Ultrasound assessment of malnutrition in infancy: a pilot case-control study.

This study aimed at determining the intra- and inter-rater reliability in ultrasound body composition measurements and investigating the differences between malnourished and non-malnourished infants. Sonographic images for measurements of fat and muscle thickness were compared between 9 malnourished and 9 non-malnourished hospitalized infants. The mean of fat and muscle thickness sums were 12.44 ± 7.58 mm and 28.98 ± 7.18 mm, respectively. The intra- and inter-rater intraclass correlation coefficient were above 0.9 for both measurements, indicating high intra- and inter-rater reliability. Compared to non-malnourished infants, malnourished infants have 45% of fat thickness sum and 71% of muscle thickness sum. Ultrasound measurements of body composition in infants were different between hospitalized malnourished and non-malnourished infants. This approach has the potential to be utilized more broadly, from assessing the nutritional status of critically ill infants in intensive care units to screening for malnutrition in high-risk infant populations.

Invasiveness potential of pneumococcal serotypes in children after introduction of PCV13 in Blantyre, Malawi.

INTRODUCTION: The introduction of PCV13 to the Malawi infant immunization schedule in 2011 has been associated with reduced disease from Streptococcus pneumoniae. Improved understanding of serotypes with high invasive potential can guide future vaccination interventions. We aimed to estimate pneumococcal serotypes associated with acute respiratory infection (ARI) and invasive pneumococcal disease (IPD) in hospitalized children in Blantyre, Malawi. METHODS: We analysed data from healthy children under 5 years in the community in Blantyre and children admitted to Queen Elizabeth Central Hospital with ARI between 2015 and 2018. Nasopharyngeal swabs from children were tested for S. pneumoniae and serotyped by latex agglutination if positive. We analysed culture-positive blood and cerebrospinal fluid samples from admitted children between 2012 and 2018 to identify cases of IPD after the introduction of PCV13. We calculated the age-adjusted odds ratio (OR) of carriage for S. pneumoniae vaccine serotypes (VT) comparing those with ARI to healthy children. We also calculated age-adjusted ORs comparing serotypes causing IPD to carriage in the community with OR > 1 indicating high invasive potential. RESULTS: Serotypes 5 (OR 24.73 [95% CI 7.90-78.56] p < 0.001), 1 (OR 23.38 [95% CI 9.75-56.06] p < 0.001), and 6B (OR 4.73 [95% CI 1.66-11.64] p = 0.001) had high invasive potential. Serotype 6B was no longer significant (OR 1.34 [95% CI 0.07-6.87] p = 0.777) in a sensitivity analysis accounting for year of recruitment. The prevalence of S. pneumoniae carriage in the community was 72.6% [95% CI 71.3-74.0] (3078/4238) and 23.4% (719/3078) of positive community samples were VT. The carriage prevalence in those hospitalised with ARI was 45.5% [95% CI 42.1-48.9] (389/855) and 43.8% of hospital attendees reported antibiotic use prior to admission. We did not identify significant associations with carriage of any serotypes in those with ARI. CONCLUSIONS: Pneumococcal serotypes 5 and 1 are associated with high invasive potential. Despite high community pneumococcal carriage, pre-hospital antibiotic usage likely reduces pneumococcal detection among children admitted in this setting and further research is needed to investigate serotypes associated with ARI. Data from this study can guide future preventative vaccination strategies in Malawi.

Evaluating blood culture collection practice in children hospitalized with acute illness at a tertiary hospital in Malawi.

