Inappropriate antibiotic prescribing and its determinants among outpatient children in 3 low- and middle-income countries: A multicentric community-based cohort study.

BACKGROUND: Antibiotic resistance is a global public health issue, particularly in low- and middle-income countries (LMICs), where antibiotics required to treat resistant infections are not affordable. LMICs also bear a disproportionately high burden of bacterial diseases, particularly among children, and resistance jeopardizes progress made in these areas. Although outpatient antibiotic use is a major driver of antibiotic resistance, data on inappropriate antibiotic prescribing in LMICs are scarce at the community level, where the majority of prescribing occurs. Here, we aimed to characterize inappropriate antibiotic prescribing among young outpatient children and to identify its determinants in 3 LMICs. METHODS AND FINDINGS: We used data from a prospective, community-based mother-and-child cohort (BIRDY, 2012 to 2018) conducted across urban and rural sites in Madagascar, Senegal, and Cambodia. Children were included at birth and followed-up for 3 to 24 months. Data from all outpatient consultations and antibiotics prescriptions were recorded. We defined inappropriate prescriptions as antibiotics prescribed for a health event determined not to require antibiotic therapy (antibiotic duration, dosage, and formulation were not considered). Antibiotic appropriateness was determined a posteriori using a classification algorithm developed according to international clinical guidelines. We used mixed logistic analyses to investigate risk factors for antibiotic prescription during consultations in which children were determined not to require antibiotics. Among the 2,719 children included in this analysis, there were 11,762 outpatient consultations over the follow-up period, of which 3,448 resulted in antibiotic prescription. Overall, 76.5% of consultations resulting in antibiotic prescription were determined not to require antibiotics, ranging from 71.5% in Madagascar to 83.3% in Cambodia. Among the 10,416 consultations (88.6%) determined not to require antibiotic therapy, 25.3% (n = 2,639) nonetheless resulted in antibiotic prescription. This proportion was much lower in Madagascar (15.6%) than in Cambodia (57.0%) or Senegal (57.2%) (p < 0.001). Among the consultations determined not to require antibiotics, in both Cambodia and Madagascar the diagnoses accounting for the greatest absolute share of inappropriate prescribing were rhinopharyngitis (59.0% of associated consultations in Cambodia, 7.9% in Madagascar) and gastroenteritis without evidence of blood in the stool (61.6% and 24.6%, respectively). In Senegal, uncomplicated bronchiolitis accounted for the greatest number of inappropriate prescriptions (84.4% of associated consultations). Across all inappropriate prescriptions, the most frequently prescribed antibiotic was amoxicillin in Cambodia and Madagascar (42.1% and 29.2%, respectively) and cefixime in Senegal (31.2%). Covariates associated with an increased risk of inappropriate prescription include patient age greater than 3 months (adjusted odds ratios (aOR) with 95% confidence interval (95% CI) ranged across countries from 1.91 [1.63, 2.25] to 5.25 [3.85, 7.15], p < 0.001) and living in rural as opposed to urban settings (aOR ranged across countries from 1.83 [1.57, 2.14] to 4.40 [2.34, 8.28], p < 0.001). Diagnosis with a higher severity score was also associated with an increased risk of inappropriate prescription (aOR = 2.00 [1.75, 2.30] for moderately severe, 3.10 [2.47, 3.91] for most severe, p < 0.001), as was consultation during the rainy season (aOR = 1.32 [1.19, 1.47], p < 0.001). The main limitation of our study is the lack of bacteriological documentation, which may have resulted in some diagnosis misclassification and possible overestimation of inappropriate antibiotic prescription. CONCLUSION: In this study, we observed extensive inappropriate antibiotic prescribing among pediatric outpatients in Madagascar, Senegal, and Cambodia. Despite great intercountry heterogeneity in prescribing practices, we identified common risk factors for inappropriate prescription. This underscores the importance of implementing local programs to optimize antibiotic prescribing at the community level in LMICs.

Plugging the leaks: antibiotic resistance at human-animal interfaces in low-resource settings.

Antibiotic resistance is one of the greatest public health challenges of our time. International efforts to curb resistance have largely focused on drug development and limiting unnecessary antibiotic use. However, in areas where water, sanitation, and hygiene infrastructure is lacking, we propose that bacterial flow between humans and animals can exacerbate the emergence and spread of resistant pathogens. Here, we describe the consequences of poor environmental controls by comparing mobile resistance elements among Escherichia coli recovered from humans and meat in Cambodia, a middle-income country with substantial human-animal connectivity and unregulated antibiotic use. We identified identical mobile resistance elements and a conserved transposon region that were widely dispersed in both humans and animals, a phenomenon rarely observed in high-income settings. Our findings indicate that plugging leaks at human-animal interfaces should be a critical part of addressing antibiotic resistance in low- and especially middle-income countries.

