Prevalence and distribution of non-typhoidal Salmonella enterica serogroups and serovars isolated from normally sterile sites: A global systematic review.

To inform coverage by potential vaccines, we aimed to systematically review evidence on the prevalence and distribution of non-typhoidal Salmonella enterica serogroups and serovars. We searched four databases from inception through 4 June 2021. Articles were included that reported at least one non-typhoidal S. enterica strain by serogroup or serovar isolated from a normally sterile site. Of serogrouped isolates, we pooled the prevalence of serogroup O:4, serogroup O:9, and other serogroups using random-effects meta-analyses. Of serotyped isolates, we pooled the prevalence of Salmonella Typhimurium (member of serogroup O:4), Salmonella Enteritidis (member of serogroup O:9), and other serovars. Of 82 studies yielding 24,253 serogrouped isolates, the pooled prevalence (95% CI) was 44.6% (36.2%-48.2%) for serogroup O:4, 45.5% (37.0%-49.1%) for serogroup O:9, and 9.9% (6.1%-13.3%) for other serogroups. Of serotyped isolates, the pooled prevalence (95%CI) was 36.8% (29.9%-44.0%) for Salmonella Typhimurium, 37.8% (33.2%-42.4%) for Salmonella Enteritidis, and 18.4% (11.4%-22.9%) for other serovars. Of global serogrouped non-typhoidal Salmonella isolates from normally sterile sites, serogroup O:4 and O:9 together accounted for 90%, and among serotyped isolates, serovars Typhimurium and Enteritidis together accounted for 75%. Vaccine development strategies covering serogroups O:4 and O:9, or serovars Typhimurium and Enteritidis, have the potential to prevent the majority of non-typhoidal Salmonella invasive disease.

Global Typhoid Fever Incidence: A Systematic Review and Meta-analysis.

BACKGROUND: Contemporary incidence estimates of typhoid fever are needed to guide policy decisions and control measures and to improve future epidemiological studies. METHODS: We systematically reviewed 3 databases (Ovid Medline, PubMed, and Scopus) without restriction on age, country, language, or time for studies reporting the incidence of blood culture-confirmed typhoid fever. Outbreak, travel-associated, and passive government surveillance reports were excluded. We performed a meta-analysis using a random-effects model to calculate estimates of pooled incidence, stratifying by studies that reported the incidence of typhoid fever and those that estimated incidence by using multipliers. RESULTS: Thirty-three studies were included in the analysis. There were 26 study sites from 16 countries reporting typhoid cases from population-based incidence studies, and 17 sites in 9 countries used multipliers to account for underascertainment in sentinel surveillance data. We identified Africa and Asia as regions with studies showing high typhoid incidence while noting considerable variation of typhoid incidence in time and place, including in consecutive years at the same location. Overall, more recent studies reported lower typhoid incidence compared to years prior to 2000. We identified variation in the criteria for collecting a blood culture, and among multiplier studies we identified a lack of a standardization for the types of multipliers being used to estimate incidence. CONCLUSIONS: Typhoid fever incidence remains high at many sites. Additional and more accurate typhoid incidence studies are needed to support country decisions about typhoid conjugate vaccine adoption. Standardization of multiplier types applied in multiplier studies is recommended.

A Systematic Review and Meta-analysis of the Prevalence of Community-Onset Bloodstream Infections among Hospitalized Patients in Africa and Asia.