BACKGROUND: Blood culture collection practice in low-resource settings where routine blood culture collection is available has not been previously described. METHODOLOGY: We conducted a secondary descriptive analysis of children aged 2-23 months enrolled in the Malawi Childhood Acute Illness and Nutrition (CHAIN) study, stratified by whether an admission blood culture had been undertaken and by nutritional status. Chi-square test was used to compare the differences between groups. RESULTS: A total of 347 children were included, of whom 161 (46%) had a blood culture collected. Children who had a blood culture collected, compared to those who did not, were more likely to present with sepsis (43% vs. 20%, p < 0.001), gastroenteritis (43% vs. 26%, p < 0.001), fever (86% vs. 73%, p = 0.004), and with poor feeding/weight loss (30% vs. 18%, p = 0.008). In addition, hospital stay in those who had a blood culture was, on average, 2 days longer (p = 0.019). No difference in mortality was observed between those who did and did not have a blood culture obtained. CONCLUSION: Blood culture collection was more frequent in children with sepsis and gastroenteritis, but was not associated with mortality. In low-resource settings, developing criteria for blood culture based on risk factors rather than clinician judgement may better utilize the existing resources.

Blood culture is key to investigating bloodstream infections, but in-hospital decisions to perform blood culture in a low-resource setting have not been previously described. We linked blood culture data to the Childhood Acute Illness and Nutrition (CHAIN) cohort at a Malawi tertiary hospital and compared clinical characteristics and outcomes of children between those who did and did not have a blood culture done on admission. Of those hospitalized, 46% of the children had a blood culture collected at admission. Only 3% of blood cultures had significant growth of pathogenic bacteria. There were significant differences in nutritional status, presenting symptoms, clinical diagnoses and hospital length of stay between those who received blood culture collection on admission and those who did not, but there was no difference in mortality. Clinical judgement used to determine blood culture collection may not best identify children most at risk.

Pharmacokinetics and Pharmacodynamics of Clofazimine for Treatment of Cryptosporidiosis.

Infection with Cryptosporidium spp. can cause severe diarrhea, leading to long-term adverse impacts and even death in malnourished children and immunocompromised patients. The only FDA-approved drug for treating cryptosporidiosis, nitazoxanide, has limited efficacy in the populations impacted the most by the diarrheal disease, and safe, effective treatment options are urgently needed. Initially identified by a large-scale phenotypic screening campaign, the antimycobacterial therapeutic clofazimine demonstrated great promise in both in vitro and in vivo preclinical models of Cryptosporidium infection. Unfortunately, a phase 2a clinical trial in HIV-infected adults with cryptosporidiosis did not identify any clofazimine treatment effect on Cryptosporidium infection burden or clinical outcomes. To explore whether clofazimine's lack of efficacy in the phase 2a trial may have been due to subtherapeutic clofazimine concentrations, a pharmacokinetic/pharmacodynamic modeling approach was undertaken to determine the relationship between clofazimine in vivo concentrations and treatment effects in multiple preclinical infection models. Exposure-response relationships were characterized using Emax and logistic models, which allowed predictions of efficacious clofazimine concentrations for the control and reduction of disease burden. After establishing exposure-response relationships for clofazimine treatment of Cryptosporidium infection in our preclinical model studies, it was unmistakable that the clofazimine levels observed in the phase 2a study participants were well below concentrations associated with anti-Cryptosporidium efficacy. Thus, despite a dosing regimen above the highest doses recommended for mycobacterial therapy, it is very likely the lack of treatment effect in the phase 2a trial was at least partially due to clofazimine concentrations below those required for efficacy against cryptosporidiosis. It is unlikely that clofazimine will provide a remedy for the large number of cryptosporidiosis patients currently without a viable treatment option unless alternative, safe clofazimine formulations with improved oral absorption are developed. (This study has been registered in ClinicalTrials.gov under identifier NCT03341767.).

Childhood Pneumonia Diagnostics in Sub-Saharan Africa: A Systematic Review.

