Community-Acquired Pneumonia (CAP) is one of the most common infectious diseases and remains an important cause of morbidity, high rates of hospitalization, and mortality in children worldwide, especially in children <5 years-old (accounts for 15% of all deaths).1 The empiric antibiotic therapy based on clinical presentation is often used for CAP because the clinical presentation of CAP is often non-specific in young children, and bacterial and viral pneumonia may be clinically indistinguishable.2 Limiting exposure to any antibiotic and identifying the causative organism is very difficult to achieve with antibiotic treatment selects for antibiotic resistance.2 An incidence of 0.29 episodes per child per year and more than 2 million children aged 0 to 5-years die (or a mortality rate of 1.3%‒2.6%) from pneumonia each year, accounting for nearly one-fifth of all deaths among children under the age of five worldwide.3 However, its incidence and mortality rate is significantly higher in developing countries than in the industrialized world (an incidence of 0.05 episodes per child per year). This is likely due to a disproportionate and multifactorial influence on the incidence of CAP in children in developing countries, including vaccine implementation, access to healthcare, nutrition, and living conditions.

Appropriate antibiotic treatment is the main weapon to reduce mortality in children with bacterial pneumonia. In contrast, inappropriate antibiotic use (like overuse of antibiotics, using the wrong dose, using the wrong time, using the wrong combination of antibiotics) contributes to antibiotic resistance, causing many side effects, reducing the effectiveness of the treatment of infections, increasing healthcare costs, and raising the burden on the National Health System.4,5 Besides, the overuse of antibiotics has become a leading health concern in many countries. According to statistics from the European Medicines Agency, it is estimated that there are about 25,000 deaths yearly due to multidrug-resistant bacterial infections and the economic burden of antibiotic resistance is up to €1.5 billion per year.6 In addition, WHO has warned that antibiotic resistance is a major threat to the ability to treat lung infections in the community and in hospitals, causing treatment failure, prolonging hospital stays, and the threat to the patient's life. Antibiotic resistance is predicted to be the cause of approximately 10 million deaths annually by 2050 and cost over $100 trillion worldwide.7 Therefore, promoting rational antibiotic prescribing is a global priority, especially in Asia, where pneumonia in children is a major driver of antibiotic use and access to antibiotics is largely unrestricted.4,8 In addition, recommendations for the use of narrow-spectrum antibiotics as first-line treatment for CAP in both outpatients and hospitalized patients for children over three months of age are reflected in current Vietnamese and international guidelines.9 So, guidelines typically recommend oral amoxicillin as the first-line treatment for non-severe pneumonia.10,11 Moreover, non-severe pneumonia can be managed as an outpatient with a 5-day course of oral antibiotics.12 Despite international recommendations and published evidence supporting this approach, broad-spectrum antibiotics continue to be over-prescribed, and prolonged treatment times create a large financial burden on families.13

The analysis of the current antibiotic use situation is necessary for doctors and managers to develop and implement a strategy for the safe and rational use of antibiotics, which is also a solution to improve the efficiency of the treatment of CAP in children. However, there is a paucity of reports from Vietnam tertiary hospitals on pediatric outpatient prescribing and the rationality of antibiotic prescriptions for CAP. Therefore, the aim of the present study is to review the outpatient prescription status and evaluate the rationality of antibiotic use to treat CAP for children in Vietnam.

The predominant (> 92%) in the 2-month-5-year-old group was found to be similar to many published studies and depicts the higher chances for inappropriate prescribing for younger children exposing them to risks of side effects.14-17 In addition, a male predominance was found in outpatient CAP treatment with a male and female ratio of 1.2:1, similar to some studies.15,18 Furthermore, more than 2,000 pediatric patients (> 50%) were admitted to the general internal ward. Besides, 80.59% (n = 2,865) of children only had pneumonia on outpatient prescriptions and 19.41% (n = 690) of children had recorded pneumonia with other diseases like fever (4.39%, n = 156), asthma (4.14%, n = 147), measles (2.05%, n = 73), upper respiratory tract infection (2.11%, n = 75), and digestive disorders (3.94%, n = 140). However, fever or digestive disorders could be explained by CAP.

