With the rise in fluoroquinolone-resistant Salmonella Typhi and the recent emergence of ceftriaxone resistance, azithromycin is one of the last oral drugs available against typhoid for which ...resistance is uncommon. Its increasing use, specifically in light of the ongoing outbreak of extensively drug-resistant (XDR) Salmonella Typhi (resistant to chloramphenicol, ampicillin, cotrimoxazole, streptomycin, fluoroquinolones and third-generation cephalosporins) in Pakistan, places selective pressure for the emergence and spread of azithromycin-resistant isolates. However, little is known about azithromycin resistance in Salmonella, and no molecular data are available on its mechanism.
We conducted typhoid surveillance in the two largest pediatric hospitals of Bangladesh from 2009-2016. All typhoidal Salmonella strains were screened for azithromycin resistance using disc diffusion and resistance was confirmed using E-tests. In total, we identified 1,082 Salmonella Typhi and Paratyphi A strains; among these, 13 strains (12 Typhi, 1 Paratyphi A) were azithromycin-resistant (MIC range: 32-64 μg/ml) with the first case observed in 2013. We sequenced the resistant strains, but no molecular basis of macrolide resistance was identified by the currently available antimicrobial resistance prediction tools. A whole genome SNP tree, made using RAxML, showed that the 12 Typhi resistant strains clustered together within the 4.3.1.1 sub-clade (H58 lineage 1). We found a non-synonymous single-point mutation exclusively in these 12 strains in the gene encoding AcrB, an efflux pump that removes small molecules from bacterial cells. The mutation changed the conserved amino acid arginine (R) at position 717 to a glutamine (Q). To test the role of R717Q present in azithromycin-resistant strains, we cloned acrB from azithromycin-resistant and sensitive strains, expressed them in E. coli, Typhi and Paratyphi A strains and tested their azithromycin susceptibility. Expression of AcrB-R717Q in E. coli and Typhi strains increased the minimum inhibitory concentration (MIC) for azithromycin by 11- and 3-fold respectively. The azithromycin-resistant Paratyphi A strain also contained a mutation at R717 (R717L), whose introduction in E. coli and Paratyphi A strains increased MIC by 7- and 3-fold respectively, confirming the role of R717 mutations in conferring azithromycin resistance.
This report confirms 12 azithromycin-resistant Salmonella Typhi strains and one Paratyphi A strain. The molecular basis of this resistance is one mutation in the AcrB protein at position 717. This is the first report demonstrating the impact of this non-synonymous mutation in conferring macrolide resistance in a clinical setting. With increasing azithromycin use, strains with R717 mutations may spread and be acquired by XDR strains. An azithromycin-resistant XDR strain would shift enteric fever treatment from outpatient departments, where patients are currently treated with oral azithromycin, to inpatient departments to be treated with injectable antibiotics like carbapenems, thereby further burdening already struggling health systems in endemic regions. Moreover, with the dearth of novel antimicrobials in the horizon, we risk losing our primary defense against widespread mortality from typhoid. In addition to rolling out the WHO prequalified typhoid conjugate vaccine in endemic areas to decrease the risk of pan-resistant Salmonella Typhi strains, it is also imperative to implement antimicrobial stewardship and water sanitation and hygiene intervention to decrease the overall burden of enteric fever.
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Abstract
We have made considerable progress in setting and scaling up surveillance systems to drive evidence-based policy decisions, but the recent epidemics highlight that current systems are not ...optimally designed. Good surveillance systems should be coordinated, comprehensive, and adaptive. They should generate data in real time for immediate analysis and intervention, whether for endemic diseases or potential epidemics. Such systems are especially needed in low-resource settings where disease burden is the highest, but tracking systems are the weakest here due to competing priorities and constraints on available resources. In this article, using the examples of 3 large, and mostly successful, infectious disease surveillance studies in Bangladesh, we identify 2 core limitations—the pathogen bias and the vaccine bias—in the way current surveillance programs are designed for low-resource settings. We highlight the strengths of the current Global Invasive Bacterial Vaccine Preventable Disease Surveillance Network of the World Health Organization and present case studies from Bangladesh to illustrate how this surveillance platform can be leveraged to overcome its limitations. Finally, we propose a set of criteria for building a comprehensive infectious disease surveillance system with the hope of encouraging current systems to use the limited resources as optimally as possible to generate the maximum amount of knowledge.
