Antimicrobial resistance patterns in bacteria causing febrile illness in Africa, South Asia, and Southeast Asia: a systematic review of published etiological studies from 1980-2015.

OBJECTIVE: In this study, we aimed to conduct a systematic review to characterize antimicrobial resistance (AMR) patterns for bacterial causes of febrile illness in Africa and Asia. METHODS: We included published literature from 1980-2015 based on data extracted from two recent systematic reviews of nonmalarial febrile illness from Africa, South Asia, and Southeast Asia. Selection criteria included articles with full bacterial identification and antimicrobial susceptibility testing (AST) results for key normally sterile site pathogen-drug combinations. Pooled proportions of resistant isolates were combined using random effects meta-analysis. Study data quality was graded using the Microbiology Investigation Criteria for Reporting Objectively (MICRO) framework. RESULTS: Of 3475 unique articles included in the previous reviews, 371 included the target pathogen-drug combinations. Salmonella enterica tested against ceftriaxone and ciprofloxacin were the two highest reported combinations (30,509 and 22,056 isolates, respectively). Pooled proportions of resistant isolates were high for third-generation cephalosporins for Klebsiella pneumoniae and Escherichia coli in all regions. The MICRO grading showed an overall lack of standardization. CONCLUSION: This review highlights a general increase in AMR reporting and in resistance over time. However, there were substantial problems with diagnostic microbiological data quality. Urgent strengthening of laboratory capacity, standardized testing, and reporting of AST results is required to improve AMR surveillance.

Systematic review of the scrub typhus treatment landscape: Assessing the feasibility of an individual participant-level data (IPD) platform.

BACKGROUND: Scrub typhus is an acute febrile illness caused by intracellular bacteria from the genus Orientia. It is estimated that one billion people are at risk, with one million cases annually mainly affecting rural areas in Asia-Oceania. Relative to its burden, scrub typhus is understudied, and treatment recommendations vary with poor evidence base. These knowledge gaps could be addressed by establishing an individual participant-level data (IPD) platform, which would enable pooled, more detailed and statistically powered analyses to be conducted. This study aims to assess the characteristics of scrub typhus treatment studies and explore the feasibility and potential value of developing a scrub typhus IPD platform to address unanswered research questions. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a systematic literature review looking for prospective scrub typhus clinical treatment studies published from 1998 to 2020. Six electronic databases (Ovid Embase, Ovid Medline, Ovid Global Health, Cochrane Library, Scopus, Global Index Medicus), ClinicalTrials.gov, and WHO ICTRP were searched. We extracted data on study design, treatment tested, patient characteristics, diagnostic methods, geographical location, outcome measures, and statistical methodology. Among 3,100 articles screened, 127 were included in the analysis. 12,079 participants from 12 countries were enrolled in the identified studies. ELISA, PCR, and eschar presence were the most commonly used diagnostic methods. Doxycycline, azithromycin, and chloramphenicol were the most commonly administered antibiotics. Mortality, complications, adverse events, and clinical response were assessed in most studies. There was substantial heterogeneity in the diagnostic methods used, treatment administered (including dosing and duration), and outcome assessed across studies. There were few interventional studies and limited data collected on specific groups such as children and pregnant women. CONCLUSIONS/SIGNIFICANCE: There were a limited number of interventional trials, highlighting that scrub typhus remains a neglected disease. The heterogeneous nature of the available data reflects the absence of consensus in treatment and research methodologies and poses a significant barrier to aggregating information across available published data without access to the underlying IPD. There is likely to be a substantial amount of data available to address knowledge gaps. Therefore, there is value for an IPD platform that will facilitate pooling and harmonisation of currently scattered data and enable in-depth investigation of priority research questions that can, ultimately, inform clinical practice and improve health outcomes for scrub typhus patients.

The Chagas disease study landscape: A systematic review of clinical and observational antiparasitic treatment studies to assess the potential for establishing an individual participant-level data platform.

