Antimicrobial Resistance Rates and Surveillance in Sub-Saharan Africa: Where Are We Now?

Introduction: Although antimicrobials have traditionally been used to treat infections and improve health outcomes, resistance to commonly used antimicrobials has posed a major challenge. An estimated 700,000 deaths occur globally every year as a result of infections caused by antimicrobial-resistant pathogens. Antimicrobial resistance (AMR) also contributes directly to the decline in the global economy. In 2019, sub-Saharan Africa (SSA) had the highest mortality rate (23.5 deaths per 100,000) attributable to AMR compared to other regions. Methods: We searched PubMed for articles relevant to AMR in pathogens in the WHO-GLASS list and in other infections of local importance in SSA. In this review, we focused on AMR rates and surveillance of AMR for these priority pathogens and some of the most encountered pathogens of public health significance. In addition, we reviewed the implementation of national action plans to mitigate against AMR in countries in SSA. Results and Discussion: The SSA region is disproportionately affected by AMR, in part owing to the prevailing high levels of poverty, which result in a high burden of infectious diseases, poor regulation of antimicrobial use, and a lack of alternatives to ineffective antimicrobials. The global action plan as a strategy for prevention and combating AMR has been adopted by most countries, but fewer countries are able to fully implement country-specific action plans, and several challenges exist in many settings. Conclusion: A concerted One Health approach will be required to ramp up implementation of action plans in the region. In addition to AMR surveillance, effective implementation of infection prevention and control, water, sanitation, and hygiene, and antimicrobial stewardship programs will be key cost-effective strategies in helping to tackle AMR.

Antimicrobial Resistance in Endemic Enteric Infections in Kenya and the Region, and Efforts Toward Addressing the Challenges.

Resistance to commonly available antimicrobials is a major threat to the fight against endemic bacterial diseases in sub-Saharan Africa, with a majority of the population unable to afford alternative effective antimicrobial options for management of these diseases. Diseases such as typhoid, cholera, and invasive nontyphoidal Salmonella are among the key enteric infections endemic in most parts of sub-Saharan Africa, especially in displaced populations and among the urban populations living in overcrowded informal settlements. Here, we explore the prevalence and the genomic epidemiology of these infections and the growing problem of multidrug resistance, including emerging resistance to the last line of treatment for these infections. Prevalence rates to commonly available antimicrobials, including ampicillin, chloramphenicol, cotrimoxazole, and tetracycline, now range between 65% and 80%, while 15%-20% of recently studied isolates show reduced susceptibility to fluoroquinolones and emerging resistance to extended-spectrum ß-lactams mediated by the CTX-M-15 gene carried on a highly mobile genetic element. The high prevalence of multidrug-resistant isolates including resistance to reserve antibiotics, calls for enhanced control and management options. It will be important for governments in the region to enhance the implementation of national action plans, as guided by the global action plan championed by the World Health Organization, to combat the threat of antimicrobial resistance. However, to yield meaningful results, these efforts will require a strong commitment and enhancement at all levels of healthcare in order. In addition, the use of World Health Organization-approved vaccines in the short to medium term and improvement of water and sanitation in the long term will reduce the burden of disease and antimicrobial resistance in the region.

Multiple introductions of multidrug-resistant typhoid associated with acute infection and asymptomatic carriage, Kenya.

Background: Understanding the dynamics of infection and carriage of typhoid in endemic settings is critical to finding solutions to prevention and control. Methods: In a 3-year case-control study, we investigated typhoid among children aged <16 years (4670 febrile cases and 8549 age matched controls) living in an informal settlement, Nairobi, Kenya. Results: 148 S. Typhi isolates from cases and 95 from controls (stool culture) were identified; a carriage frequency of 1 %. Whole-genome sequencing showed 97% of cases and 88% of controls were genotype 4.3.1 (Haplotype 58), with the majority of each (76% and 88%) being multidrug-resistant strains in three sublineages of the H58 genotype (East Africa 1 (EA1), EA2, and EA3), with sequences from cases and carriers intermingled. Conclusions: The high rate of multidrug-resistant H58 S. Typhi, and the close phylogenetic relationships between cases and controls, provides evidence for the role of carriers as a reservoir for the community spread of typhoid in this setting. Funding: National Institutes of Health (R01AI099525); Wellcome Trust (106158/Z/14/Z); European Commission (TyphiNET No 845681); National Institute for Health Research (NIHR); Bill and Melinda Gates Foundation (OPP1175797).

High relatedness of invasive multi-drug resistant non-typhoidal Salmonella genotypes among patients and asymptomatic carriers in endemic informal settlements in Kenya.

