Inappropriate Use of Antibiotics and Their Predictors in Pediatric Patients Admitted at the Hospital Central De Nampula, Mozambique

Antibiotics are synthetic or natural substances used to treat diseases of infectious origin. When used incorrectly, they can be a factor in the development of antimicrobial resistance, increased treatment time, costs, and mortality. The present study aimed to assess the pattern inappropriate use of antibiotics and their predictors in pediatric patients admitted to the Hospital Central de Nampula, Mozambique A cross-sectional, retrospective study with a quantitative approach was conducted between January and July 2019. The population consisted of children aged 0 to 10 years hospitalized in the pediatric ward I. Binary logistic regression was used to determine risk factors for inappropriate use of antibiotics with 95% CI.


Results
The prevalence of antibiotic use among pediatric patients was 97.5%. Of the 464 antibiotics prescribed, 39.9% were for patients suffering from gastroenteritis, 21.8% and 9.1% Affected with pneumonia and malaria. Most antibiotics were for systemic use (95.9%, 445/464). Most (36.5%) of prescriptions had errors. Duration of treatment (74.6%) and dosage (25.4%) were the most frequent errors. Binary logistic regression analysis revealed that patients were prescribed with ≥ 3 antibiotics (OR = 2.920, 95% CI = 1.283-6.646, p-value = 0.011) and with a short hospitalization time (OR = 1.726, 95% CI = 1.040-2.864, p-value = 0.035) were more likely to experience some inappropriate use of antibiotics.

Conclusion
The study showed a higher prevalence of antibiotic use, however, a greater number of prescriptions contained errors. Errors related to dose and duration of treatment were the most common among pediatric patients. These results reveal a concern, since inappropriate and excessive use of antibiotics is a major factor for the development of antibiotic resistant microorganisms. Therefore, strategies concerning the use of antibiotics in order to reduce their inappropriate and excessive use are necessary.

Background
Antibiotics are drugs used to treat infectious diseases, which can be of natural or synthetic origin, with the ability to inhibit the proliferation or destroy microorganisms, and are the most used drugs in pediatric age, and play a vital role in the treatment of infectious diseases worldwide (1)(2)(3). Studies have shown that about 86% of hospitalized children received at least one antibiotic (4). Currently, these drugs are overused inappropriately, putting users at risk, such as the development of microorganisms resistance and ineffective treatment (5). The worldwide excessive use of antibiotics in human medicine and agriculture results in the proliferation and dissemination of a multitude of antibiotic-resistant genes, which constitutes the biggest and main public health problem Globally (6-8). This practice of excessive and inappropriate use of antibiotics is the main cause of bacterial resistance globally, which is considered a major public health problem (9)(10)(11). The inappropriate use of antibiotics has been the most common mode of irrational use of these drugs worldwide and includes errors in prescription, administration, dosage and duplication of the same product (12). Some studies have shown that the percentage of Improper use of some antibiotics in hospitals ranges from 20-80% (13,14). Moreover, patients with antibiotic resistant infections are more likely to experience ineffective treatment, recurrent infection, delayed recovery and even death (15). Therefore, about 6.5% of morbidity and mortality in hospital admissions is associated with inappropriate antibiotic prescription (16). In the United States and Canada, 30% − 50% of antibiotics are used incorrectly, similarly in some Asian and African nations, 50% of prescribed antibiotics are identi ed as inappropriate (17,18). According to the World Health Organization (WHO), antimicrobial resistance among pathogens responsible for common infections is alarmingly high (19). The Centers for Disease Control and Prevention (CDC) estimates that in the United States of America, less than 2 million illnesses and about 2300 deaths are due to bacterial resistance to antibiotics. According to the WHO, 25,000 deaths per year are registered in European hospitals and 700,000 worldwide are associated with antibiotic resistance (20,21). In Middle East regions, 90% of hospitalized newborns with sepsis had bacterial resistance to antibiotics (22). In sub-Saharan Africa, 66% of neonatal sepsis and meningitis are caused by antibiotic-resistant bacteria (23). It was predicted by European Commission (2018) that by 2050, antimicrobial resistance will be responsible for more deaths than cancerous diseases (24). A current, high-level report estimates that by 2050, 10 million people will die every year because of antimicrobial resistance unless there is global action against this problem (25). Reduce misuse is essential to reduce not only antibiotic resistance but adverse reactions as well (18). In this case, several actions are essential, resulting in a positive effect. These actions aim to reduce the complex consumption and use of broad-spectrum antibiotics. The use of antibiotics should be careful and limited to certain circumstances. Therefore, proper prescription is the main strategy to prevent the rapid growth of bacterial resistance to antibiotics (5,22). Finally, having knowledge about the patterns of incorrect use of antibiotics and their risk factors in the pediatric population is essential to create programs, policies and actions related to the dispensing of these drugs in this population. Thus, the present study aimed to assess the pattern improper use of antibiotics and their predictors in pediatric patients admitted to the Nampula Central Hospital, Mozambique

