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.

Challenges of Antibiotic Formulations and Administration in the Treatment of Bloodstream Infections in Children Under Five Admitted to Kisantu Hospital, Democratic Republic of Congo.

Severe bacterial infections in children need prompt, appropriate antibiotic treatment. We report challenges observed within a prospective, cohort study on antibiotic efficacy in non-typhi Salmonella bloodstream infection (NCT04850677) in Kisantu district hospital (Democratic Republic of Congo). Children (aged > 28 days to < 5 years) admitted with suspected bloodstream infection (August 1, 2021 through July 31, 2022) were enrolled and followed until day 3 or discharge for non-typhi Salmonella patients. Antibiotics were administered to 98.4% (1,838/1,867) of children, accounting for 2,296 antibiotic regimens (95.7% intravenous, 4.3% oral). Only 78.3% and 61.8% of children were, respectively, prescribed and administered antibiotics on the admission day. At least one dose was not administered in 3.6% of children, mostly because of mismatch of the four times daily cefotaxime schedule with the twice-daily administration rounds. Inappropriate intravenous administration practices included multidose use, air-venting, and direct injection instead of perfusion. There was inaccurate aliquoting in 18.0% (32/178) of intravenous ciprofloxacin regimens, and thus administered doses were > 16% below the intended dose. Dosing accuracy of oral suspensions was impaired by lack of instructions for reconstitution, volume indicators, and/or dosing devices. Adult-dose tablets were split without/beyond scoring lines in 84.4% (27/32) of tablets. Poor availability and affordability of age-appropriate oral formulations contributed to low proportions of intravenous-to-oral switch (33.3% (79/237) of non-typhi Salmonella patients). Other quality issues included poor packaging, nonhomogeneous suspensions, and unsafe water for reconstitution. In conclusion, poor antibiotic products (no age-appropriate formulations, poor quality and access), processes (delayed prescription/administration, missed doses), and practices (inaccurate doses, [bio]safety risks) must be urgently addressed to improve pediatric antibiotic treatment.

A global genomic analysis of Salmonella Concord reveals lineages with high antimicrobial resistance in Ethiopia.

Antimicrobial resistant Salmonella enterica serovar Concord (S. Concord) is known to cause severe gastrointestinal and bloodstream infections in patients from Ethiopia and Ethiopian adoptees, and occasional records exist of S. Concord linked to other countries. The evolution and geographical distribution of S. Concord remained unclear. Here, we provide a genomic overview of the population structure and antimicrobial resistance (AMR) of S. Concord by analysing genomes from 284 historical and contemporary isolates obtained between 1944 and 2022 across the globe. We demonstrate that S. Concord is a polyphyletic serovar distributed among three Salmonella super-lineages. Super-lineage A is composed of eight S. Concord lineages, of which four are associated with multiple countries and low levels of AMR. Other lineages are restricted to Ethiopia and horizontally acquired resistance to most antimicrobials used for treating invasive Salmonella infections in low- and middle-income countries. By reconstructing complete genomes for 10 representative strains, we demonstrate the presence of AMR markers integrated in structurally diverse IncHI2 and IncA/C2 plasmids, and/or the chromosome. Molecular surveillance of pathogens such as S. Concord supports the understanding of AMR and the multi-sector response to the global AMR threat. This study provides a comprehensive baseline data set essential for future molecular surveillance.

Nontyphoidal Salmonella Invasive Disease: Challenges and Solutions.

