Antibiotics have greatly reduced morbidity and mortality from classical and opportunistic infections in the last few decades.1 Contrasting the gains made, the accelerated global consumption of antibiotics and lapses in the infection prevention and control practices, have hastened the frequency and severity of antibiotic resistance (AR). On average, 2 million people become infected with antibiotic-resistant bacteria and 23 000 people die each year in the US. In the European Union, AR causes 25 000 deaths and 2.5 million extra hospital days per year.2 Mediterranean countries record the highest prevalence of AR. Relatively, southern, Mediterranean, and eastern countries tend to have higher overall use of antibiotics (daily doses/1000 people) than the northern European countries.3,4 Among the Gulf Cooperation Council (GCC) countries, with probable unregulated prescribing practice and an unaudited use of antibiotics, the prevalence of AR has been reported to be rising.5

Antibiotic-resistant bacteria were defined as bacterial isolates that became resistant to the administered drug with a change from ‘susceptible’ to ‘intermediate’ or ‘resistant,’ or from ‘intermediate’ to ‘resistant’ in the susceptibility pattern.6 The main drivers of AR are misuse and overuse of antibiotics due to presumptive treatment and inappropriate use of broad-spectrum antibiotics with erratic dosing.7 Other factors include transmission of resistant bacteria between patients, from healthcare workers to patients and vice versa, prophylactic use in animal husbandry and lack of guidelines and policies for the use of antibiotics. A report from the World Bank forewarned that antimicrobial resistance that includes AR could cause as much damage to the global economy as the 2008 financial crisis.8

Antibiotic development

Obtaining regulatory approval takes approximately 7.2 years, and this excludes phases of research discovery and preclinical and animal testing. Clinical approval success is only 16%.9,10 A report from the European Medicines Agency and the European Centre for Disease Prevention and Control cautioned of an almost barren pipeline with only two new drugs with a mechanism of action. There have been no novel target agents for gram-negative organisms (the cause of two-thirds of multidrug-resistant deaths) for decades.11 Research has revealed that the probability of reversing AR once it established in healthcare settings, the community, and the environment is low. Further, there is a broken market model for making new antibiotics; they do not appear profitable compared to drugs used for chronic diseases. An estimate suggests a risk-adjusted net present value of 100 for antibiotics, compared to 300 for an anticancer drug, 720 for a neuropsychiatric medication, and 1150 for musculoskeletal drugs.12,13

WHO global priority list of antibiotic-resistant bacteria

The World Health Organization’s (WHO) first multicountry public awareness survey on AR revealed a serious worldwide threat to public health compromising the treatment of infectious diseases making tackling AR a high priority.14 On 27 February 2017, the WHO published the list of global priority pathogens (GPP) – a catalog of 12 species of bacteria grouped under three priority tiers according to their AR: critical (three species), high (six species), and medium (three species). The major objective was to encourage the prioritization of funding and incentives, align research and development priorities of public health relevance, and garner global coordination in the fight against AR bacteria.15

The GCC consists of six Arab states: Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the UAE. Bahrain, in the Arabian Gulf, has a population of around 1.4 million, which includes Bahrainis and multiethnic expatriates. The Ministry of Health provides health care services through three hospitals, 24 health centers, and three clinics. The Salmaniya Medical Complex (SMC) is the oldest and largest multispecialty health care facility. Private health care of varying capacities compliments the public services.

The AR of the GPP coupled with the grim projections of antibiotic development call for immediate attention to recognize and review the existing research documents on AR of pathogens on this list. Translational research, such as knowledge mobilization refers to moving available knowledge, often from formal research. More than just ‘bridging the gap,’ knowledge mobilization seeks to make connections between research/expertise and policy/practice to improve outcomes in healthcare.16,17 Knowledge mobilization is expected to inhibit AR particularly in times of the loss of antibiotics from our armamentarium (i.e., moving available knowledge of Bedside to Bench for research and development priorities, risk communication, and infection prevention and control practices into active use).