Prevalence and factors associated with faecal carriage of extended-spectrum ß-lactamase-producing Enterobacterales among peripartum women in the community in Cambodia.

BACKGROUND: In Southeast-Asia, where many conditions associated with dissemination of ESBL-producing Enterobacterales (ESBL-E) in the community are met, data from the community are scarce but show high ESBL-E carriage prevalence. Maternal ESBL-E colonization is considered a risk factor for neonatal colonization, which is the first step towards developing neonatal sepsis. Despite this, ESBL-E carriage prevalence and its risk factors during pregnancy or postpartum remain undefined in Southeast-Asia. OBJECTIVES: To estimate the prevalence of ESBL-E faecal colonization among peripartum women in the community of an urban and a rural area in Cambodia, to investigate ESBL-E genomic characteristics and to identify associated risk factors. METHODS: Epidemiological data and faecal samples from 423 peripartum women were collected in an urban and rural areas in Cambodia (2015-16). Bacterial cultures, antibiotic susceptibility tests and ESBL gene sequencing were performed. Risk factor analysis was conducted using logistic regression. RESULTS: The prevalence of ESBL-E faecal carriage was 79.2% (95% CI 75.0%-82.8%) among which Escherichia coli (n = 315/335, 94.0%) were most frequent. All isolates were multidrug resistant. Among 318 ESBL-E, the genes most frequently detected were blaCTX-M-15 (41.5%), blaCTX-M-55 (24.8%), and blaCTX-M-27 (15.1%). Low income, undernutrition, multiparity, regular consumption of pork, dried meat, and raw vegetables, were associated with ESBL-E faecal carriage. CONCLUSIONS: The high prevalence of ESBL-E carriage observed among peripartum women in Southeast-Asia and the identified associated factors underline the urgent need for public health measures to address antimicrobial resistance, including a 'One Health' approach.

Severe bacterial neonatal infections in Madagascar, Senegal, and Cambodia: A multicentric community-based cohort study.

BACKGROUND: Severe bacterial infections (SBIs) are a leading cause of neonatal deaths in low- and middle-income countries (LMICs). However, most data came from hospitals, which do not include neonates who did not seek care or were treated outside the hospital. Studies from the community are scarce, and few among those available were conducted with high-quality microbiological techniques. The burden of SBI at the community level is therefore largely unknown. We aimed here to describe the incidence, etiology, risk factors, and antibiotic resistance profiles of community-acquired neonatal SBI in 3 LMICs. METHODS AND FINDINGS: The BIRDY study is a prospective multicentric community-based mother and child cohort study and was conducted in both urban and rural areas in Madagascar (2012 to 2018), Cambodia (2014 to 2018), and Senegal (2014 to 2018). All pregnant women within a geographically defined population were identified and enrolled. Their neonates were actively followed from birth to 28 days to document all episodes of SBI. A total of 3,858 pregnant women (2,273 (58.9%) in Madagascar, 814 (21.1%) in Cambodia, and 771 (20.0%) in Senegal) were enrolled in the study, and, of these, 31.2% were primigravidae. Women enrolled in the urban sites represented 39.6% (900/2,273), 45.5% (370/814), and 61.9% (477/771), and those enrolled in the rural sites represented 60.4% (1,373/2,273), 54.5% (444/814), and 38.1% (294/771) of the total in Madagascar, Cambodia, and Senegal, respectively. Among the 3,688 recruited newborns, 49.6% were male and 8.7% were low birth weight (LBW). The incidence of possible severe bacterial infection (pSBI; clinical diagnosis based on WHO guidelines of the Integrated Management of Childhood Illness) was 196.3 [95% confidence interval (CI) 176.5 to 218.2], 110.1 [88.3 to 137.3], and 78.3 [59.5 to 103] per 1,000 live births in Madagascar, Cambodia, and Senegal, respectively. The incidence of pSBI differed between urban and rural sites in all study countries. In Madagascar, we estimated an incidence of 161.0 pSBI per 1,000 live births [133.5 to 194] in the urban site and 219.0 [192.6 to 249.1] pSBI per 1,000 live births in the rural site (p = 0.008). In Cambodia, estimated incidences were 141.1 [105.4 to 189.0] and 85.3 [61.0 to 119.4] pSBI per 1,000 live births in urban and rural sites, respectively (p = 0.025), while in Senegal, we estimated 103.6 [76.0 to 141.2] pSBI and 41.5 [23.0 to 75.0] pSBI per 1,000 live births in urban and rural sites, respectively (p = 0.006). The incidences of culture-confirmed SBI were 15.2 [10.6 to 21.8], 6.5 [2.7 to 15.6], and 10.2 [4.8 to 21.3] per 1,000 live births in Madagascar, Cambodia, and Senegal, respectively, with no difference between urban and rural sites in each country. The great majority of early-onset infections occurred during the first 3 days of life (72.7%). The 3 main pathogens isolated were Klebsiella spp. (11/45, 24.4%), Escherichia coli (10/45, 22.2%), and Staphylococcus spp. (11/45, 24.4%). Among the 13 gram-positive isolates, 5 were resistant to gentamicin, and, among the 29 gram-negative isolates, 13 were resistant to gentamicin, with only 1 E. coli out of 10 sensitive to ampicillin. Almost one-third of the isolates were resistant to both first-line drugs recommended for the management of neonatal sepsis (ampicillin and gentamicin). Overall, 38 deaths occurred among neonates with SBI (possible and culture-confirmed SBI together). LBW and foul-smelling amniotic fluid at delivery were common risk factors for early pSBI in all 3 countries. A main limitation of the study was the lack of samples from a significant proportion of infants with pBSI including 35 neonatal deaths. Without these samples, bacterial infection and resistance profiles could not be confirmed. CONCLUSIONS: In this study, we observed a high incidence of neonatal SBI, particularly in the first 3 days of life, in the community of 3 LMICs. The current treatment for the management of neonatal infection is hindered by antimicrobial resistance. Our findings suggest that microbiological diagnosis of SBI remains a challenge in these settings and support more research on causes of neonatal death and the implementation of early interventions (e.g., follow-up of at-risk newborns during the first days of life) to decrease the burden of neonatal SBI and associated mortality and help achieve Sustainable Development Goal 3.