Nontyphoidal Salmonella are a leading cause of community-onset bacteremia and other serious infections in sub-Saharan African countries where large studies indicate that they are an uncommon cause of moderate-to-severe diarrhea. Approximately 535 000 nontyphoidal Salmonella invasive disease illnesses and 77 500 deaths were estimated to occur in 2017; 422 000 (78.9%) illnesses and 66 500 (85.9%) deaths in countries in sub-Saharan Africa. Lineages of Salmonella enterica serovar Typhimurium sequence type (ST) 313 and lineages of Salmonella enterica serovar Enteritidis ST11 dominate as causes of invasive disease. A major reservoir for these specific strains outside of humans has not been identified to date. Human fecal shedding of such strains is common in areas where nontyphoidal Salmonella invasive disease incidence is high. The case-fatality ratio of nontyphoidal Salmonella invasive disease is approximately 15%. Early diagnosis and treatment are needed to avert fatal outcomes. Antimicrobial resistance, including multiple drug resistance, decreased fluoroquinolone susceptibility, and resistance to third-generation cephalosporins, is increasing in prevalence and is likely to further compromise patient outcomes. Naturally acquired immunity against invasive disease develops in children aged >3 years in endemic areas, likely mediated in part by the sequential acquisition of T-cell immunity, followed by antigen-specific immunoglobulin G antibodies. Vaccines in preclinical or clinical development include live-attenuated S. enterica serovar Typhimurium, nontyphoidal S. enterica core and O-polysaccharide glycoconjugates, multiple antigen-presenting system complexes, and generalized modules for membrane antigens vaccines. The latter are in phase I trials in Europe and Africa. Both vaccine use, and other effective, evidence-based nonvaccine interventions, are needed to prevent and control nontyphoidal Salmonella invasive disease.

Health itinerary-related survival of children under-five with severe malaria or bloodstream infection, DR Congo.

BACKGROUND: Prompt appropriate treatment reduces mortality of severe febrile illness in sub-Saharan Africa. We studied the health itinerary of children under-five admitted to the hospital with severe febrile illness in a setting endemic for Plasmodium falciparum (Pf) malaria and invasive non-typhoidal Salmonella infections, identified delaying factors and assessed their associations with in-hospital death. METHODOLOGY: Health itinerary data of this cohort study were collected during 6 months by interviewing caretakers of children (>28 days - <5 years) admitted with suspected bloodstream infection to Kisantu district hospital, DR Congo. The cohort was followed until discharge to assess in-hospital death. PRINCIPAL FINDINGS: From 784 enrolled children, 36.1% were admitted >3 days after fever onset. This long health itinerary was more frequent in children with bacterial bloodstream infection (52.9% (63/119)) than in children with severe Pf malaria (31.0% (97/313)). Long health itinerary was associated with in-hospital death (OR = 2.1, p = 0.007) and two thirds of deaths occurred during the first 3 days of admission. Case fatality was higher in bloodstream infection (22.8% (26/114)) compared to severe Pf malaria (2.6%, 8/309). Bloodstream infections were mainly (74.8% (89/119)) caused by non-typhoidal Salmonella. Bloodstream infections occurred in 20/43 children who died in-hospital before possible enrolment and non-typhoidal Salmonella caused 16 out of these 20 bloodstream infections. Delaying factors associated with in-hospital death were consulting traditional, private and/or multiple providers, rural residence, prehospital intravenous therapy, and prehospital overnight stays. Use of antibiotics reserved for hospital use, intravenous therapy and prehospital overnight stays were most frequent in the private sector. CONCLUSIONS: Long health itineraries delayed appropriate treatment of bloodstream infections in children under-five and were associated with increased in-hospital mortality. Non-typhoidal Salmonella were the main cause of bloodstream infection and had high case fatality. TRIAL REGISTRATION: NCT04289688.

Epidemiological cut-off value and antibiotic susceptibility test methods for azithromycin in a collection of multi-country invasive non-typhoidal Salmonella.

