Aetiology and use of antibiotics in pregnancy-related infections: results of the WHO Global Maternal Sepsis Study (GLOSS), 1-week inception cohort.

BACKGROUND: Pregnancy-related infections are important contributors to maternal sepsis and mortality. We aimed to describe clinical, microbiological characteristics and use of antibiotics by source of infection and country income, among hospitalized women with suspected or confirmed pregnancy-related infections. METHODS: We used data from WHO Global Maternal Sepsis Study (GLOSS) on maternal infections in hospitalized women, in 52 low-middle- and high-income countries conducted between November 28th and December 4th, 2017, to describe the frequencies and medians of maternal demographic, obstetric, and clinical characteristics and outcomes, methods of infection diagnosis and causative pathogens, of single source pregnancy-related infection, other than breast, and initial use of therapeutic antibiotics. We included 1456 women. RESULTS: We found infections of the genital (n = 745/1456, 51.2%) and the urinary tracts (UTI) (n = 531/1456, 36.5%) to be the most frequent. UTI (n = 339/531, 63.8%) and post-caesarean skin and soft tissue infections (SSTI) (n = 99/180, 55.0%) were the sources with more culture samples taken and microbiological confirmations. Escherichia coli was the major uropathogen (n = 103/118, 87.3%) and Staphylococcus aureus (n = 21/44, 47.7%) was the commonest pathogen in SSTI. For 13.1% (n = 191) of women, antibiotics were not prescribed on the same day of infection suspicion. Cephalosporins (n = 283/531, 53.3%) were the commonest antibiotic class prescribed for UTI, while metronidazole (n = 303/925, 32.8%) was the most prescribed for all other sources. Ceftriaxone with metronidazole was the commonest combination for the genital tract (n = 98/745, 13.2%) and SSTI (n = 22/180, 12.2%). Metronidazole (n = 137/235, 58.3%) was the most prescribed antibiotic in low-income countries while cephalosporins and co-amoxiclav (n = 129/186, 69.4%) were more commonly prescribed in high-income countries. CONCLUSIONS: Differences in antibiotics used across countries could be due to availability, local guidelines, prescribing culture, cost, and access to microbiology laboratory, despite having found similar sources and pathogens as previous studies. Better dissemination of recommendations in line with antimicrobial stewardship programmes might improve antibiotic prescription.

Core sepsis-related competencies for medical students: an international consensus by Delphi technique.

BACKGROUND: Sepsis is a life-threatening condition which may arise from infection in any organ system and requires early recognition and management. Healthcare professionals working in any specialty may need to manage patients with sepsis. Educating medical students about this condition may be an effective way to ensure all future doctors have sufficient ability to diagnose and treat septic patients. However, there is currently no consensus on what competencies medical students should achieve regarding sepsis recognition and treatment. This study aims to outline what sepsis-related competencies medical students should achieve by the end of their medical student training in both high or upper-middle incomes countries/regions and in low or lower-middle income countries/regions. METHODS: Two separate panels from high or upper-middle income and low or lower-middle income countries/regions participated in a Delphi method to suggest and rank sepsis competencies for medical students. Each panel consisted of 13-18 key stakeholders of medical education and doctors in specialties where sepsis is a common problem (both specialists and trainees). Panelists came from all continents, except Antarctica. RESULTS: The panels reached consensus on 38 essential sepsis competencies in low or lower-middle income countries/regions and 33 in high or upper-middle incomes countries/regions. These include competencies such as definition of sepsis and septic shock and urgency of antibiotic treatment. In the low or lower-middle income countries/regions group, consensus was also achieved for competencies ranked as very important, and was achieved in 4/5 competencies rated as moderately important. In the high or upper-middle incomes countries/regions group, consensus was achieved in 41/57 competencies rated as very important but only 6/11 competencies rated as moderately important. CONCLUSION: Medical schools should consider developing curricula to address essential competencies, as a minimum, but also consider addressing competencies rated as very or moderately important.