Isolation of Nontuberculous Mycobacteria in Southeast Asian and African Human Immunodeficiency Virus-infected Children With Suspected Tuberculosis.

We enrolled 427 human immunodeficiency virus-infected children (median age, 7.3 years), 59.2% severely immunodeficient, with suspected tuberculosis in Southeast Asian and African settings. Nontuberculous mycobacteria were isolated in 46 children (10.8%); 45.7% of isolates were Mycobacterium avium complex. Southeast Asian origin, age 5-9 years, and severe immunodeficiency were independently associated with nontuberculous mycobacteria isolation. CLINICAL TRIALS REGISTRATION: NCT01331811.

Meat and Fish as Sources of Extended-Spectrum ß-Lactamase-Producing Escherichia coli, Cambodia.

We compared extended-spectrum ß-lactamase-producing Escherichia coli isolates from meat and fish, gut-colonized women, and infected patients in Cambodia. Nearly half of isolates from women were phylogenetically related to food-origin isolates; a subset had identical multilocus sequence types, extended-spectrum ß-lactamase types, and antimicrobial resistance patterns. Eating sun-dried poultry may be an exposure route.

Tuberculosis in children with sickle cell anaemia: a retrospective study in French tertiary care centres.

Tuberculosis (TB) and sickle cell anaemia (SCA) may affect the same population of patients, particularly in Africa but also in high-TB incidence areas in developed countries. However, few data are available from children with SCA who develop TB. The aim of this study was to describe the clinical features and outcome of TB diagnosed in children with SCA. We conducted a retrospective, descriptive study in three referral centre of Sickle Cell Disease in Paris, France. We included 11 patients with SCA who develop TB. The median age at TB diagnosis was 11 years [7.5-14.5]. Two patients were asymptomatic and nine patients were symptomatic. Six patients had pulmonary TB (pulmonary, pleural and mediastinal lesions). Five patients had extrapulmonary TB (osteoarticular TB, hepatic TB, cervical and mediastinal TB). Mycobacterium tuberculosis was isolated in four of the 11 cases. All patients recovered after a median of 6 months of anti-TB treatment. The localisation of TB and outcome after treatment in our SCA patients were similar to the one observed in an age-and sex-matched control group of non-SCA patient with TB. CONCLUSION: despite the low number of patients included in our study, SCA does not seem to be a risk factor for severe TB. What is Known: • Tuberculosis (TB) remains a global health problem particularly in developing countries, and Sickle cell anaemia (SCA) is currently one of the most common genetic diseases in the world that mainly affects African populations. • Very few data are available on TB in SCA patients. What is New: • The features of TB in children with SCA seem to be comparable to those expected in general population, with favourable outcomes in response to standard treatment. • Monitoring the dosage of anti-TB treatments could be of interest because of the possible impact of SCA on drug metabolism.

