A mixed method multi-Country assessment of barriers to implementing pediatric inpatient care guidelines

Introduction: Accelerating progress in reducing child deaths is needed in order to achieve the Sustainable Development Goal child mortality target. This will require a focus on vulnerable children-including young children, those who are undernourished or with acute illnesses requiring hospitalization. Improving adherence to inpatient guidelines may be an important strategy to reduce child mortality, including among the most vulnerable. The aim of our assessment of nine sub-Saharan African and South Asian hospitals was to determine adherence to pediatric inpatient care recommendations, in addition to capacity for and barriers to implementation of guideline-adherent care prior to commencing the Childhood Acute Illness and Nutrition (CHAIN) Cohort study. The CHAIN Cohort study aims to identify modifiable risk factors for poor inpatient and post discharge outcomes above and beyond implementation of guidelines.Methods: Hospital infrastructure, staffing, durable equipment, and consumable supplies such as medicines and laboratory reagents, were evaluated through observation and key informant interviews. Inpatient medical records of 2-23 month old children were assessed for adherence to national and international guidelines. The records of children with severe acute malnutrition (SAM) were oversampled to reflect the CHAIN study population. Seven core adherence indicators were examined: oximetry and oxygen therapy, fluids, anemia diagnosis and transfusion, antibiotics, malaria testing and antimalarials, nutritional assessment and management, and HIV testing.Results: All sites had facilities and equipment necessary to implement care consistent with World Health Organization and national guidelines. However, stockouts of essential medicines and laboratory reagents were reported to be common at some sites, even though they were mostly present during the assessment visits. Doctor and nurse to patient ratios varied widely. We reviewed the notes of 261 children with admission diagnoses of sepsis (17), malaria (47), pneumonia (70), diarrhea (106), and SAM (119); 115 had multiple diagnoses. Adherence to oxygen therapy, antimalarial, and malnutrition refeeding guidelines was \u3e75%. Appropriate antimicrobials were prescribed for 75% of antibiotic-indicative conditions. However, 20/23 (87%) diarrhea and 20/27 (74%) malaria cases without a documented indication were prescribed antibiotics. Only 23/122 (19%) with hemoglobin levels meeting anemia criteria had recorded anemia diagnoses. HIV test results were infrequently documented even at hospitals with universal screening policies (66/173, 38%). Informants at all sites attributed inconsistent guideline implementation to inadequate staffing.Conclusion: Assessed hospitals had the infrastructure and equipment to implement guideline-consistent care. While fluids, appropriate antimalarials and antibiotics, and malnutrition refeeding adherence was comparable to published estimates from low- and high-resource settings, there were inconsistencies in implementation of some other recommendations. Stockouts of essential therapeutics and laboratory reagents were a noted barrier, but facility staff perceived inadequate human resources as the primary constraint to consistent guideline implementation

Effect of 3 Days of Oral Azithromycin on Young Children With Acute Diarrhea in Low-Resource Settings A Randomized Clinical Trial

Importance: World Health Organization (WHO) guidelines do not recommend routine antibiotic use for children with acute watery diarrhea. However, recent studies suggest that a significant proportion of such episodes have a bacterial cause and are associated with mortality and growth impairment, especially among children at high risk of diarrhea-associated mortality. Expanding antibiotic use among dehydrated or undernourished children may reduce diarrhea-associated mortality and improve growth. Objective: To determine whether the addition of azithromycin to standard case management of acute nonbloody watery diarrhea for children aged 2 to 23 months who are dehydrated or undernourished could reduce mortality and improve linear growth. Design, Setting, and Participants: The Antibiotics for Children with Diarrhea (ABCD) trial was a multicountry, randomized, double-blind, clinical trial among 8266 high-risk children aged 2 to 23 months presenting with acute nonbloody diarrhea. Participants were recruited between July 1, 2017, and July 10, 2019, from 36 outpatient hospital departments or community health centers in a mixture of urban and rural settings in Bangladesh, India, Kenya, Malawi, Mali, Pakistan, and Tanzania. Each participant was followed up for 180 days. Primary analysis included all randomized participants by intention to treat. Interventions: Enrolled children were randomly assigned to receive either oral azithromycin, 10 mg/kg, or placebo once daily for 3 days in addition to standard WHO case management protocols for the management of acute watery diarrhea. Main Outcomes and Measures: Primary outcomes included all-cause mortality up to 180 days after enrollment and linear growth faltering 90 days after enrollment. Results: A total of 8266 children (4463 boys [54.0%]; mean [SD] age, 11.6 [5.3] months) were randomized. A total of 20 of 4133 children in the azithromycin group (0.5%) and 28 of 4135 children in the placebo group (0.7%) died (relative risk, 0.72; 95% CI, 0.40-1.27). The mean (SD) change in length-for-age z scores 90 days after enrollment was -0.16 (0.59) in the azithromycin group and -0.19 (0.60) in the placebo group (risk difference, 0.03; 95% CI, 0.01-0.06). Overall mortality was much lower than anticipated, and the trial was stopped for futility at the prespecified interim analysis. Conclusions and Relevance: The study did not detect a survival benefit for children from the addition of azithromycin to standard WHO case management of acute watery diarrhea in low-resource settings. There was a small reduction in linear growth faltering in the azithromycin group, although the magnitude of this effect was not likely to be clinically significant. In low-resource settings, expansion of antibiotic use is not warranted. Adherence to current WHO case management protocols for watery diarrhea remains appropriate and should be encouraged. Trial Registration: ClinicalTrials.gov Identifier: NCT03130114.publishedVersionPeer reviewe