Community-onset bloodstream infections (CO-BSI) are major causes of severe febrile illness and death worldwide. In light of new data and the growing problem of antimicrobial resistance (AMR) among pathogens causing BSI, we undertook a systematic review of hospital-based studies of CO-BSI among patients hospitalized with fever. Without restriction to language or country, we searched PubMed, Web of Science, and Scopus for prospective hospital-based studies of culture-confirmed CO-BSI among febrile inpatients. We determined by study the prevalence of BSI among participants, the pathogens responsible for BSI, and the antimicrobial susceptibility patterns of pathogens causing BSI, according to place and time. Thirty-four (77.3%) of 44 eligible studies recruited 29,022 participants in Africa and Asia combined. Among participants in these two regions, the median prevalence of BSI was 12.5% (range, 2.0 to 48.4%); of 3,220 pathogens isolated, 1,119 (34.8%) were Salmonella enterica, 425 (13.2%) Streptococcus pneumoniae, and 282 (8.8%) Escherichia coli Antimicrobial susceptibility testing was reported in 16 (36.4%) studies. When isolates collected prior to 2008 were compared to those collected in the period of 2008 through 2018, the proportions of typhoidal Salmonella and Staphylococcus aureus isolates resistant to several clinically relevant antimicrobials increased over time, while S. pneumoniae susceptibility was stable. CO-BSI remain a major cause of severe febrile illness among hospitalized patients in Africa and Asia, with S. enterica, S. pneumoniae, and E. coli predominating. There is a concerning increase in AMR among serious infections caused by community-onset pathogens. Ongoing surveillance is needed to inform empirical management and strategies to control AMR.

Using hospital-based studies of community-onset bloodstream infections to make inferences about typhoid fever incidence.

OBJECTIVES: Hospital-based studies of community-onset bloodstream infections (CO-BSI) are less resource-intensive to carry out than population-based incidence studies. We examined several metrics capturing the potential role of Salmonella Typhi as a cause of CO-BSI for making inferences about incidence. METHODS: We systematically reviewed three databases for hospital-based studies of CO-BSI. We determined, by study, the prevalence and rank order of Salmonella among pathogenic bloodstream isolates, and the prevalence ratio of Salmonella Typhi to Escherichia coli (S:E ratio). We then describe these hospital-based study metrics in relation to population-based typhoid fever incidence data from a separate systematic review. RESULTS: Forty-four studies met the inclusion criteria, of which 23 (52.3%) isolated Salmonella Typhi at least once. Among studies isolating Salmonella Typhi, the median (interquartile range) prevalence and rank order of Salmonella Typhi compared to other pathogens isolated in BSI was 8.3% (3.2-37.9%) and 3 (1-6), respectively. The median (interquartile range) S:E ratio was 1.0 (0.4-3.0). With respect to incidence, in Pemba Island, Tanzania, prevalence, rank order, S:E ratio, and incidence was 64.8%, 1, 9.2 and 110 cases per 100 000, respectively, and in Boulkiemdé, Burkina Faso, was 13.3%, 3, 2.3 and 249 cases per 100 000. CONCLUSIONS: We describe considerable variation in place and time for Salmonella Typhi prevalence, rank order, and S:E ratio among hospital-based studies of CO-BSI. Data from simultaneous typhoid prevalence and incidence studies are limited. We propose that hospital-based study metrics warrant evaluation for making inference about typhoid incidence and as covariates in typhoid incidence models.

OBJECTIFS: Les études hospitalières d'infections d'origine sanguine acquises dans la communauté (IS-AC) consomment moins de ressources que les études d'incidence basées sur la population. Nous avons examiné plusieurs paramètres permettant de déterminer le rôle de Salmonella typhi comme cause des IS-AC pour permettre des déductions sur l'incidence. MÉTHODES: Nous avons systématiquement passé en revue trois bases de données sur des études hospitalières d'IS-AC. Par étude, nous avons déterminé la prévalence et l'ordre de classement de Salmonella parmi les isolats de pathogènes sanguins, ainsi que le rapport de prévalence de Salmonella typhi et Escherichia coli (rapport S:E). Nous décrivons ensuite ces résultats d'étude en milieu hospitalier en relation avec les données d'incidence de la fièvre typhoïde basées sur la population, tirées d'une revue systématique distincte. RÉSULTATS: Quarante-quatre études remplissaient les critères d'inclusion, dont 23 (52,3%) avaient isolé au moins une fois Salmonella typhi. Parmi les études isolant Salmonella typhi, la prévalence médiane (intervalle interquartile) et l'ordre de classement de Salmonella typhi par rapport aux autres agents pathogènes isolés de sangs étaient de 8,3% (3,2 à 37,9%) et de 3 (1-6), respectivement. Le rapport S:E médian (intervalle interquartile) était de 1,0 (0,4 à 3,0). En ce qui concerne l'incidence, sur l'île de Pemba, en Tanzanie, la prévalence, l'ordre de classement, le rapport S:E et l'incidence étaient respectivement de 64,8% ; 1 ; 9,2 et 110 cas pour 100.000, et dans le Boulkiemdé, au Burkina Faso, de 13,3% ; 3 ; 2,3 et 249 cas pour 100.000 habitants. CONCLUSIONS: Nous décrivons une variation considérable selon le lieu et le moment de la prévalence, de l'ordre de classement et du rapport S:E de Salmonella typhi parmi les études hospitalières sur les IS-AC. Les données provenant d'études simultanées sur la prévalence et l'incidence de la typhoïde sont limitées. Au vu des variations, nous proposons que les métriques d'étude en milieu hospitalier soient évaluées en tant que covariables dans les modèles de détermination de l'incidence de la typhoïde.