The majority (> 50%) of pediatric patients tried home medication before visiting a hospital, especially children living outside Ho Chi Minh City (the largest city in Vietnam). The practice of antibiotic self-medication is a known risk factor for the development of antibiotic resistance.19 This finding is similar to some studies in India and Nigeria with the rate of CAP children of home-based treatment being 80.7% and 75.2%, respectively.20,21 In addition, inappropriate antibiotic use is associated with easy access due to the lack of adequate drug regulatory mechanisms in most countries.22

The majority of pediatric patients fulfill WHO pneumonia criteria, which were supported by a chest radiograph (63.8%), peripheral blood test (33.6%), and C-reactive protein (27.4%) analysis. The majority (74.4%) of cases where antibiotics were prescribed ordered lab investigation for “non-severe” CAP pediatric patients such as chest radiograph, peripheral blood test, and C-reactive protein analysis. Whereas 24.6% of cases were prescribed antibiotics without any lab investigation. Moreover, no pediatric patients are indicated for simple biomarker tests like procalcitonin, cultures, and viral rapid tests to distinguish between viral and bacterial infections, especially in non-severe cases. Therefore, the rate of prescriptions diagnosed with pneumonia with an unknown agent was high (61.5%, n = 2,186). The study results showed that antibiotics were prescribed for outpatient treatment of pneumonia without any confirmed bacterial infection. Before the age of 5-years old, a significant proportion of infections had a viral origin and would not require antibiotics. Although respiratory viruses are the most commonly isolated respiratory pathogens, many doctors are uncomfortable excluding bacterial pneumonia. This may be due to limited experience with WHO pneumonia management guidelines and low rates of pneumococcal vaccination in Vietnam. The diagnostic value of biomarkers and rapid viral tests has limitations, but these tests can help increase appropriate antibiotic use,9 whether to be de-escalated, broadened, stopped, or identify viral etiology in some cases.16,23 Therefore, the designation of rapid viral testing for CAP children should be encouraged to be carried out regularly in hospitals to reduce antimicrobial use in children with non-severe viral CAP.

An increase in antibiotic use in pediatric patients has been found in the outpatient treatment of CAP in Vietnam, similar to that in Italy,16,24 UK,24 Netherlands,24 India,15 Nigeria,14 and Saudi Arabia.25 Two-thirds (> 60%) of CAP prescriptions contained single antibiotics, similar to that reported in Nigeria (71.4%).26 In the single antibiotics prescriptions, amoxicillin contributed the highest percentage share at 66.5% (n = 1,564/2,352) followed by cefuroxime (15.1%, n = 354/2,352), azithromycin (12.8%, n = 300/2,352), and cefpodoxime (4.0%, n = 95/2,352). The β-lactam antibiotics were the most prescribed, accounting for two-thirds of antibiotic prescriptions for outpatient CAP in Vietnam children, especially amoxicillin/ clavulanic acid accounting for about 50% of antibiotic prescriptions. In addition to the broad antimicrobial spectrum, antibiotic costs are also considered in prescribing alternative antibiotics and antibiotic combinations on the essential medicines list in Vietnam. Choosing an oral antibiotic from a system-available formulary reduces costs and the potential for infection if applicable.27 Most guidelines recommend the use of amoxicillin as the first-line antibiotic in non-severe pneumonia unless the patient has an allergy.10,12 It is possible that clinicians are more cautious and prone to prescribe broad-spectrum antimicrobials such as amoxicillin/ clavulanic acid because of the inability to observe the clinical outcome of patients on a daily basis.28 Besides, penicillins, particularly amoxicillin, are cheap, covered by health insurance, and readily available over the counter from community drug outlets. Moreover, high-dose amoxicillin remains an excellent antibiotic choice in pediatric pneumonia cases because Streptococcus pneumoniae isolated from respiratory tract specimens is highly susceptible to penicillins and lowly susceptible to cephalosporins and macrolides in Vietnam.29 These are the main reasons explaining the finding of oral amoxicillin/clavulanic acid as the most common antibiotic from which the prescriptions were made.26 Most published studies have also shown amoxicillin to be the most commonly prescribed antibiotic and the use of broad-spectrum β-lactams is increasing.18

Azithromycin (macrolide) antibiotic is also highly prescribed in about one-third of all outpatient prescriptions, similar to some other studies.30 Meanwhile, one-sixth of outpatient CAP prescriptions contained 2nd and 3rd generation cephalosporin antibiotics. Cefuroxime (2nd generation cephalosporin) and cefpodoxime (3rd generation cephalosporin) were often prescribed in this antibiotic class as standard practice without any disease severity or microbiological consideration. Unfortunately, the use of oral third-generation cephalosporins has shown an upward trend in outpatient treatment in Vietnam, similar to other Asian regions where its use is widespread.29,31 Although there is no proven benefit in CAP children, most doctors generally assume that most children have received antibiotics before going to the hospital and prefer to use broad-spectrum antibiotics.

Moreover, one-third of CAP prescriptions contained two antibiotics, suggestive of a high rate of combination therapy to broaden the spectrum of antimicrobial action. The most common antibiotic combination is amoxicillin/clavulanic acid and azithromycin (76.44% of prescriptions for two antibiotics). The cefuroxime ‒ azithromycin (8.80%) and cefpodoxime ‒ azithromycin (7.68%) combinations are frequently used similarly in other Asian countries.13 These combinations help to extend the antibacterial spectrum to include both typical and atypical bacteria organisms such as Streptococcus pneumoniae, Haemophilus influenzae type b, and Mycoplasma pneumoniae, which are widely considered to be the leading cause of CAP. However, high rates of macrolide resistance recorded in multiple settings suggest futility and unnecessary costs.8 Unfortunately, combination prescriptions have shown an increasing trend in prescribing for CAP in the present study. This means using more antibiotics in a prescription, which can lead to antibiotic resistance, increased side effects, increased risk of harmful drug interactions, dispensing errors, non-adherence to medications, and increased financial costs for families.

