Scaling-up co-trimoxazole prophylaxis in HIV-exposed and HIV-infected children in high HIV-prevalence countries.

Co-trimoxazole (trimethoprim-sulfamethoxazole) is a widely available antibiotic that substantially reduces HIV-related morbidity and mortality in both adults and children. Prophylaxis with co-trimoxazole is a recommended intervention of proven benefit that could serve not only as an initial step towards improving paediatric care in young children with limited access to antiretroviral treatment, but also as an important complement to antiretroviral therapy in resource-limited settings. Despite co-trimoxazole's known clinical benefits, the potential operational benefits, and favourable recommendations by WHO, UNAIDS, and UNICEF, its routine use in developing countries--particularly sub-Saharan Africa--has remained limited. Out of an estimated 4 million children in need of co-trimoxazole prophylaxis (HIV-exposed and HIV-infected), only 4% are currently receiving this intervention. We discuss some of the major barriers preventing the scale-up of co-trimoxazole prophylaxis for children in countries with a high prevalence of HIV and propose specific actions required to tackle these challenges

Trends in antimicrobial resistance in bloodstream infection isolates at a large urban hospital in Malawi (1998-2016): a surveillance study.

BACKGROUND Bacterial bloodstream infection is a common cause of morbidity and mortality in sub-Saharan Africa, yet few facilities are able to maintain long-term surveillance. The Malawi-Liverpool-Wellcome Trust Clinical Research Programme has done sentinel surveillance of bacteraemia since 1998. We report long-term trends in bloodstream infection and antimicrobial resistance from this surveillance. METHODS In this surveillance study, we analysed blood cultures that were routinely taken from adult and paediatric patients with fever or suspicion of sepsis admitted to Queen Elizabeth Central Hospital, Blantyre, Malawi from 1998 to 2016. The hospital served an urban population of 920 000 in 2016, with 1000 beds, although occupancy often exceeds capacity. The hospital admits about 10 000 adults and 30 000 children each year. Antimicrobial susceptibility tests were done by the disc diffusion method according to British Society of Antimicrobial Chemotherapy guidelines. We used the Cochran-Armitage test for trend to examine trends in rates of antimicrobial resistance, and negative binomial regression to examine trends in icidence of bloodstream infection over time. FINDINGS Between Jan 1, 1998, and Dec 31, 2016, we isolated 29 183 pathogens from 194 539 blood cultures. Pathogen detection decreased significantly from 327·1/100 000 in 1998 to 120·2/100 000 in 2016 (p<0·0001). 13 366 (51·1%) of 26 174 bacterial isolates were resistant to the Malawian first-line antibiotics amoxicillin or penicillin, chloramphenicol, and co-trimoxazole; 68·3% of Gram-negative and 6·6% of Gram-positive pathogens. The proportions of non-Salmonella Enterobacteriaceae with extended spectrum beta-lactamase (ESBL) or fluoroquinolone resistance rose significantly after 2003 to 61·9% in 2016 (p<0·0001). Between 2003 and 2016, ESBL resistance rose from 0·7% to 30·3% in Escherichia coli, from 11·8% to 90·5% in Klebsiella spp and from 30·4% to 71·9% in other Enterobacteriaceae. Similarly, resistance to ciprofloxacin rose from 2·5% to 31·1% in E coli, from 1·7% to 70·2% in Klebsiella spp and from 5·9% to 68·8% in other Enterobacteriaceae. By contrast, more than 92·0% of common Gram-positive pathogens remain susceptible to either penicillin or chloramphenicol. Meticillin-resistant Staphylococcus aureus (MRSA) was first reported in 1998 at 7·7% and represented 18·4% of S aureus isolates in 2016. INTERPRETATION The rapid expansion of ESBL and fluoroquinolone resistance among common Gram-negative pathogens, and the emergence of MRSA, highlight the growing challenge of bloodstream infections that are effectively impossible to treat in this resource-limited setting. FUNDING Wellcome Trust, H3ABionet, Southern Africa Consortium for Research Excellence (SACORE)

Ten Years of Surveillance for Invasive Streptococcus pneumoniae during the Era of Antiretroviral Scale-Up and Cotrimoxazole Prophylaxis in Malawi