BACKGROUND: The prompt and accurate aetiological diagnosis of childhood pneumonia remains a challenge, especially in sub-Saharan Africa (SSA) because of limited resources for disease management. OBJECTIVE: To review existing diagnostics for childhood pneumonia and potential modalities available to differentiate between bacterial and viral aetiologies in SSA. METHODS: Online databases were searched for relevant articles published between January 2010 and December 2020 regarding childhood pneumonia diagnosis, conducted in SSA in children less than 18 years of age. The 2020 PRISMA checklist was utilized in appraising the selected studies and the QUADAS-2 tool was employed to assess the risk of bias in each of the studies selected. RESULTS: A total of 1542 study titles and abstracts were screened following which 45 studies (39 on childhood pneumonia diagnostics and 6 on discriminating between bacterial and viral childhood pneumonia) were selected for review. Microbiological investigations (79.7%) constituted the most utilized index tests with blood-related specimen (32.8%) being the most utilized specimen. The most performed index diagnostic modality was polymerase chain reaction (PCR) (53.1%). The commonest reference gold standard technique was based on clinical diagnosis of the disease (46.2%). Only six studies in SSA attempted at using serum biomarkers, either singly or in combination to distinguish between aetiologies with use of combined biomarkers showing promise. CONCLUSION: Microbiological investigations are the most employed diagnostic methods for childhood pneumonia in SSA. More studies are required to evaluate the potential use of serum biomarkers; either singly or in combination with the goal of discriminating bacterial and viral childhood pneumonia.

Childhood pneumonia remains a disease of global health significance, contributing greatly to childhood morbidity and mortality especially in SSA. The effective management of the disease anchors on prompt diagnosis and identification of the likely aetiologic agent in order to guide appropriate therapeutic interventions. Though a global challenge, the diagnosis of the disease remains a major concern particularly in low- and middle-income settings given the limited resources. This study aimed at systematically reviewing childhood pneumonia diagnostics in SSA which is a high burden area with limited resources. The review also aimed at identifying potential modalities available to differentiate between bacterial and viral aetiologies as these findings will have implications on antimicrobial stewardship in the region. Following a review of three online databases, microbiological investigations (79.7%) constituted the most utilized index tests in SSA while blood-related specimen (32.8%) being the most utilized specimen. There was no study in the region assessing the potential usefulness of radiological modalities like lung ultrasonography for childhood pneumonia diagnostics which emphasizes a need for further research in that regard given its non-invasive nature and diagnostic validity from research carried out in more developed countries. Furthermore, only six studies aimed at discriminating bacterial or viral aetiology in the region which is limited and is an area for further research.

Association of Neonatal Hypothermia with Morbidity and Mortality in a Tertiary Hospital in Malawi.

OBJECTIVES: To evaluate associations with neonatal hypothermia in a tertiary-level neonatal unit (NU) in Malawi. METHODS: Neonates with a birth weight >1000 g were recruited and temperatures were recorded 5 min after birth, on admission and 4 h thereafter. Clinical course and outcome were reviewed. Data were analysed using Stata v.15 and p < 0.05 was considered statistically significant. RESULTS: Between August 2018 to March 2019, 120 neonates were enrolled, and 112 were included in the data analysis. Hypothermia at 5 min after birth was noted in 74%, 77% on admission to the NU and 38% at 24 h. Neonates who had hypothermia 5 min after birth were more likely to have hypothermia on admission to the NU compared with normothermic subjects (p < 0.01). All neonates with hypothermia on admission to the NU died (100 vs.72%, p = 0.02), but hypothermia at 5 min nor at 24 h were not associated with mortality. After adjusting for potential confounders, the odds ratio of hypothermia at 5 min for hypothermia on admission to NU was 13.31 (95% CI 4.17-42.54). DISCUSSION: A large proportion of hospitalized neonates is hypothermic on admission and has associated morbidity and mortality. Our findings suggest that a strong predictor of mortality is neonatal hypothermia on admission to the NU, and that early intervention in the immediate period after delivery could decrease the incidence of hypothermia and reduce associated morbidity and mortality.

Emerging Resistance to Empiric Antimicrobial Regimens for Pediatric Bloodstream Infections in Malawi (1998-2017).