OBJECTIVE: Azithromycin is an alternative to treat invasive non-typhoidal Salmonella (iNTS) infections. We determined its epidemiological cut-off (ECOFF) and compared azithromycin susceptibility testing methods for iNTS. METHODS: We used EUCAST ECOFFinder to determine the minimum inhibitory concentrations (MIC; obtained by broth microdilution) ECOFF and corresponding disk zone diameters of 515 iNTS from blood cultures in Democratic Republic of Congo, Burkina Faso, Rwanda, and Cambodia. Transferable resistance mechanisms were determined by polymerase chain reaction. We compared azithromycin susceptibility testing by semi-automated broth microdilution (customized Sensititre panel; reference), agar dilution, gradient tests (bioMérieux, Liofilchem, HiMedia; read at 80% (MIC80%) and 100% inhibition (MIC100%)), and disk diffusion (Rosco, Oxoid, BD, Liofilchem) for 161 wild- and 198 non-wild-type iNTS. RESULTS: Azithromycin MIC ECOFF was 16 mg/L corresponding to a 12 mm zone diameter; mphA was detected in 192/197 non-wild- and 0/47 wild-type iNTS. Categorical agreement was excellent (≥98%) for all methods. Essential agreement was very good for agar dilution (>90%) but moderate for gradient tests (MIC80%: 52% to 71% and MIC100%: 72% to 91%). Repeatability was good for all methods/brands. Interreader agreement was high for broth microdilution and agar dilution (all ≤1 twofold dilution difference) and disk diffusion (>96% ≤3 mm difference) but lower for gradient tests (MIC80% & MIC100%: 83% to 94% ≤1 twofold dilution difference). DISCUSSION: Azithromycin ECOFF of iNTS was 16 mg/L, i.e. equal to Salmonella Typhi. Disk diffusion is an accurate, precise, and user-friendly alternative for agar dilution and broth microdilution. Reading gradient tests at 100% instead of 80% inhibition improved accuracy and precision.

Antibiotic use from formal and informal healthcare providers in the Democratic Republic of Congo: a population-based study in two health zones.

OBJECTIVE: In the Democratic Republic of Congo and other low-resource countries, community-acquired pathogens are increasingly resistant to most locally available antibiotics. To guide efforts to optimize antibiotic use to limit antibiotic resistance, we quantified healthcare provider-specific and community-wide antibiotic use. METHODS: From household surveys, we estimated monthly healthcare visit rates by provider. From healthcare visit exit surveys, we estimated prevalence, defined daily doses, and access/watch/reserve distribution of antibiotic use by provider. Combining both, we estimated community-wide antibiotic use rates. RESULTS: Of 88.7 (95% CI 81.9-95.4) healthcare visits per 1000 person-months (n = 31221), visits to private clinics (31.0, 95% CI 30.0-32.0) and primary health centres (25.5, 95% CI 24.6-26.4) were most frequent. Antibiotics were used during 64.3% (95% CI 55.2-73.5%, 162/224) of visits to private clinics, 51.1% (95% CI 45.1-57.2%, 245/469) to health centres, and 48.8% (95% CI 44.4-53.2%, 344/454) to medicine stores. Antibiotic defined daily doses per 1000 inhabitants per day varied between 1.75 (95% CI 1.02-2.39) in rural Kimpese and 10.2 (95% CI 6.00-15.4) in (peri) urban Kisantu, mostly explained by differences in healthcare utilisation (respectively 27.8 versus 105 visits per 1000 person-months), in particular of private clinics (1.23 versus 38.6 visits) where antibiotic use is more frequent. The fraction of Watch antibiotics was 30.3% (95% CI 24.6-35.9%) in private clinics, 25.6% (95% CI 20.2-31.1%) in medicine stores, and 25.1% (95% CI 19.0-31.2%) in health centres. Treatment durations <3 days were more frequent at private clinics (5.3%, 9/169) and medicine stores (4.1%, 14/338) than at primary health centres (1.8%, 5/277). DISCUSSION: Private healthcare providers, ubiquitous in peri-urban settings, contributed most to community-wide antibiotic use and more frequently dispensed Watch antibiotics and shortened antibiotic courses. Efforts to optimize antibiotic use should include private providers at community level.

Field Experiences with Handheld Diagnostic Devices to Triage Children under Five Presenting with Severe Febrile Illness in a District Hospital in DR Congo.