Clinical management decisions for adults with prolonged acute cough: Frequency and associated factors.

BACKGROUND: Uncomplicated episodes of prolonged acute cough are usually viral and self-limited, but despite evidence and recommendations to the contrary, they are often treated with antibiotics. METHODS: Mixed cross-sectional and prospective observational study of adults 18 years or older presenting to two urgent care centers with a cough of 7 to 56 days as their chief complaint. Factors associated with cough duration and clinical decisions were analyzed by univariate and multivariate logistic regression. RESULTS: Of the 125 enrolled patients, 118 (94%) received an antibiotic, 97 (78%) a cough suppressant, 87 (70%) a systemic corticosteroid, and 39 (31%) a chest X-ray (CXR). Longer duration of cough was associated with the presence of self-reported wheezing or noises (adjusted odds ratio 6.29, 95% CI 1.36-29.16) while the presence of both wheezing and crackles on a clinician chest exam was associated with shorter duration (aOR 0.03, 95% CI 0.00-0.27). A clinician was more likely to order a CXR in patients with dyspnea (aOR 3.01, 95% CI 1.21-7.49), less likely to prescribe a systemic corticosteroid in patients with crackles (aOR 0.27, 95% CI 0.09-0.82), and more likely to prescribe a cough suppressant to older patients (1.04 per additional year of age, 95% CI 1.01-1.07). CONCLUSIONS: Systemic corticosteroids and cough suppressants are being prescribed at high rates in patients with uncomplicated acute cough in the urgent care setting. Additional studies to determine if similar rates are seen in other urgent care centers, or in other contemporary ambulatory settings are warranted.

Examining geospatial and temporal distribution of invasive non-typhoidal Salmonella disease occurrence in sub-Saharan Africa: a systematic review and modelling study.

BACKGROUND: Invasive non-typhoidal Salmonella (iNTS) disease is a significant health concern in sub-Saharan Africa. While our knowledge of a larger-scale variation is growing, understanding of the subnational variation in iNTS disease occurrence is lacking, yet crucial for targeted intervention. METHOD: We performed a systematic review of reported occurrences of iNTS disease in sub-Saharan Africa, consulting literature from PubMed, Embase and Web of Science published since 2000. Eligibility for inclusion was not limited by study type but required that studies reported original data on human iNTS diseases based on the culture of a normally sterile site, specifying subnational locations and the year, and were available as full-text articles. We excluded studies that diagnosed iNTS disease based on clinical indications, cultures from non-sterile sites or serological testing. We estimated the probability of occurrence of iNTS disease for sub-Saharan Africa on 20 km × 20 km grids by exploring the association with geospatial covariates such as malaria, HIV, childhood growth failure, access to improved water, and sanitation using a boosted regression tree. RESULTS: We identified 130 unique references reporting human iNTS disease in 21 countries published from 2000 through 2020. The estimated probability of iNTS occurrence grids showed significant spatial heterogeneity at all levels (20 km × 20 km grids, subnational, country and subregional levels) and temporal heterogeneity by year. For 2020, the probability of occurrence was higher in Middle Africa (0.34, 95% CI: 0.25 to 0.46), followed by Western Africa (0.33, 95% CI: 0.23 to 0.44), Eastern Africa (0.24, 95% CI: 0.17 to 0.33) and Southern Africa (0.08, 95% CI: 0.03 to 0.11). Temporal heterogeneity indicated that the probability of occurrence increased between 2000 and 2020 in countries such as the Republic of the Congo (0.05 to 0.59) and Democratic Republic of the Congo (0.10 to 0.48) whereas it decreased in countries such as Uganda (0.65 to 0.23) or Zimbabwe (0.61 to 0.37). CONCLUSION: The iNTS disease occurrence varied greatly across sub-Saharan Africa, with certain regions being disproportionately affected. Exploring regions at high risk for iNTS disease, despite the limitations in our data, may inform focused resource allocation. This targeted approach may enhance efforts to combat iNTS disease in more affected areas.