Antimicrobial Resistance in Children at Hospital Discharge in Western Kenya

Thesis (Ph.D.)--University of Washington, 2022Introduction: Antimicrobial resistance (AMR) is associated with millions of deaths per year worldwide. The global burden of AMR is disproportionately high in Sub-Saharan Africa, primarily as a result of the high incidence of infectious diseases. Children who have been hospitalized and subsequently discharged in this region are at high risk for morbidity and mortality. It is possible that AMR plays a role in these poor outcomes through treatment failure due to antibiotic resistant pathogens or through the acquisition of new resistant infections either during hospitalization or the post-discharge period. In addition, children carrying resistance determinants may serve as an important reservoir of AMR that can be transferred to other household and community members. Conditions favorable to the spread of bacteria, and therefore AMR, such as crowded living conditions, insufficient sanitation and hygiene facilities and contaminated water sources, may exacerbate community transmission from these children to others. Methods: This dissertation used bacterial isolates from fecal samples from a recently completed clinical trial examining whether azithromycin reduced death and rehospitalization during the discharge period in children aged 6 – 59 months in western Kenya. Fecal samples were collected at the time of enrollment, prior to the administration of the first dose of the study drug or placebo. Study staff performed medical record extractions, conducted interviews with caregivers, and study clinicians performed a medical examination. Fecal samples were also collected at follow-up visits 3-months and 6-months post-enrollment. Bacterial isolates, including Escherichia coli (E. coli), Salmonella, and Shigella were isolated and underwent antimicrobial susceptibility testing (AST). Additionally, a random subset of caregivers were enrolled and provided fecal samples for the isolation of E. coli and subsequent AST. The proportion of E. coli isolated from children at enrollment resistant to a panel of antibiotics and extended-spectrum beta-lactamase (ESBL) production and risk factors for carriage of ESBL-producing E. coli was determined (Chapter 1). Patterns of AMR in E. coli isolated from children and their caregivers at the time of hospital discharge were examined and correlates of concordance assessed (Chapter 2). Agreement of susceptibility to antibiotics in Salmonella or Shigella with E. coli isolated from the same fecal sample were also examined (Chapter 3). Results: The proportion of E. coli isolated from children resistant to ampicillin (95%), gentamicin (44%), ceftriaxone (46%), and the presence of ESBL (44%) was high. Use of antibiotics during the hospitalization (adjusted prevalence ration [aPR] = 2.23; 95% CI: 1.29 – 3.83) and being hospitalized within the prior year (aPR = 1.32 [1.07 – 1.69]) were associated with the presence of ESBL producing E. coli. Additionally, being female (aPR = 1.42; 95% CI: 1.15 – 1.76), practicing open defecation (aPR = 2.02; 95% CI: 1.39 – 2.94), and having a toilet shared with other households (aPR = 1.49; 95% CI: 1.17 – 1.89) were also associated with carriage of ESBL E. coli. Across all antibiotics tested, caregivers had less AMR than children. Concordance of AMR was more common when resistance to a particular antibiotic was particularly high (cefoxitin, chloramphenicol, and cotrimoxazole) or low (imipenem). ESBL concordance was less common in child-caregiver pairs where there was more than one child in the household compared to those without additional children (55.0% vs. 79.9% [p = 0.02]) and with caregivers who reported being employed or a student than those who were not employed or a student (45.0% vs. 55.0%) [p = 0.05]). E. coli had high concordance for susceptibility and was a reliable predictor of the outcome to cephalosporins and gentamicin but was a poor predictor of susceptibility to azithromycin and ciprofloxacin. Conclusion: Children who have been discharged from hospital have a high burden of AMR, which may contribute to poor outcomes in the post-discharge period. Given the frequency of AMR in this high risk population, new guidelines for the treatment of common infectious syndromes in children with a recent hospitalization should be considered. Additionally, because these children are likely to carry AMR from the hospital back into the community, they may pass AMR to family and other community members. Interventions which reduce the transmission of infectious agents may also reduce the transmission of AMR

