respect regarding the large number of private institutions present all across the region (Mushira, 2015).
The most extensive difference between countries of the Peninsula and those of the western countries with similar level of clinical medicine is the antimicrobial surveillance systems that are rather underdeveloped in the region. While hospitals may compile their own susceptibility data, their collection at the regional or national level is not regular. Even if such databases are created, they are not publicly available.
Country-wide reports are based on literature review, instead of compilation of national
data (Aly and Balkhy, 2012; Yezli et al., 2012; Yezli et al., 2014). Hence, data from the region available for international comparison are sparse (WHO, 2014).
Although ambitious plans exist to improve this situation (Balkhy et al., 2016), to the best of our knowledge, currently the only exception from this lack of coordinated surveillance is the Abu Dhabi Antimicrobial Resistance Surveillance (AD AMRS) project. Since 2009 antimicrobial resistance data from major governmental hospitals in Abu Dhabi for selected pathogens have been collected, compiled and analyzed at Health Authority Abu Dhabi (HAAD). Although internal reports have been prepared, these data have never been made public. The first publicly available data appeared in the 1st quarterly summary report of the Communicable Disease Bulletin of HAAD (HAAD, 2017). Although planned, so far, no similar data are available from other Emirates.
A further major shortage in getting a realistic picture on the epidemiology of antimicrobial resistance, and in particular on that of CRE in the region is that there are no reference laboratories (or just having been formally established are still to be equipped with the proper technology, e.g. Oman) dedicated to run tests, mostly molecular assays, not available in clinical laboratories. To improve this situation, in 2013, a recommendation, without any binding power, was issued by the Director General of HAAD suggesting that CRE isolated in government hospitals in Abu Dhabi should be submitted for molecular characterization to the Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, UAE University, Al Ain (HAAD, 2013). The efficacy of this call, as it has affected the topic of this thesis, will be discussed in the Results section of this dissertation. Currently, we are not aware if similar programmes exist in any of the regional countries.
Therefore, testing for a variety of resistance genes, or typing of organisms have been done as small-scale research projects, only. Consequently, these studies are currently the exclusive sources of practically all of our knowledge regarding the epidemiology, common resistance genes, etc. of CRE organisms.
Without regular, systematic reporting and compiling AMR data, the only source one can rely on when estimating the rate of regional CRE is the AD AMRS database. According to these hospital reports-based data, meropenem resistance in K.
pneumoniae has continuously increased since 2010 to 5.4 % (Figure 11).
Figure 11: Trends in antimicrobial resistance of K. pneumoniae in Abu Dhabi (HAAD, 2017)
The several, small scale, local studies (Poirel et al., 2011; Potron et al., 2011;
Shakil et al., 2011; Dortet et al., 2012; Jamal et al., 2012; Al-Agamy et al., 2013; Shibl et al., 2013; Zowawi et al., 2013; Dash et al., 2014; Uz Zaman et al., 2014; Abdalhamid et al., 2016; Jamal et al., 2016; Leangapichart et al., 2016; Mantilla-Calderon et al., 2016; Al-Agamy et al., 2018; Al-Zahrani and Alsiri, 2018), as well as the few
investigating larger collections (Zowawi et al., 2014; Memish et al., 2015; Sonnevend et al., 2015; Zahedi bialvaei et al., 2015; Pal et al., 2017) all draw the same, or similar conclusion, i.e. the dominating carbapenemase in the region is OXA-48-like followed by NDM. The presence of VIM is rare and sporadic. The only exception from this trend was a temporary increase in the rate of VIM positive strains in Kuwait (Jamal et al., 2013; Sonnevend et al., 2015). Recently, our laboratory showed that this was due to the spread of a 165 kb IncA/C incompatibility type plasmid with a specific, blaVIM- 4 -containing integron In416 (Sonnevend et al., 2012).
IMP, and in particular KPC is rarely detected in the region. The first instance was reported from an E. coli ST131 strain (Dashti et al., 2011) and the first detailed characterization of the blaKPC-2 carrying plasmid was provided for two identical isolates recovered in Dubai in the same hospital 6 months apart (Sonnevend et al., 2015).
Regarding tigecycline resistance, no representative data are available, either. A study including 200 CRE isolates collected between 2009-2013 from across the Peninsula, resistance rate of 22.0%, the highest being in the UAE (28.6%) and the lowest in the Kingdom of Saudi Arabia (KSA) (7.4%) (Sonnevend et al., 2015).
As far as colsitin resistance in the region is concerned, surveillance data generated by the microdilution method are completely missing. The only study comparing results of different regional countries, using the E-test method, found colistin resistance among CRE to be 4.1%, the highest being in the KSA (7.5%) (Sonnevend et al., 2015). It should be noted, that pan-resistant strains, causing a small- scale outbreak, with an insertion-inactivated mgrB leading to colistin resistance, have been described in the UAE (Sonnevend et al., 2017).
So far, no large-scale study addressed the issue of mobile colistin resistance in the region, although the gene has been detected in the UAE, Bahrain and KSA, including CRE isolates, as well (Sonnevend et al., 2016). Recently, the mcr-1 gene was also detected in an isolate from Oman, (Mohsin et al., 2017) and in the fecal culture of pilgrims returning from Hajj (Leangapichart et al., 2016).
Taken together, the data available suggest that countries of the Arabian Peninsula do have a severe problem of CRE infections, although very few details are known. Despite their unique demography and the fact that neighboring countries (e.g.
India, Pakistan etc) all have a high prevalence of such strains, it seems that by now the majority of local infections are not imported but are due to autochthonous transmission (Sonnevend et al., 2015). While it is known that local isolates are dominated by OXA- 48-like and NDM producing strains, almost nothing is known about the allele distribution of these carbapenemases, the clonality of the strains, and in particular about dynamics and the timely changes during the local emergence of CRE. Therefore, the very aim our study has been to shed light on some of these aspects of the problem by subjecting a collection of strains isolated in Abu Dhabi hospitals during 2009-2015 to a detailed investigation.