OBJECTIVE: To document trends in invasive pneumococcal disease (IPD) in a central hospital in Malawi during the period of national scale-up of antiretroviral therapy (ART) and cotrimoxazole prophylaxis. METHODS: Between 1 January 2000 and 31 December 2009 almost 100,000 blood cultures and 40,000 cerebrospinal fluid (CSF) cultures were obtained from adults and children admitted to the Queen Elizabeth Central Hospital, Blantyre, Malawi with suspected severe bacterial infection. RESULTS: 4,445 pneumococcal isolates were obtained over the 10 year period. 1,837 were from children: 885 (19.9%) from blood and 952 (21.4%) from CSF. 2,608 were from adults: 1,813 (40.8%) from blood and 795 (17.9%) from CSF. At the start of the surveillance period cotrimoxazole resistance was 73.8% and at the end was 92.6%. Multidrug resistance (MDR) was present in almost one third of isolates and was constant over time. Free ART was introduced in Malawi in 2004. From 2005 onwards there was a decline in invasive pneumococcal infections with a negative correlation between ART scale-up and the decline in IPD (Pearson's correlation r = -0.91; p<0.001). CONCLUSION: During 2004-2009, national ART scale-up in Malawi was associated with a downward trend in IPD at QECH. The introduction of cotrimoxazole prophylaxis in HIV-infected groups has not coincided with a further increase in pneumococcal cotrimoxazole or multidrug resistance. These data highlight the importance of surveillance for high disease burden infections such as IPD in the region, which will be vital for monitoring pneumococcal conjugate vaccine introduction into national immunisation programmes

Bloodstream infections at a tertiary level paediatric hospital in South Africa

BACKGROUND: Bloodstream infection (BSI) in children causes significant morbidity and mortality. There are few studies describing the epidemiology of BSI in South African children. METHODS: A retrospective descriptive cohort study was conducted at a paediatric referral hospital in Cape Town, South Africa. The National Health Laboratory Service (NHLS) microbiology database was accessed to identify positive blood culture specimens during the period 2011-2012. Demographic and clinical details, antimicrobial management and patient outcome information were extracted from medical and laboratory records. Antibiotic susceptibility results of identified organisms were obtained from the NHLS database. RESULTS: Of the 693 unique bacterial and fungal BSI episodes identified during the study period, 248 (35.8%) were community-acquired (CA), 371 (53.5%) hospital-acquired (HA) and 74 (10.7%) healthcare-associated (HCA). The overall risk was 6.7 BSI episodes per 1000 admissions. Escherichia coli, Staphylococcus aureus and Streptococcus pneumoniae were the most frequent causes of CA-BSI and Klebsiella pneumoniae, Acinetobacter baumanii and S.aureus were most commonly isolated in HA-BSI. On multivariable analysis, severe underweight, severe anaemia at the time of BSI, admission in the ICU at the time of BSI, and requiring ICU admission after BSI was diagnosed were significantly associated with 14-day mortality. CONCLUSION: This study adds to the limited literature describing BSI in children in Africa. Further studies are required to understand the impact that BSI has on the paediatric population in sub-Saharan Africa

Modelling the Contributions of Malaria, HIV, Malnutrition and Rainfall to the Decline in Paediatric Invasive Non-typhoidal Salmonella Disease in Malawi

Introduction Nontyphoidal Salmonellae (NTS) are responsible for a huge burden of bloodstream infection in Sub-Saharan African children. Recent reports of a decline in invasive NTS (iNTS) disease from Kenya and The Gambia have emphasised an association with malaria control. Following a similar decline in iNTS disease in Malawi, we have used 9 years of continuous longitudinal data to model the interrelationships between iNTS disease, malaria, HIV and malnutrition. Methods Trends in monthly numbers of childhood iNTS disease presenting at Queen’s Hospital, Blantyre, Malawi from 2002 to 2010 were reviewed in the context of longitudinal monthly data describing malaria slide-positivity among paediatric febrile admissions, paediatric HIV prevalence, nutritional rehabilitation unit admissions and monthly rainfall over the same 9 years, using structural equation models (SEM). Results Analysis of 3,105 iNTS episodes identified from 49,093 blood cultures, showed an 11.8% annual decline in iNTS (p < 0.001). SEM analysis produced a stable model with good fit, revealing direct and statistically significant seasonal effects of malaria and malnutrition on the prevalence of iNTS disease. When these data were smoothed to eliminate seasonal cyclic changes, these associations remained strong and there were additional significant effects of HIV prevalence. Conclusions These data suggest that the overall decline in iNTS disease observed in Malawi is attributable to multiple public health interventions leading to reductions in malaria, HIV and acute malnutrition. Understanding the impacts of public health programmes on iNTS disease is essential to plan and evaluate interventions