Plasmid-mediated quinolone resistance genes detected in Ciprofloxacin non-susceptible Escherichia coli and Klebsiella isolated from children under five years at hospital discharge, Kenya

Abstract Background The increasing spread of fluoroquinolone resistant enteric bacteria is a global public health concern. Children recently discharged from the hospital are at high risk of carriage of antimicrobial resistance (AMR) due to frequent exposure to antimicrobials during inpatient stays. This study aimed to determine the prevalence, correlates of ciprofloxacin (CIP) non-susceptibility, and distribution of plasmid-mediated quinolone resistance (PMQR) genes in Escherichia coli (E. coli) and Klebsiella spp isolated from children under five years being discharged from two Kenyan Hospitals. Methods E. coli and Klebsiella spp were isolated from fecal samples from children discharged from hospital and subjected to antimicrobial susceptibility testing (AST) by disc diffusion and E-test. CIP non-susceptible isolates were screened for seven PMQR genes using multiplex polymerase chain reaction (PCR). Poisson regression was used to determine the association between the carriage of CIP non-susceptible isolates and patient characteristics. Results Of the 280 CIP non-susceptible isolates: 188 E. coli and 92 Klebsiella spp isolates identified among 266 discharged children, 195 (68%) were CIP-non-susceptible with minimum inhibitory concentrations (MICs) of ≥ 1 µg/mL. Among these 195 isolates, 130 (67%) had high-level CIP MIC =  ≥ 32 µg/mL). Over 80% of the isolates had at least one PMQR gene identified: aac(6’)lb-cr (60%), qnrB (24%), oqxAB (22%), qnrS (16%), and qepA (6%), however, qnrA was not identified in any isolates tested. Co-carriage of qnrB with acc(6’)-lb-cr was the most predominant accounting for 20% of all the isolates. Ceftriaxone use during hospital admission and the presence of extended spectrum beta-lactamase (ESBL) production were significantly associated with the carriage of CIP non-susceptible E. coli and Klebsiella spp. Conclusion CIP non-susceptibility is common among E. coli and Klebsiella spp isolated from hospital discharged children in Kenya. Carriage and co-carriage of PMQR, including the newly identified qepA gene, were frequently observed. These findings suggest that children leaving the hospital may serve as an important reservoir for transmission of resistant E. coli and Klebsiella spp to the community. Enhanced surveillance for AMR determinants is critical to inform interventions to control antimicrobial-resistant bacteria

Pediatric Inpatient Antibiotic Prescription Practices in the Chain Network Hospitals at Baseline

This analysis describes adherence to antibiotic guidelines during the first 48 hours of admission. Adherence was defined as a regimen consistent with institutional, national, or international recommendations.Antimicrobial resistance (AMR) is a growing global concern. Antibiotic stewardship is being promoted to reduce AMR. However, few studies have documented inpatient antibiotic prescription practices in low resource settings. We audited the 240 clinical notes of 2-23 month-old inpatient children in Bangladesh (2), Kenya (3), Malawi (1), Pakistan (1) and Uganda (1) as part of a baseline assessment in a study to identify risk factors for mortality in acutely ill inpatients, particularly in undernourished children. This analysis describes adherence to antibiotic guidelines during the first 48 hours of admission. Adherence was defined as a regimen consistent with institutional, national, or international recommendations. The cases reviewed included diagnoses of diarrhea (n:107), severe acute malnutrition (n:101), pneumonia (n:76), malaria (n:35), sepsis (n:25), meningitis (n:12), and shock (n:8). Antibiotics were prescribed to 98% with at least one documented indication for antibiotics (n:173); 80% of these were consistent with recommended regimens. Antibiotics were prescribed in 93% of admitted diarrhea cases, 85% of whom had a comorbidity warranting antimicrobials (n:85) or dysentery (n:1). Among children with malaria noted as a diagnosis and without a documented indication for antibiotics (n:22), those who did not receive a malaria test (n:6) were all prescribed antibiotics. In comparison, 63% of those with a documented positive malaria test (n:16) were prescribed antibiotics without indication. Among those with diarrhea (n:15) and malaria (n:16) without a documented indication for antibiotics, 58% were prescribed an antimicrobial regimen consistent with treatment for a severe bacterial infection. Antibiotics were almost universally prescribed when indicated and adherence to a recommend regimen was comparable to other studie

A mixed method multi-country assessment of barriers to implementing pediatric inpatient care guidelines.