BACKGROUND: Chagas disease (CD), caused by the parasite Trypanosoma cruzi, affects ~6-7 million people worldwide. Significant limitations still exist in our understanding of CD. Harnessing individual participant data (IPD) from studies could support more in-depth analyses to address the many outstanding research questions. This systematic review aims to describe the characteristics and treatment practices of clinical studies in CD and assess the breadth and availability of research data for the potential establishment of a data-sharing platform. METHODOLOGY/PRINCIPAL FINDINGS: This review includes prospective CD clinical studies published after 1997 with patients receiving a trypanocidal treatment. The following electronic databases and clinical trial registry platforms were searched: Cochrane Library, PubMed, Embase, LILACS, Scielo, Clintrials.gov, and WHO ICTRP. Of the 11,966 unique citations screened, 109 (0.9%) studies (31 observational and 78 interventional) representing 23,116 patients were included. Diagnosis for patient enrolment required 1 positive test result in 5 (4.6%) studies (2 used molecular method, 1 used molecular and serology, 2 used serology and parasitological methods), 2 in 60 (55.0%), 3 in 14 (12.8%) and 4 or more in 4 (3.7%) studies. A description of treatment regimen was available for 19,199 (83.1%) patients, of whom 14,605 (76.1%) received an active treatment and 4,594 (23.9%) were assigned to a placebo/no-treatment. Of the 14,605 patients who received an active treatment, benznidazole was administered in 12,467 (85.4%), nifurtimox in 825 (5.6%), itraconazole in 284 (1.9%), allopurinol in 251 (1.7%) and other drugs in 286 (1.9%). Assessment of efficacy varied largely and was based primarily on biological outcome; parasitological efficacy relied on serology in 67/85 (78.8%) studies, molecular methods in 52/85 (61.2%), parasitological in 34/85 (40.0%), microscopy in 3/85 (3.5%) and immunohistochemistry in 1/85 (1.2%). The median time at which parasitological assessment was carried out was 79 days [interquartile range (IQR): 30-180] for the first assessment, 180 days [IQR: 60-500] for second, and 270 days [IQR: 18-545] for the third assessment. CONCLUSIONS/SIGNIFICANCE: This review demonstrates the heterogeneity of clinical practice in CD treatment and in the conduct of clinical studies. The sheer volume of potential IPD identified demonstrates the potential for development of an IPD platform for CD and that such efforts would enable in-depth analyses to optimise the limited pharmacopoeia of CD and inform prospective data collection.

Serious adverse events following treatment of visceral leishmaniasis: A systematic review and meta-analysis.

BACKGROUND: Despite a historical association with poor tolerability, a comprehensive review on safety of antileishmanial chemotherapies is lacking. We carried out an update of a previous systematic review of all published clinical trials in visceral leishmaniasis (VL) from 1980 to 2019 to document any reported serious adverse events (SAEs). METHODS: For this updated systematic review, we searched the following databases from 1st Jan 2016 through 2nd of May 2019: PUBMED, Embase, Scopus, Web of Science, Cochrane, clinicaltrials.gov, WHO ICTRP, and the Global Index Medicus. We included randomised and non-randomised interventional studies aimed at assessing therapeutic efficacy and extracted the number of SAEs reported within the first 30 days of treatment initiation. The incidence rate of death (IRD) from individual treatment arms were combined in a meta-analysis using random effects Poisson regression. RESULTS: We identified 157 published studies enrolling 35,376 patients in 347 treatment arms. Pentavalent antimony was administered in 74 (21.3%), multiple-dose liposomal amphotericin B (L-AmB) in 52 (15.0%), amphotericin b deoxycholate in 51 (14.7%), miltefosine in 33 (9.5%), amphotericin b fat/lipid/colloid/cholesterol in 31 (8.9%), and single-dose L-AmB in 17 (4.9%) arms. There was a total of 804 SAEs reported of which 793 (including 428 deaths) were extracted at study arm level (11 SAEs were reported at study level only). During the first 30 days, there were 285 (66.6%) deaths with the overall IRD estimated at 0.068 [95% confidence interval (CI): 0.041-0.114; I2 = 81.4%; 95% prediction interval (PI): 0.001-2.779] per 1,000 person-days at risk; the rate was 0.628 [95% CI: 0.368-1.021; I2 = 82.5%] in Eastern Africa, and 0.041 [95% CI: 0.021-0.081; I2 = 68.1%] in the Indian Subcontinent. In 21 study arms which clearly indicated allowing the inclusion of patients with HIV co-infections the IRD was 0.575 [95% CI: 0.244-1.355; I2 = 91.9%] compared to 0.043 [95% CI: 0.020-0.090; I2 = 62.5%] in 160 arms which excluded HIV co-infections. CONCLUSION: Mortality within the first 30 days of VL treatment initiation was a rarely reported event in clinical trials with an overall estimated rate of 0.068 deaths per 1,000 person-days at risk, though it varied across regions and patient populations. These estimates may serve as a benchmark for future trials against which mortality data from prospective and pharmacovigilance studies can be compared. The methodological limitations exposed by our review support the need to assemble individual patient data (IPD) to conduct robust IPD meta-analyses and generate stronger evidence from existing trials to support treatment guidelines and guide future research.