Abstract
Typhoid is endemic in many countries in South Asia and sub-Saharan Africa. The high burden of this age-old, preventable disease exacerbates constraints on the health systems of these ...countries. Currently, most patients are treated effectively in the community or outpatient departments, but with rising antimicrobial resistance and the dearth of novel antimicrobials in the horizon, we risk losing our primary defense against typhoid. Extensively drug-resistant Salmonella Typhi is spreading, and azithromycin is the last oral drug to continue treating typhoid in the community. With increasing azithromycin resistance, emergence of pan-oral drug resistant Salmonella Typhi is imminent. The high burden of typhoid is also an underlying cause of the unnecessary use of antimicrobials. In addition to implementing water sanitation and hygiene interventions to prevent typhoid, it is imperative to rapidly roll out typhoid conjugate vaccines in endemic countries. This will not only reduce the burden of typhoid but will also help interrupt the trend of increasing antimicrobial resistance.
The rising prevalence of antimicrobial resistance in
serovars Typhi and Paratyphi A, causative agents of typhoid and paratyphoid, have led to fears of untreatable infections. Of specific concern is ...the emerging resistance against azithromycin, the only remaining oral drug to treat extensively drug resistant (XDR) typhoid. Since the first report of azithromycin resistance from Bangladesh in 2019, cases have been reported from Nepal, India, and Pakistan. The genetic basis of this resistance is a single point mutation in the efflux pump AcrB (R717Q/L). Here, we report 38 additional cases of azithromycin-resistant (AzmR)
Typhi and Paratyphi A isolated in Bangladesh between 2016 and 2018. Using genomic analysis of 56 AzmR isolates from South Asia with AcrB-R717Q/L, we confirm that this mutation has spontaneously emerged in different
Typhi and Paratyphi A genotypes. The largest cluster of AzmR Typhi belonged to genotype 4.3.1.1; Bayesian analysis predicts the mutation to have emerged sometime in 2010. A travel-related Typhi isolate with AcrB-R717Q belonging to 4.3.1.1 was isolated in the United Kingdom, increasing fears of global spread. For real-time detection of AcrB-R717Q/L, we developed an extraction-free, rapid, and low-cost mismatch amplification mutation assay (MAMA). Validation of MAMA using 113 AzmR and non-AzmR isolates yielded >98% specificity and sensitivity versus phenotypic and whole-genome sequencing assays currently used for azithromycin resistance detection. With increasing azithromycin use, AcrB-R717Q/L is likely to be acquired by XDR strains. The proposed tool for active detection and surveillance of this mutation may detect pan-oral drug resistance early, giving us a window to intervene.
In the early 1900s, with mortality of ∼30%, typhoid and paratyphoid ravaged parts of the world; with improved water, sanitation, and hygiene in resource-rich countries and the advent of antimicrobials, mortality dwindled to <1%. Today, the burden rests disproportionately on South Asia, where the primary means for combatting the disease is antimicrobials. However, prevalence of antimicrobial resistance is rising and, in 2016, an extensively drug resistant Typhi strain triggered an ongoing outbreak in Pakistan, leaving only one oral drug, azithromycin, to treat it. Since the description of emergence of azithromycin resistance, conferred by a point mutation in
(AcrB-R717Q/L) in 2019, there have been increasing numbers of reports. Using genomics and Bayesian analysis, we illustrate that this mutation emerged in approximately 2010 and has spontaneously arisen multiple times. Emergence of pan-oral drug resistant
Typhi is imminent. We developed a low-cost, rapid PCR tool to facilitate real-time detection and prevention policies.