Towards an evidence base in the treatment of severe febrile illness in East African children

Febrile illness is the primary cause of childhood outpatient attendance, admission to hospital and death in Africa. This series of studies were aimed at ascertaining the treatable causes of infection in children admitted to a district hospital typical of those found throughout East Africa, in an area of high transmission of malaria. The studies were also designed to determine the clinical correlates of infection and predictors of mortality, looking in particular at malaria, invasive bacterial disease and HIV infection. These studies also explored to what extent clinical examination by one group of staff was replicable by another.After informed consent a detailed history and structured examination was performed on all children admitted to the hospital. Blood was drawn for culture, microscopy for malaria, HIV testing, full blood count, bedside haemoglobin, blood glucose and lactate measurement and HRP-2 based rapid diagnostic test for falciparum malaria. Outcomes were recorded at death or discharge.Sufficient data was available on 3,639 children including 184 deaths (5.1%). Invasive bacterial disease was detected in 341 children (9.4%) and HIV in 142 (3.9%). Children with HIV and those with evidence of recent malaria were significantly more likely to have invasive bacterial disease. The most common organisms isolated were non-typhi Salmonella (46.9%), Strep, pneumoniae (16.4%) and Haemophilus influenzae b (11.4%). The most frequently encountered pathogen was P. falciparum, with 2,195 children found to have asexual parasitaemia (60.3%). Falciparum parasitaemia was detected in 100 children with invasive bacterial disease (29.3%). Falciparum malaria was detected in over half (51.6%) of childhood deaths, invasive bacterial disease was documented in 31.5%.In children with a positive blood slide for malaria, WHO severe malaria criteria identified 91.6% of the children that died. A multivariate analysis showed that signs of malnutrition, respiratory distress, altered consciousness, hypoxia according to pulse oximetry, hypoglycaemia, raised blood lactate, invasive bacterial disease and female sex were all associated with an increased risk of death. In children with negative blood slides signs of malnutrition, respiratory distress, altered consciousness, hypoglycaemia, raised blood lactate and invasive bacterial disease were all independently associated with mortality by multivariate analysis.WHO defined criteria of syndromes which would warrant antibiotics predicted 56% of cases of coinfection with invasive bacterial disease and malaria and 69.7% of cases of invasive bacterial disease in slide negative children. Treating all children with severe malaria for bacterial disease would result in 71% of children with coinfection being treated. In children with negative slides including severe anaemia or prostration as syndromes requiring antibiotic therapy would have resulted in 74.7% of children with invasive bacterial disease receiving antibiotic therapy. There was moderate agreement between staff over the presence of clinical signs in children, with hospital nurses performing as well as hospital clinical officers. Agreement was better in children over 18 months of age and in children who were not crying during examination.Current WHO guidelines on antibiotic use performed poorly in this setting. Gram negative infections were the most common cause of invasive infection and many of these are likely to be resistant to penicillin and other commonly used antibiotics. Consideration should be given to expanding the indications for antibiotic use and using more broad-spectrum antibiotics in severely ill children

Clinical and microbiological characterisation of invasive enteric pathogens in a South African population: the interaction with HIV