BACKGROUND: The adequacy of the World Health Organization's Integrated Management of Childhood Illness (IMCI) antimicrobial guidelines for the treatment of suspected severe bacterial infections is dependent on a low prevalence of antimicrobial resistance (AMR). We describe trends in etiologies and susceptibility patterns of bloodstream infections (BSI) in hospitalized children in Malawi. METHODS: We determined the change in the population-based incidence of BSI in children admitted to Queen Elizabeth Central Hospital, Blantyre, Malawi (1998-2017). AMR profiles were assessed by the disc diffusion method, and trends over time were evaluated. RESULTS: A total 89643 pediatric blood cultures were performed, and 10621 pathogens were included in the analysis. Estimated minimum incidence rates of BSI for those ≤5 years of age fell from a peak of 11.4 per 1000 persons in 2002 to 3.4 per 1000 persons in 2017. Over 2 decades, the resistance of Gram-negative pathogens to all empiric, first-line antimicrobials (ampicillin/penicillin, gentamicin, ceftriaxone) among children ≤5 years increased from 3.4% to 30.2% (P < .001). Among those ≤60 days, AMR to all first-line antimicrobials increased from 7.0% to 67.7% (P < .001). Among children ≤5 years, Klebsiella spp. resistance to all first-line antimicrobial regimens increased from 5.9% to 93.7% (P < .001). CONCLUSIONS: The incidence of BSI among hospitalized children has decreased substantially over the last 20 years, although gains have been offset by increases in Gram-negative pathogens' resistance to all empiric first-line antimicrobials. There is an urgent need to address the broader challenge of adapting IMCI guidelines to the local setting in the face of rapidly-expanding AMR in childhood BSI.

Evaluating respiratory cryptosporidiosis in pediatric diarrheal disease: protocol for a prospective, observational study in Malawi.

BACKGROUND: Cryptosporidium is among the most common causes of severe diarrhea in African children 0-23 months old. It is associated with excess mortality, stunting and malnutrition. The most common manifestation of cryptosporidium is intestinal diarrheal disease. However, respiratory cryptosporidiosis has been documented in up to a third of children presenting with diarrhea. It is unclear whether respiratory involvement is a transient phenomenon or a reservoir for gastrointestinal (GI) disease. This study aims to evaluate the role of respiratory cryptosporidiosis in pediatric diarrheal disease. METHODS: This is a prospective, observational study conducted at Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi. Young children aged 2-24 months hospitalized with diarrhea will be enrolled. Enrolled children will have induced sputum, nasopharyngeal (NP) swab and stool samples collected. All participants positive for cryptosporidium on sputum/NP/stool PCR testing will be followed up fortnightly after discharge from the hospital up to 8 weeks post-discharge. Sputum/NP/stool sample collection will be done at each visit. The primary outcomes will be presence of Cryptosporidium spp. in sputum/NP/stool. The secondary outcome will be presence of respiratory and GI symptoms, mortality and stunting. Ethical approval was obtained from the University of Malawi College of Medicine Research Ethics Committee (COMREC) and the Liverpool School of Tropical Medicine (LSTM) research ethics committee. DISCUSSION: The study began recruitment activities at QECH in February 2019. The protocol allows for expansion of recruitment to secondary sites within Blantyre and Chikwawa districts in the event that targets are not met at QECH. Study recruitment is expected to continue until early 2020.

Diagnostics for neonatal sepsis: current approaches and future directions.

Progress has been made in the reduction of morbidity and mortality from neonatal sepsis. However, diagnosis continues to rely primarily on conventional microbiologic techniques, which can be inaccurate. The objective of this review is to provide the clinician with an overview of the current information available on diagnosing this condition. We review currently available diagnostic approaches for documenting neonatal sepsis and also describe novel approaches for diagnosing infection in neonates who are under development and investigation. Substantial progress has been made with molecular approaches and further development of non-culture-based methods offer promise. The potential ability to incorporate antimicrobial resistance gene testing in addition to pathogen identification may provide a venue to incorporate a predominantly molecular platform into a larger program of neonatal care.