Risk Factors, Temporal Dependence, and Seasonality of Human Extended-Spectrum ß-Lactamases-Producing Escherichia coli and Klebsiella pneumoniae Colonization in Malawi: A Longitudinal Model-Based Approach.

BACKGROUND: Sub-Saharan Africa has the highest estimated death rate attributable to antimicrobial resistance, especially from extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E). However, the dynamics of human colonization in the community with ESBL-E are not well described. Inadequate water, sanitation, and hygiene infrastructure and associated behaviors are believed to play an important role in transmission of ESBL-E, and an improved understanding of the temporal dynamics of within-household transmission could help inform the design of future policies. METHODS: In this 18-month study, using microbiological data and household surveys, we built a multivariable hierarchical harmonic logistic regression model to identify risk factors for colonization with ESBL-producing Escherichia coli and Klebsiella pneumoniae, reflecting household structure and temporal correlation of colonization status. RESULTS: Being male was associated with a lower risk of colonization with ESBL-producing E. coli (odds ratio [OR], 0.786; credible interval [CrI], .678-.910), whereas the use of a tube well or a borehole was associated with an increased risk (OR, 1.550; CrI, 1.003-2.394). For ESBL-producing K. pneumoniae, recent antibiotic exposure increased risk of colonization (OR, 1.281; CrI, 1.049-1.565), whereas sharing plates decreased that risk (OR, 0.672; CrI, .460-.980). Finally, the temporal correlation range of 8 to 11 weeks provided evidence that within-household transmission occurs within this time frame. CONCLUSIONS: We describe different risks for colonization with different enteric bacterial species. Our findings suggest interventions to reduce transmission targeted at the household level need to focus on improving water, sanitation, and hygiene infrastructure and associated behaviors, whereas at the community level, they should focus on both environmental hygiene and antibiotic stewardship.

On prioritising global health's triple crisis of sepsis, COVID-19 and antimicrobial resistance: a mixed-methods study from Malawi.

Sepsis causes 20% of global deaths, particularly among children and vulnerable populations living in developing countries. This study investigated how sepsis is prioritised in Malawi's health system to inform health policy. In this mixed-methods study, twenty multisectoral stakeholders were qualitatively interviewed and asked to quantitatively rate the likelihood of sepsis-related medium-term policy outcomes being realised. Respondents indicated that sepsis is not prioritised in Malawi due to a lack of local sepsis-related evidence and policies. However, they highlighted strong linkages between sepsis and maternal health, antimicrobial resistance and COVID-19, which are already existing national priorities, and offers opportunities for sepsis researchers as policy entrepreneurs. To address the burden of sepsis, we recommend that funding should be channelled to the generation of local evidence, evidence uptake, procurement of resources and treatment of sepsis cases, development of appropriate indicators for sepsis, adherence to infection prevention and control measures, and antimicrobial stewardship.

Etiology of Sepsis in Uganda Using a Quantitative Polymerase Chain Reaction-based TaqMan Array Card.

Background: Knowledge of causes of sepsis in sub-Saharan Africa is limited. A better understanding of the microbiology of bloodstream infections could improve outcomes. Methods: We used a quantitative polymerase chain reaction (qPCR)-based TaqMan Array Card (TAC) to directly test for 43 targets from whole blood. We analyzed 336 cryopreserved specimens from adult Ugandans with sepsis enrolled in a multisite study; 84% were infected with human immunodeficiency virus. We compared qPCR TAC results with blood culture and determined the association of qPCR with study participant outcomes using logistic regression. Results: The most frequently detected targets were cytomegalovirus (CMV, n = 139, 41%), Mycobacterium tuberculosis (TB, n = 70, 21%), Plasmodium (n = 35, 10%), and Streptococcus pneumoniae (n = 31, 9%). Diagnostic performance varied by target with qPCR sensitivity averaging 61 ± 28% and specificity 98 ± 3% versus culture. In multivariable analysis, independent factors associated with in-hospital mortality included CMV viremia (adjusted odds ratio [aOR] 3.2, 95% confidence interval [CI], 1.8-5.5; p < .01) and TB qPCR-positivity, whether blood culture-positive (aOR 4.6, 95% CI, 2.1-10.0; p < .01) or blood culture-negative (aOR 2.9, 95% CI, 1.2-6.9; p = .02). Conclusions: Using qPCR TAC on direct blood specimens, CMV and TB were the most commonly identified targets and were independently associated with increased in-hospital mortality. qPCR TAC screening of blood for multiple targets may be useful to guide triage and treatment of sepsis in sub-Saharan Africa.