Effect of decentralising childhood tuberculosis diagnosis to primary health centre versus district hospital levels on disease detection in children from six high tuberculosis incidence countries: an operational research, pre-post intervention study.

Background: Childhood tuberculosis (TB) remains underdiagnosed largely because of limited awareness and poor access to all or any of specimen collection, molecular testing, clinical evaluation, and chest radiography at low levels of care. Decentralising childhood TB diagnostics to district hospitals (DH) and primary health centres (PHC) could improve case detection. Methods: We conducted an operational research study using a pre-post intervention cross-sectional study design in 12 DHs and 47 PHCs of 12 districts across Cambodia, Cameroon, Côte d'Ivoire, Mozambique, Sierra Leone and Uganda. The intervention included 1) a comprehensive diagnosis package at patient-level with tuberculosis screening for all sick children and young adolescents <15 years, and clinical evaluation, Xpert Ultra-testing on respiratory and stool samples, and chest radiography for children with presumptive TB, and 2) two decentralisation approaches (PHC-focused or DH-focused) to which districts were randomly allocated at country level. We collected aggregated and individual data. We compared the proportion of tuberculosis detection in children and young adolescents <15 years pre-intervention (01 August 2018-30 November 2019) versus during intervention (07 March 2020-30 September 2021), overall and by decentralisation approach. This study is registered with ClinicalTrials.gov, NCT04038632. Findings: TB was diagnosed in 217/255,512 (0.08%) children and young adolescent <15 years attending care pre-intervention versus 411/179,581 (0.23%) during intervention, (OR: 3.59 [95% CI 1.99-6.46], p-value<0.0001; p-value = 0.055 after correcting for over-dispersion). In DH-focused districts, TB diagnosis was 80/122,570 (0.07%) versus 302/86,186 (0.35%) (OR: 4.07 [1.86-8.90]; p-value = 0.0005; p-value = 0.12 after correcting for over-dispersion); and 137/132,942 (0.10%) versus 109/93,395 (0.11%) in PHC-focused districts, respectively (OR: 2.92 [1.25-6.81; p-value = 0.013; p-value = 0.26 after correcting for over-dispersion). Interpretation: Decentralising and strengthening childhood TB diagnosis at lower levels of care increases tuberculosis case detection but the difference was not statistically significant. Funding source: Unitaid, Grant number 2017-15-UBx-TB-SPEED.

Vaccination Coverage and Risk Factors Associated With Incomplete Vaccination Among Children in Cambodia, Madagascar, and Senegal.

Background: Vaccination reduces mortality from infectious disease, which is the leading cause of death in children under 5 and bears a particularly high burden in low- and middle-income countries. The Global Vaccine Action Plan (2011-2020) has set a target of 90% vaccine coverage for all vaccines included in national immunization programs by 2020. The objectives of this study were to estimate vaccine coverage among children in Madagascar, Cambodia, and Senegal and to identify the risk factors associated with incomplete vaccination. Methods: Using data from a community-based prospective cohort that included all newborn of some areas from 2012 to 2018 in these 3 countries, vaccine coverage was estimated for BCG, hepatitis B, oral polio, pentavalent (targeting diphtheria, tetanus, pertussis, hepatitis B, and Haemophilus influenzae type b), and measles vaccines. Risk factor analysis was performed with logistic regression models to identify correlates of incomplete vaccination. Results: A total of 3606 children were followed up, and vaccine coverage was below the 90% threshold for most vaccines in all countries. Coverage was higher for vaccines recommended at birth and at 6 weeks, while a decrease in coverage for subsequent doses was observed for vaccines requiring several doses (23-47 points). Low birth weight (<2500 g) was an important risk factor for nonvaccination for vaccines recommended at birth in all 3 countries (adjusted odds ratio [95% confidence interval] ranging from 1.93 [1.11-3.38] to 4.28 [1.85-9.37]). Conclusions: Vaccine coverage for common childhood vaccines was lower than World Health Organization recommendations, and multidisciplinary approaches may help to improve vaccine coverage and timeliness.

Stillbirths and neonatal mortality in LMICs: A community-based mother-infant cohort study.