Child acute illness presentation and referrals at primary health clinics in Malawi: a secondary analysis of ASPIRE.

OBJECTIVES: We aimed to assess the prevalence, presentation and referral patterns of children with acute illness attending primary health centres (PHCs) in a low-resource setting. DESIGN, SETTING AND PARTICIPANTS: We conducted a secondary analysis of ASPIRE. Children presenting at eight PHCs in urban Blantyre district in southern Malawi with both recorded clinician and mHealth (non-clinician) triage data were included, and patient records from different data collection points along the patient healthcare seeking pathway were consolidated and analysed. RESULTS: Between April 2017 and September 2018, a total of 204 924 children were triaged, of whom 155 931 had both recorded clinician and mHealth triage data. The most common presenting symptoms at PHCs were fever (0.3%), cough (0.2%) and difficulty breathing (0.2%). The most common signs associated with referral for under-5 children were trauma (26.7%) and temperature (7.4%). The proportion of emergency and priority clinician triage were highest among young infants <2 months (0.2% and 81.4%, respectively). Of the 3004 referrals (1.9%), 1644 successfully reached the referral facility (54.7%). Additionally, 372 children were sent home from PHC who subsequently self-referred to the referral facility (18.7%). CONCLUSIONS: Fever and respiratory symptoms were the most common presenting symptoms, and trauma was the most common reason for referral. Rates of referral were low, and of successful referral were moderate. Self-referrals constituted a substantial proportion of attendance at the referral facility. Reducing gaps in care and addressing dropouts as well as self-referrals along the referral pathway could improve child health outcomes.

Risk factors for mortality in culture-negative neonatal sepsis in Malawi: a propensity score-matched analysis.

We conducted a propensity score-matched multivariable regression analysis of 1050 culture-negative neonatal sepsis cases in Malawi, where 160 (15.2%) died. Mortality among neonates with culture-negative sepsis was associated with very low birth weight (adjusted OR (AOR) 12.82, 95% CI 1.23 to 137.49), respiratory distress syndrome (AOR 13.20, 95% CI 2.58 to 83.66), a low Apgar score at 1 min (AOR 3.50, 95% CI 1.21 to 10.72) and at 5 min (AOR 4.77, 95% CI 1.94 to 12.50). Addressing maternal and perinatal factors around health and delivery of care is key to improving outcomes in the context of culture-negative sepsis in neonates from low-income country settings like Malawi.

Improving care pathways for children with severe illness through implementation of the ASPIRE mHealth primary ETAT package in Malawi.

Providing emergency care in low resource settings relies on delivery by lower cadres of health workers (LCHW). We describe the development, implementation and mixed methods evaluation of a mobile health (mHealth) triage algorithm based on the WHO Emergency, Triage, Assessment, and Treatment (ETAT) for primary-level care. We conducted an observational study design of implementation research. Key stakeholders were engaged throughout implementation. Clinicians and LCHW at eight primary health centres in Blantyre district were trained to use an mHealth algorithm for triage. An mHealth patient surveillance system monitored patients from presentation through referral to tertiary and final outcome. A total of 209,174 children were recorded by ETAT between April 2017 and September 2018, and 155,931 had both recorded mHealth and clinician triage outcome data. Concordance between mHealth triage by lower cadres of HCW and clinician assessment was 81·6% (95% CI [81·4, 81·8]) over all outcomes (kappa: 0·535 (95% CI [0·530, 0·539]). Concordance for mHealth emergency triage was 0.31 with kappa 0.42. The most common mHealth recorded emergency sign was breathing difficulty (74·1% 95% CI [70·1, 77·9]) and priority sign was raised temperature (76·2% (95% CI [75·9, 76·6]). A total of 1,644 referrals out of 3,004 (54·7%) successfully reached the tertiary site. Both providers and carers expressed high levels of satisfaction with the mHealth ETAT pathway. An mHealth triage algorithm can be used by LCHWs with moderate concordance with clinician triage. Implementation of ETAT through an mHealth algorithm documented successful referrals from primary to tertiary, but half of referred patients did not reach the tertiary site. Potential harms of such systems, such as cases requiring referral being missed during triage, require further evaluation. The ASPIRE mHealth primary ETAT approach can be used to prioritise acute illness and support future resource planning within both district and national health system.