We hypothesized that infection prevention and control is the major option at hand to reduce the burden of AR due to GPP through knowledge mobilization. Therefore, our goals were to search and quantify the documented evidence of AR in this group of pathogens using the Medline-PubMed databases.18 We also sought to quantify, compare, and rank the top five reported evidence of AR globally, regionally and locally, and describe the reported evidence from Bahrain as a source of knowledge mobilization for infection prevention and control, and use the Bedside to Bench evidence to help align research and development priorities.

Methods

Uninterrupted, accessible, and indispensable information from a reliable source is central to knowledge mobilization to achieve the WHO goals for combating AR of GPP. The most popular, peer-reviewed, reliable, and accessible biomedical literature is the Medline-PubMed literature database of the National Library of Medicine. Medline-PubMed has free access and easy-to-use databases with a focus on medicine and biomedical sciences, whereas Scopus and Web of Science cover most scientific fields. The keyword search with Medline-PubMed offers optimal update frequency and includes online early articles. Scopus automatically index all Medline-indexed journals. Scopus is currently limited to recent articles (published after 1995). Scopus and Web of Science do not include online early versions.19 Thus, healthcare professionals and researchers often rely on Medline-PubMed for scientific information as it is considered the most exhaustive database in the biomedical field. Infrequently, this unique criterion may exclude articles published in other biomedical literature databases.

Bibliometric studies systematically evaluate and analyze the research output on a specific topic through an understanding of the growth, impact, trends, and flow of knowledge within a chosen field of scientific research and contribute to the advancement of public health. The documents indexed in the Medline-PubMed literature database are considered for producing evidence in knowledge mobilization to inform infection prevention and control practices and help align research and development priorities of GPP.

We conducted a bibliometric, retrospective, descriptive review to search the Medline-PubMed database for reports specific to the WHO GPP list published globally, regionally, and locally up to 19 April 2017. We used the advanced search option to search for each GPP with their correlated resistant antibiotic. We used the common term quinolone for the AR of fluoroquinolones, and for third generation cephalosporin-resistant, extended-spectrum beta-lactamases (ESBL) was used. We followed a similar search algorithm for the GCC and Bahrain. For the GCC, we conducted a country-specific search of the number of documents reported on each GPP with their correlated resistant antibiotic, and the results were pooled to sum up the regional list. Likewise, we carried out a similar search algorithm for Bahrain, and the documents were reviewed and illustrated cumulatively as a case study. Two independent researchers extracted the data and abstracted the literature from the returned searches. When there were disagreements between them, the results were discussed with the other co-authors to resolve. No ethical approval was needed for this study due to the use of bibliometric data abstraction and review of publicly available data, which does not involve human subjects directly.

Results

We identified 42 136 documents (including original research, reviews, editorials, letters to the editor) indexed by Medline-PubMed up to 19 April 2017. There has been an increase in the number of publications in the last five years (one-third of the documents). Globally, there were more ‘high’ tier pathogen documents (33 640) than ‘critical’ (6405) and ‘medium’ (2091) tier pathogen documents [Table 1]. Among the WHO GPP list, methicillin-resistant Staphylococcus aureus (MRSA) was the highest reported (28 023 documents with 25 986 original research articles), followed by ESBL resistant Enterobacteriaceae (4001 documents, all were original research articles), and vancomycin-resistant Enterococcus faecium (2622 documents with 2484 original research articles); penicillin-non-susceptible Streptococcus pneumoniae was the least reported with 164 documents [Table 1]. Nine out of the 12 pathogens were gram-negative.

MRSA was the topmost documented pathogen globally and in the GCC, whereas ESBL resistant Enterobacteriaceae ranked top in Bahrain. Likewise, there were two critical tier pathogens globally, and in the GCC region and Bahrain. Articles from Saudi Arabia led the list among the GCC countries.

Of the 14 articles documented from Bahrain [Table 2], we found four articles on ESBL resistant Enterobacteriaceae (critical tier), three articles on MRSA (high tier), two on carbapenem-resistant Acinetobacter baumannii (CRAB; critical tier), and five articles on five different pathogens. An article that reported the occurrence of MRSA/vancomycin-resistant enterococci (VRE) co-colonization was accounted for both MRSA and CRAB. We found one article each from the Bahrain Specialist Hospital and Bahrain Defence Forces Hospital, and the remaining 12 from SMC. The articles reported from Bahrain were reviewed, synthesized, and presented in Table 2 according to their tiers listed in the WHO GPP list.