Background: The exact timing, causes, and circumstances of stillbirth and neonatal mortality in low- and middle-income countries (LMICs) remain poorly described, especially for antenatal stillbirths and deaths occurring at home. We aimed to provide reliable estimates of the incidence of stillbirth and neonatal death in three LMICs (Madagascar, Cambodia and Senegal) and to identify their main causes and associated risk factors. Methods: This study is based on data from an international, multicentric, prospective, longitudinal, community-based mother-infant cohort. We included pregnant mothers and prospectively followed up their children in the community. Stillbirths and deaths were systematically reported; information across healthcare settings was collected and verbal autopsies were performed to document the circumstances and timing of death. Results: Among the 4436 pregnancies and 4334 live births, the peripartum period and the first day of life were the key periods of mortality. The estimated incidence of stillbirth was 11 per 1000 total births in Cambodia, 15 per 1000 in Madagascar, and 12 per 1000 in Senegal. We estimated neonatal mortality at 18 per 1000 live births in Cambodia, 24 per 1000 in Madagascar, and 23 per 1000 in Senegal. Based on ultrasound biometric data, 16.1% of infants in Madagascar were born prematurely, where 42% of deliveries and 33% of deaths occurred outside healthcare facilities. Risk factors associated with neonatal death were mainly related to delivery or to events that newborns faced during the first week of life. Conclusions: These findings underscore the immediate need to improve care for and monitoring of children at birth and during early life to decrease infant mortality. Surveillance of stillbirth and neonatal mortality and their causes should be improved to mitigate this burden in LMICs.

Effect of systematic tuberculosis detection on mortality in young children with severe pneumonia in countries with high incidence of tuberculosis: a stepped-wedge cluster-randomised trial.

BACKGROUND: Tuberculosis diagnosis might be delayed or missed in children with severe pneumonia because this diagnosis is usually only considered in cases of prolonged symptoms or antibiotic failure. Systematic tuberculosis detection at hospital admission could increase case detection and reduce mortality. METHODS: We did a stepped-wedge cluster-randomised trial in 16 hospitals from six countries (Cambodia, Cameroon, Côte d'Ivoire, Mozambique, Uganda, and Zambia) with high incidence of tuberculosis. Children younger than 5 years with WHO-defined severe pneumonia received either the standard of care (control group) or standard of care plus Xpert MTB/RIF Ultra (Xpert Ultra; Cepheid, Sunnyvale, CA, USA) on nasopharyngeal aspirate and stool samples (intervention group). Clusters (hospitals) were progressively switched from control to intervention at 5-week intervals, using a computer-generated random sequence, stratified on incidence rate of tuberculosis at country level, and masked to teams until 5 weeks before switch. We assessed the effect of the intervention on primary (12-week all-cause mortality) and secondary (including tuberculosis diagnosis) outcomes, using generalised linear mixed models. The primary analysis was by intention to treat. We described outcomes in children with severe acute malnutrition in a post hoc analysis. This study is registered with ClinicalTrials.gov (NCT03831906) and the Pan African Clinical Trial Registry (PACTR202101615120643). FINDINGS: From March 21, 2019, to March 30, 2021, we enrolled 1401 children in the control group and 1169 children in the intervention group. In the intervention group, 1140 (97·5%) children had nasopharyngeal aspirates and 942 (80·6%) had their stool collected; 24 (2·1%) had positive Xpert Ultra. At 12 weeks, 110 (7·9%) children in the control group and 91 (7·8%) children in the intervention group had died (adjusted odds ratio [OR] 0·986, 95% CI 0·597-1·630, p=0·957), and 74 (5·3%) children in the control group and 88 (7·5%) children in the intervention group had tuberculosis diagnosed (adjusted OR 1·238, 95% CI 0·696-2·202, p=0·467). In children with severe acute malnutrition, 57 (23·8%) of 240 children in the control group and 53 (17·8%) of 297 children in the intervention group died, and 36 (15·0%) of 240 children in the control group and 56 (18·9%) of 297 children in the intervention group were diagnosed with tuberculosis. The main adverse events associated with nasopharyngeal aspirates were samples with blood in 312 (27·3%) of 1147 children with nasopharyngeal aspirates attempted, dyspnoea or SpO2 less than 95% in 134 (11·4%) of children, and transient respiratory distress or SpO2 less than 90% in 59 (5·2%) children. There was no serious adverse event related to nasopharyngeal aspirates reported during the trial. INTERPRETATION: Systematic molecular tuberculosis detection at hospital admission did not reduce mortality in children with severe pneumonia. High treatment and microbiological confirmation rates support more systematic use of Xpert Ultra in this group, notably in children with severe acute malnutrition. FUNDING: Unitaid and L'Initiative. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

TNF-α/IL-2 ratio discriminates latent from active tuberculosis in immunocompetent children: a pilot study.

