Factors contributing to antibiotic use among children younger than five years old with fever, acute respiratory illness, and diarrhea in Bangladesh

Introduction: Increasing antibiotic usage is a leading health threat that develops antibiotic resistance. The current practice of antibiotic use among under-five children are unavailable in Bangladesh. We aim to identify the factors of antibiotic use among under-five children with infectious diseases. Methodology: A cross-sectional multiple indicators cluster survey (MICS) was conducted in 2019 across Bangladesh. This survey of 23,099 children under the age of five was randomly selected by using a two-stage stratified sampling method. The first stage involved randomly selecting 32,200 enumeration clusters. In second stage, households where 15-45-years-old women lived were randomly selected from within each cluster. The Poisson regression models were performed to estimate the prevalence ratio (PR). Results: We found 36.7% (8447/23,099) under-five children with infectious diseases. The proportion of antibiotic use was reported as 32.6%. Antibiotic use was associated with wealth (poorest vs. rich adjusted prevalence ratio (APR) = 1.07; 95% CI: 0.94-1.22) and mother’s education (pre-primary vs. higher: APR = 1.14; 95% CI: 1.03-1.27). Oral and injectable antibiotics were used in cases of fever (30.5%), diarrhea (4.5%), fever with cough (47.6%). Cotrimoxazole (31.0%) and amoxicillin (29.0%) were consumed for fever with cough while cotrimoxazole (14.0%) and amoxicillin (11.0%) were consumed for fever with diarrhea. They received antibiotics from drug stores (71.9%) without prescription and private healthcare (52.1%). Conclusions: Overall, one-third of the under-five children in Bangladesh consumed antibiotics to treat infectious diseases. Multiple factors contribute to the prevalence of antibiotic use. The results highlight the need to regulate antibiotic use and prioritize national intervention programs.


Introduction
Antibiotic resistance in bacterial pathogens is a leading cause of global health challenges associated with the high prevalence of contagious diseases.The overuse, misuse, and improper use of broad-spectrum antibiotics in animals, agriculture, and healthcare settings, as well as poor infection control practices, are all contributing to the steady rise in antibiotic resistance [1].Consequently, bacteria resistance can quickly spread to patients around the globe [2].Furthermore, poor surveillance systems and available poor-quality antibiotics in resource-poor settings are implicated in the emergence of antibiotic resistance [3].Additionally, antibiotic use plays a significant role in developing antibiotic resistance [3,4].Since 2000, the antibiotic consumption rate has increased by 77% from 7.6 to 13.5 defined daily doses (DDDs) per 1,000 people per day in low-income countries [5].Therefore, multi-drug resistance in resource-poor settings, which has a strong positive correlation with antibiotic use, has led to mortality and morbidity [6][7][8][9].
The increasing prevalence of antibiotic resistance threatens child health, particularly in low-income countries.The Sustainable Development Goals for reducing child mortality are not currently achieved due to the emergence of multi-drug resistance in infectious diseases [10,11].Mainly, the excessive use of antibiotics for treating infectious diseases is higher in low-income countries than in high-income countries [12], and antibiotic use is more in children than adults due to increased vulnerability [4].Therefore, optimizing antibiotic use should be maintained and it is a significant challenge in resource-poor settings with a high rate of infectious diseases where broad-spectrum antimicrobials are usually used [13].So, the World Health Organization (WHO) has recommended that antimicrobial agents should be prioritized in the global action plan on antibiotic resistance [14].This objective is still behind the target as there is limited data on antibiotic use among children under five years of age in low-income countries, particularly Bangladesh.
To understand the antibiotic use, we need data to access the antibiotic use of a country.However, data regarding antibiotic use is limited in resource-poor countries like Bangladesh [5].The primary evaluation of antibiotic use depends on hospital-based surveys, which are helpful in individual-level exposure to antibiotic use in the institution but do not directly measure the factors of population-level antibiotic use.While the hospital-based antibiotic data are well documented to address antibiotic use in Bangladesh, it may be biased because it does not include nonprescribed antibiotics use which comprises a large portion of total antibiotic usage [15].These data gaps affect the national representativeness of the existing antibiotics use and reliable population characteristics.Additionally, young children in the community are more likely to consume antibiotics because the morbidity and mortality associated with infectious diseases are higher among children than adults [16,17].A primary population-based survey in Bangladesh was conducted to collect data on child health and antibiotic use among under-five children for treating infectious diseases.The objectives of this survey were to assess and monitor the current status of health indicators [18], but it didn't discover a set of significant distinct factors causing antibiotic use.Therefore, a secondary analysis of this data which aims to identify the factors contributing to antibiotic use among under-five children for treating infectious diseases in Bangladesh is needed.