Evidence-based guidelines for supportive care of patients with Ebola virus disease.

The 2013-16 Ebola virus disease outbreak in west Africa was associated with unprecedented challenges in the provision of care to patients with Ebola virus disease, including absence of pre-existing isolation and treatment facilities, patients' reluctance to present for medical care, and limitations in the provision of supportive medical care. Case fatality rates in west Africa were initially greater than 70%, but decreased with improvements in supportive care. To inform optimal care in a future outbreak of Ebola virus disease, we employed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to develop evidence-based guidelines for the delivery of supportive care to patients admitted to Ebola treatment units. Key recommendations include administration of oral and, as necessary, intravenous hydration; systematic monitoring of vital signs and volume status; availability of key biochemical testing; adequate staffing ratios; and availability of analgesics, including opioids, for pain relief.

Clinical presentation of patients with Ebola virus disease in Conakry, Guinea.

BACKGROUND: In March 2014, the World Health Organization was notified of an outbreak of Zaire ebolavirus in a remote area of Guinea. The outbreak then spread to the capital, Conakry, and to neighboring countries and has subsequently become the largest epidemic of Ebola virus disease (EVD) to date. METHODS: From March 25 to April 26, 2014, we performed a study of all patients with laboratory-confirmed EVD in Conakry. Mortality was the primary outcome. Secondary outcomes included patient characteristics, complications, treatments, and comparisons between survivors and nonsurvivors. RESULTS: Of 80 patients who presented with symptoms, 37 had laboratory-confirmed EVD. Among confirmed cases, the median age was 38 years (interquartile range, 28 to 46), 24 patients (65%) were men, and 14 (38%) were health care workers; among the health care workers, nosocomial transmission was implicated in 12 patients (32%). Patients with confirmed EVD presented to the hospital a median of 5 days (interquartile range, 3 to 7) after the onset of symptoms, most commonly with fever (in 84% of the patients; mean temperature, 38.6°C), fatigue (in 65%), diarrhea (in 62%), and tachycardia (mean heart rate, >93 beats per minute). Of these patients, 28 (76%) were treated with intravenous fluids and 37 (100%) with antibiotics. Sixteen patients (43%) died, with a median time from symptom onset to death of 8 days (interquartile range, 7 to 11). Patients who were 40 years of age or older, as compared with those under the age of 40 years, had a relative risk of death of 3.49 (95% confidence interval, 1.42 to 8.59; P=0.007). CONCLUSIONS: Patients with EVD presented with evidence of dehydration associated with vomiting and severe diarrhea. Despite attempts at volume repletion, antimicrobial therapy, and limited laboratory services, the rate of death was 43%.

The Malaria TaqMan Array Card Includes 87 Assays for Plasmodium falciparum Drug Resistance, Identification of Species, and Genotyping in a Single Reaction.

Antimalarial drug resistance exacerbates the global disease burden and complicates eradication efforts. To facilitate the surveillance of resistance markers in countries of malaria endemicity, we developed a suite of TaqMan assays for known resistance markers and compartmentalized them into a single array card (TaqMan array card, TAC). We included 87 assays for species identification, for the detection of Plasmodium falciparum mutations associated with chloroquine, atovaquone, pyrimethamine, sulfadoxine, and artemisinin resistance, and for neutral single nucleotide polymorphism (SNP) genotyping. Assay performance was first optimized using DNA from common laboratory parasite lines and plasmid controls. The limit of detection was 0.1 to 10 pg of DNA and yielded 100% accuracy compared to sequencing. The tool was then evaluated on 87 clinical blood samples from around the world, and the malaria TAC once again achieved 100% accuracy compared to sequencing and in addition detected the presence of mixed infections in clinical samples. With its streamlined protocol and high accuracy, this malaria TAC should be a useful tool for large-scale antimalarial resistance surveillance.