Study design
A cross-sectional study with a quantitative approach was conducted in patients hospitalized at the Hospital Central de Nampula (HCN), Mozambique. Pediatrics I is a ward that welcomes patients with various pathologies, categorized into gastrointestinal, respiratory and general diseases. Clinical les and medical prescriptions of hospitalized patients from January to July 2019 were used. In the clinical les, information was obtained on independent variables such as sex, age, medical diagnosis, treatment time, discharge, and information were obtained from the cardex on the prescribed antibiotics, dosage and route of administration. The survey was carried out in the year 2020.
Population and sample size From January to July 2019, a total of 1745 patients were registered, the sample size was obtained, taking into account the exclusion and inclusion criteria. The sample consisted of 315 patients. The simple randomization technique was used, a technique that allows obtaining a representative sample size, where each element of the population has an equal chance of being selected to be part of the sample. The logbook was used to obtain the master list containing numbered population. From the master list, randomization was performed to select the research participants. All clinical les with the respective cardex of patients aged between 1 and 120 months, hospitalized in that ward during the period from January to July 2019 were included in the study. To obtain the sample size, a formula was used based on a known population, as illustrated below.

Study variables
The use of antibiotics was considered the dependent variable and considered as the study outcome variable, in which it was classi ed as dichotomous categorical. It was coded using code one (1) for misuse, which is inappropriate antibiotic use, and zero (0) for correct use, which is proper use. The variable of interest was code 1. The independent variables were sex, age, weight, medical diagnosis, outcome (discharge, dropout and death), prescribed antibiotics, dose, frequency, route of administration, duration of treatment and length of hospitalization, also considered as clinical predictors, were classi ed as numerical and categorical. The numerical ones were age, weight, number of antibiotics prescribed and duration of treatment. Categorical variables were gender, medical diagnosis, outcome, dosage, dose, route of administration and length of hospitalization. The variable age was also considered as categorical, where it was categorized into: child (1-3 years), infant (28 days-12 months), preschool (3-5 years) and school (6 -10 years). The variable weight was transformed into categorical: <10, 10 -18.9 and ≥19. The dose was categorized into underdose and overdose, and duration of treatment was transformed into categorical, according to table 1. The variables used to predict the outcome of interest were age, weight, length of hospital stay and number of antibiotics prescribed.

Determining Prescription Errors
The antibiotics used were considered appropriate for the patient, if the dose present in the cardex (medical prescription) was in accordance with their respective weight. Antibiotics were considered inappropriate if the prescribed dose was lower or higher (dose error) than recommended by international guidelines and databases, classi ed overdose and underdose; association of antibiotics of the same class (irrational selection), wrong antibiotic prescription for the disease, dosage error, non-recommended route of administration, wrong duration of antibiotic use. Regarding the dose error, a signi cance level (error margin) of 10% was considered. Prescription doses with an error above 10% were considered overdose, while prescribed doses below 10% were considered underdose. To determine prescription errors, guidelines and international databases, WHO guidelines (27)(28)(29)(30), British National Formulary (BNF) 2019 -2020 were used (31,32). NICE (National Institute for Health and Care Excellence) was used as guidance (33)(34)(35), for both the dose and the dosage and indication of the antibiotic. The indicators used in this study to weight the appropriate or inappropriate use of antibiotics were antibiotic selection, dosage, antibiotic dose and amount of antibiotics prescribed per prescription and duration of treatment.

Data analysis
Descriptive analysis was applied to frequency distribution, measures of central tendency, and variables dispersion (standard deviation). Also, binary logistic regression was used to determine risk factors for inappropriate use (prescription errors) of antibiotics. The Odds Ratio (OR) was applied to determine the chances of inappropriate use of antibiotics occurring with a Con dence Interval (CI) of 95% and p -Value < 0.05 for statistically signi cant differences between the independent variables with the outcome of interest. To verify the collinearity analysis also was performed linear regression.
The analyses were performed in the Microsoft Excel 2019 and SPSS 25.0 software.

