Prevalence and Antimicrobial-Resistant Features of Shigella Species in East Africa from 2015–2022: A Systematic Review and Meta-Analysis

Background Shigellosis is the most common cause of epidemic dysentery found worldwide, particularly in developing countries, where it causes infant diarrhea and mortality. The prevalence of Shigella species resistant to commonly used antimicrobial drugs has steadily increased. The purpose of this review is to describe the prevalence and antimicrobial resistance (AMR) characteristics of Shigella species in East Africa between 2015 and 2022. Methods Studies were identified using a computerized search of Medline/PubMed, Google Scholar, and Web of Science databases, with a detailed search strategy and cross-checking of reference lists for studies published between 2015 and 2022. Articles presenting data on prevalence and AMR, accessibility of the full-length article, and publication dates between 2015 and 2022 were the eligibility criteria for inclusion in the review. Original research reports written in English were considered. The heterogeneities of the studies were examined, and a meta-analysis was performed to estimate the pooled prevalence and AMR using a random effects model. Results The pooled prevalence of Shigella species in East Africa was 6.2% (95% CI −0.20–12.60), according to an analysis of 22 studies. Shigella species prevalence was 4.0% in Ethiopia, 14.6% in Kenya, 0.7% in Sudan, 5.2% in South Sudan, and 20.6% in Somalia. The association of Shigella infection significantly varied among the countries (p = 0.01). Among the antibiotics tested, most Shigella isolates were susceptible to ciprofloxacin, norfloxacin, nalidixic acid, and ceftriaxone. Despite the fact that the reports varied in study sites and time, Shigella species were resistant to tetracycline, ampicillin, amoxicillin, chloramphenicol, and co-trimoxazole. Conclusion The pooled estimate indicates high burden of Shigella infection in East Africa, as well as a high proportion of drug resistance pattern to tetracycline, ampicillin, chloramphenicol, and amoxicillin. Therefore, initiating and scale-up of performing drug susceptibility test for each shigellosis case need to be considered and strengthened.


Background
Shigellosis is caused by the ingestion of bacteria of the genus Shigella.Kiyoshi Shiga discovered the bacterium in the stool of patients sufering from severe bloody diarrhea in Japan in 1897 [1].Shigella is a Gram-negative bacterium that causes diarrhea and dysentery in humans.Tere are four species of Shigella based upon serological and biochemical characteristics: Shigella dysenteriae (S. dysenteriae), S. fexneri, S. boydii, and S. sonnei [2].Serogroup A (S. dysenteriae) has 15 serotypes and 2 provisional serotypes [1,3], serogroup B (S. fexneri) has 6 serotypes and 16 subserotypes, serogroup C (S. boydii) has 20 serotypes, and serogroup D (S. sonnei) has only 1 serotype [4].
Te burden of diarrheal disease is the greatest in developing countries with poor sanitation, insufcient hygiene, contaminated drinking water, and poorer overall health and nutritional status [5].In comparison to other causes of gastroenteritis, it is a highly infectious microorganism because only 10 bacilli of microorganisms are required to cause infection [6].Fever, fatigue, anorexia, and malaise are common symptoms of the disease.Some patients sufer from mild to severe dysentery, with systemic complications such as electrolyte imbalance, seizures, and hemolytic uremic syndrome [7].
Shigellosis is the leading cause of infant diarrhea and mortality in developing countries [2].Te domination of S. fexneri is observed in Africa and Asia, whereas S. sonnei, the most dominant in South America, is primarily isolated in one study in Ethiopia [8].Tis may give a clue to the scientifc world about the migration and movement of strains from one region to the other.Such variations could be attributed to diferences in disease epidemiology between study sites.Te prevalence of Shigella species reports varies across studies, which may be due to location diference, study methods, and techniques used [7].In developing countries, it is difcult to evaluate the burden of Shigella infection because of the limited scope of studies and lack of coordinated epidemiological surveillance systems.In addition, under-reporting of cases and the presence of other diseases considered to be of high priority may have overshadowed the problem of shigellosis.
Te emergence of multidrug-resistant (MDR) Shigella strains and the development of the disease state have complicated case management [9].An increment of MDR to shigellosis among several serotypes of Shigella species isolated from acute diarrheal patients [3,10].Regardless of the serogroup or serotype, the majority of the strains carried similar gene-encoding resistance to specifc antimicrobials.Tis drug resistance emergency necessitates the prudent use of efective drugs and emphasizes the need for alternative drugs to treat infections caused by resistant strains.Te pattern of AMR varies by location and between two regions within the same location [1].Te emergence of MDR to available antimicrobials, the lack of reliable vaccination, the disease's increasing occurrence worldwide, and the disease's high incidence in high-risk populations all provide compelling reasons to conduct this review.Despite the high prevalence of shigellosis, summary data on Shigella species in East Africa are scarce.Terefore, this reviewer focused on prevalence and antimicrobial-resistant features of Shigella species in East Africa from 2015 to 2022.

