Investigation of Amoxicillin Use in Fever Clinic Patients: Standardized Application of Antibiotics is Still Challenging

Abstract

Amoxicillin is widely used by the Chinese population and available in pharmacies without prescription. We performed a retrospective study on patients with fever who took amoxicillin before going to the fever clinic of the Second Affiliated Hospital of Nanchang University from March 1, 2020 to March 31, 2021. Among the total of 9093 patients attending the fever clinic, 446 patients had a history of taking amoxicillin, from which 100 cases were randomly selected to evaluate the therapeutic effects of non-prescribed amoxicillin by changes in clinical symptoms, counts of white blood cells, neutrophils, and lymphocytes, and levels of C-reactive protein (CRP). The control group consisted of 100 randomly selected patients for who it was verified that they did not take antibiotics before attending the fever clinic. Our study showed that there were no significant differences between the group of patients taking amoxicillin and the control group in terms of symptom improvement, white blood cell, neutrophil or lymphocyte counts, or the levels of CRP. Therefore, our study indicated that although non-prescribed amoxicillin is widely used among patients with fever, it does not provide significant beneficial therapeutic effects. There is still a long way to go to standardize the application of antibiotics and popularize knowledge on proper antibiotics use among the population.

Amoxicillin has been a widely prescribed antibiotic in primary care settings since the 1970s. It is a semisynthetic penicillin with enhanced activity against a variety of Gram-positive and Gramnegative bacteria, such as Streptococcus species, Listeria monocytogenes, Clostridium species, and Escherichia coli.^1,2 In China, almost every pharmacy sells amoxicillin without the need for a prescription, which brings great convenience to people, but also poses striking challenges to keeping development of drug resistance under control.^3,4 Here, we investigated the clinical impact of non-prescribed amoxicillin usage in patients before attending the fever clinic of the Second Affiliated Hospital of Nanchang University from March 1, 2020 to March 31, 2021. We aimed to understand the basic situation of amoxicillin usage to provide support for the prevention and control of antibiotic abuse.

According to medical records, a total of 9093 patients went to the fever clinic of the Second Affiliated Hospital of Nanchang University from March 2020 to March 2021. Investigation of amoxicillin usage in these patients showed that 446 patients (4.9%) admitted taking amoxicillin and no other antibiotics before going to the fever clinic. Among these patients, 100 cases were selected by adopting a simple random sampling method for further investigation. As the control group, another 100 cases were randomly selected with the same method from patients who did not take any antibiotics. Clinical manifestations, including febrile symptoms, signs, laboratory tests, amoxicillin usage, and primary diagnosis, were included in the statistics to compare the amoxicillin and control groups. Medical laboratory data were collected, including a complete blood cell count (white blood cells, neutrophils, lymphocytes) and C-reactive protein (CRP) levels. All medical laboratory data were generated from the Department of Clinical Laboratory of the Second Affiliated Hospital of Nanchang University. As shown in Table 1, more than half of the patients were initially diagnosed with upper respiratory tract infections, and the duration of amoxicillin use was basically similar as the duration of fever. Patients from the amoxicillin group and the control group displayed no marked differences in terms of age, sex, and symptoms, including the duration of fever, temperature, chills, cough, expectoration, swelling of tonsils, acute pharyngeal discomfort, gastrointestinal distress, and urinary tract discomfort. In laboratory tests, there were no significant differences between the groups in counts of total white blood cells, neutrophils and lymphocytes, or the levels of CRP. Besides the primary diagnoses of upper respiratory tract infections (59%), lung infections (11%), acute gastroenteritis (9%), and urinary tract infections (5%) were also common. There was no significant difference in the primary diagnosis between the amoxicillin group and the control group. The pathogenesis of upper respiratory tract infections involves complex interactions between bacterial and viral pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, respiratory syncytial virus, Bocavirus and Adenovirus, and the host inflammatory responses.⁵ Therefore, it is inappropriate to choose oral amoxicillin therapy or other antibiotics without evidence of etiology, or blood routine and inflammatory markers. Our data indicates that amoxicillin is extensively used by the investigated population at an alarming rate, while it does not achieve the aimed antiinfective effects.