Complications and mortality of non-typhoidal salmonella invasive disease: a global systematic review and meta-analysis.

BACKGROUND: Non-typhoidal salmonella can cause serious, life-threatening invasive infections involving the bloodstream and other normally sterile sites. We aimed to systematically review the prevalence of complications and case-fatality ratio (CFR) of non-typhoidal salmonella invasive disease to provide contemporary global estimates and inform the development of vaccine and non-vaccine interventions. METHODS: We did a global systematic review and meta-analysis of studies investigating the complications and mortality associated with non-typhoidal salmonella invasive disease. We searched Embase, MEDLINE, Web of Science, and PubMed for peer-reviewed, primary research articles published from database inception up to June 4, 2021, with no restrictions on language, country, date, or participant demographics. Only studies reporting the proportion of complications or deaths associated with non-typhoidal salmonella invasive disease, confirmed by culture of samples taken from a normally sterile site (eg, blood or bone marrow) were included. We excluded case reports, case series, policy reports, commentaries, editorials, and conference abstracts. Data on the prevalence of complications and CFR were abstracted. The primary outcomes were to estimate the prevalence of complications and CFR of non-typhoidal salmonella invasive disease. We calculated an overall pooled CFR estimate and pooled CFR stratified by UN region, subregion, age group, and by serovar when available with a random-effects meta-analysis. A risk-of-bias assessment was done, and heterogeneity was assessed with Cochran's Q Test, I2, and τ2. This study was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, and is registered with PROSPERO, CRD42020202293. FINDINGS: The systematic review returned a total of 8770 records. After duplicates were removed, 5837 titles and abstracts were screened, yielding 84 studies from 35 countries after exclusions. Of these included studies, 77 (91·7%) were hospital-based and 66 (78·6%) were located in Africa or Asia. Among 55 studies reporting non-typhoidal salmonella disease-associated complications, a total of 45 different complications were reported and 1824 complication events were identified among 6974 study participants. The most prevalent complication was septicaemia, occurring in 171 (57·2%) of 299 participants, followed by anaemia in 580 (47·3%) of 1225 participants. From 81 studies reporting the CFR of non-typhoidal salmonella invasive disease, the overall pooled CFR estimate was 14·7% (95% CI 12·2-17·3). When stratified by UN region, the pooled CFR was 17·1% (13·6-21·0) in Africa, 14·0% (9·4-19·4) in Asia, 9·9% (6·4-14·0) in Europe, and 9·6% (0·0-25·1) in the Americas. Of all 84 studies, 66 (78·6%) had an overall high risk of bias, 18 (21·4%) had a moderate risk, and none had a low risk. Substantial heterogeneity (I2>80%) was observed in most (15 [65·2%] of 23) CFR estimates. INTERPRETATION: Complications were frequent among individuals with non-typhoidal salmonella invasive disease and approximately 15% of patients died. Clinicians, especially in African countries, should be aware of non-typhoidal salmonella invasive disease as a cause of severe febrile illness. Prompt diagnoses and management decisions, including empiric antimicrobial therapy, would improve patient outcomes. Additionally, investments in improving clinical microbiology facilities to identify non-typhoidal salmonella and research efforts towards vaccine development and non-vaccine prevention measures would prevent non-typhoidal salmonella invasive disease-associated illness and death. FUNDING: EU Horizon 2020 research and innovation programme.