As part of a field study (NCT04473768) in children presenting with severe febrile illness to Kisantu hospital (DR Congo), we retrospectively compiled user experiences (not performance) with handheld diagnostic devices assisting triage: tympanic thermometer, pulse oximeter (measuring heart rate, respiratory rate and oxygen saturation), hemoglobinometer and glucometer. Guidance documents for product selection were generic and scattered. Stock rupture, market withdrawal and unaffordable prices interfered with procurement. Challenges at implementation included environmental temperature, capillary blood sampling (antisepsis, order of multiple tests, filling microcuvettes and glucose strips), calibration (environmental temperature, cold chain) and liability-oriented communication with a manufacturer. Instructions for use were readable and contained symbol keys; two devices had printed French-language instructions. Shortcomings were poor integration of figures with text and distinct procedures for the oximeter and its sensor. Usability interview revealed appreciations for quick results, visibility of the display and memory function (three devices) but also problems of capillary blood sample transfer, cleaning, too long of a time-to-results (respiratory rate) and size, fitting and disposal of thermometer probes. Pictorial error messages were preferred over alphanumeric error codes but interpretation of symbols was poor. Alarm sounds of the oximeter caused unrest in children and caretakers perceived the device as associated with poor prognosis.

Performance of Automated Point-of-Care Respiratory Rate Counting versus Manual Counting in Children under Five Admitted with Severe Febrile Illness to Kisantu Hospital, DR Congo.

To improve the early recognition of danger signs in children with severe febrile illness in low resource settings, WHO promotes automated respiratory rate (RR) counting, but its performance is unknown in this population. Therefore, we prospectively evaluated the field performance of automated point-of-care plethysmography-based RR counting in hospitalized children with severe febrile illness (<5 years) in DR Congo. A trained research nurse simultaneously counted the RR manually (comparative method) and automatically with the Masimo Rad G pulse oximeter. Valid paired RR measurements were obtained in 202 (83.1%) children, among whom 43.1% (87/202) had fast breathing according to WHO criteria based on manual counting. Automated counting frequently underestimated the RR (median difference of -1 breath/minute; p2.5-p97.5 limits of agreement: -34-6), particularly at higher RR. This resulted in a failure to detect fast breathing in 24.1% (21/87) of fast breathing children (positive percent agreement: 75.9%), which was not explained by clinical characteristics (p > 0.05). Children without fast breathing were mostly correctly classified (negative percent agreement: 98.3%). In conclusion, in the present setting the automated RR counter performed insufficiently to facilitate the early recognition of danger signs in children with severe febrile illness, given wide limits of agreement and a too low positive percent agreement.

Direct association between rainfall and non-typhoidal Salmonella bloodstream infections in hospital-admitted children in the Democratic Republic of Congo.

Non-typhoidal Salmonella (NTS) ranks first among causes of bloodstream infection in children under five years old in the Democratic Republic of Congo and has a case fatality rate of 15%. Main host-associated risk factors are Plasmodium falciparum malaria, anemia and malnutrition. NTS transmission in sub-Saharan Africa is poorly understood. NTS bloodstream infections mostly occur during the rainy season, which may reflect seasonal variation in either environmental transmission or host susceptibility. We hypothesized that environment- and host-associated factors contribute independently to the seasonal variation in NTS bloodstream infections in children under five years old admitted to Kisantu referral hospital in 2013-2019. We used remotely sensed rainfall and temperature data as proxies for environmental factors and hospital data for host-associated factors. We used principal component analysis to disentangle the interrelated environment- and host-associated factors. With timeseries regression, we demonstrated a direct association between rainfall and NTS variation, independent of host-associated factors. While the latter explained 17.5% of NTS variation, rainfall explained an additional 9%. The direct association with rainfall points to environmental NTS transmission, which should be explored by environmental sampling studies. Environmental and climate change may increase NTS transmission directly or via host susceptibility, which highlights the importance of preventive public health interventions.

COVID-19 Antibody Detecting Rapid Diagnostic Tests Show High Cross-Reactivity When Challenged with Pre-Pandemic Malaria, Schistosomiasis and Dengue Samples.