Typhoid-conjugate vaccines (TCVs) provide an opportunity to reduce the burden of typhoid fever, caused by Salmonella Typhi, in endemic areas. As policymakers design vaccination strategies, accurate ...and high-resolution data on disease burden is crucial. However, traditional blood culture-based surveillance is resource-extensive, prohibiting its large-scale and sustainable implementation. Salmonella Typhi is a water-borne pathogen, and here, we tested the potential of Typhi-specific bacteriophage surveillance in surface water bodies as a low-cost tool to identify where Salmonella Typhi circulates in the environment. In 2021, water samples were collected and tested for the presence of Salmonella Typhi bacteriophages at two sites in Bangladesh: urban capital city, Dhaka, and a rural district, Mirzapur. Salmonella Typhi-specific bacteriophages were detected in 66 of 211 (31%) environmental samples in Dhaka, in comparison to 3 of 92 (3%) environmental samples from Mirzapur. In the same year, 4,620 blood cultures at the two largest pediatric hospitals of Dhaka yielded 215 (5%) culture-confirmed typhoid cases, and 3,788 blood cultures in the largest hospital of Mirzapur yielded 2 (0.05%) cases. 75% (52/69) of positive phage samples were collected from sewage. All isolated phages were tested against a panel of isolates from different Salmonella Typhi genotypes circulating in Bangladesh and were found to exhibit a diverse killing spectrum, indicating that diverse bacteriophages were isolated. These results suggest an association between the presence of Typhi-specific phages in the environment and the burden of typhoid fever, and the potential of utilizing environmental phage surveillance as a low-cost tool to assist policy decisions on typhoid control.
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Introduction: The 2015 Global Meningococcal Initiative (GMI) meeting discussed the global importance of meningococcal disease (MD) and its continually changing epidemiology.
Areas covered: Although ...recent vaccination programs have been successful in reducing incidence in many countries (e.g. Neisseria meningitidis serogroup MenC in Brazil, MenA in the African meningitis belt), new clones have emerged, causing outbreaks (e.g. MenW in South America, MenC in Nigeria and Niger). The importance of herd protection was highlighted, emphasizing the need for high vaccination uptake among those with the highest carriage rates, as was the need for boosters to maintain individual and herd protection following decline of immune response after primary immunization.
Expert commentary: The GMI Global Recommendations for Meningococcal Disease were updated to include a recommendation to enable access to whole-genome sequencing as for surveillance, guidance on strain typing to guide use of subcapsular vaccines, and recognition of the importance of advocacy and awareness campaigns.
Skin conditions are the fourth leading cause of nonfatal disease globally, with atopic dermatitis (AD) a major and rising contributor. Though atopic dermatitis (AD) is rising in prevalence, little is ...known about its psychosocial effects on children and families in low- and middle-income countries (LMICs).
We conducted a community-based, cross-sectional survey of 2242 under-5 children in rural Bangladesh using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire to measure AD prevalence and severity, the Patient-Oriented Eczema Measure (POEM) to measure severity, and the Infants' Dermatitis Quality of Life index (IDQoL) and Dermatitis Family Index (DFI) to measure quality of life.
Overall AD prevalence in under-five children was 11.9% 95% confidence interval (CI) 10.6-13.3%. Prevalence was highest in children age 30-35 months 16.2% (95% CI 11.4-21.0). IDQoL was significantly higher in males (2.67) vs. females (1.95, p = 0.015), the lowest (3.06) vs. highest (1.63) wealth quintile (p<0.001), and among mothers with < primary (2.41) vs. > secondary (1.43) education (p = 0.039). POEM severity was correlated with IDQoL (r = 0.77, p<0.001) and DFI (r = 0.56, p<0.001). Severe disease as rated by caretakers was correlated with POEM (r = 0.73, p<0.001), IDQoL (r = 0.82, p<0.001) and DFI (r = 0.57, p<0.001).