Demographic and clinical features of patients
Of the 315 pediatric patients selected for the study, 63.2% were male. The majority (162; 51.4%) had an age between 1 and 3 years. The mean age in months was 30 (Table 3).

Discussion
Antibiotics are the most commonly prescribed drugs, and their use in the pediatric population is a huge concern in some countries (36,37). Today, antibiotic resistance is one of the biggest serious public health problems that has grown through the excessive and inappropriate use of antibiotics, both in humans and animals (38).

Description of antibiotics used
Studies have shown that antibiotics are more used among pediatric patients. This study found a higher prevalence (97.5%) of using these medications. This prevalence converges with that found by Abubakar , followed by gentamicin (14.5%) and ceftriaxone (12.8%) as the most common antibiotics used (42,43). These antibiotic prescribing rates are alarming, being extremely high than those recommended By WHO, which recommends that frequency of antibiotic use in hospitals should be 20.0-26.8%, while injectables (systemic or parenteral) should be 13.4-24.1 % (46). This high use of antibiotics may be due to the range age of patients and the severity of infections and their clinical conditions. It could also be because of the country's limited resources. However, when antibiotics are used unnecessarily and excessively, they can provide a means for the development of antibiotic-resistant microorganisms, which can lead to ineffective treatment, recurrent infections, increased treatment costs or even worse, mortality.  (53). These results are alarming, since the inappropriate use of these drugs constitutes a main issue for the emergence, growth and dissemination of resistant microorganisms. Therefore, the high inappropriate use of antibiotics may be due to the careless or poor judgment of prescribers regarding the proper use (prescription) of these drugs, considering the characteristics of patients and guidelines.

Analysis to determine risk factors for inappropriate use of antibiotics
The study showed that patients prescribed ≥3 antibiotics per prescription are more likely (about 3 times more) to have some inappropriate use of antibiotics than those prescribed an antibiotic, and that patients with a short hospital stay have about 2 times more chances of experiencing some inappropriate use of antibiotics. Iftikhar et al., they found similar results that prescribing three antibiotics or more (OR = 1.7, 95% CI = 1.1-2.1, p-value = 0.020) is a greater risk factor for inappropriate use of antibiotics compared to patients prescribed one antibiotic by medical prescription and, in contrast, these authors found that long hospital stay (OR = 12.5, 95% CI = 10.1-17.6, p-value < 0.001) constitutes a risk factor for experiencing some incorrect use of antibiotics (47). Some reasons may lead prescribers to Recommend three or more antibiotics per prescription, such as an uncertain diagnosis due to the clinician's poor hability to differentiate viral from bacterial infections, non-compliance with guidelines, and poor practice of antibiotic prescribing principles. Meanwhile, the pressure exerted on physicians by family members and guardians of pediatric patients may be a reason for their short hospital stay. However, antibiotics are the widely prescribed therapeutic agents and their use in pediatrics is concern in some countries (54). Antimicrobial resistance is the biggest health problem especially in countries where resources are limited and levels of infectious diseases are high (42,55). The inappropriate use of this class of drugs is one of the major factors for the development of resistant microorganisms. Indeed, interventions on the use of these antibiotics in order to reduce their use taking into account this age group, consequently reducing antimicrobial resistance are necessary. These interventions aim to improve the appropriate use of antibiotics by promoting selection of the best therapeutic regimen, dose, duration of treatment and route of administration, obtaining better clinical results related to the use of antibiotics, reduction of adverse effects, such as toxicity or others, reduction of costs, and limit the selection of resistant microorganisms (54).

Conclusion
Antibiotic use among hospitalized pediatric patients was so prevalent. Most medical prescriptions were inappropriate, in which dosage and duration of treatment were the most frequent errors. Prescription of three or more antibiotics and short hospital stay were the risk factors for inappropriate use of these drugs. These results reveal a concern, as overuse and inappropriate use of antibiotics are a major factor in the development of antibiotic resistant microorganisms. Prioritizing the design and development of new antibacterial agents is not a great strategy to solve this major public health problem around the world, creating or improving policies, programs and methods on the use and dispensing of these drugs must be a priority. Multiple interventions, such as educating both health professionals and the general public about the rational use of antibiotics is essential, through lectures and poster distributions. It is essential to have up-to-date, internal forms and guidelines on the most commonly used antibiotics, which can assist in decision-making on the need to use antibiotics according to the needs of each individual patient.  Figure 1 Antibiotics prescribed among hospitalized pediatrics patients