On the other hand, the adherence to dose interval prescribing guidelines for antibiotics was found to be higher than for dose in the present study. Amoxicillin/clavulanic acid showed the largest proportion (> 60%) of non-compliance with dose guidelines, emphasizing the need for information on antibiotic use per clinical care setting to direct Antibiotic Stewardship Programs.32 Most children were treated with doses of amoxicillin antibiotic lower than those recommended by national and international guidelines. In Australia, above 50.0% of antibiotic prescriptions were contrary to the guidelines.33 Similar to this study, a high rate of noncompliance in antibiotic prescribing in the outpatient setting has also been demonstrated in many previous studies for respiratory tract infections.34,35 The findings of this study suggest that amoxicillin/clavulanic acid is not only the most frequently prescribed antibiotic in hospital outpatient clinics but also the most common inappropriately prescribed antibiotic for dose guidelines. Resistance of Klebsiella pneumoniae and Escherichia coli to amoxicillin/clavulanic acid has become a significant and clinically relevant problem due to the extensive use of this antibiotic. Fortunately, limiting the use of amoxicillin/clavulanic acid effectively reduces amoxicillin/clavulanic acid resistance.36

In fact, outpatient care is cheaper and safer than hospital admission for children with non-severe pneumonia. The prescribing cost for amoxicillin/clavulanic acid and azithromycin antibiotics was the highest, accounting for 57.15% and 23.00%, respectively due to their high frequency of prescriptions. Besides, the cost of consumption of foreign antibiotics was found to be 9.0 times higher than that of Vietnam antibiotics. The amount and cost of consuming brand-name antibiotics were also found to be 2.0 times higher than that of generic antibiotics if calculated by packaging units. When calculated by dose units, brand-name antibiotics (56.5%, n=13,909) were also prescribed more often than generic antibiotics (46.5%, n=10,729). This may be due to the higher effectiveness of foreign medicine/brand name medicine in pneumonia treatment than Vietnam medicine/generic medicine and the request for better prescriptions containing foreign or brand name medicine from the patient's family. However, it has been established that the risks associated with the use of brand names could increase financial costs for families.37 WHO and DOH have encouraged healthcare facilities to start offering more generic medicine options to give patients better value for money. The optimal percentage of drugs prescribed by the generic name of WHO was 100%. Therefore, many countries around the world have followed the WHO and succeeded in encouraging the use of generic medicine over brand-name medicine. For instance, the prescription rates for generic medicine in Germany, the UK, and UAE were 80.0%, 78.0%, and 100.0%, respectively.38 whereas the prescription rate of generic medicine in Vietnam was found to be low (about 35%) for outpatient CAP treatment of children in this study.

In summary, this retrospective study presents important long-term data in a tertiary pediatric hospital and provides further insight into the outpatient antibiotic treatment of children with pneumonia in Vietnam. Outpatient CAP prescriptions were found more frequently in males than in females and were more commonly prescribed in the age group 0 to 60 months. The antibiotics amoxicillin/clavulanic acid and azithromycin were most frequently prescribed and generally had good guideline adherence rates, except for high non-adherence to the dose guidelines for amoxicillin. Clinicians generally prefer the combination of amoxicillin/clavulanic acid (penicillin) and azithromycin (macrolide) for the treatment of non-severe pneumonia. The proportion of combination antibiotics was found to be high and showed an increasing trend in the outpatient treatment of non-severe CAP in Vietnam. Because all pediatric patients were not assigned bacterial and viral testing for non-severe CAP, clinicians empirically prescribed antibiotics, which is a known risk factor for drug resistance. Moreover, the low prescription rate of generic antibiotics is the main reason for the increase in the patient's treatment costs. Antibiotic treatment (one and two antibiotics), antibiotic class, and antibiotic origin exhibited significant association with rational and irrational antibiotic prescriptions (dose and dose interval) with p-values<0.05. Similarities with previous studies have emphasized that outpatient antibiotic use for CAP should be examined locally.

Tuong Vi Le Thi: Methodology, Supervision, Data curation, Investigation, Formal analysis, Resources, Writing – original draft. Em Canh Pham: Methodology, Supervision, Data curation, Conceptualization, Investigation, Writing – original draft, Writing – review & editing. Doan-Trang Dang-Nguyen: Methodology, Conceptualization, Investigation, Supervision, Writing – review & editing.