COVID-19 Antibody Detecting Rapid Diagnostic Tests (COVID-19 Ab RDTs) are the preferred tool for SARS-CoV-2 seroprevalence studies, particularly in low- and middle-income countries. The present study challenged COVID-19 Ab RDTs with pre-pandemic samples of patients exposed to tropical pathogens. A retrospective study was performed on archived serum (n = 94) and EDTA whole blood (n = 126) samples obtained during 2010-2018 from 196 travelers with malaria (n = 170), schistosomiasis (n = 25) and dengue (n = 25). COVID-19 Ab RDTs were selected based on regulatory approval status, independent evaluation results and detecting antigens. Among 13 COVID-19 Ab RDT products, overall cross-reactivity was 18.5%; cross-reactivity for malaria, schistosomiasis and dengue was 20.3%, 18.1% and 7.5%, respectively. Cross-reactivity for current and recent malaria, malaria antibodies, Plasmodium species and parasite densities was similar. Cross-reactivity among the different RDT products ranged from 2.7% to 48.9% (median value 14.5%). IgM represented 67.9% of cross-reactive test lines. Cross-reactivity was not associated with detecting antigens, patient categories or disease (sub)groups, except for schistosomiasis (two products with ≥60% cross-reactivity). The high cross-reactivity for malaria, schistosomiasis and-to a lesser extent-dengue calls for risk mitigation when using COVID-19 Ab RDTs in co-endemic regions.

A semi-automated method for unbiased alveolar morphometry: Validation in a bronchopulmonary dysplasia model.

Reproducible and unbiased methods to quantify alveolar structure are important for research on many lung diseases. However, manually estimating alveolar structure through stereology is time consuming and inter-observer variability is high. The objective of this work was to develop and validate a fast, reproducible and accurate (semi-)automatic alternative. A FIJI-macro was designed that automatically segments lung images to binary masks, and counts the number of test points falling on tissue and the number of intersections of the air-tissue interface with a set of test lines. Manual selection remains necessary for the recognition of non-parenchymal tissue and alveolar exudates. Volume density of alveolar septa ([Formula: see text]) and mean linear intercept of the airspaces (Lm) as measured by the macro were compared to theoretical values for 11 artificial test images and to manually counted values for 17 lungs slides using linear regression and Bland-Altman plots. Inter-observer agreement between 3 observers, measuring 8 lungs both manually and automatically, was assessed using intraclass correlation coefficients (ICC). [Formula: see text] and Lm measured by the macro closely approached theoretical values for artificial test images (R2 of 0.9750 and 0.9573 and bias of 0.34% and 8.7%). The macro data in lungs were slightly higher for [Formula: see text] and slightly lower for Lm in comparison to manually counted values (R2 of 0.8262 and 0.8288 and bias of -6.0% and 12.1%). Visually, semi-automatic segmentation was accurate. Most importantly, manually counted [Formula: see text] and Lm had only moderate to good inter-observer agreement (ICC 0.859 and 0.643), but agreements were excellent for semi-automatically counted values (ICC 0.956 and 0.900). This semi-automatic method provides accurate and highly reproducible alveolar morphometry results. Future efforts should focus on refining methods for automatic detection of non-parenchymal tissue or exudates, and for assessment of lung structure on 3D reconstructions of lungs scanned with microCT.

Invasive non-typhoidal Salmonella infections in sub-Saharan Africa: a systematic review on antimicrobial resistance and treatment.