Methodology
We used a Multiple Indicator Cluster Survey (MICS), Bangladesh in 2019 data.United Nations Children's Fund (UNICEF) and the Government of the People's Republic of Bangladesh conducted this crosssectional survey.The MICS 2019 provides community survey data on socio-economic characteristics, 15-49year-old women, mothers or caregivers, reported disease episodes, and health conditions of under-five children.This survey was conducted from January 2019 to June 2019 with 3,220 Primary Sampling Units (PSU), enumeration areas (EAs) of Bangladesh Census of Population and Housing 2011 in rural and urban areas of Bangladesh.The 64,400 households were enrolled by using a 2-stage stratified cluster probability proportional to size (PPS) sampling method, detailed in the MICS preliminary report [16].

Statistical analysis
We performed descriptive statistics to calculate the proportion for categorical variables, the prevalence of sick children under five with fever, diarrhea, and ARI cases, and the proportion of antibiotic use among sick children with illness.We defined a sick child who experienced fever, diarrhea, cough, short/ rapid or fast breathing, and problems in the chest during breathing in the preceding two weeks.According to the World Health Organization (WHO), a diarrheal episode was defined as loose or watery stools occurring at least three times a day, and ARI was defined as rapid or difficult breathing and a problem in the chest with or without cough [17].An antibiotic user who had consumed any antibiotics for treating their infectious diseases encounters [12].Children were categorized into six groups; 0 to 5 months, 6-11 months, 12-23 months, 24-35 months, 36-47 months, and 48-59 months.The Principal Component Analysis (PCA) was performed in the list of household assets for indexing wealth.Households were classified into poorest, poor, middle, upper-middle, and rich by quintiles [18].The composite index of anthropometric failure (CIAF), undernutrition, is defined as a child who experienced either stunting, wasting, or being underweight [19][20][21].Their nutritional status; A long-term nutrition insufficiency was considered by stunting (HAZ < -2 SD); a shortterm nutrition insufficiency was evaluated by wasting (WHZ < -2 SD) and underweight (WAZ < -2 SD) children referred to change in nutrition over time [19].The level of education for mothers/ caregivers was classified into four groups: pre-primary, primary, secondary, and higher.The improved toilet sanitation facility was defined as the households having flush/pour flush, septic tank, pit latrine, ventilated improved pit, and a pit with slabs toilet [16].We defined improved drinking water sources as households collecting drinking water from piped water, public taps, standpipes, tube wells, boreholes, protected dug wells and springs, bottled water, sachet water, tanker trucks and cart with small drums or tanks.Based on the careseeking health facilities, we categorized the facility providers into five sectors: public, private, and community health providers, recommendations from relatives or friends, drug shops, and traditional healers.The public sector included medical college hospitals, specialized government hospitals, district hospitals, mother and child welfare centers, Upazilla health complex, union health, and family welfare centers.The private sector included private medical college hospitals, private hospitals, private clinics, and qualified doctor's chambers.Community health providers included community health workers and mobile/outreach clinics [22].In these analyses, we used the sampling weights to adjust for sampling variation between regions [22].We used a waffle chart to present the percentage of various symptom complaints, and a forest plot to show the proportions of antibiotic use among different symptom complaints.Bivariate analysis was conducted using the Poisson regression model to identify the significant variables associated with reported antibiotic use at level α = 0.05.
Multivariate analysis included the selected variables that are significant.Poisson regression was performed to estimate the adjusted prevalence ratio (APR) associated with a 95% confidence interval (CI) for age and sex as confounders; other significant covariates accounted for the clustering effect in households.We also performed a subgroup analysis among the different combinations of symptoms to identify the inappropriate use of antibiotics.STATA version 13.1 was used for managing and analyzing data, and Python 3.6 was used for presenting data in interactive graphs.