Baseline results of a living systematic review for COVID-19 clinical trial registrations.

Background: Since the coronavirus disease 2019 (COVID-19) outbreak was first reported in December 2019, many independent trials have been planned that aim to answer similar questions. Tools allowing researchers to review studies already underway can facilitate collaboration, cooperation and harmonisation. The Infectious Diseases Data Observatory (IDDO) has undertaken a living systematic review (LSR) to provide an open, accessible and frequently updated resource summarising characteristics of COVID-19 study registrations. Methods: Review of all eligible trial records identified by systematic searches as of 3 April 2020 and initial synthesis of clinical study characteristics were conducted. In partnership with Exaptive, an open access, cloud-based knowledge graph has been created using the results.  Results: There were 728 study registrations which met eligibility criteria and were still active. Median (25 th, 75 th percentile) sample size was 130 (60, 400) for all studies and 134 (70, 300) for RCTs. Eight lower middle and low income countries were represented among the planned recruitment sites. Overall 109 pharmacological interventions or advanced therapy medicinal products covering 23 drug categories were studied. Majority (57%, 62/109) of them were planned only in one study arm, either alone or in combination with other interventions. There were 49 distinct combinations studied with 90% (44/49) of them administered in only one or two study arms. The data and interactive platform are available at https://iddo.cognitive.city/. Conclusions:  Baseline review highlighted that the majority of investigations in the first three months of the outbreak were small studies with unique treatment arms, likely to be unpowered to provide solid evidence.  The continued work of this LSR will allow a more dependable overview of interventions tested, predict the likely strength of evidence generated, allow fast and informative filtering of relevant trials for specific user groups and provide the rapid guidance needed by investigators and funders to avoid duplication of efforts.

Prevalence and Determinants of Antibiotic Self-Medication among Adult Patients with Respiratory Tract Infections in the Mboppi Baptist Hospital, Douala, Cameroon: A Cross-Sectional Study.

Antibiotic self-medication in patients with respiratory tract infections (RTI) is increasing globally and has been reported to be one of the prime contributors to antimicrobial resistance (AMR). Our study aims to provide data on the prevalence of antibiotic self-medication and identify the factors contributing to self-medication in adult patients with respiratory tract infection in an urban setting in Cameroon. This was cross-sectional study carried out at Mboppi Baptist Hospital, Douala, Cameroon. A validated structured questionnaire was administered to 308 consenting participants with diagnosed RTIs, to collect data on socio-demographic characteristics and history of antibiotic self-medication. Significance was set at a p-value < 0.05. The prevalence of antibiotic self-medication amongst individuals with RTIs was 41.9% (95% CI 36.5% to 47.5%). Patients with a history of pulmonary tuberculosis (TB) were significantly less likely to self-medicate with antibiotics (p-value = 0.043). The most common source of antibiotic self-medication was pharmacies (62%) and Cotrimoxazole and Amoxicillin were the most commonly used antibiotics (38.8% (50), 26.4% (34), respectively). Self-medication with antibiotics in adult patients with RTIs is common in Cameroon. Control of the use of antibiotics, organisation of medication stewardship programs, and education of the general population on the adverse consequences of antibiotic self-medication are required.

Prevalence and determinants of selected cardio-metabolic risk factors among people living with HIV/AIDS and receiving care in the South West Regional Hospitals of Cameroon: a cross-sectional study.