Discussion

Knowledge mobilization through bibliometric studies on the AR of GPP has provided useful and objective data for infection prevention and control, and to minimize morbidity and mortality due to these pathogens. Nine (75%) of the 12 GPPs were gram-negative. ESBL producing bacteria have increased worldwide; Escherichia coli and Klebsiella pneumoniae were commonly reported. The reports on ESBL, the third generation cephalosporin-resistant Enterobacteriaceae, a critical tier GPP from Bahrain, were the highest yielding four publications, whereas these ranked second globally and in the GCC in terms of original research publications. The majority of ESBL isolates were E. coli and K. pneumoniae. The bla (CTX-M) gene was found predominantly indicating bacterial evolution due to over prescription or weak enforcement of existing antibiotics policies.26 The use of extended-spectrum cephalosporins and others are compromised leaving carbapenems as the therapeutic option.25

S. aureus is one of the most frequent causes of bacterial infections. MRSA is the most reported AR GPP globally and regionally; it was ranked second among the publications from Bahrain and the GCC publications account for 1%. A multiresistant SCCmec type III and coagulase type 36 genotype, and a non-multiresistant SCCmec type IV with different genetic backgrounds of MRSA were identified in Bahrain.28 Overuse or misuse of methicillin and flouting simple hand washing has contributed to the development of MRSA.22 The burden of MRSA infections escalated the use of vancomycin leading to the vancomycin-intermediate and resistant S. aureus strains to which we found 775 global and three GCC documentations. MRSA/VRE co-colonization with MRSA trafficking between the hospital and community environment was reported from Bahrain.27

Carbapenems are used as ‘last resort’ antibiotics. We found that CRAB – a critical GPP has been reported globally, regionally, and in Bahrain, and has dramatically increased over the last decade.34 The heterogeneity of carbapenem-hydrolyzing class D Β-Lactamases (CHDL)-encoding genes as the source of CRAB isolates was identified among eight patients in different units of SMC, leading to the death of four patients.20 Also, the first GCC regional study of the molecular epidemiology of CRAB found that the OXA-23-type was the major carbapenemase mechanism for the resistance phenotype; one-fourth represented healthcare-associated infections, while half associated with nosocomial infections indicating the need for optimizing infection control practices and antibiotic stewardship.21

Besides ESBL, MRSA, and CRAB, clarithromycin-resistant Helicobacter pylori, fluoroquinolone-resistant Campylobacter jejuni, third generation cephalosporin-resistant Neisseria gonorrhoeae, and ampicillin-resistant Haemophilus influenzae were other documented AR GPP found in the GCC region and Bahrain. The isolates of H. influenzae from Bahrain and its neighbors found that the resistance to ampicillin was 70% with considerable variability in susceptibility.33

The GCC is one of the wealthiest regions.35 However, among the top five GPP, two reports from the GCC and Bahrain were similar.36 Moreover, the GCC has a dependent international workforce, tourists traveling to GCC states have grown, and Hajj attracts many visitors to Saudi Arabia.37 Pilgrims transit through Bahrain to Saudi Arabia, which is deemed to be a risk factor for the acquisition and transmission of AR bacteria in Bahrain and the GCC.38 The issue of AR is further compounded by the free/subsidized healthcare services in the region (overuse/misuse of antibiotics). Although non-prescription sales of antibiotics are illegal in the GCC, a study reported that 68% of pharmacies in Abu Dhabi and many pharmacies in Saudi Arabia had sold antibiotics without a prescription. Besides, 75% of patients who received antibiotics in the intensive care unit of a hospital in Qatar did not have a microbiologically-proven infection.39 Thus, it is not surprising that high numbers of critical tier GPP are found in Bahrain and the GCC compared to the global trend.5 Our analysis has concluded that overuse or misuse of antibiotics has contributed to the development of AR requiring clear guidelines, policies, and audits for the judicious use of antibiotics.