A Thesis Submitted to the School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Doctor of Philosophy Johannesburg, South Africa 2016.Introduction Human immunodeficiency virus (HIV) has been associated with invasive enteric infections in HIV-infected patients, since it was first described in the 1980s. In South Africa, HIV remains an important health challenge, despite the introduction of antiretroviral therapy (ART) in 2003. In association with this, is an ongoing problem of invasive enteric infections, including those due to Shigella and Salmonella, including Salmonella enterica serovar Typhi (Salmonella Typhi). There are few South African data available as to the incidence of invasive disease due to these pathogens and how these data may contrast with the presentation and outcome in HIV-uninfected patients. The associated risk factors for mortality due to invasive enteric pathogens and whether there has been a response with ART as an intervention also needs further elucidation. Aims This work was undertaken to better describe the burden of invasive enteric infections (Shigella, nontyphoidal Salmonella and Salmonella Typhi) in association with HIV, define risk factors for mortality and establish whether the introduction of ART has impacted on disease burdens due to these pathogens. Methods Laboratory-based surveillance for enteric pathogens was initiated in 2003. Basic demographic details (age and gender) were collected on all patients where possible. In 25 hospital sites in all nine provinces, additional clinical information was collected by trained surveillance officers, including HIV status, data reflecting severity of illness, other immune suppressive conditions, antimicrobial and antiretroviral usage and outcome (survival versus death). Laboratories were requested to transport all isolates to the Centre for Enteric Diseases (CED) at the National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS) in Johannesburg for further characterisation, including serotyping, antimicrobial susceptibility testing and molecular typing where relevant (whether isolates could respectively be classified as Salmonella Typhimurium ST313 and Salmonella Typhi H58). Additional cases were sought through audits of the Central Data Warehouse (CDW) of the NHLS. Annual incidence rates were calculated according to published estimates of population by age group by the Actuarial Society of South Africa for the Department of Statistics of the South African government. Analyses were specifically directed at invasive shigellosis, Salmonella meningitis, typhoid fever in South Africa and nontyphoidal salmonellosis in Gauteng Province, South Africa. Data were recorded in an Access database and analysed using chisquared test to establish differences between HIV-infected and uninfected individuals and univariate and multivariate analysis to compare risk factors for mortality. Data in the number of patients accessing ART were derived through audits of the CDW, by using the numbers of patients on whom viral loads were done annually as a proxy. Results Between 2003 and 2013, a total of 10111 invasive enteric isolates were received by CED. For patients for whom sex was recorded, 3283/6244 (52.6%) of patients presenting with invasive enteric infections were male; invasive disease was predominantly observed in children less than five years of age (1605/6131; 26.2%) and those who were aged between 25 and 54 years (3186/6131; 52.0%), with the exception of typhoid fever where the major burden was in patients aged 5 to 14 years (302/855; 35.3%). KH Keddy 81-11384 PhD iv More HIV-infected adult women were observed with invasive shigellosis (P=0.002) and with typhoid fever compared with adult men (P=0.009). Adults aged ≥ 15 years were more likely to die than children aged < 15 years (invasive shigellosis, odds ratio [OR]=3.2, 95% confidence interval [CI]=1.6 – 6.6, P=0.001; Salmonella meningitis, OR=3.7, 95% CI=1.7 – 8.1, P=0.001; typhoid fever, OR=3.7, 95% CI=1.1 – 14.9, P=0.03; invasive nontyphoidal salmonellosis, OR=2.0, 95% CI=1.6 – 2.5, P<0.001). HIV-infected patients had a significantly higher risk of mortality compared with HIVuninfected patients (invasive shigellosis, OR=4.1, 95% CI=1.5 – 11.8, P=0.008; Salmonella meningitis OR=5.3, 95% CI=1.4-20.0, P=0.013; typhoid fever, OR=11.3, 95% CI=3.0 – 42.4, P<0.001; invasive nontyphoidal salmonellosis OR=2.5, 95% CI=1.7 – 3.5, P<0.001). In all patients, severity of illness was the most significant factor contributing to mortality (invasive shigellosis, OR=22.9, 95% CI=2.7 – 194.2, P=0.004; Salmonella meningitis OR=21.6, 95% CI=3.5 – 133.3, P=0.01; typhoid fever, OR=10.8, 95% CI=2.9 – 39.5, P<0.001; invasive nontyphoidal salmonellosis OR=5.4, 95% CI=3.6 – 8.1, P<0.001). Between 2003 and 2013, ART was significantly associated with decreasing incidence rates of invasive nontyphoidal salmonellosis in adults aged 25 - 49 years (R=-0.92; P<0.001), but not in children (R=-0.50; P=0.14). Conclusion Decreasing incidence rates of invasive nontyphoidal salmonellosis and shigellosis suggest that ART is having an impact on opportunistic enteric disease in HIV. Further work is necessary however, to fully understand the associations between age, sex and invasive enteric pathogens. Specifically, this work would include typhoid fever, Shigella transmission from child to adult carer, development of invasive enteric infections in HIV-exposed children and whether the decreasing incidence rates can be sustained. Moving forward, an understanding of invasive enteric infections in the HIV-uninfected patient may assist in targeting severity of illness as a risk factor for mortality.MT201

Febrile diseases in young children in Burkina Faso:Etiologies and the value of rapid diagnostic test in primary healthcare settings

The aim of this thesis is to address the problem of the diagnosis and management of febrile diseases in young children living in rural settings in Burkina Faso. Our aim is to provide more insight into the etiology of febrile disease in the study region, to determine the performance of current diagnostic practices and their effect on drug prescriptions, and to propose some diagnostic alternatives to improve the diagnosis and management of febrile diseases