OBJECTIVE: Metabolic disorders and cardiovascular risk factors are not routinely assessed in the care of HIV patients in developing countries, known to have the highest disease burden. We described the prevalence and factors associated with major cardio-metabolic risk factors (obesity, diabetes and hypertension) in HIV/AIDS patients. RESULTS: The prevalence of diabetes, hypertension and obesity were 11.3% (95% CI 8.10-15.43), 24.8% (95% CI 20.1-30.0) and 14.5% (95% CI 11.1-19.3) respectively. Central obesity and high alcohol intake were the factors significantly associated with diabetes mellitus, while central obesity and overweight/obesity were significantly associated with having hypertension. Short duration of antiretroviral therapy was the significant predisposing factor for obesity. On multivariate analyses, the only association observed was between central obesity and diabetes (Adjusted OR 2.52, 95% CI 1.01-6.30, P = 0.048). Conclusively, DM, HTN and obesity are highly prevalent in HIV/AIDS patients in the SWR hospitals of Cameroon, with that of DM and obesity being higher than that seen in the general population while that of HTN equaling that of the general population. Awareness of these data among clinicians involved in the management of these patients should be emphasized.

Markers of adiposity in HIV/AIDS patients: Agreement between waist circumference, waist-to-hip ratio, waist-to-height ratio and body mass index.

BACKGROUND: Waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) are all independent predictors of cardio-metabolic risk and therefore important in HIV/AIDS patients on antiretroviral therapy at risk of increased visceral adiposity. This study aimed to assess the extent of agreement between these parameters and the body mass index (BMI), as anthropometric parameters and in classifying cardio-metabolic risk in HIV/AIDS patients. METHODS: A secondary analysis of data from a cross-sectional study involving 200 HIV/AIDS patients was done. Anthropometric parameters were measured from participants using standard guidelines and central obesity defined according to recommended criteria. Increased cardio-metabolic risk was defined according to the standard cut-off values for all four parameters. Data were analyzed using STATA version 14.1. RESULTS: The prevalence of WC-defined central obesity, WHR-defined central obesity and WHtR > 0.50 were 33.5%, 44.5% and 36.5%, respectively. The prevalence of BMI-defined overweight and obesity was 40.5%. After adjusting for gender and HAART status, there was a significant linear association and correlation between WC and BMI (regression equation: WC (cm) = 37.184 + 1.756 BMI (Kg/m2) + 0.825 Male + 1.002 HAART, (p < 0.001, r = 0.65)), and between WHtR and BMI (regression equation: WHtR = 0.223 + 0.011 BMI (Kg/m2)- 0.0153 Male + 0.003 HAART, (p < 0.001, r = 0.65)), but not between WHR and BMI (p = 0.097, r = 0.13). There was no agreement between the WC, WHtR and BMI, and minimal agreement between the WHR and BMI, in identifying patients with an increased cardio-metabolic risk. CONCLUSION: Despite the observed linear association and correlation between these anthropometric parameters, the routine use of WC, WHR and WHtR as better predictors of cardio-metabolic risk should be encouraged in these patients, due to their minimal agreement with BMI in identifying HIV/AIDS patients with increased cardio-metabolic risk. HAART status does not appear to significantly affect the association between these anthropometric parameters.

Depression Among HIV/AIDS Patients on Highly Active Antiretroviral Therapy in the Southwest Regional Hospitals of Cameroon: A Cross-Sectional Study.

INTRODUCTION: HIV patients are now having longer life expectancies with the use of antiretroviral therapy (ART). However, the issue of mental illness has surfaced with depression being the most common in these patients, which has markedly reduced patient adherence to ART. In Cameroon, the management of HIV/AIDS does not incorporate psychiatric manifestations and depression is therefore underdiagnosed. The aim of our study was to determine the prevalence and determinants of depressive symptoms and their association with adherence to ART among HIV/AIDS patients on HAART in the Southwest Regional Hospitals of Cameroon. METHODS: This was a cross-sectional hospital-based study carried out in the BRH and LRH over a 3-month period. Three hundred HIV patients aged 21 and above were recruited. Depression and adherence to treatment were assessed using the nine-item Patient Health Questionnaire (PHQ-9) and eight-item Morisky Medication Adherence Scale questionnaires, respectively. Data were analysed using Epi-info version 3.4.5. RESULTS: The prevalence of depression was 26.7% (95% CI 20.6-33.7%); 75.0% of those with depression were non-adherent to HAART compared to 37.3% of those without depression (p value <0.001). The statistically significant risk factors associated with depression were unemployment (OR 2.38; 95% CI 1.26-4.50), age ≤40 years (OR 2.13; 95% CI 1.20-3.70) and CD4 counts ≤200 cells/µl (OR 3.70; 95% CI 1.45-9.09). CONCLUSION: The prevalence of depression was high and depression was significantly associated with non-adherence to HAART. Interventions to enhance early identification and treatment of depression in patients with HIV/AIDS are needed. Depression screening should be included as part of the routine consultation of HIV/AIDS patients to ensure early detection and treatment.