Invasive Non-typhoidal Salmonella (iNTS) disease is a major public health challenge, especially in Sub-Saharan Africa (SSA). In Kenya, mortality rates are high (20-25%) unless prompt treatment is instituted. The most common serotypes are Salmonella enterica serotype Typhimurium (S. Typhimurium) and Salmonella enterica serotype Enteritidis (S. Enteritidis). In a 5 year case-control study in children residing in the Mukuru informal settlement in Nairobi, Kenya, a total of 4201 blood cultures from suspected iNTS cases and 6326 fecal samples from age-matched controls were studied. From the laboratory cultures we obtained a total of 133 S. Typhimurium isolates of which 83(62.4%) came from cases (53 blood and 30 fecal) and 50(37.6%) from controls (fecal). A total of 120 S. Enteritidis consisted of 70(58.3%) from cases (43 blood and 27 fecal) and 50(41.7%) from controls (fecal). The S. Typhimurium population fell into two distinct ST19 lineages constituting 36.1%, as well as ST313 lineage I (27.8%) and ST313 lineage II (36.1%) isolates. The S. Enteritidis isolates fell into the global epidemic lineage (46.6%), the Central/Eastern African lineage (30.5%), a novel Kenyan-specific lineage (12.2%) and a phylogenetically outlier lineage (10.7%). Detailed phylogenetic analysis revealed a high level of relatedness between NTS from blood and stool originating from cases and controls, indicating a common source pool. Multidrug resistance was common throughout, with 8.5% of such isolates resistant to extended spectrum beta lactams. The high rate of asymptomatic carriage in the population is a concern for transmission to vulnerable individuals and this group could be targeted for vaccination if an iNTS vaccine becomes available.

Factors associated with occurrence of salmonellosis among children living in Mukuru slum, an urban informal settlement in Kenya.

BACKGROUND: In Kenya, typhoid fever and invasive non-typhoidal salmonellosis present a huge burden of disease, especially in poor-resource settings where clean water supply and sanitation conditions are inadequate. The epidemiology of both diseases is poorly understood in terms of severity and risk factors. The aim of the study was to determine the disease burden and spatial distribution of salmonellosis, as well as socioeconomic and environmental risk factors for these infections, in a large informal settlement near the city of Nairobi, from 2013 to 2017. METHODS: Initially, a house-to-house baseline census of 150,000 population in Mukuru informal settlement was carried out and relevant socioeconomic, demographic, and healthcare utilization information was collected using structured questionnaires. Salmonella bacteria were cultured from the blood and faeces of children < 16 years of age who reported at three outpatient facilities with fever alone or fever and diarrhea. Tests of association between specific Salmonella serotypes and risk factors were conducted using Pearson Chi-Square (χ2) test. RESULTS: A total of 16,236 children were recruited into the study. The prevalence of bloodstream infections by Non-Typhoidal Salmonella (NTS), consisting of Salmonella Typhimurium/ Enteriditis, was 1.3%; Salmonella Typhi was 1.4%, and this was highest among children < 16 years of age. Occurrence of Salmonella Typhimurium/ Enteriditis was not significantly associated with rearing any domestic animals. Rearing chicken was significantly associated with high prevalence of S. Typhi (2.1%; p = 0.011). The proportion of children infected with Salmonella Typhimurium/ Enteriditis was significantly higher in households that used water pots as water storage containers compared to using water directly from the tap (0.6%). Use of pit latrines and open defecation were significant risk factors for S. Typhi infection (1.6%; p = 0.048). The proportion of Salmonella Typhimurium/ Enteriditis among children eating street food 4 or more times per week was higher compared to 1 to 2 times/week on average (1.1%; p = 0.032). CONCLUSION: Typhoidal and NTS are important causes of illness in children in Mukuru informal settlement, especially among children less than 16 years of age. Improving Water, Sanitation and Hygiene (WASH) including boiling water, breastfeeding, hand washing practices, and avoiding animal contact in domestic settings could contribute to reducing the risk of transmission of Salmonella disease from contaminated environments.

Multidrug-resistant Nontyphoidal Salmonella Hotspots as Targets for Vaccine Use in Management of Infections in Endemic Settings.

BACKGROUND: Salmonella infections cause a disproportionately high number of deaths in Africa, especially among poor urban populations. The increasing level of multidrug-resistant (MDR) infections is a major cause of concern in these settings where alternative effective treatment is unavailable. Other options for management of these infections must be sought. The knowledge of hotspots in endemic settings can help to prioritize management and control measures in Kenya and the region. METHODS: Using blood cultures, we investigated children presenting with fever of unknown origin for Salmonella infections. We performed antimicrobial susceptibility testing and whole genome sequencing to further characterize Salmonella isolates. Using Global Positioning System technologies, we mapped Salmonella isolates to households of patients in the study site and determined risk factors associated with high concentration of cases in particular sites. RESULTS: A total of 281 Salmonella species (149 from blood and 132 from fecal samples) from febrile children <5 years of age were studied. These consisted of 85 Salmonella Typhimurium, 58 Salmonella Enteritidis, 32 other nontyphoidal Salmonella (NTS) serotypes, and 126 Salmonella Typhi. The prevalence of MDR invasive NTS (iNTS) was 77.2%, with 15% resistant to ceftriaxone, a drug that is last-line treatment for iNTS and other severe gram-negative infections in Kenya. Invasive NTS and S. Typhi together mapped around common water vending points and close to sewer convergence points in the highly populated village. CONCLUSIONS: These hotspots could be targeted for management and control strategies, including a combined introduction of typhoid and iNTS vaccines, aimed at reducing transmission in these endemic settings.