BACKGROUND: Non-typhoidal Salmonella (NTS) are a frequent cause of invasive infections in sub-Saharan Africa. They are frequently multidrug resistant (co-resistant to ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol), and resistance to third-generation cephalosporin and fluoroquinolone non-susceptibility have been reported. Third-generation cephalosporins and fluoroquinolones are often used to treat invasive NTS infections, but azithromycin might be an alternative. However, data on antibiotic treatment efficacy in invasive NTS infections are lacking. In this study, we aimed to assess the spatiotemporal distribution of antimicrobial resistance in invasive NTS infections in sub-Saharan Africa and to describe the available evidence and recommendations on antimicrobial treatment. METHODS: We conducted a systematic review of all available literature on antimicrobial resistance and treatment in invasive NTS infections. We performed a random effects meta-analysis to assess the temporal distribution of multidrug resistance, third-generation cephalosporin resistance, and fluoroquinolone non-susceptibility. We mapped these data to assess the spatial distribution. We provided a narrative synthesis of the available evidence and recommendations on antimicrobial treatment. RESULTS: Since 2001, multidrug resistance was observed in 75% of NTS isolates from all sub-Saharan African regions (95% confidence interval, 70-80% and 65-84%). Third-generation cephalosporin resistance emerged in all sub-Saharan African regions and was present in 5% (95% confidence interval, 1-10%) after 2010. Fluoroquinolone non-susceptibility emerged in all sub-Saharan African regions but did not increase over time. Azithromycin resistance was reported in DR Congo. There were no reports on carbapenem resistance. We did not find high-quality evidence on the efficacy of antimicrobial treatment. There were no supranational guidelines. The "Access group" antibiotics ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol and "Watch group" antibiotics ceftriaxone, cefotaxime, and ciprofloxacin were recommended as the first-choice antibiotics in national guidelines or reviews. These also recommended (a switch to) oral fluoroquinolones or azithromycin. CONCLUSIONS: In addition to the widespread multidrug resistance in invasive NTS infections in sub-Saharan Africa, resistance to third-generation cephalosporins and fluoroquinolone non-susceptibility was present in all regions. There was a lack of data on the efficacy of antimicrobial treatment in these infections, and supranational evidence-based guidelines were absent.

Non-typhoidal Salmonella bloodstream infections in Kisantu, DR Congo: Emergence of O5-negative Salmonella Typhimurium and extensive drug resistance.

BACKGROUND: Non-typhoidal Salmonella (NTS) are a major cause of bloodstream infection (BSI) in sub-Saharan Africa. This study aimed to assess its longitudinal evolution as cause of BSI, its serotype distribution and its antibiotic resistance pattern in Kisantu, DR Congo. METHODS: As part of a national surveillance network, blood cultures were sampled in patients with suspected BSI admitted to Kisantu referral hospital from 2015-2017. Blood cultures were worked-up according to international standards. Results were compared to similar data from 2007 onwards. RESULTS: In 2015-2017, NTS (n = 896) represented the primary cause of BSI. NTS were isolated from 7.6% of 11,764 suspected and 65.4% of 1371 confirmed BSI. In children <5 years, NTS accounted for 9.6% of suspected BSI. These data were in line with data from previous surveillance periods, except for the proportion of confirmed BSI, which was lower in previous surveillance periods. Salmonella Typhimurium accounted for 63.1% of NTS BSI and Salmonella Enteritidis for 36.4%. Of all Salmonella Typhimurium, 36.9% did not express the O5-antigen (i.e. variant Copenhagen). O5-negative Salmonella Typhimurium were rare before 2013, but increased gradually from then onwards. Multidrug resistance was observed in 87.4% of 864 NTS isolates, decreased ciprofloxacin susceptibility in 7.3%, ceftriaxone resistance in 15.7% and azithromycin resistance in 14.9%. A total of 14.2% of NTS isolates, that were all Salmonella Typhimurium, were multidrug resistant and ceftriaxone and azithromycin co-resistant. These Salmonella isolates were called extensively drug resistant. Compared to previous surveillance periods, proportions of NTS isolates with resistance to ceftriaxone and azithromycin and decreased ciprofloxacin susceptibility increased. CONCLUSION: As in previous surveillance periods, NTS ranked first as the cause of BSI in children. The emergence of O5-negative Salmonella Typhimurium needs to be considered in the light of vaccine development. The high proportions of antibiotic resistance are worrisome.

Simvastatin attenuates lung functional and vascular effects of hyperoxia in preterm rabbits.