Table 1 - Baseline characteristics and laboratory findings of 200 patients

Basic characteristics and laboratory findings			All patients (n = 200)	Amoxicillin group (n = 100)	Control group (n =100)	P value
Age, years			32 (25, 45)	29 (19, 47)	25 (21, 45)	0.38
Sex
	Women		95 (47%)	46 (46%)	49 (49%)	-
	Men		105 (53%)	54 (54%)	51 (51%)	-
Course of amoxicillin, days			-	2.2 (1.0, 3.8)	-	-
Signs and symptoms
	Duration of fever, days		2.6 (4.8,18.3)	3.1 (1.0, 5.4)	2.2 (1.0, 3.7)	0.28
	Temperature, °C
		37.3-38.0	70 (35%)	22 (22%)	48 (48%)	-
		38.1-39.0	88 (44%)	51 (51%)	37 (37%)	-
		>39.0	42 (21%)	27 (27%)	15 (15%)	-
	Chills		42 (21%)	27 (27%)	15 (15%)	0.29
	Cough		85 (43%)	45 (45%)	40 (40%)	0.74
	Expectoration		72 (36%)	42 (42%)	30 (30%)	0.42
	Swelling of tonsil		43 (22%)	28 (28%)	15 (15%)	0.30
	Acute pharyngeal discomfort		131 (66%)	62 (62%)	69 (69%)	0.57
	Diarrhea		27 (14%)	12 (12%)	15 (15%)	0.50
	Stomachache		11 (6%)	7 (7%)	4 (4%)	0.11
	Nausea		13 (7%)	6 (6%)	7 (7%)	0.52
	Vomiting		9 (5%)	4 (4%)	5 (5%)	0.70
	Frequent micturition, urgent urination and/or odynuria		6 (3%)	3 (3%)	3 (3%)	0.86
Laboratory findings
	White blood cell count, × 109/L		9.5 (5.8, 12.7)	9.4 (6.0, 13.1)	9.6 (5.7, 11.6)	0.72
	Neutrophil count, × 109/L		8.5 (4.1, 9.9)	9.5 (3.7, 10.1)	7.2 (4.3, 8.9)	0.47
	Lymphocyte count, × 109/L		1.5 (0.9, 1.8)	1.5 (0.9, 1.8)	1.4 (0.9, 1.9)	0.35
	C-reactive protein, mg/L		26.1 (2.3, 38.3)	21.0 (5.5, 38.9)	11.8 (0.5, 15.7)	0.06
Primary diagnosis
	Upper respiratory infection		118 (59%)	53 (53%)	65 (65%)	0.32
	Lung infection		21 (11%)	13 (13%)	8 (8%)	0.07
	Acute gastroenteritis		17 (9%)	7 (7%)	10 (10%)	0.45
	Urinary tract infection		10 (5%)	6 (6%)	4 (4%)	0.50
	Others		34 (17%)	21 (21%)	13 (13%)	0.17

Categorical data were summarized as frequencies (%) and compared by x² test or Fisher exact test between groups when applicable. Continuous variables were described as median and interquartile range (IQR) values and compared with the Mann-Whitney U test. All analyses were performed with GraphPad Prism 8 (GraphPad Software, UK). Differences with P < 0.05 between group means were considered statistically significant.

Overall, our study highlights the extensive use of amoxicillin among fever patients, while therapeutic effects appear unsatisfactorily. This phenomenon is probably associated with the following reasons: (1) Amoxicillin is a well-known and inexpensive antibiotic, which is available in almost every pharmacy in China and can be purchased under a real-name registration system, even without a prescription. In addition, many Chinese families keep a supply of medicines, including antibiotics, in case of an emergency. (2) Having been used extensively for many years, the rate of amoxicillin resistance has increased significantly. For example, the reported frequency of amoxicillin resistance was 85.7% for Salmonella isolates, while E. coli and Staphylococcus aureus displayed resistance to amoxicillin in more than 13% and 90% of the isolates, respectively.^6,7 (3) The use of amoxicillin was inappropriate because either the course of treatment was of insufficient length or dose, or this antibiotic was not recommended to target the specific etiological agent of the infection. An antibiotic treatment course usually takes 3-7 days. However, our data indicated that the median time of amoxicillin usage in this study was 2.2 days, which was short in course and therefore might limit the therapeutic effect of the antibiotic. Furthermore, pathogens of upper respiratory tract infections are complex.⁵ When people purchase medicines in pharmacies, they may get unsuitable antibiotics due to limited knowledge and a lack of necessary pathogen evidence.

In summary, irregular use of antibiotics is still a serious problem. Standardized application of antibiotics not only needs to be carried out in hospitals, but also needs to be supervised in clinics and pharmacies. Therefore, it is imminent to educate the public about the scientific application of antibiotics.

Acknowledgments

The authors thank the patients for complying with the epidemic regulations and going to the fever clinic.