An Outbreak of Ebola Virus Disease in the Lassa Fever Zone.

BACKGROUND: Kenema Government Hospital (KGH) has developed an advanced clinical and laboratory research capacity to manage the threat of Lassa fever, a viral hemorrhagic fever (VHF). The 2013-2016 Ebola virus (EBOV) disease (EVD) outbreak is the first to have occurred in an area close to a facility with established clinical and laboratory capacity for study of VHFs. METHODS: Because of its proximity to the epicenter of the EVD outbreak, which began in Guinea in March 2014, the KGH Lassa fever Team mobilized to establish EBOV surveillance and diagnostic capabilities. RESULTS: Augustine Goba, director of the KGH Lassa laboratory, diagnosed the first documented case of EVD in Sierra Leone, on 25 May 2014. Thereafter, KGH received and cared for numbers of patients with EVD that quickly overwhelmed the capacity for safe management. Numerous healthcare workers contracted and lost their lives to EVD. The vast majority of subsequent EVD cases in West Africa can be traced back to a single transmission chain that includes this first diagnosed case. CONCLUSIONS: Responding to the challenges of confronting 2 hemorrhagic fever viruses will require continued investments in the development of countermeasures (vaccines, therapeutic agents, and diagnostic assays), infrastructure, and human resources.

Development of a TaqMan Array Card for Acute-Febrile-Illness Outbreak Investigation and Surveillance of Emerging Pathogens, Including Ebola Virus.

Acute febrile illness (AFI) is associated with substantial morbidity and mortality worldwide, yet an etiologic agent is often not identified. Convalescent-phase serology is impractical, blood culture is slow, and many pathogens are fastidious or impossible to cultivate. We developed a real-time PCR-based TaqMan array card (TAC) that can test six to eight samples within 2.5 h from sample to results and can simultaneously detect 26 AFI-associated organisms, including 15 viruses (chikungunya, Crimean-Congo hemorrhagic fever [CCHF] virus, dengue, Ebola virus, Bundibugyo virus, Sudan virus, hantaviruses [Hantaan and Seoul], hepatitis E, Marburg, Nipah virus, o'nyong-nyong virus, Rift Valley fever virus, West Nile virus, and yellow fever virus), 8 bacteria (Bartonella spp., Brucella spp., Coxiella burnetii, Leptospira spp., Rickettsia spp., Salmonella enterica and Salmonella enterica serovar Typhi, and Yersinia pestis), and 3 protozoa (Leishmania spp., Plasmodium spp., and Trypanosoma brucei). Two extrinsic controls (phocine herpesvirus 1 and bacteriophage MS2) were included to ensure extraction and amplification efficiency. Analytical validation was performed on spiked specimens for linearity, intra-assay precision, interassay precision, limit of detection, and specificity. The performance of the card on clinical specimens was evaluated with 1,050 blood samples by comparison to the individual real-time PCR assays, and the TAC exhibited an overall 88% (278/315; 95% confidence interval [CI], 84% to 92%) sensitivity and a 99% (5,261/5,326, 98% to 99%) specificity. This TaqMan array card can be used in field settings as a rapid screen for outbreak investigation or for the surveillance of pathogens, including Ebola virus.

Ebola virus disease and critical illness.