Point-prevalence surveys of antimicrobial consumption and resistance at a paediatric and an adult tertiary referral hospital in Yangon, Myanmar.

BACKGROUND: Antimicrobial resistance is increasingly prevalent worldwide. The inappropriate use of antimicrobials, including in the hospital setting, is considered a major driver of antimicrobial resistance. AIM: To inform improvements in antimicrobial stewardship, we undertook point prevalence surveys of antimicrobial prescribing at Yangon Children's Hospital and Yangon General Hospital in Yangon, Myanmar. METHODS: We conducted our surveys using the Global Point-Prevalence Survey of Antimicrobial Consumption and Resistance (Global-PPS) method. All inpatients who were prescribed an antimicrobial on the day of the survey were included in the analysis. FINDINGS: We evaluated a total of 1,980 patients admitted to two hospitals during December 2019. Of these, 1,255 (63.4%) patients were prescribed a total of 2,108 antimicrobials. Among antimicrobials prescribed, 722 (34.3%) were third-generation cephalosporins, the most commonly prescribed antimicrobial class. A total of 940 (44.6%) antimicrobials were prescribed for community-acquired infection, and 724 (34.3%) for surgical prophylaxis. Of 2,108 antimicrobials, 317 (15.0%) were prescribed for gastrointestinal tract prophylaxis, 305 (14.5%) for skin, soft tissue, bone and joint prophylaxis, and 303 (14.4%) for pneumonia treatment. A stop or review date was documented for 350 (16.6%) antimicrobial prescriptions, 673 (31.9%) antimicrobial prescriptions were guideline compliant, and 1,335 (63.3%) antimicrobials were administered via the parenteral route. Of 1,083 antimicrobials prescribed for a therapeutic use, 221 (20.4%) were targeted therapy. CONCLUSION: Our findings underscore the need to update and expand evidence-based guidelines for antimicrobial use, promote the benefits of targeted antimicrobial therapy, and support the implementation of hospital-based antimicrobial stewardship programmes at the hospitals surveyed.

Incidence of non-typhoidal Salmonella invasive disease: A systematic review and meta-analysis.

OBJECTIVES: We sought to collate and summarize high-quality data on non-typhoidal Salmonella invasive disease (iNTS) incidence to provide contemporary incidence estimates by location and year. METHODS: We systematically searched the databases Embase + MEDLINE, Web of Science, and PubMed for articles published on the incidence of iNTS from inception of the database through 8 May 2020 with no language, country, date, or demographic restrictions applied. A meta-analysis was performed to report pooled iNTS incidence as a rate of cases per 100,000 per year. RESULTS: Among 13 studies eligible for analysis, there were 68 estimates of incidence. Overall pooled incidence (95% CI) was 44.8 (31.5-60.5) per 100,000 persons per year. When stratified by region, pooled incidence was significantly higher in Africa than Asia, 51.0 (36.3-68.0) compared to 1.0 (0.2-2.5), respectively. Incidence was consistently higher in children aged <5 years compared with older age groups. Incidence displayed considerable heterogeneity in both place and time, varying substantially between locations and over consecutive years in the same location. CONCLUSIONS: iNTS incidence varies by region, location, age group, and over time. Concerted efforts are needed to address the limited high-quality data available on iNTS disease incidence.

Complications and mortality of typhoid fever: A global systematic review and meta-analysis.