INTRODUCTION:Accelerating progress in reducing child deaths is needed in order to achieve the Sustainable Development Goal child mortality target. This will require a focus on vulnerable children-including young children, those who are undernourished or with acute illnesses requiring hospitalization. Improving adherence to inpatient guidelines may be an important strategy to reduce child mortality, including among the most vulnerable. The aim of our assessment of nine sub-Saharan African and South Asian hospitals was to determine adherence to pediatric inpatient care recommendations, in addition to capacity for and barriers to implementation of guideline-adherent care prior to commencing the Childhood Acute Illness and Nutrition (CHAIN) Cohort study. The CHAIN Cohort study aims to identify modifiable risk factors for poor inpatient and post discharge outcomes above and beyond implementation of guidelines. METHODS:Hospital infrastructure, staffing, durable equipment, and consumable supplies such as medicines and laboratory reagents, were evaluated through observation and key informant interviews. Inpatient medical records of 2-23 month old children were assessed for adherence to national and international guidelines. The records of children with severe acute malnutrition (SAM) were oversampled to reflect the CHAIN study population. Seven core adherence indicators were examined: oximetry and oxygen therapy, fluids, anemia diagnosis and transfusion, antibiotics, malaria testing and antimalarials, nutritional assessment and management, and HIV testing. RESULTS:All sites had facilities and equipment necessary to implement care consistent with World Health Organization and national guidelines. However, stockouts of essential medicines and laboratory reagents were reported to be common at some sites, even though they were mostly present during the assessment visits. Doctor and nurse to patient ratios varied widely. We reviewed the notes of 261 children with admission diagnoses of sepsis (17), malaria (47), pneumonia (70), diarrhea (106), and SAM (119); 115 had multiple diagnoses. Adherence to oxygen therapy, antimalarial, and malnutrition refeeding guidelines was >75%. Appropriate antimicrobials were prescribed for 75% of antibiotic-indicative conditions. However, 20/23 (87%) diarrhea and 20/27 (74%) malaria cases without a documented indication were prescribed antibiotics. Only 23/122 (19%) with hemoglobin levels meeting anemia criteria had recorded anemia diagnoses. HIV test results were infrequently documented even at hospitals with universal screening policies (66/173, 38%). Informants at all sites attributed inconsistent guideline implementation to inadequate staffing. CONCLUSION:Assessed hospitals had the infrastructure and equipment to implement guideline-consistent care. While fluids, appropriate antimalarials and antibiotics, and malnutrition refeeding adherence was comparable to published estimates from low- and high-resource settings, there were inconsistencies in implementation of some other recommendations. Stockouts of essential therapeutics and laboratory reagents were a noted barrier, but facility staff perceived inadequate human resources as the primary constraint to consistent guideline implementation

Clinical and nutritional correlates of bacterial diarrhoea aetiology in young children: a secondary cross-sectional analysis of the ABCD trial

Objective The objective was to assess the association between nutritional and clinical characteristics and quantitative PCR (qPCR)-diagnosis of bacterial diarrhoea in a multicentre cohort of children under 2 years of age with moderate to severe diarrhoea (MSD).Design A secondary cross-sectional analysis of baseline data collected from the AntiBiotics for Children with Diarrhoea trial (NCT03130114).Patients Children with MSD (defined as >3 loose stools within 24 hours and presenting with at least one of the following: some/severe dehydration, moderate acute malnutrition (MAM) or severe stunting) enrolled in the ABCD trial and collected stool sample.Study period June 2017–July 2019.Interventions None.Main outcome measures Likely bacterial aetiology of diarrhoea. Secondary outcomes included specific diarrhoea aetiology.Results A total of 6692 children with MSD had qPCR results available and 28% had likely bacterial diarrhoea aetiology. Compared with children with severe stunting, children with MAM (adjusted OR (aOR) (95% CI) 1.56 (1.18 to 2.08)), some/severe dehydration (aOR (95% CI) 1.66 (1.25 to 2.22)) or both (aOR (95% CI) 2.21 (1.61 to 3.06)), had higher odds of having likely bacterial diarrhoea aetiology. Similar trends were noted for stable toxin-enterotoxigenic Escherichia coli aetiology. Clinical correlates including fever and prolonged duration of diarrhoea were not associated with likely bacterial aetiology; children with more than six stools in the previous 24 hours had higher odds of likely bacterial diarrhoea (aOR (95% CI) 1.20 (1.05 to 1.36)) compared with those with fewer stools.Conclusion The presence of MAM, dehydration or high stool frequency may be helpful in identifying children with MSD who might benefit from antibiotics