Discussion
Our analysis identified the present scenario of infectious diseases and antibiotics used for treating infectious diseases among under-five children.The results show that the prevalence of under-five sick children with fever, diarrhea, and ARI was available, and most mothers/caregivers used oral and injectable antibiotics for several symptoms in Bangladesh.Furthermore, the findings highlight that the high prevalence of excessive use of antibiotics was reported among children under five with symptom complaints.Our investigation also highlights that household wealth and the mother's education were significantly associated with the reported excessive antibiotic usage.Additionally, access to private healthcare facilities, recommendations from relatives or friends, and available drug stores were crucial drivers of access to antibiotics.This study's results show the factors of reported antibiotic usage similar to a previous systematic review study between 2005 and 2017 conducted on 132 surveys from 73 countries.Although they did not determine the associated factors of antibiotic usage in their study, they estimated the prevalence of antibiotic use in South Asia at 30.1% in 2017 among sick children under-five with fever, diarrhea, or ARI.The study identified the excessive use of amoxicillin and cotrimoxazole for fever and diarrhea alone, which is consistent with our findings.A population-based study in 2016 in Nepal on the reported antibiotics use among children under five years old [23] showed a similar pattern and determinants.Both studies revealed the importance of the non-government health sectors, wealthier households, and educated mothers in the use of antibiotics among children under five.A study was conducted among 2,144 children under-five with a similar methodology in the same community in Bangladesh in 2014 [24] which was performed among sick children under-five with only ARI irrespective of fever or diarrhea.The proportion of reported use of antibiotics among sick children under five with only ARI was approximately 11%, and the associated sociodemographic factors for antibiotic usage differed from our findings.These differences could be attributed to the distinct symptom complaints, study time and rapidly increased access to healthcare facilities across the country [25].
We found that every two in five children under five experienced illness in the preceding two weeks.Among the symptom complaints, the proportion of under-five sick children with fever alone was the highest reported compared with cough only, diarrhea, ARI, and cough with difficulty breathing.The non-government health sector in Bangladesh was the largest healthcare provider for children under five conditions.Our study findings highlight that one-third of sick children under five with symptom complaints reported using antibiotics for fever, diarrhea, or ARI.Our results showed that many young children in Bangladesh received an oral or injectable form of antibiotics for fever alone, diarrhea alone, diarrhea with fever alone, or fever with cough alone.We also found that many mothers or caregivers purchased antibiotics from traditional healers and drug sellers without prescriptions, some health professionals prescribed antibiotics for mild cases, and some mothers or caregivers did not use antibiotics for severe pneumonia cases.These findings indicate antibiotics are excessively used among children with fever, diarrhea, and ARI cases in Bangladesh regarding Integrated Management of Childhood Illness (IMCI) guidelines [26].The resource-poor settings, where there are poor health systems, inadequate diagnosis, higher prevalence of infectious diseases, and childhood mortality, there may be excessive use of antibiotics among sick underfive children [27].This result is almost uniform with the previous population-based survey in Bangladesh regarding the study design [24,28], though results cannot be directly comparable due to different time periods case definitions, and program settings.Besides, our analysis focused on mutually exclusive symptom complaints, whereas the prior study was based on only ARI cases.We found that 4.5% -69.8% of antibiotics were used for different symptom complaints.The proportion of antibiotic use among severe pneumonia cases was more than 51% among children under five higher than 39% in a previous study [24].This result is not unexpected, as there have been rapidly increasing healthcare facilities across the country in the last five years [25], and a high portion of children were found to visit non-government healthcare facilities in our study.However, mothers or caregivers may inappropriately use antibiotics for their children under five because they do not have sufficient knowledge of doses for antibiotics and access to healthcare facilities [29][30][31][32].
Our study results showed that private healthcare facilities were a common place for treating infectious diseases in Bangladesh.There are more registered private hospitals and clinics than public healthcare facilities, along with many unregistered private hospitals or clinics in Bangladesh [25].Many physicians of public sector practices in private sectors, difficult-to-reach healthcare facilities, limited services, and high cost of diagnostic tests, and medicines impeded access to the healthcare facilities in public sectors [32].Consequently, most caregivers seek private healthcare facilities or self-medication for their children [33].Prior studies showed that private healthcare facilities and self-medication are crucial factors in treating sick under-five children in lowincome countries [23,[34][35][36].Our data is sufficient to indicate that antibiotics were more likely to be prescribed in private healthcare facilities compared with public healthcare sectors for sick children under five with fever, diarrhea, or ARI.The wide use of antibiotics may reflect that a large number of patients visited private healthcare facilities [23], limited access to appropriate diagnostics facilities [37], improper diagnoses [38], patient preferences for antibiotics [39,40], and incentives for prescribing antibiotics [38].Some mothers or caregivers decided to self-medication based on their children's illnesses which instigated them to seek inappropriate healthcare and take antibiotics from drug sellers and traditional healers [34,36,[40][41][42].Our data similarly indicates that drug stores and traditional healers are critical sources of excessive antibiotic usage for sick children under five with fever, diarrhea, and ARI.There is an urgent requirement to reduce inappropriate antibiotic prescribing in private healthcare sectors, drug shops, and traditional healers, particularly in limited-resource settings [43].
Our study found that the 95% CI of adjusted prevalence ratio (APR) for many distinct factors included the null value (1.0) but the APR apart from the null value.Nevertheless, our results showed a significantly lower prevalence of sick children under five in wealthier households, but the reported use of antibiotics among children under five was higher in more affluent households than in poor households.The highest percentage of access to private healthcare facilities explained this higher proportion of antibiotic usage among children under five in wealthier households.These similar findings have been found in many previous studies in LMICs [12,23].Richest people are strongly associated with traveling to other areas, which can lead to the transmission of infectious diseases [44], which may contribute to the association between seeking private healthcare facilities and the excessive use of antibiotics for sick under-five children [5].Many experimental and observational studies on antibiotic resistance showed that antibiotics among children under five in more affluent households are more likely to be consumed than in poor households [45][46][47][48].A community-based cross-sectional study showed that the burden of excessive use of antibiotics among children under five in wealthy families was explained by using the recent antibiotics of other members [48].It is anticipated that the low number of healthcare visits by sick children from low-income households and lack of proper diagnosis are more likely to receive antibiotics [49].Hence, wealthier households are an important factor in the excessive use of antibiotics among under-five children.
One of the key results is that maternal education was strongly associated with antibiotic usage.Educated mothers/caregivers can manipulate the excessive use of antibiotics by influencing their knowledge, attitude, and behaviors.They seek healthcare with their children and consult with physicians or self-medication.They also frequently classify their child's illness and expect to prescribe antibiotics.Therefore, many private practitioners seek information for prescribing antibiotics inappropriately [50], and some educated mothers unnecessarily take antibiotics by practicing self-medication [51].This finding is consistent with the trend analysis of sick children under five with fever or diarrhea study in Nepal [23] and previous systematic review studies on respiratory infection in children under five [52].
The limitations of this study were that a high recall error occurred due to the data collection method in the MICS, as the primary outcome was self-reporting.The mothers or caregivers were asked about their children's illnesses in the preceding 14 days, health care facilities for each disease, type of health care seeking facilities, and the use of antibiotics for illness and did not verify medicines in the prescriptions.Due to the small samples in the sub-group, it is difficult to identify specific associations.The disease prevalence may be affected by seasonal bias because data collection was conducted within only the first two seasons of the year.