BACKGROUND: Distinguishing latent tuberculosis (LTB) from tuberculosis (TB) disease may be challenging in children. Here, we analyzed cytokine profiles that can distinguish the two infection stages in a nonendemic country (France). METHODS: Immunocompetent children with LTB (n = 6) or TB disease (n = 8) (median age: 6.2 and 5.7 years, respectively) were analyzed. Four young uninfected children were included as controls. A Luminex assay evaluated cytokine responses to Mycobacterium tuberculosis antigens. RESULTS: Poor interleukin-4 (IL-4) and IL-10 responses precluded analysis of these cytokines. Interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), IL-2, and T-helper type 1 (Th1) cytokines and IL-5, IL-13, T-helper type 2 (Th2) cytokines were simultaneously induced by antigens in 14/14 infected but 0/4 uninfected children. Th1 cytokine levels were similar in LTB and TB disease: IFN-γ: 12,254 and 10,495 pg/ml; IL-2: 2,097 and 1,869 pg/ml; and TNF-α: 1,020 and 2,875 pg/ml, respectively. Th2 cytokine levels were similar and even higher in LTB than in TB disease: IL-5: 23 and 10 pg/ml; IL-13: 284 and 109 pg/ml, respectively. Positive correlation of cytokine levels, whether Th1 or Th2, was observed. Higher (P = 0.008) TNF-α/IL-2 ratios distinguished 6/8 active TB disease cases from 6/6 LTB cases. CONCLUSION: TNF-α/IL-2 ratio may discriminate TB disease from LTB in immunocompetent children. Larger studies in TB endemic settings must verify these results.

Excess risk of subsequent infection in hospitalized children from a community cohort study in Cambodia and Madagascar.

BACKGROUND: Children in low- and middle-income countries are particularly vulnerable in the months following an initial health event (IHE), with increased risk of mortality caused mostly by infectious diseases. Due to exposure to a wide range of environmental stressors, hospitalization in itself might increase child vulnerability at discharge. The goal of this study was to disentangle the role of hospitalization on the risk of subsequent infection. METHODS: Data from a prospective, longitudinal, international, multicenter mother-and-child cohort were analysed. The main outcome assessed was the risk of subsequent infection within 3 months of initial care at hospital or primary healthcare facilities. First, risk factors for being hospitalized for the IHE (Step 1) and for having a subsequent infection (Step 2) were identified. Then, inpatients were matched with outpatients using propensity scores, considering the risk factors identified in Step 1. Finally, adjusted on the risk factors identified in Step 2, Cox regression models were performed on the matched data set to estimate the effect of hospitalization at the IHE on the risk of subsequent infection. RESULTS: Among the 1312 children presenting an IHE, 210 (16%) had a subsequent infection, mainly lower-respiratory infections. Although hospitalization did not increase the risk of subsequent diarrhoea or unspecified sepsis, inpatients were 1.7 (95% Confidence Intervals [1.0-2.8]) times more likely to develop a subsequent lower-respiratory infection than comparable outpatients. CONCLUSION: For the first time, our findings suggest that hospitalization might increase the risk of subsequent lower-respiratory infection adjusted on severity and symptoms at IHE. This highlights the need for robust longitudinal follow-up of at-risk children and the importance of investigating underlying mechanisms driving vulnerability to infection.

Escherichia coli ST410 among humans and the environment in Southeast Asia.

Escherichia coli ST410 (Ec-ST410) is an emerging, multidrug-resistant clone. Recent investigations of its global epidemiology and evolution have been based almost exclusively on isolates from Europe and North America. It is unclear whether Southeast Asian-origin Ec-ST410 (SEA-Ec-ST410) belong to these same clones or represent regionally disseminated variants. Antimicrobial resistance mechanisms among SEA-Ec-ST410 were characterised, and whether they belonged to regional variants was investigated by contextualising them within a global collection. Seven Ec-ST410 were identified among a recent collection of expanded-spectrum cephalosporin-resistant E. coli recovered from 91 healthy women (stool) and 26 infected patients (blood and urine) living in Phnom Penh, Cambodia. Nine additional Ec-ST410 genomes were identified from Thailand (n = 7) and Vietnam (n = 2) through EnteroBase and PubMed searches. The assembled genomes were characterised and a SNP-based phylogenetic tree was created comparing these 16 SEA-Ec-ST410 with a previously published Ec-ST410 collection, primarily sourced from Europe (97/128) and North America (24/128). SEA-Ec-ST410 belonged to several distinct branches within previously described clonal clades. SEA-Ec-ST410 within the B3/H24Rx sublineage encoded blaCTX-M-55 (8/12) and F18:A-:B1 plasmid replicons (6/12), neither of which were detected among other Ec-ST410 belonging to this clade. Three of four SEA-Ec-ST410 within the B4/H24RxC sublineage lacked both blaOXA-181 and an IncX3 plasmid replicon that were harboured by 97% and 100% of all other Ec-ST410 in this sublineage (n = 64), respectively. In conclusion, Ec-ST410 are present in Southeast Asia following multiple introductions. The unique pattern of antimicrobial resistance elements harboured by SEA-Ec-ST410 suggests independent circulation in the region.