As of 20 May 2016 there have been 28,646 cases and 11,323 deaths resulting from the West African Ebola virus disease (EVD) outbreak reported to the World Health Organization. There continue to be sporadic flare-ups of EVD cases in West Africa.EVD presentation is nonspecific and characterized initially by onset of fatigue, myalgias, arthralgias, headache, and fever; this is followed several days later by anorexia, nausea, vomiting, diarrhea, and abdominal pain. Anorexia and gastrointestinal losses lead to dehydration, electrolyte abnormalities, and metabolic acidosis, and, in some patients, acute kidney injury. Hypoxia and ventilation failure occurs most often with severe illness and may be exacerbated by substantial fluid requirements for intravascular volume repletion and some degree of systemic capillary leak. Although minor bleeding manifestations are common, hypovolemic and septic shock complicated by multisystem organ dysfunction appear the most frequent causes of death.Males and females have been equally affected, with children (0-14 years of age) accounting for 19 %, young adults (15-44 years) 58 %, and older adults (≥45 years) 23 % of reported cases. While the current case fatality proportion in West Africa is approximately 40 %, it has varied substantially over time (highest near the outbreak onset) according to available resources (40-90 % mortality in West Africa compared to under 20 % in Western Europe and the USA), by age (near universal among neonates and high among older adults), and by Ebola viral load at admission.While there is no Ebola virus-specific therapy proven to be effective in clinical trials, mortality has been dramatically lower among EVD patients managed with supportive intensive care in highly resourced settings, allowing for the avoidance of hypovolemia, correction of electrolyte and metabolic abnormalities, and the provision of oxygen, ventilation, vasopressors, and dialysis when indicated. This experience emphasizes that, in addition to evaluating specific medical treatments, improving the global capacity to provide supportive critical care to patients with EVD may be the greatest opportunity to improve patient outcomes.

Macrophage migration inhibitory factor (MIF) is a critical mediator of the innate immune response to Mycobacterium tuberculosis.

Macrophage migration inhibitory factor (MIF), an innate cytokine encoded in a functionally polymorphic genetic locus, contributes to detrimental inflammation but may be crucial for controlling infection. We explored the role of variant MIF alleles in tuberculosis. In a Ugandan cohort, genetic low expressers of MIF were 2.4-times more frequently identified among patients with Mycobacterium tuberculosis (TB) bacteremia than those without. We also found mycobacteria-stimulated transcription of MIF and serum MIF levels to be correlated with MIF genotype in human macrophages and in a separate cohort of US TB patients, respectively. To determine mechanisms for MIF's protective role, we studied both aerosolized and i.v. models of mycobacterial infection and observed MIF-deficient mice to succumb more quickly with higher organism burden, increased lung pathology, and decreased innate cytokine production (TNF-α, IL-12, IL-10). MIF-deficient animals showed increased pulmonary neutrophil accumulation but preserved adaptive immune response. MIF-deficient macrophages demonstrated decreased cytokine and reactive oxygen production and impaired mycobacterial killing. Transcriptional investigation of MIF-deficient macrophages revealed reduced expression of the pattern recognition receptor dectin-1; restoration of dectin-1 expression recovered innate cytokine production and mycobacterial killing. Our data place MIF in a crucial upstream position in the innate immune response to mycobacteria and suggest that commonly occurring low expression MIF alleles confer an increased risk of TB disease in some populations.

Proposed Framework for Conducting Clinically Relevant Translational Biomarker Research for the Diagnosis, Prognosis and Management of Sepsis.

Although the diagnosis of sepsis requires the identification of the three components of infection, a systemic inflammation response, and organ dysfunction, there is currently no consensus on gold-standard criteria. There are however suggested tools and tests, which have been proposed in international guidelines, including those produced by the Surviving Sepsis Campaign. Biomarkers play an important role in these tools and tests, and numerous heterogeneous studies have been performed to evaluate their respective clinical utility. Our review of the current practice shows that no biomarkers of infection, systemic inflammation response, organ dysfunction and sepsis are currently specifically recommended, which is probably due to the lack of standardization of studies. We therefore propose to define a framework for conducting clinically relevant translational biomarker research and seek to establish ideal criteria that can be applied to an infection, systemic inflammation response, organ dysfunction and sepsis biomarkers, which can enable early screening of sepsis, diagnosis of sepsis at the time of clinical suspicion and monitoring of sepsis treatment efficacy.

Implementing health worker training on sepsis in South Eastern Nigeria using innovative digital strategies: an interventional study.