BACKGROUND: Bronchopulmonary dysplasia (BPD) remains a frequent complication following preterm birth, affecting respiratory health throughout life. Transcriptome analysis in a preterm rabbit model for BPD revealed dysregulation of key genes for inflammation, vascular growth and lung development in animals exposed to hyperoxia, which could be prevented by simvastatin. METHODS: Preterm rabbits were randomized to either normoxia (21% O2) or hyperoxia (95% O2) and within each condition to treatment with 5 mg/kg simvastatin daily or control. Lung function, structure and mRNA-expression was assessed on day 7. RESULTS: Simvastatin partially prevented the effect of hyperoxia on lung function, without altering alveolar structure or inflammation. A trend towards a less fibrotic phenotype was noted in simvastatin-treated pups, and airways were less muscularized. Most importantly, simvastatin completely prevented hyperoxia-induced arterial remodeling, in association with partial restoration of VEGFA and VEGF receptor 2 (VEGFR2) expression. Simvastatin however decreased survival in pups exposed to normoxia, but not to hyperoxia. CONCLUSION: Repurposing of simvastatin could be an advantageous therapeutic strategy for bronchopulmonary dysplasia and other developmental lung diseases with pulmonary vascular disease. The increased mortality in the treated normoxia group however limits the translational value at this dose and administration route.

Salmonella Typhi From Blood Cultures in the Democratic Republic of the Congo: A 10-Year Surveillance.

BACKGROUND: This study gives an overview of a decade (2007-2017) of hospital-based Salmonella Typhi bloodstream infection (BSI) surveillance in the Democratic Republic of the Congo (DRC), at 4 main sampling sites. METHODS: Blood cultures were sampled in hospital-admitted patients with suspected BSI, according to standardized clinical indications. The results of the surveillance period 2015-2017 were compiled with those of previous surveillance periods (2007-2010 and 2011-2014). Whole genome sequencing of isolates with decreased ciprofloxacin susceptibility (DCS) was performed. RESULTS: Salmonella Typhi was isolated in 1.4% (531/37 388) and 10.3% (531/5177) of suspected and culture-confirmed BSI episodes, respectively. Salmonella Typhi ranked first among the BSI pathogens in adults (n = 220), but was mostly (n = 301 [56.7%]) isolated from children, of which 72.1% (217/301) and 31.6% (95/301) were <10 years and <5 years old, respectively. Multidrug resistance (MDR), DCS, and combined MDR/DCS were found in 38.3% (n = 180), 24.5% (n = 115), and 11.9% (n = 56) of 470 first isolates, respectively. MDR and DCS rates had increased since 2007, but remained stable during 2015-2017 with no geographical clustering at the province level. Most (91/93 [97.8%]) DCS isolates sequenced belonged to Genotyphi genotype 2.5.1, and gyr S83 was the most frequent DCS mutation (76/93 [81.7%]). Infections occurred perennially, but increased during the rainy season. CONCLUSIONS: Salmonella Typhi was a frequent cause of BSI in adults and children in DRC, with high rates of antibiotic resistance. Sustainable surveillance and implementation of vaccination are compelling.

Modelling Bronchopulmonary Dysplasia in Animals: Arguments for the Preterm Rabbit Model.

Bronchopulmonary dysplasia (BPD) remains a frequent and disabling consequence of preterm birth, despite the recent advances in neonatal intensive care. There is a need to further improve outcomes and many novel therapeutic or preventive strategies are therefore investigated in animal models. We discuss in this review the aspects of human BPD pathophysiology and phenotype, which ideally should be mimicked by an animal model for this disease. Prematurity remains the common denominator in the heterogeneous spectrum of human BPD, and preterm animal models thus have a clear translational advantage. Additional factors, like excessive oxygen, mechanical ventilation and infection, which frequently have been studied in animal models, can contribute to preterm lung injury however are not indispensable to develop BPD. The phenotype of human BPD is characterized by alveolar developmental arrest with extracellular matrix remodeling, signs of obstructive airway disease and pulmonary vascular disease. Many animal models mimic this phenotype and have their place in BPD research, but results should be interpreted bearing in mind the specific advantages and disadvantages of the model. Term mice and rats are well suited for basic explorative research on specific disease mechanisms, essential for the generation of new hypotheses, while the larger ventilated preterm baboons and lambs provide a good platform for the ultimate translation of these strategies towards clinical application. The preterm rabbit model seems a promising model as it the smallest model that includes a factor of prematurity and has a unique position between the small and large animal models.