Antimicrobial resistance in Cambodia: a review.

OBJECTIVES: Following the launch of the Global Antimicrobial Resistance Surveillance System (GLASS), antimicrobial resistance (AMR) rates in many countries remain poorly described. This review provides an overview of published AMR data from Cambodia in the context of recently initiated national human and food-animal surveillance. METHODS: PubMed and the Cochrane Database of Systematic Reviews were searched for articles published from 2000 to 2018, which reported antimicrobial susceptibility testing (AST) data for GLASS specific organisms isolated from Cambodia. Articles were screened using strict inclusion/exclusion criteria. AST data was extracted, with medians and ranges of resistance rates calculated for specific bug-drug combinations. RESULTS: Twenty-four papers were included for final analysis, with 20 describing isolates from human populations. Escherichia coli was the most commonly described organism, with median resistance rates from human isolates of 92.8% (n=6 articles), 46.4% (n=4), 55.4% (n=8), and 46.4% (n=5) to ampicillin, 3rd generation cephalosporins, fluoroquinolones, and gentamicin respectively. CONCLUSIONS: Whilst resistance rates are high for several GLASS organisms, there were insufficient data to draw robust conclusions about the AMR situation in Cambodia. The recently implemented national AMR surveillance systems will begin to address this data gap.

Real-time PCR measurement of persistence of Bordetella pertussis DNA in nasopharyngeal secretions during antibiotic treatment of young children with pertussis.

We used real-time PCR to examine the persistence of Bordetella pertussis DNA in serial nasopharyngeal aspirates from 22 children treated for pertussis. After 5 days of treatment, PCR was positive for all 21 assessable patients. After 14 and 21 days, PCR was still positive for 83% (10/12) and 66% (4/6) of assessable patients, respectively. One patient was tested 1 month after treatment initiation, and B. pertussis DNA was still detectable. Quantitative analysis showed that the DNA concentration diminished during treatment in all except one case. The PCR cycle threshold at which B. pertussis DNA became detectable increased by a mean of 1.7 cycles per day (range, 0.86 to 3.68 cycles per day). Real-time PCR can thus be used to diagnose pertussis in young children for up to 3 weeks after treatment initiation. Its potential value for assessing the treatment outcome remains to be determined.

Enteric fever among children: 50 cases in a French tertiary care centre.

Background: Enteric fever in France is primarily travel-associated. Characteristics of paediatric cases are scarce and information from field studies in endemic countries might not be generalizable to non-endemic countries. Methods: In this retrospective study, we reviewed all cases of typhoid and paratyphoid fever treated in a French paediatric tertiary care centre from 1993 to 2015. Results: Fifty cases of enteric fever due to Salmonella enterica serovar Typhi (n = 44) and Paratyphi (n = 6) were identified. Sixty-one percent of the children had travelled to Africa and 34% to the Indian subcontinent. Among travel-associated cases, 85% were visiting friends and relatives (VFR). Ninety-six percent had high fever associated with gastrointestinal symptoms. Anaemia (66%), elevated C-reactive protein (80%), transaminitis (87%) and mild hyponatremia (50%) were the main biological findings. Blood cultures were positive in 90% of cases. Twelve strains (24%) were resistant at least to one antibiotic, and all of them had been isolated since 2003, increasing the resistance rate during this last period to 43% (12/28). Ceftriaxone was administered to 71 patients for a median duration of 6 days (interquartile range (IQR): 4-8). The median time to apyrexia after the onset of treatment was 4 days (IQR: 2-5 days). Complications occurred in nine children with five (10%) presenting neurologic disorders. All 50 patients recovered. Conclusion: In France, paediatric enteric fever is mainly a travel-associated disease and occurs in patients returning from a prolonged stay in an endemic area. Children VFR are at high risk and should be a priority target group for pre-travel preventive measures. The increase in antibiotic resistance reflects the situation in endemic countries and is a major concern.

Acquisition of extended spectrum beta-lactamase-producing enterobacteriaceae in neonates: A community based cohort in Madagascar.