Background: Sepsis is a leading cause of morbidity and mortality especially in low- and middle-income countries such as Nigeria. Training of health workers using digital platforms may improve knowledge and lead to better patient outcomes. Objectives: To assess the effectiveness of a digital health educational module on sepsis in improving the knowledge of medical doctors in Cross River State Nigeria on the diagnosis and management of patients presenting with sepsis. Design: Quasi-experimental analytical study. Methods: We developed and deployed a sepsis module through an innovative application (Sepsis tutorial app) to doctors in Calabar, Nigeria. We assessed quantitative pre- and post-intervention knowledge scores for those completing the tutorial on sepsis between both assessments. A user satisfaction survey evaluated the content of the tutorial and the usability of the app. Results: One hundred and two doctors completed the course. There were more males than females (58.8% versus 41.2%). Over half (52%) were junior doctors, a minority were general practitioners and house officers (3% and 5%, respectively), and 72.6% had practiced for periods ranging from 1 to 15 years post-qualification. Gender and age appeared to have no significant association with pre- and post-test scores. The oldest age group (61-70) had the lowest mean pre- and post-test scores, while general practitioners had higher mean pre- and post-test scores than other cadres. The majority (95%) of participants recorded higher post-test than pre-test scores with a significant overall increase in mean scores (25.5 ± 14.7%, p < 0.0001). Participants were satisfied with the content and multimodal delivery of the material and found the app usable. Conclusion: Digital training using context-responsive platforms is feasible and may be used to close the critical knowledge gap required to respond effectively to medical emergencies such as sepsis in low- to middle-income settings.

Training health workers on sepsis using digital strategies Sepsis occurs when the body injures itself as it attempts to fight an infection. It is now recognized as a leading cause of death especially in low- and middle-income countries such as Nigeria. Training of health workers using digital platforms may improve knowledge and lead to better patient outcomes. We assessed the effectiveness of a digital health educational course on sepsis in improving the knowledge of medical doctors in Cross River State, Nigeria on the diagnosis and management of patients presenting with sepsis. One hundred and two doctors completed the course. Most participants recorded higher post-test than pre-test scores, were generally satisfied with the content and delivery of the material, and found the app usable. We conclude that digital training using digital platforms may be useful in bridging the critical knowledge gap required to respond effectively to sepsis in low- to middle-income settings.

Caregivers' and nurses' perceptions of the Smart Discharges Program for children with sepsis in Uganda: A qualitative study.

Sepsis arises when the body's response to an infection injures its own tissues and organs. Among children hospitalized with suspected sepsis in low-income country settings, mortality rates following discharge are high, similar to mortality rates in hospital. The Smart Discharges Program uses a mobile health (mHealth) platform to identify children at high risk of post-discharge mortality to receive enhanced post-discharge care. This study sought to explore the perceptions and experiences of the caregivers and nurses of children enrolled into the Smart Discharges Program and the program's effect on post-discharge care. We conducted an exploratory qualitative study, which included in-person focus group discussions (FGDs) with 30 caregivers of pediatric patients enrolled in the Smart Discharges Program and individual, semi-structured interviews with eight Smart Discharges Program nurses. The study was carried out at four hospitals in Uganda in 2019. Following thematic analysis, three key themes pertaining to the Smart Discharges program were identified: (1) Facilitators and barriers to follow-up care after discharge; (2) Changed caregiver behavior following discharge; and (3) Increased involvement of male caregivers. Facilitators included telephone/text message reminders, positive nurse-patient relationship, and the complementary aspects of the program. Barriers included resource constraints and negative experiences during post-discharge care seeking. With regards to behavior, when provided with relevant and well-timed information, caregivers reported increased knowledge about post-discharge care and improvements in their ability to care for their child. Enrolment in the Smart Discharges Program also increased male caregiver involvement, increased provision of resources and improved communication within the family and with the healthcare system. The Smart Discharges approach is an impactful strategy to improve pediatric post-discharge care, and similar approaches should be considered to improve the hospital to home transition in similar low-income country settings.