Clofazimine pharmacokinetics in HIV-infected adults with diarrhea: Implications of diarrheal disease on absorption of orally administered therapeutics.

Oral drug absorption kinetics are usually established in populations with a properly functioning gastrointestinal tract. However, many diseases and therapeutics can alter gastrointestinal physiology and cause diarrhea. The extent of diarrhea-associated impact on drug pharmacokinetics has not been quantitatively described. To address this knowledge gap, we used a population pharmacokinetic modeling approach with data collected in a phase IIa study of matched human immunodeficiency virus (HIV)-infected adults with/without cryptosporidiosis and diarrhea to examine diarrhea-associated impact on oral clofazimine pharmacokinetics. A population pharmacokinetic model was developed with 428 plasma samples from 23 HIV-infected adults with/without Cryptosporidium infection using nonlinear mixed-effects modeling. Covariates describing cryptosporidiosis-associated diarrhea severity (e.g., number of diarrhea episodes, diarrhea grade) or HIV infection (e.g., viral load, CD4+ T cell count) were evaluated. A two-compartment model with lag time and first-order absorption and elimination best fit the data. Maximum diarrhea grade over the study duration was found to be associated with a more than sixfold reduction in clofazimine bioavailability. Apparent clofazimine clearance, intercompartmental clearance, central volume of distribution, and peripheral volume of distribution were 3.71 L/h, 18.2 L/h (interindividual variability [IIV] 45.0%), 473 L (IIV 3.46%), and 3434 L, respectively. The absorption rate constant was 0.625 h-1 (IIV 149%) and absorption lag time was 1.83 h. In conclusion, the maximum diarrhea grade observed for the duration of oral clofazimine administration was associated with a significant reduction in clofazimine bioavailability. Our results highlight the importance of studying disease impacts on oral therapeutic pharmacokinetics to inform dose optimization and maximize the chance of treatment success.

Vaccine value profile for Klebsiella pneumoniae.

Klebsiella pneumoniae causes community- and healthcare-associated infections in children and adults. Globally in 2019, an estimated 1.27 million (95% Uncertainty Interval [UI]: 0.91-1.71) and 4.95 million (95% UI: 3.62-6.57) deaths were attributed to and associated with bacterial antimicrobial resistance (AMR), respectively. K. pneumoniae was the second leading pathogen in deaths attributed to AMR resistant bacteria. Furthermore, the rise of antimicrobial resistance in both community- and hospital-acquired infections is a concern for neonates and infants who are at high risk for invasive bacterial disease. There is a limited antibiotic pipeline for new antibiotics to treat multidrug resistant infections, and vaccines targeted against K. pneumoniae are considered to be of priority by the World Health Organization. Vaccination of pregnant women against K. pneumoniae could reduce the risk of invasive K.pneumoniae disease in their young offspring. In addition, vulnerable children, adolescents and adult populations at risk of K. pneumoniae disease with underlying diseases such as immunosuppression from underlying hematologic malignancy, chemotherapy, patients undergoing abdominal and/or urinary surgical procedures, or prolonged intensive care management are also potential target groups for a K. pneumoniae vaccine. A 'Vaccine Value Profile' (VVP) for K.pneumoniae, which contemplates vaccination of pregnant women to protect their babies from birth through to at least three months of age and other high-risk populations, provides a high-level, holistic assessment of the available information to inform the potential public health, economic and societal value of a pipeline of K. pneumoniae vaccines and other preventatives and therapeutics. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public-private partnerships, and multi-lateral organizations, and in collaboration with stakeholders from the WHO. All contributors have extensive expertise on various elements of the K.pneumoniae VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

Protocols, policies and practices for antimicrobial stewardship in hospitalized patients in least-developed and low-income countries: a systematic review.

