In this retrospective study, 75 primary care institutions in Guizhou Province were selected to describe the prescription patterns of antibacterial drugs among children in 2020. Overall, the rate of antibiotic prescriptions was highest in the fourth quarter, followed by the first quarter. Among the antibiotics prescribed, penicillins and cephalosporins were the most used antibiotics groups. The most common childhood diseases were the diseases of the respiratory system (86.8%), followed by diseases of the digestive system (6.0%) and diseases of the skin and subcutaneous tissue (2.1%). Overall, 80.5% of antibiotic prescriptions were inappropriate. Physicians with lower professional titles and more than 40 years of work duration were relatively more likely to prescribe inappropriate antibiotics.
In this study, acute upper respiratory infections of multiple and unspecified sites (J06, 58.7%) and acute tonsillitis (J03, 13.7%) were the most common upper respiratory diseases for which antibiotics were administered in children, accounting for 72.4%. A study from China reported an antibiotic prescription rate for acute upper respiratory tract infections in children of 77.6% while in other countries reported rates ranged from 28.7% (Japan) - 76.2% (Albania) [30,31,32,33,34]. However, the Guidelines for the Clinical Application of Antibiotics in China , Practical Diagnosis and Treatment of Pediatric Diseases  and the United States CDC  state that acute upper respiratory tract infections are the most common community-acquired infections, most commonly caused by viruses such as rhinoviruses, coronaviruses, and influenza viruses. The course of disease is generally self-limited and does not require antibiotic treatment. Treatment of symptoms if often the best form of care, especially in children, and symptoms usually subside within a few days.
Therefore, in Table 1, J06 (Acute upper respiratory infections of multiple and unspecified sites) does involve prescription of all antibiotics need not be used (U: unnecessary use). For J03 (Acute tonsillitis), penicillin is preferred in more severe cases where bacterial infection is suspected (e.g., tonsillitis caused by streptococcus) (P: preferred medication). Cephalosporins, macrolides, and quinolones also can be used. If lincosamides, aminoglycosides and nitroimidazoles were used, the antibiotic spectrum is incorrect (I: incorrect spectrum of antibiotics).
Lower respiratory tract infections, which include acute bronchitis (15.2%) and bronchitis, not specified as acute or chronic (4.8%), was the second most common childhood disease class in our study. Studies in China , Japan  and France  found that antibiotic prescription rates for bronchitis were 10.9%, 11.9% and 14.6%, respectively. However, for bronchitis, it should be clear whether it is viral infection or bacterial infection. Viral infection without antibiotics. Suspected bacterial infection can be used penicillin intramuscular injection or oral cephalosporin . Therefore, in Table 1, J20 (Acute bronchitis) shows that all antibiotics need not be used (U: unnecessary use). For J40 (Bronchitis, not specified as acute or chronic), penicillins, cephalosporins, macrolides and quinolones shown antibiotic can be used or substituted (A: antibiotic can be used or substituted). If lincosamides, aminoglycoside, nitroimidazole were used, the antibiotic spectrum is incorrect (I: incorrect spectrum of antibiotics).
The use of antibiotics for acute upper respiratory tract infections of multiple and unspecified sites (J06) or acute bronchitis (J20) is inappropriate because it may trigger allergies, infections, and even endanger the child’s life . This scenario likely to lead to ABR in children. The use of antibiotics in children is more likely to kill susceptible strains, leading to proliferation of resistant strains and replacement of susceptible strains, resulting in a sharp increase in drug resistance of bacteria .
In this study, the number of children diagnosed with acute otitis media and urinary tract infections was lower than other studies [37, 40]. Although otitis media usually occurs in children, otoscopy is necessary for a definitive diagnosis. Primary care institutions have the lowest testing capacity in China. They have no instrument to examine the inner ear canal. Most primary physicians also have no expertise in otorhinolaryngology. Patients with ear, nose and throat problems are referred to superior hospitals. In addition, in this study, we only analyzed systemic antibiotic prescriptions, excluding local antibiotic prescriptions such as ear drops. This may indirectly lead to low prescriptions for otitis media. For urinary tract infection, most primary care institutions are general outpatient departments, and primary physicians do not have professional knowledge of urinary system diagnosis and treatment. If a child develops symptoms of urinary tract infection, most patients will go to the specialized outpatient clinic of a superior hospital.
Overall, the unnecessary use of antibiotics occurred in all 10 systemic disease classifications in the study, accounting for 63.6% of all antibiotic prescriptions. This included diseases of the respiratory system (J06, J39, J00, J31, J20, J98, J21), diseases of the digestive system (K52, K30, K13, K08, K14, K59, K11, K92), diseases of the skin and subcutaneous tissue (L08, L23, L04, L30, L24, L50, L70), symptoms, signs and abnormal clinical and laboratory findings not elsewhere classified (R10, R05, R59, R50, R04, R07, R51, R22, R21, R11), injury, poisoning and certain other consequences of external causes (T14, T11), diseases of the genitourinary system (N39, N48), diseases of the circulatory system (I88, I84, I67), diseases of the ear and mastoid process (H65, H61), certain infectious and parasitic diseases (B00, A08, B08), and diseases of the eye and adnexa (H02). It should be noted that the 10 sub-diseases under symptoms, signs and abnormal clinical and laboratory findings not elsewhere classified (R10, R05, R59, R50, R04, R07, R51, R22, R21, R11) were all diseases for which antibiotics are unnecessary. The rate of inappropriate antibiotics use for these diseases often reached 100%. When treating such childhood diseases, physicians should make specific clinical diagnoses based on typical signs and symptoms [17, 28]. It is particularly important to stress that when physicians suspect a child has severe pneumonia according to typical signs and symptoms, the child should be transferred to a superior hospital in a timely manner . According to National Health Commission of China for Guiding Principle of Clinical Use of Antibiotics introduced in 2015, there is a very limited range of antibiotics suitable for use by those aged 18 years and under . Physicians should be more cautious about prescribing antibiotics for children as widespread use could exacerbate ABR.
