Transmission of Antimicrobial Resistant Bacteria at the Hajj: A Scoping Review

Background: The Hajj is an annual religious mass gathering event held in Makkah, Saudi Arabia. With millions of participants from across the globe attending the Hajj, the risk of importation, transmission, and global spread of infectious diseases is high. The emergence of antimicrobial resistant (AMR) bacteria is of worldwide concern and the Hajj poses a serious risk to its dissemination. This review aims to synthesize published literature on AMR bacteria acquisition and transmission associated with the Hajj. Methods: We searched electronic databases to identify literature published between January 1990 and December 2021. The search strategy included medical subject headings and keyword terms related to AMR bacteria and the Hajj. Results: After screening 2214 search results, 51 studies were included in the analysis. The review found 6455 AMR bacteria transmissions related to the Hajj. Thirty predominantly enteric or respiratory disease-causing AMR bacterial species were reported with isolates identified in cases on five continents. Most were male, aged above 50 years and were diagnosed in Makkah. Most cases were identified through hospital-based research; few cases were detected in community or primary health care settings. Conclusions: This review provides a contemporary account of knowledge related to AMR transmission at the Hajj. It emphasizes the need for the enhancement of surveillance for AMR bacteria globally.


Introduction
Antimicrobial resistance has emerged as a global threat to public health and health systems [1]. Antimicrobials are chemical compounds or drugs, including antibiotics, used therapeutically to stop the replication of disease-causing microorganisms in humans, animals, and plants [2]. Antimicrobial resistance (AMR) refers to a situation when microorganisms that would otherwise be susceptible to the antimicrobial agents undergo intrinsic changes over time that result in them developing an ability to survive (or resist) the effect of these agents [2]. AMR is accelerated by the over-and inappropriate use of antibiotics in agriculture and by humans [3].
Therapeutically, AMR has reduced the ability to effectively treat some disease-causing microorganisms, leading to increased mortality and morbidity [2]. This is perhaps most notably the case for Mycobacterium tuberculosis (TB), where around 29% of deaths among TB patients have been attributable to AMR TB [4]. Globally, the burden of disease associated with AMR in 2019 was estimated at 48 million disability-adjusted life years lost (DALYs), including 1.3-million deaths [5]. By 2050, AMR is predicted to be responsible for 10 million deaths annually and to cost the world's economy US$100 trillion [6].
The epidemiology of AMR is complex. Globally, there are spatial differences in AMR bacteria occurrence (or at least detection) [7]. For example, in 2019, the global detected rate for methicillin-resistant Staphylococcus aureus (MRSA) was 12.1%; however, as claimed by the WHO, the rate is not representative as not all member countries provided their national rate [2]. This lack of reporting of AMR incidence and rates by countries may contribute to global monitoring and detection differences. Reasons for such limitations may include lack of reliable testing, availability of materials, and national AMR surveillance programs, especially in low-income countries [8]. The ability to move people and animals vast distances quickly through air and sea transport and the subsequent intermingling of people from high and low incidence regions is considered a major challenge to global efforts to mitigate the risks posed by AMR [9,10]. Major mass gathering events, such as the Hajj, exacerbate this risk [11].
Mass gatherings are defined by WHO as "the concentration of people at a specific location for a specific purpose over a set period and which has the potential to strain the planning and response resources of the country or community." [12]. The Hajj pilgrimage is an annual 5-6-day mass gathering that attracts over 2 million people from across the world [13]. The Hajj involves a series of rituals in and around the holy city of Makkah, Saudi Arabia [13].
There have been public health challenges associated with the Hajj in the past. Notably, infectious disease events related to the Hajj have included a cholera epidemic in 1821 that resulted in an estimated 20,000 deaths [14] and meningitis outbreaks in 1987 and 2000, which led to mandating meningococcal vaccination for all pilgrims [15][16][17]. These events highlight the risk of transmission of infectious diseases at the event [18,19]. The threat of AMR bacteria transmission and global spread associated with the Hajj has been noted as a global health concern [20].
Several researchers have explored AMR-related outbreaks associated with the Hajj [21,22], and, in 2017, a systematic review on AMR events at the Hajj in the preceding 15 years (i.e., 2002-2017) was published [19]. Our research supplements this work and adds to the body of understanding by providing a contemporary (up to December 2021) account of the literature related to AMR and the Hajj. In addition, we offer an account of AMR pathogen-specific incidence and associated antibiotic resistance profiles.

Article Identification
A systematic search of the literature using four databases (CINAHL, Embase, PubMed, and Scopus) was conducted between 9 and 20 February 2022. The search was performed by SA. The search strategy involved Medical Subject Headings and keywords related to two domains. These were (i) AMR and (ii) the Hajj. The search strategy is presented in full in Supplementary Material S1.