BACKGROUND: We aimed to identify interventions used to implement antimicrobial stewardship practices among hospitalized patients in least-developed countries. METHODS: The research team searched PubMed, EMBASE, and Cochrane Central Register of Controlled Trials for studies of AMS interventions in the least developed and low-income countries, published between 2000 and 2023. Included studies had a population of hospitalized patients of all age groups in least-developed countries, implemented an AMS intervention, and reported its impact on prescription practices, clinical outcomes, or microbiological results. The risk of bias was assessed using the integrated quality criteria for review of multiple study designs. A total of 443 articles were identified, 386 articles were screened, 16 full-text papers were reviewed, and 10 studies were included in the analysis. RESULTS: The ten studies included three controlled before and after, two qualitative, one controlled interrupted time series, two non-controlled interrupted time series, one quasi-experimental study, and one randomized controlled trial. Three studies implemented either enabling, persuasive, or structural interventions respectively. The rest used bundled strategies, including a combination of persuasive, enabling, structural, and restrictive interventions. Bundled interventions using enabling and persuasive strategies were the most common. These involved creating a prescription guideline, training prescribers on updated methods, and subsequent review and feedback of patient files by members of an AMS team. Improved microbiological surveillance was important to most studies but, sustained improvement in appropriate prescriptions was dependent on enabling or persuasive efforts. Studies noted significant improvements in appropriate prescriptions and savings on the costs of antibiotics. None evaluated the impact of AMS on AMR. CONCLUSION: AMS practices generally involve multiple strategies to improve prescription practices. In the setting of least-developed countries, enabling and persuasive interventions are popular AMS measures. However, measured outcomes are heterogeneous, and we suggest that further studies assessing the impact of AMS should report changes in AMR patterns (microbiological outcomes), patient length of stay and mortality (patient outcomes), and changes in prescription practices (prescription outcomes). Reporting on these as outcomes of AMS interventions could make it easier for policymakers to compare which interventions have desirable outcomes that can be generalized to similar settings.

Antimicrobial resistance control activities at a tertiary hospital in a low-resource setting: an example of Queen Elizabeth Central Hospital in Malawi.

Background: Addressing AMR has been most problematic in low- and middle-income countries, which lack infrastructure, diagnostic capacity, and robust data management systems, among other factors. The implementation of locally-led efforts in a low-income country to develop sustainability and build capacity for AMR control within the existing infrastructure has not been well documented. Methods: We detail current AMR control initiatives at Queen Elizabeth Central Hospital, a tertiary referral government hospital in Malawi with limited resources, and present the activities accomplished to date, lessons learned, and challenges ahead. Results: The key areas of AMR control initiatives that the group focused on included laboratory diagnostics and surveillance, antimicrobial stewardship, infection prevention and control, pharmacy, leadership, education, and funding. Discussion: The hospital AMR Control Working Group increased awareness, built capacity, and implemented activities around AMR control throughout the hospital, in spite of the resource limitations in this setting. Our results are based on the substantial leadership provided by the working group and committed stakeholders who have taken ownership of this process. Conclusion: Limited resources pose a challenge to the implementation of AMR control activities in low- and middle-income countries. Leadership is central to implementation. Future efforts will need to transition the initiative from an almost fully personal commitment to one with wider engagement to ensure sustainability.

Clinical predictors of bacteraemia in neonates with suspected early-onset sepsis in Malawi: a prospective cohort study.