OBJECTIVES: Updated estimates of the prevalence of complications and case fatality ratio (CFR) among typhoid fever patients are needed to understand disease burden. METHODS: Articles published in PubMed and Web of Science from 1 January 1980 through 29 January 2020 were systematically reviewed for hospital or community-based non-surgical studies that used cultures of normally sterile sites, and hospital surgical studies of typhoid intestinal perforation (TIP) with intra- or post-operative findings suggestive of typhoid. Prevalence of 21 pre-selected recognized complications of typhoid fever, crude and median (interquartile range) CFR, and pooled CFR estimates using a random effects meta-analysis were calculated. RESULTS: Of 113 study sites, 106 (93.8%) were located in Asia and Africa, and 84 (74.3%) were non-surgical. Among non-surgical studies, 70 (83.3%) were hospital-based. Of 10,355 confirmed typhoid patients, 2,719 (26.3%) had complications. The pooled CFR estimate among non-surgical patients was 0.9% for the Asia region and 5.4% for the Africa region. Delay in care was significantly correlated with increased CFR in Asia (r = 0.84; p<0.01). Among surgical studies, the median CFR of TIP was 15.5% (6.7-24.1%) per study. CONCLUSIONS: Our findings identify considerable typhoid-associated illness and death that could be averted with prevention measures, including typhoid conjugate vaccine introduction.

A Systematic Review on Antimicrobial Resistance among Salmonella Typhi Worldwide.

Understanding patterns and trends of antimicrobial resistance (AMR) in Salmonella Typhi can guide empiric treatment recommendations and contribute to country decisions about typhoid conjugate vaccine (TCV) introduction. We systematically reviewed PubMed and Web of Science for articles reporting the proportion of Salmonella Typhi isolates resistant to individual antimicrobials worldwide from any time period. Isolates resistant to chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole were classified as multidrug resistant (MDR), and isolates that were MDR plus resistant to a fluoroquinolone and a third-generation cephalosporin were extensively drug resistant (XDR). Among the 198 articles eligible for analysis, a total of 55,459 Salmonella Typhi isolates were tested for AMR (median 80; range 2-5,191 per study). Of isolates from 2015 through 2018 in Asia, 1,638 (32.6%) of 5,032 were MDR, 167 (5.7%) of 2,914 were resistant to third-generation cephalosporins, and 148 (8.3%) of 1,777 were resistant to azithromycin. Two studies from Pakistan reported 14 (2.6%) of 546 isolates were XDR. In Africa, the median proportion of Salmonella Typhi isolates that were MDR increased each consecutive decade from 1990 to 1999 through 2010 to 2018. Salmonella Typhi has developed resistance to an increasing number of antimicrobial classes in Asia, where XDR Salmonella Typhi is now a major threat, whereas MDR has expanded in Africa. We suggest continued and increased surveillance is warranted to inform empiric treatment decisions and that AMR data be incorporated into country decisions on TCV introduction.

Signs and Symptoms That Rule out Community-Acquired Pneumonia in Outpatient Adults: A Systematic Review and Meta-Analysis.

BACKGROUND: A systematic review of clinical decision rules to identify patients at low risk for community-acquired pneumonia (CAP) has not been previously presented in the literature. METHODS: A systematic review of MEDLINE for prospective studies that used at least 2 signs, symptoms, or point-of-care tests to determine the likelihood of CAP. We included studies that enrolled adults and adolescents in the outpatient setting where all or a random sample of patients received a chest radiograph as the reference standard. We excluded retrospective studies and studies that recruited primarily patients with hospital-acquired CAP. RESULTS: Our search identified 974 articles, 12 of which were included in the final analysis. The simple heuristic of normal vital signs (temperature, respiratory rate, and heart rate) to identify patients at low risk for CAP was reported by 4 studies and had a summary estimate of the negative likelihood ratio (LR-) of 0.24 (95% CI, 0.17 to 0.34) and a sensitivity of 0.89 (95% CI, 0.79 to 0.94). The simple heuristic of normal vital signs combined with a normal pulmonary examination to identify patients at low risk for CAP was reported by 3 studies, and had a summary estimate of LR- of 0.10 (95% CI, 0.07 to 0.13) with an area under the receiver operating characteristic curve of 0.92. CONCLUSIONS: Adults with an acute respiratory infection who have normal vital signs and a normal pulmonary examination are very unlikely to have CAP. Given a baseline CAP risk of 4%, these patients have only a 0.4% likelihood of CAP.