Conclusions
Overall, the results highlight the multiple significant factors leading to antibiotic use in the distinct symptom complaints among under-five children.The primary contributors to the high prevalence of antibiotic use for treating infectious diseases include socio-economic, maternal, and healthcare facilities.At the same time, the high prevalence of infectious diseases, non-prescribed antibiotic use and self-medication play a role in excessive use of antibiotic.Intervention programs in the community should be required to reduce excessive antibiotic use.At the same time, the most necessary children will likely use antibiotics, and strengthened surveillance systems for the use of antibiotics are required in resource-poor settings.allow us to use these data.The author(s) would like to acknowledge the contribution of caregivers/ mothers of the study participants for their consent to enroll children in the study.ICDDR, B is also grateful to the Governments of Bangladesh and Canada for providing core/unrestricted support.

Figure 1 .
Figure 1.Distribution of clinical symptoms among children under five years of age in 2019, Bangladesh.

Figure 2 .
Figure 2. Proportion of antibiotic used among sick children under five years of age according to different clinical symptoms in 2019, Bangladesh.

Figure 3 .
Figure 3. Use of antibiotics Amoxicillin and Cotrimoxazole among sick children under five years of age with different clinical symptoms in 2019, Bangladesh

Figure 5 .
Figure 5. (A) Factors associated with antibiotic use among sick children under five years of age with only fever.(B) Factors associated with antibiotic use among sick children under five years of age with only diarrhea.(C) Factors associated with antibiotic use among sick children under five years of age with fever and cough.(D) Factors associated with antibiotic use among sick children under five years of age with fever, diarrhea, and ARI.

Figure 4 .
Figure 4. Use of injectable antibiotics among sick children under five years of age received according to different clinical symptoms in 2019, Bangladesh

Table 1 .
Demographic characteristics and antibiotic usage among sick children under five years of age during 2019 in Bangladesh.