Article Screening
The title and abstracts of identified articles were screened independently by two researchers (SA and HB) using established inclusion and exclusion criteria. To be included, an article needed to: be a research paper or lesson from the field-type articles; have been published between 1 January 1990 and 31 December 2021; be available in English; and include content related to AMR bacteria transmission, cases, or outbreaks associated with the Hajj pilgrimage. Articles that were systematic reviews, opinion pieces, or editorials were excluded, as were articles that studied organisms other than bacteria, focused on the biology of AMR, or were not available in English.

Data Extraction
Articles retained after screening were read in their entirety and data was extracted from them by SA and HB using a pre-developed data collection tool developed in Microsoft Excel (Microsoft Excel 365, Version 16.60, Microsoft Corporation, Redmond, Washington, DC, USA.) (Supplementary Material S2). Data extracted related to (i) the articles' metadata (authors, title, date of publication, journal); (ii) the pathogen (bacterial species and genus, resistance profile, detection methods, clinical settings, and the number of isolates); and (iii) relationship with the Hajj pilgrimage (Supplementary Material S2).

Analysis
A mixed method approach to analysis was used. First, we conducted a meta-analysis extracting and tabulating data about AMR cases. Second, we used descriptive statistical method to summarize date. Proportions and confidence (CI) were calculated as per published statistical equations and methods [23][24][25]. Third, we used deductive and inductive thematic analysis methods to categorize information and distil pertinent themes. The study was undertaken in line with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines [26]. Find the PRISMA checklist in Supplementary Material S3.

Ethics
Ethical approval was not required as this research relied on publicly available data.

Results
Of the 2214 studies identified during our systematic search, 51 were retained after screening. Figure 1 summarizes the data collection and screening process. The 51 articles kept were published between 1990 and 2020. The pooled population sample from these studies included in this review was 20,947 participants. The total number of female and male participants were 5566 and 8048, respectively (1:1.4; female to male ratio); sex was not reported by the research papers' authors for 7333 (35.01%) participants. The average age of cases was 50 years (range from 14 to 101); this did not include one study that focused on children involved in a meningitis outbreak investigation [24]. A summary of these articles is presented in Table 1. Twenty-six of the 51 papers reported the results of AMR-related research conducted in hospital settings  while eight were case reports [31,38,40,41,[53][54][55][56]. One was an outbreak report [21], one hospital-based case-control study [45], and one article was an environmental to detect AMR in Makkah [57]. Twenty-six of the 51 papers reported the results of AMR-related research conducted in hospital settings  while eight were case reports [31,38,40,41,[53][54][55][56]. One was an outbreak report [21], one hospital-based case-control study [45], and one article was an environmental to detect AMR in Makkah [57].
3.1. What AMR Bacteria Are Reported in the Literature?
Thirty unique AMR bacterial species from 6455 isolates were reported across the 51 articles. These were predominantly enteric or respiratory disease-causing bacteria.

Geospatial Distribution of Respiratory Illness-Causing AMR Bacteria
Eleven articles studied 1330 respiratory illness-causing AMR bacteria (out of 2145 tested) isolated from travelling pilgrims, and five studies for pilgrims who had travelled from Asia (India and Pakistan) to the Hajj [55,72], or vice versa (India, Indonesia, Saudi Arabia, and Malaysia) [54,65,72,73]. Moreover, one study looked at an outbreak caused by returning pilgrims to Africa (Sudan) [21]. Three studies reported AMR among pilgrims returning to Europe (the UK and France) [22,56,64], or vice versa (France) [56,64]. Two studies looked at respiratory illness-causing AMR bacteria among pilgrims traveling from different countries (12 countries in Africa, Asia, USA, and Europe) to the Hajj [71] or returning from Hajj (Algeria, Chad, Comoros, Egypt, Ethiopia, Guinea, India, Indonesia, Libya, Mauritania, Nigeria, and Sudan) [70].
Methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis (TB) are two important respiratory-related infections that merit further investigation.

Discussion
Our research provided an up-to-date account of the literature related to AMR bacteria acquisition and transmission associated with the Hajj pilgrimage. Enteric and respiratory disease-causing, beta-lactam resistance bacteria were the most reported organisms. In this section, we discuss preventive and surveillance measures that may be adopted to reduce the risk of AMR bacteria transmission during the Hajj.