Search Strategy and Eligibility Criteria.
Original research that provided information on the prevalence and AMR of Shigella species was used to review published publications.Studies were identifed through a computerized search using databases of Medline/PubMed, Google Scholar, and Web of Science which were included with a detailed search strategy and cross-checking of reference lists for studies published from 2015 to 2022 in East Africa.Te criteria for studies' eligibility were in accordance with study sites and the PRISMA statement' outcome approach.Studies in Ethiopia, Kenya, Sudan, South Sudan, and Somalia were reviewed; however, due to requirements for article inclusion, the remaining East African nations were not provided.Te study outcome search concentrated on the prevalence of Shigella species and the AMR on the patterns of Shigella species' susceptibility to antibiotics.Articles containing prevalence and AMR statistics, full-text primary studies published in English, and publication dates between 2015 and 2020 were required for inclusion in the review (Figure 1).Papers that lacked the necessary details as well as unpublished theses and dissertations were not included.After completing the searches, all the retrieved records were downloaded and stored in a single library in EndNote 20 (Tompson Reuters).

Data Abstraction for Analysis.
In cases where there was insufcient detail supplied, the complete article was reviewed to determine whether it should be included or excluded.To choose which studies to include in the narrative synthesis, the reviewer (BA) deleted duplicates from the EndNote library both automatically and manually.Te remaining records were then screened by the same reviewer, frst based on the title and then based on the abstract.Te shortlisted articles were then retrieved in full text to determine their suitability for fnal inclusion.Te extraction sheet format was piloted in 5% of the studies chosen randomly before being deployed.Te article was included based on a full-text analysis.Because of diferences in the study, publications were extensively evaluated when data were extracted.Te reviewer (BA) was contacted (at least three times) through email to provide clarifcation where necessary information was needed but lacking.Te heterogeneities of the studies were examined.Using comprehensive meta-analysis, overall pooled prevalence and AMR of Shigella species were estimated by the random efects model.Analysis with a 95% confdence interval (CI), P ≤ 0.05, was considered as statistically signifcant.

3.1.
Prevalence of Shigella Species.22 studies with 5694 samples were included in our review of 450 titles and abstracts, including 16 research from Ethiopia, 3 studies from Kenya, and 3 studies each from South Sudan, Sudan, and Somalia (Figure 2).Te included studies' enrollment periods spanned 2015 to 2022.Te reviewed studies included 144 sample sizes with the smallest and 422 samples with the largest in Sudan and Ethiopia, respectively (Table 1).Majority of the studies were performed on the genus level.Seven studies were performed on asymptomatic food handlers.Seven studies were performed under fve children and the remaining studies were included without age restriction patients with diarrhea and nondiarrheic in this review.Children and diarrheic patients were more associated with shigellosis.Of the adult subject studies, males were more associated with Shigella infection.Te overall prevalence of Shigella species was in the range of 0.7-23.6%with S. fexneribeing the most frequently isolated which revealed 2 Interdisciplinary Perspectives on Infectious Diseases this species as predominant in the etiology of shigellosis followed by S. dysenteriae, S. boydii, and S. sonneifrom the serogroup studies in East Africa.Te analysis of 22 studies, according to the DerSimonian-Laird random-efects model, revealed that the pooled prevalence of Shigella species in East Africa was 6.2% (95% CI −0.20-12.60)(Figures 3 and 4).Pooled prevalence of Shigella species signifcantly varied among the countries (p � 0.01), with 4.0% in Ethiopia, 14.6% in Kenya, 0.7% in Sudan, 5.2% in South Sudan, and 20.6% in Somalia.In most of the investigations performed in Ethiopia, Shigella infection rates did not change signifcantly (p > 0.05) (Table 2 and Figure 3).