OBJECTIVES: We studied neonates with suspected early-onset sepsis (EOS, sepsis developing in the first 72 hours after delivery) in Malawi to (1) describe clinical characteristics and microbiological findings, (2) identify which patient characteristics may be associated with pathogen positivity on blood culture, and (3) describe mortality and its potential determinants. DESIGN: Prospective observational study (May 2018-June 2019). SETTING: Neonatal ward in Queen Elizabeth Central Hospital, the largest government hospital in Malawi. PATIENTS: All neonates with suspected EOS in whom a blood culture was obtained. RESULTS: Out of 4308 neonatal admissions, 1244 (28.9%) had suspected EOS. We included 1149 neonates, of which 109 blood cultures had significant growth (9.5%). The most commonly isolated pathogens were Staphylococcus aureus, Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli and Acinetobacter baumanii. Many of the Gram negatives were extended-spectrum beta lactamase-producing Enterobacteriaceae, and these were 40-100% resistant to first-line and second-line antimicrobials. Gestational age (GA) of <32 weeks was associated with pathogen-positive blood cultures (<28 weeks: adjusted OR (AOR) 2.72, 95% CI 1.04 to 7.13; 28-32 weeks: AOR 2.26, 95% CI 1.21 to 4.21; p=0.005). Mortality was 17.6% (202/1149) and associated with low birth weight (<1000 g: AOR 47.57, 95% CI 12.59 to 179.81; 1000-1500 g: AOR 11.31, 95% CI 6.97 to 18.36; 1500-2500 g: AOR 2.20, 95% CI 1.42 to 3.39; p<0.001), low Apgar scores at 5 min (0-3: AOR 18.60, 95% CI 8.81 to 39.27; 4-6: AOR 4.41, 95% CI 2.81 to 6.93; p<0.001), positive maternal venereal disease research laboratory status (AOR 2.53, 95% CI 1.25 to 5.12; p=0.001) and congenital anomalies (AOR 7.37, 95% CI 3.61 to 15.05; p<0.001). Prolonged rupture of membranes was inversely associated with mortality (AOR 0.43, 95% CI 0.19 to 0.98; p 0.007). CONCLUSION: In Malawi, EOS was suspected in nearly a third of neonatal admissions and had a high mortality. Ten per cent were culture-confirmed and predicted by low GA. To reduce the impact of suspected neonatal sepsis in least developed countries, improved maternal and antenatal care and development of rapid point of care methods to more accurately guide antimicrobial use could simultaneously improve outcome and reduce antimicrobial resistance.

Examination of ELISA against PCR for assessing treatment efficacy against Cryptosporidium in a clinical trial context.

BACKGROUND: Cryptosporidium is a gastrointestinal pathogen that presents a serious opportunistic infection in immunocompromised individuals including those living with human immunodeficiency syndrome. The CRYPTOFAZ trial, previously published, was conducted in Malawi to evaluate the efficacy of clofazimine in response to an unmet need for drugs to treat cryptosporidiosis in HIV populations. A combination of rapid diagnostic tests, ELISA, qPCR, and conventional sequencing were employed to detect Cryptosporidium in 586 individuals during pre-screening and monitor oocyst shedding and identify enteric co-pathogens in 22 enrolled/randomized participants during the in-patient period and follow-up visits. METHODOLOGY: Oocyst shedding as measured by qPCR was used to determine primary trial outcomes, however pathogen was detected even at trial days 41-55 in individuals randomized to either clofazimine or placebo arms of the study. Therefore, in this work we re-examine the trial outcomes and conclusions in light of data from the other diagnostics, particularly ELISA. ELISA data was normalized between experiments prior to comparison to qPCR. The amount of all identified enteric pathogens was examined to determine if co-pathogens other than Cryptosporidium were major causative agents to a participant's diarrhea. CONCLUSION: ELISA had higher sample-to-sample variability and proved to be equally or less sensitive than qPCR in detecting Cryptosporidium positive samples. Compared to qPCR, ELISA had equal or greater specificity in detecting Cryptosporidium negative samples. Sequencing identified several Cryptosporidium species including viatorum which has never been identified in Malawi and Southern Africa. In addition to Cryptosporidium, enterotoxigenic E. coli was also identified as a pathogen in diarrheagenic amounts in 4 out of 22 participants.