Enteric Disease-Causing Beta-Lactam Resistance Bacteria
Our literature review found that 72.27% [95% CI: 70.92%- 73.63%] of the tested enteric infection-causing bacteria were resistant to beta-lactams. This was similar to what other studies have found. For instance, Santos et al. (2020) found that phenotypically 74% and genetically 94% of tested enteric samples were resistant to at least one beta-lactam antibiotic [76]. Resistance to beta-lactams expressed by enteric bacteria poses health threats that increase morbidity and mortality rates [77,78], and a mismatch between treatment and susceptibility profile leads to a worse prognosis [77,78]. Studies showed that the mortality rate ranged from 42% to 100% for patients with enteric diseases who were infected with beta-lactam-resistant bacteria but were still treated with beta-lactam antibiotics [77,78]. We recommend that physicians considering using beta-lactams to treat pilgrims and their close contacts for enteric diseases consider the AMR risk profile of these patients, and factor this into their clinical decision-making accordingly. Implementation for such recommendation can be strengthened with the availability of data and enhanced surveillance of AMR for commonly used beta-lactams and communicating recommended protocols and guidelines between health authorities related to the Hajj and destination countries.

Respiratory Disease-Causing Beta-Lactam Resistance Bacteria
Our findings show that the most common (68.58% [95% CI: 66.87%-70.29%]) AMR expressed in respiratory infection-causing bacteria was beta-lactams and that this rate was significantly higher among cases detected in Makkah. The higher detected rate of betalactam resistance in Makkah compared to outside Makkah could be due to the high rate of respiratory infections among the Hajj pilgrims [79] or simply the result of measurement bias. The high rate of inappropriate antibiotic prescriptions for respiratory infections in the Hajj that is reported in literature [80,81], may also have contributed to this high detected rate of beta-lactam resistance within respiratory bacteria in the Hajj. Due to the high rate of respiratory infections reported in the Hajj [79], we recommend that health authorities in the Hajj support updating and developing guidelines, that are specific for the Hajj [82], for physicians when treating Hajj pilgrims with respiratory infections.

AMR Isolated from Hospital Settings
We found 56.07% [95% CI: 55.06%-57.09%] of sampled bacteria collected in hospital settings in Makkah were resistant to at least one antibiotic; this is in line with the range reported elsewhere (27% to 82%) [83]. Moreover, our work found that the most common AMR bacteria was Acinetobacter spp. with about 88% of isolates collected resistant to at least one beta-lactam antibiotic. This is similar to a similar study's findings [84]. Infection with Acinetobacter spp. is a serious health issue, as these organisms are robust and can survive in different environmental conditions, increasing the chance of antimicrobial resistance developing [85]. Therefore, hospitalized patients and pilgrims suspected to be infected with enteric bacteria, such as Acinetobacter spp. infections, are recommended to be tested for antimicrobial susceptibility to avoid inappropriate prescribing and thus minimise the risk of AMR development and improve treatment outcomes.

Surveillance of AMR Bacteria
Sixty-five percent of the studies included in our review reported AMR detection through hospital-based research. Both routine and incidental hospital and communitybased surveillance are crucial to assess, predict, and follow up on the development and transmission of AMR bacteria within the Hajj [86]. Moreover, tracking the use of antibiotics (e.g., prescription and dispensing) within the Hajj event may help find foci of unwanted antibiotic usage, such as self-medication and low regimen compliance in the Hajj [86,87]. To ensure adequate surveillance mechanisms are in place to detect AMR associated with the Hajj a comprehensive strategy integrated with broader health protection planning measures are essential. A comprehensive surveillance strategy should incorporate routine hospital-based data collection, community-based surveillance (i.e., private health providers and laboratories), and active case finding when required.

Preventive Measures for AMR Bacteria
The prevalence of AMR transmission at the Hajj should be emphasised on prevention, early detection, and rapid response. Measures that should be considered include the development of policies that require mandatory vaccination (e.g., meningococcal) and prophylaxis before coming to Hajj; strategies to strengthen hospitals' infection controls; the development of Hajj-specific guidelines for AMR prevention, detection and control; enhancement of hospital-and community-based surveillance for AMR; streamlining testing processes; establishment of governance arrangements that support the adoption of novel (or improved) methods of tackling AMR risk; and investing in social, clinical, and operational research to better understand transmission dynamics.

Limitations
This study has several limitations. First, most of the included studies provided limited information about participants' demographics. Demographic data (such as age and gender) are important, as some diseases have high occurrence rates associated with specific ages. Second, we relied on the information provided in the reviewed articles and could not interrogate or validate their findings. Third, some studies were excluded as they were not available in English, which may have resulted in relevant information being missed. Forth, most studies were based on data collected as part of the research conducted in Makkah and hence, AMR detection associated with Makkah is likely overrepresented. Finally, presence of bias was not universally discussed in the manuscripts review. Existence of bias in the literature reviewed may impact the validity and generalizability of our results.

Conclusions
This scoping review provides a point-in-time collation of available scientific information related to AMR transmission associated with the Hajj. It provides an accessible resource for researchers and practitioners seeking insights into AMR-associated incidence and burden and identifies knowledge gaps that may be filled. Finally, the work offers generalizable advice that those responsible for the management of AMR at mass gatherings may refer to inform their efforts.