In low and middle income countries (LMICs), where the burden of neonatal sepsis is the highest, the spread of extended spectrum beta-lactamase-producing enterobacteriaceae (ESBL-PE) in the community, potentially contributing to the neonatal mortality, is a public health concern. Data regarding the acquisition of ESBL-PE during the neonatal period are scarce. The routes of transmission are not well defined and particularly the possible key role played by pregnant women. This study aimed to understand the neonatal acquisition of ESBL-PE in the community in Madagascar. The study was conducted in urban and semi-rural areas. Newborns were included at birth and followed-up during their first month of life. Maternal stool samples at delivery and six stool samples in each infant were collected to screen for ESBL-PE. A Cox proportional hazards model was performed to identify factors associated with the first ESBL-PE acquisition. The incidence rate of ESBL-PE acquisition was 10.4 cases/1000 newborn-days [95% CI: 8.0-13.4 cases per 1000 newborn-days]. Of the 83 ESBL-PE isolates identified, Escherichia coli was the most frequent species (n = 28, 34.1%), followed by Klebsiella pneumoniae (n = 20, 24.4%). Cox multivariate analysis showed that independent risk factors for ESBL-PE acquisition were low birth weight (adjusted Hazard-ratio (aHR) = 2.7, 95% CI [1.2; 5.9]), cesarean-section, (aHR = 3.4, 95% CI [1.7; 7.1]) and maternal use of antibiotics at delivery (aHR = 2.2, 95% CI [1.1; 4.5]). Our results confirm that mothers play a significant role in the neonatal acquisition of ESBL-PE. In LMICs, public health interventions during pregnancy should be reinforced to avoid unnecessary caesarean section, unnecessary antibiotic use at delivery and low birth weight newborns.

Ethambutol-related impaired visual function in childrens less than 5 years of age treated for a mycobacterial infection: diagnosis and evolution.

BACKGROUND: The effects of ethambutol (EMB) on vision are particularly difficult to detect in children less than 5 years of age because of a lack of complaints and objective clinical signs. The aim of this study was to assess the frequency of visual abnormalities and the utility of visual-evoked potentials (VEPs) recordings in monitoring the visual function of children less than 5 years of age who were exposed to EMB during anti-mycobacterial treatment. METHODS: We performed a retrospective study in Robert-Debré University Hospital, Paris, France, including all children less than 5 years of age, who were treated with EMB for a mycobacterial infection from January 2002 to December 2012. RESULTS: Fourteen patients were enrolled, including 12 treated for Mycobacterium tuberculosis infection. The sex ratio was 1:1. The median age was 1.65 years (0.3 to 4.7). Five patients had subarachnoid involvement. The median EMB dose was 22 mg/kg/day (15 to 27). Only 11 patients were monitored using VEPs. Three children (27.3%) developed a visual impairment secondary to EMB, with delays of 4, 7 and 36 weeks. One of the 3 patients developed an impairment of the retrochiasmatic visual pathways, and 2 other patients developed classical retrobulbar optic neuritis. In all cases, the discontinuation of EMB resulted in a normalization of these findings. CONCLUSION: Alterations in visual function related to the use of EMB are not uncommon in young children and are most likely underestimated. Systematic close monitoring using VEPs recordings is needed in young children treated with EMB.

Altered cytokine profiles in children with indeterminate quantiferon results and common infections.

OBJECTIVES: An increased rate of indeterminate quantiferon results (low IFN-γ release in the phytohemagglutinin-stimulated tube) has been reported in children with clinical signs compatible with tuberculosis but with the final diagnosis of infectious diseases different from tuberculosis. Here, we addressed the mechanisms involved and assessed potential alternative biomarkers to overcome indeterminate quantiferon results under these conditions. METHODS: Cytokine concentrations were measured in residual plasma from quantiferon assays performed in immunocompetent children (cases, median age: 3 years 9 months) with indeterminate results and community acquired pneumonia (n = 7) or meningoencephalitis (n = 1). Controls were age-matched immunocompetent children with determinate quantiferon results (infected with mycobacterium tuberculosis, n = 7 or not, n = 8). RESULTS: Lower IFN-γ expression in phytohemagglutinin-stimulated cultures from cases was accompanied by lower Th1 (IL-2, TNF-α, IP-10) and Th2 (IL-5, IL-13), but similar IL-10 secretion capacities as the controls. CONCLUSIONS: A state of hyporesponsiveness that resembles the concept of immunoparalysis in severe infection was observed in children with milder infections. Though IP-10, IL-2, IL-5 and IL-13 were confirmed as promising alternative biomarkers for discriminating controls with and without tuberculosis in this study, defective induction of these biomarkers by phytohemagglutinin in cases precluded their usefulness in overcoming quantiferon indeterminate results in the above-mentioned clinical conditions.