We also found from those antibiotic prescriptions with incorrect spectrum of antibiotics accounted for 2.4% of all antibiotic prescriptions. Except for the systemic disease of symptoms, signs and abnormal clinical and laboratory findings not elsewhere classified, the other 9 systemic diseases all had the condition of incorrect spectrum of antibiotics. Diseases of the eye and adnexa had the highest proportion of incorrect spectrum of antibiotics (37.0%). The proportion of incorrect spectrum of antibiotics was highest in the sub-disease (keratitis) of diseases of the eye and adnexa (97.8%). Penicillins, cephalosporins, macrolides, lincosamides and nitroimidazoles are the incorrect spectrum of antibiotics for these particular diseases. According to Ophthalmology Clinical Guidelines of American Academy of Ophthalmology (2nd edition) , Ophthalmology of China (9th edition)  and National Health Commission of China for Guiding Principle of Clinical Use of Antibiotics introduced in 2015 , quinolones and aminoglycosides are the preferred medication treatment of keratitis treatment, especially in children.
In our study, “Incorrect spectrum of antibiotics” (2.4%) and “Combined use of antibiotics” (2.4%) were the two types of inappropriate antibiotics use that accounted for the least proportion. The proportion of “Incorrect spectrum of antibiotics” in this study was low, mainly because the proportion was distributed differently among different diseases. For example, the proportion for keratitis and acute myocarditis was more than 75% of cases. The low inappropriate rate of “Combined use of antibiotics” was primarily due to the absence of diseases such as tuberculosis, leprosy or other diseases requiring combination therapy in primary care institutions . In addition, we used a very strict definition of drug combinations: more than one systemic antibiotic by injection or oral administration at a time by an outpatient physician without any indication. Previous studies [44,45,46] have raised the issue of antibiotic combinations. Therefore, even if the numbers are low, “Incorrect spectrum of antibiotics” and “Combined use of antibiotics” are still a non-negligible problem in antibiotic prescription overuse.
In our study, the majority of inappropriate antibiotic prescriptions were prescribed by physicians older than 40 years, with lower professional titles (resident physician / attending physician) and more than 40 years of work duration. Their education was mostly non-undergraduate, and their professional knowledge and experience are often inadequate. Based on this result, it may be necessary to provide refresher courses in antibiotic prescribing for these primary care physicians [47, 48]. Training should emphasize avoiding incorrect and unnecessary use of antibiotic prescriptions in children.
In this study, children insured by new rural cooperative medical system were more likely to be prescribed inappropriate antibiotics than those who had to pay fully out-of-pocket. One possible reason is that many antibiotics in China are included in the National Essential Medicine List . The children enrolled in the new rural cooperative medical system can use these antibiotics for free or partially free. This increases the risk of inappropriate use of antibiotics. Therefore, it is necessary to educate the physicians and patients about the dangers of inappropriate use of antibiotics, so as to establish a correct concept of medication.
The proportion of antibiotics prescribed inappropriately was higher in the third and fourth quarters compared to the first quarter of the year. This may be due to the higher incidence of infectious diseases in autumn and winter . However, most of treated patients were diagnosed with viral infectious diseases.
We also found that inappropriate antibiotic prescriptions in children may be correlated with sex of children. This may be related with the fact that left-behind children in rural areas of China are often cared for by poorly educated grandparents, as well as sex discrimination. In addition, children aged 0–1 were more likely than any other age group to be prescribed inappropriate antibiotics. In our team’s preliminary survey of primary care institutions in Guizhou Province, we found that the educational level of child caregivers was low and were unaware of the dangers of antibiotic resistance. They generally believe that antibiotics are a panacea. However, infants have an immature immune function, weak anti-infection ability, and are prone to various diseases . In order to heal infants as quickly as possible, the caregivers often ask the physicians for prescriptions of antibiotics . This may increase the risk of inappropriate antibiotic use in the infants. Therefore, more information about antibiotic use, such as easy-to-understand brochures and learning videos, should be provided to caregivers of children.
In China, during the COVID-19 pandemic in 2020, the National Health Commission noted that primary care institutions had the lowest level of access and treatment conditions than secondary and above hospitals. Therefore, they were not eligible for COVID-19 treatment. All suspected febrile patients are transferred to a secondary or higher-level hospital for treatment. Therefore, there were no febrile patients in outpatient clinics of primary care institutions. No COVID-19 related patients were seen in this study.
Our study has several limitations. First, the study subjects in primary care institutions may not fully represent the general population of children in China. Second, the time frame of the survey was limited to 1 year, thus we could not judge whether the prevalence of pediatric diseases and antibiotic use differed over several years [53, 54]. Third, the primary care institutions in Guizhou Province generally do not do laboratory testing; the physicians give drugs by experience. Therefore, we cannot find relevant content for further analysis in HIS system. Fourth, due to being unable to obtain more etiological information, the clinical pharmacists in our team can only assume that “the cause of acute pharyngitis and acute tonsillitis is Group A Hemolytic Streptococcus infection (GABHS)”. Hence, the unnecessary use antibiotics may be underestimated.