Human adaptation to the new niche has been relatively short; virulent pathogens confront and target the immune system.40 Microbes select for more than just antibiotic resistance with enhanced gene transfer abilities and many non-antibiotic agents or settings select for or maintain AR traits.41 Therefore, antibiotic stewardship forms a crucial intervention, supporting access to and appropriate use of antibiotics. Antibiotic stewardship programs that included heterogeneous interventions (auditing, restriction, treatment duration, cycling, or combination of antibiotics) have significantly reduced hospital costs and antibiotics use.42

Recently, the WHO revised the antibiotics section (essential medicines list) by grouping into categories of access, watch, and reserve to combat AR by ensuring the best use of antibiotics, prescribing the right antibiotics, and preserving the ‘last resort’ antibiotics,43 suggesting optimization of antibiotic stewardship as the priority for Bahrain and the GCC.

The evidence on AR characterizing the genogroups and molecular types are fragmentary from the GCC and Bahrain. Identification of the multiresistant and non-multiresistant SCCmec types of MRSA, heterogeneity of CHDL-encoding genes of CRAB, OXA-23-type as the major carbapenemase mechanism, and the presence of CTX-M-55 of CTX-M β-lactamases would aid in research and development priorities globally. More studies addressing community-acquired AR infections and a focus on pediatric or geriatric populations should be prioritized. However, more regional and country-specific studies are needed, especially from the Bedside to Bench of AR at a molecular level. Understanding the role of resistance determinants (e.g., carbapenemases and efflux pumps) is crucial.

We recommend integrated infection prevention and control strategies to address the immediate and long-term threats of AR in Bahrain and the GCC. To corroborate, the infection control protocol introduced in the Bahrain Specialist Hospital has been successful in reducing hemodialysis-related bacteremia and eliminating vascular access infection.29 Similarly, an active surveillance program after an outbreak of VRE at the University of Virginia Hospital drastically reduced the primary VRE bacteremia.44 Likewise, a program of intensive surveillance and infection control reduced the risk of hospital-acquired ventilator-associated pneumonia at the University of Massachusetts Medical Center.45 Further, a recent systematic review revealed that antibiotic stewardship programs with infection control measures were more effective (31% reduction), and programs emphasizing hand hygiene reduced the incidence of AR by 66%.46 Hand hygiene had the greatest impact when co-implemented with antibiotic cycling (51% reduction).46

Our review is not bereft of limitations. First, articles were taken from the Medline-PubMed literature database only, which may have excluded articles published in journals indexed in other databases. Nonetheless, the Medline-PubMed literature database is the most exhaustive database in the biomedical field. Second, the global distribution of AR of GPP was not carried out owing to the enormity of the documents. Moreover, our aim was restricted to rank only the top five reported evidence on AR globally, regionally, and locally. Third, this study was restricted to the selection of English-only articles as Medline-PubMed consists largely of English-language journals. Fourth, we did not assess the bias and validity of studies as this was a bibliometric review.

Conclusion

We were able to substantially describe the major AR pathogens on the WHO’s GPP list found in Bahrain and, to a lesser extent, in the GCC as well as a glimpse at the global scenario. Our findings suggest the need for a comprehensive, multipronged policy response since the antibiotic pipeline is barren. In Bahrain, there is a need for antibiotic stewardship and enforcement of stringent infection prevention and control practices in hospitals and community healthcare settings. Additionally, active surveillance of antibiotic resistance and research on AR of GPP will continue to grow to shape policy solutions to prolong antibiotic effectiveness and research and development to add new antibiotics. To our knowledge, this is the first study to examine and compare the frequency of GPP and characterize the studies published.

Disclosure

The authors declared no conflicts of interest. No funding was received for this study.

Acknowledgements

The authors would like to thank Mr. Abbas Al Khatam, chief medical librarian, Ahmed Al Farsi, Library, University of Bahrain, Bahrain for the support provided to carry out the study.

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