Severe AD significantly affects quality of life for children and families in Bangladesh. As access to healthcare expands in LMICs, identification and treatment of both the medical and psychosocial morbidities associated with the disease are needed.
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Left ventricular (LV) ejection fraction (EF) is a routine clinical standard to assess cardiac function. Global longitudinal strain (GLS) and global circumferential strain (GCS) have emerged as ...important LV functional measures. The objective of this study was to determine the relationships of GLS and GCS by speckle-tracking echocardiography and featuring-tracking cardiac magnetic resonance (CMR) to CMR EF as a standard of reference in the same patients.
A total of 73 consecutive patients aged 55 ± 15 years clinically referred for both CMR and echocardiography (EF range, 8%-78%) were studied. Routine steady-state free precession CMR images were prospectively analyzed offline using feature-tracking software for LV GLS, GCS, volumes, and EF. GLS was averaged from three standard longitudinal views and GCS from the mid-LV short-axis plane. Echocardiographic speckle-tracking was used from the similar imaging planes for GLS, GCS, LV volumes, and EF.
Feature-tracking CMR strain was closely correlated with speckle-tracking strain in the same patients: GLS, r = -0.87; GCS, r = -0.92 (P < .0001). End-diastolic and end-systolic volumes and EF by feature-tracking CMR were significantly correlated with standard manual tracing of multiple CMR short-axis images (r = 0.97, r = 0.98, and r = 0.97, P < .0001 for all). GLS and GCS by echocardiography and CMR feature-tracking were closely correlated with standard CMR EF: r = -0.85 and r = -0.95, respectively (P < .001). Global strain measures (in absolute values) were correlated with EF using the formula EF = 3(GLS) + 8% or EF = 2.5(GCS) + 8%.
GLS and GCS by feature-tracking CMR analysis was a rapid means to obtain myocardial strain similar to speckle-tracking echocardiography. GLS and GCS were closely correlated with CMR EF in this patient series and may play a role in the clinical assessment of LV function.
We aimed to provide the first comprehensive estimates of the burden of group B Streptococcus (GBS), including invasive disease in pregnant and postpartum women, fetal infection/stillbirth, and ...infants. Intrapartum antibiotic prophylaxis is the current mainstay of prevention, reducing early-onset infant disease in high-income contexts. Maternal GBS vaccines are in development.
For 2015 live births, we used a compartmental model to estimate (1) exposure to maternal GBS colonization, (2) cases of infant invasive GBS disease, (3) deaths, and (4) disabilities. We applied incidence or prevalence data to estimate cases of maternal and fetal infection/stillbirth, and infants with invasive GBS disease presenting with neonatal encephalopathy. We applied risk ratios to estimate numbers of preterm births attributable to GBS. Uncertainty was also estimated.
Worldwide in 2015, we estimated 205000 (uncertainty range UR, 101000-327000) infants with early-onset disease and 114000 (UR, 44000-326000) with late-onset disease, of whom a minimum of 7000 (UR, 0-19000) presented with neonatal encephalopathy. There were 90000 (UR, 36000-169000) deaths in infants <3 months age, and, at least 10000 (UR, 3000-27000) children with disability each year. There were 33000 (UR, 13000-52000) cases of invasive GBS disease in pregnant or postpartum women, and 57000 (UR, 12000-104000) fetal infections/stillbirths. Up to 3.5 million preterm births may be attributable to GBS. Africa accounted for 54% of estimated cases and 65% of all fetal/infant deaths. A maternal vaccine with 80% efficacy and 90% coverage could prevent 107000 (UR, 20000-198000) stillbirths and infant deaths.
Our conservative estimates suggest that GBS is a leading contributor to adverse maternal and newborn outcomes, with at least 409000 (UR, 144000-573000) maternal/fetal/infant cases and 147000 (UR, 47000-273000) stillbirths and infant deaths annually. An effective GBS vaccine could reduce disease in the mother, the fetus, and the infant.
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