Knowledge of Hypertension and Compliance with Therapy Among Hypertensive Patients in the Bamenda Health District of Cameroon: A Cross-sectional Study.

INTRODUCTION: The prevalence of hypertension has continued to increase and is now a great burden for health care providers. Obtaining information on the factors affecting compliance to antihypertensive drugs is thus important. The aim of this study was to assess knowledge of hypertension and to determine factors affecting the compliance of hypertensive patients to their antihypertensive drugs. METHODS: This was a cross-sectional study involving 221 hypertensive patients in the Bamenda Health District. Validated questionnaires were used. From December 2014 to March 2015, knowledge of hypertension was assessed using a 15-item scale, while compliance was assessed using the 8-item Morisky Medication Adherence Scale. Statistical analysis was performed using SPSS version 20. RESULTS: 14.0%, 53.4%, and 32.6% of participants had adequate, average, and poor knowledge of hypertension, respectively. The antihypertensive compliance rate was 43.9%. Independent predictors of noncompliance were forgetfulness (OR = 0.011, 95% CI = 0.002-0.063), lack of motivation due to the incurable nature of the disease (OR = 0.068, 95% CI = 0.017-0.274), and lack of symptoms of the disease (OR = 0.019, 95% CI = 0.02-0.23). There was a significant association between compliance and blood pressure control (p < 0.001). CONCLUSION: Knowledge of hypertension was poor. Compliance rate to treatment was low. Some medication-related, patient attitude, and health care provider factors affected compliance. Knowledge positively affected compliance, and good compliance was associated with good blood pressure control. Emphasis should be placed on patient education and reminders to patients to take their drugs.

The current status of malaria epidemiology in Bolifamba, atypical Cameroonian rainforest zone: an assessment of intervention strategies and seasonal variations.

BACKGROUND: Global malaria has been on the decline over the past decade due to expansion of interventions. The present study aimed at determining the current status of malaria epidemiology in the context of sustained interventions and seasonal variations in Bolifamba, which represents a typical semi-urban malaria endemic community in the Cameroonian rainforest. METHODS: A monthly cross-sectional survey was carried out in Bolifamba, a multi ethnic semi-urban locality on the eastern flanks of Mt Cameroon, for a year during which blood samples were collected from participants and examined for malaria parasites by microscopy. Correlation analysis of seasonal/monthly malaria prevalence was done with weather data from Ekona, a nearby village with a meteorological station. Intervention strategy such as use of Insecticide Treated Bed Net (ITBN) and risk factors such as duration of stay in the locality, age and housing type were also investigated. RESULTS: The results revealed a malaria prevalence of 38.3 % in the rainy season, which was significantly higher than 24.4 % observed in the dry season (P < 0.0001). A high prevalence of asymptomatic malaria which was more than double the prevalence of symptomatic malaria on a monthly basis was observed, 30.7 % vs 17.8 % in the rainy and dry season respectively (p < 0.0001) and asymptomatic malaria was significantly associated with anemia (p < 0.005). April was the peak month of malaria prevalence and coincided with peak periods of both asymptomatic and symptomatic malaria. The Plasmodium falciparum parasite rates in the 2- up to 10-years age group (PfPR(2-10)) was 40.8 %. The regular use of ITBN was significantly associated with low prevalence of 31.7 % as opposed to irregular or non-usage of ITBN 38.2 % (p < 0.05). Log of parasite load was found to initially increase to 2.49 with less than 5 years of stay, and decreased gradually with increasing duration of stay in the locality (p = 0.046). Climatic factors were significantly and positively associated with monthly malaria prevalence and the strongest predictors of malaria prevalence were rainfall and minimum temperature with r values of 0.563 and 0.6 respectively. CONCLUSIONS: The study highlights the role of seasonal change in modifying malaria prevalence during the year and the beneficial effect of ITBN. It also underscores a sublime problem of asymptomatic malaria associated with anemia, and indicates that partial immunity is acquired with prolonged stay in Bolifamba. This preliminary result is the basis of ongoing work to identify the antigens involved in acquired immunity.