Discussion
A lot of studies were conducted in diferent parts of the world even if those studies were performed on the genus level of Shigella.Tis review study described prevalence and AMR patterns of Shigella species in East Africa from 2015 to 2022.In this review, children and diarrheic patients were more associated with shigellosis.Tis might be that the children at this age are naturally taking contaminated soils, food, and water into their mouth and may acquire diseasecausing microbes including Shigella species [19,33].In the review study in Ethiopia [34], the pooled prevalence of shigellosis in children was 7.0%, while in adult population, it was 2.2%.Tis confrms that Shigella causes diarrheal morbidity among infants and young children than adults.
Children who drank from unimproved water sources, untrimmed fnger nails, and that which was served by parents who did not wash their hands before meal were more likely to be exposed to Shigella infection [33].Unimmunized children also had higher infection risk than those who were immunized to diferent infectious diseases [20,21].Due to the ability of the bacteria to invade and replicate in cells lining the colon and rectum, patients with bloody diarrhea and mixed (mucus and blood) were more positive to Shigella species [22].Tis study reviewed that males were more associated with Shigella species on the adult subject studies.Tis might be that males travel more to the diferent regions and seek diagnosis [35][36][37].In addition, this could be the study population by itself, as Chattaway et al. stated that a high male to female ratio with 97% of cases being adult males in the cluster [38].Tis review determined the pooled prevalence of Shigella species in East Africa using 22 studies.According to the results of this review, the pooled prevalence was 6.2%.Tis fnding is comparable with 6.6% Shigella prevalence in the systematic review among US military and similar populations [39] and meta-analysis in Ethiopia [34].Prevalence of Shigella species among East African countries was also calculated; hence, a higher prevalence of Shigella species (20.6%) was reported in Somalia, which was nearly 5 and 29 times higher than the fndings from Ethiopia (4.0%) and Sudan (0.7%), even though the studies conducted and included in this review from this country was only one study.Te variations in prevalence estimates may be due to differences in the study populations, year of study, and number of studies.As a study confrmed that the prevalence of Shigella species reports varies in diferent regions and time [7], the decreased in prevalence might be due to decrease in poverty, increase quality of life, rise of awareness on sanitation and hygiene, and prevention and control strategy of communicable diseases through deploying of health extension workers at community level across the country.
Based on the data obtained from 22 published articles, Shigella species showed high resistance to tetracycline, ampicillin, chloramphenicol, and amoxicillin.Tis fnding is in line with the study performed on AMR [34,40].Commonly in East Africa, the drug of choice on shigellosis treatment is norfoxacin, ciprofoxacin, and ceftriaxone for adults.However, this review showed that slightly high resistance was reported on norfoxacin, ciprofoxacin, and ceftriaxone.Furthermore, the occurrences of MDR of Shigella isolates were reported high.Tis increment may be due to mobile genetic units (including plasmids, gene cassettes in integrons, and transposons), inadequate access to efective drugs, unregulated dispensing, truncated antimicrobial therapy, medication sharing, counterfeit drugs, bacterial evolution, climate changes, lack of medical practitioner with proper training, poor quality, and unhygienic sanitary conditions [37].Except a few studies, all are performed on the genus level.High rates of resistance against multiple antimicrobials were also observed in most of the isolates.Te most resistant isolates from Shigella species were S. fexneri, which showed 87.5% resistance to ampicillin, 75% to tetracycline, and 62.5% to ciprofoxacin.S. dysenteriae was the second most resistant bacteria, which showed 80% resistance to chloramphenicol and tetracycline, 70% to ampicillin, and 60% to ciprofoxacin [26].Another study conducted in       -Treatments need to be based on species identifcation [26] Interdisciplinary Perspectives on Infectious Diseases  -Among the serogroups, most of the MDR phenotypes were found in S. fexneri (65.9%)Tere is an urgent need for AMR surveillance and continuous monitoring [32] Note: "-" means not done or did not get the information.Note: "-" means not done or did not get the information.
Interdisciplinary Perspectives on Infectious Diseases Somalia [32] showed the highest resistance to ceftriaxone occurred among S. sonnei (66.7%) serogroup, followed by S. dysenteriae type 1 (40%) and S. fexneri (38.5%).In this review, included studies primarily used stool culture for Shigella identifcation.Tis estimate appears to be a less sensitive method than molecular methods and may underestimate the actual occurrence of Shigella species [36].

Conclusion
Tis review study suggests that the current treatment mechanism might not be addressing the full burden of Shigella-associated mortality in East Africa.Te pooled estimate provides high burden of Shigella infection and its high proportion of drug resistance pattern to tetracycline, ampicillin, chloramphenicol, and amoxicillin in East Africa.Clinicians should continue to aggressively aware shigellosis, particularly vulnerable children with diarrhea, such as those younger than 5 years or identifcation and treatment of Shigella infection which might be life-saving.As a result, initiating and scaling-up drug susceptibility testing for each shigellosis case, educating the community and health care providers on appropriate antibiotic use, and conducting clinical trials are all urgently needed to support the development of management guidelines for Shigella infections.Interdisciplinary Perspectives on Infectious Diseases

Figure 2 :
Figure 2: Study of Shigella species by region.
frequency of MDR; however, there is still a chance to use ciprofoxacin and ceftriaxone as a treatment option in the setting because of their low frequency of resistance rate [14] Feleke et al. (2018)among under fve children with the isolated Shigella species were MDR Tere is an urgent need for a rational use of antimicrobials[28] Onyango et al. (

Figure 3 :Figure 4 :
Figure 3: Forest plot for the prevalence of Shigella species in East Africa.

Figure 5 :
Figure 5: Forest plot for the prevalence of antibiotics resistance in East Africa.

Figure 6 :
Figure 6: Funnel plot for the prevalence of antibiotics resistance in East Africa.

8
Figure1: Chosen recording items for systematic reviews and meta-analysis fowchart for the selection of studies incorporated in the systematic review and meta-analysis.

Table 1 :
Summary of 22 studies reporting the prevalence of Shigella and its drug resistance in East Africa, from 2015 to 2022.

Table 2 :
Pooled proportions of Shigella prevalence and its drug resistance in East Africa from 2015 to 2022.