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Research Article: Meta-Analysisof Observ Studies in Epidemiology

A Systematic Review of Antibiotic Prescription Associated With Upper Respiratory Tract Infections in China

Li, Jing MS; Song, Xingyue MPH; Yang, Tingting MS; Chen, Yawen MS; Gong, Yanhong PhD; Yin, Xiaoxv PhD; Lu, Zuxun MD, PhD

Editor(s): Esposito., Susanna

Author Information
doi: 10.1097/MD.0000000000003587



Overuse of antibiotics is a serious public health problem worldwide, which not only results in waste of healthcare resources but also leads to the development of antibiotic resistance.1–4 The most common condition associated with excessive use of antibiotics is upper respiratory tract infections (URTIs). Etiological studies suggest that the main cause of URTI is virus; only less than 10% of URTI cases are caused by bacteria, which require antibiotic treatment.5 Therefore, the percentage of URTI cases prescribed antibiotics has been used as a key indicator for assessing overuse of antibiotics.6 The World Health Organization (WHO) has been using this indicator to systematically review the use of antibiotics for URTI cases.7–9 In a report entitled, Medicines Use in Primary Care in Developing and Transitional Countries, the WHO estimated that the percentage of URTI cases prescribed antibiotics increased over time from 43% to 71% during the 1982 to 2006 period,10 despite systematic that reviews have shown that antibiotics are of limited effectiveness in the treatment of URTI.11

China is one of the countries with severe abuse of antibiotics.12 Many studies have been conducted on the overuse of antibiotics in China. However, there are few articles were published in English, and most of these studies were published in Chinese. Because of the limited publication in English literature, global antibiotic researchers have not appreciated the relevant data from China.13 For example, the 2004 World Medicines Situation Report stated that reliable data about antibiotic utilization in the large pharmaceutical market of the world's most populous country, the People's Republic of China, were in short supply.7 This is not conducive to a comprehensive understanding of the global antibiotics usage and to a comparative analysis between research results from China and those from other countries. In view of this, we conducted a meta-analysis about the use of antibiotics in China in 2013 and found that 50.3% of Chinese outpatients were prescribed 1 or more antibiotics.14 Recently, the number of studies published in English about antibiotic utilization in China has been increasing;14–17 however, such studies have not been extended to particular diseases or conditions. Our current meta-analysis focuses on the use of antibiotics for URTI outpatients in China, for which the overuse is most prevalent worldwide.


We conducted the meta-analysis according to the Meta-analysis of Observational Studies in Epidemiology guidelines.18

Search Strategy

To identify relevant studies, we searched 4 Chinese biomedical databases and PubMed up to December 31, 2014. The 4 Chinese databases are the China National Knowledge Infrastructure, WANFANG database, VIP Information/Chinese Scientific Journals database, and Chinese Biomedical Literature database. We searched the Chinese databases using the following terms (in Chinese): “antibiotic,” “antibacterial,” “anti-infective/anti-infection,” “rational drug use,” “prescription,” “upper respiratory infection,” “acute upper respiratory infections,” “acute nasopharyngitis,” “acute sinusitis,” “acute pharyngitis,” “acute tonsillitis,” “acute laryngitis,” “acute tracheitis,” “acute obstructive laryngitis,” “acute epiglottitis,” “common cold,” or “acute laryngotracheitis.”

PubMed was searched using the following terms: ((antibacterial[Title/Abstract] OR antibiotic[Title/Abstract] OR antimicrobial[Title/Abstract] OR antibiotics[Title/Abstract]) AND (Upper respiratory tract infections[Title/Abstract] OR Acute upper respiratory tract infections[Title/Abstract] OR Acute nasopharyngitis[Title/Abstract] OR Acute sinusitis[Title/Abstract] OR Acute pharyngitis[Title/Abstract] OR Acute tonsillitis[Title/Abstract] OR Acute laryngitis[Title/Abstract] OR Tracheitis[Title/Abstract] OR Acute obstructive laryngitis[Title/Abstract] OR Epiglottitis[Title/Abstract] OR Cold[Title/Abstract])) AND (China[Title/Abstract] OR Chinese[Title/Abstract]) AND (“humans”[MeSH Terms] AND English[lang]).

Identification of relevant studies was accomplished by 1 researcher and checked by 2 other researchers. First, we examined the titles and abstracts yielded by searching bibliographic databases. Then, we retrieved and examined the full publications of possibly relevant studies for inclusion or exclusion. In addition, lists of references of the extracted articles were reviewed, and relevant studies were extracted and added into the meta-analysis.

Inclusion and Exclusion Criteria

Observational studies, published in Chinese or English before December 31, 2014 were included, and the theme of published research should be the percentage of URTI outpatients prescribed antibiotics in Mainland China. The site must be hospital outpatient departments, community health service centers, or township hospitals. A study would be included; if it have used the WHO/International Network for the Rational Use of Drugs (INRUD) methods and followed the guideline to determine what antimicrobial agents could be counted as antibiotics for prescribing indicators analysis, which was recommended by WHO.19 In addition, the study should have the following information: study site, enrolment time, the total number of sampled outpatient encounters with URTI, the total number of outpatient antibiotic encounters with URTI, the number of outpatient encounters with URTI with 1 antibiotic, and the number of outpatient encounters with URTI with 2 antibiotics and with more than 2 antibiotics. For duplicate publications of the same study, we included the version published first or published in English. Conference abstracts, review articles, and data from regions of China other than the Mainland (Hong Kong, Macao, and Taiwan) were excluded.

Quality Assessment of Included Studies

We assessed the methodological quality of the included studies according to the WHO/INRUD methods and United States Agency for International Development (USAID) methods.19,20 Six criteria in the quality assessment were defined as follows:

  1. Whether a study gave the definition which drugs to be considered as antibiotics according to the WHO/INRUD indicator methodology.
  2. Whether the sample size was adequate. According to the survey methods on “How to Investigate Antimicrobial Use in Hospitals: Selected Indicator,” which were recommended by the USAID, the number of prescribing encounters should be ≥100 in any retrospective or prospective study.
  3. Whether the study gave a definition of URTI.
  4. Whether a study described the data collection methods. For instance, data may be collected retrospectively or prospectively.
  5. Whether the statistical methods were eligible according to the WHO/INRUD indicator methodology.
  6. Whether the study period was appropriate. According to the survey methods on “How to Investigate Antimicrobial Use in Hospitals: Selected Indicators,” which were recommended by the USAID, antimicrobial assessments should cover 12 consecutive months to ensure that any seasonal variations are taken into consideration.

Each criterion was assigned 1 point if a study met a WHO or USAID recommendation. The qualities of the included studies were assessed by 2 independent reviewers. Studies that scored 5 or higher were considered as high quality, 3 or 4 as moderate quality, and 2 or lower as low quality. The results of quality assessment are shown in Supplemental Digital Content-Table 1,

Data Extraction

The following data from each included study were extracted: first author, year of publication, enrolment time, sample size (number of URTI outpatients), the total number of URTI outpatients who were prescribed antibiotics, and the number of URTI outpatients who were prescribed 1, 2, and more antibiotics. We also extracted data on study designs, settings, and regions.

Statistical Analysis

Following standard meta-analysis methodology, we obtained summary rates of URTI outpatients who were prescribed 1, 2, and 3, or more antibiotics. Subgroup analyses were conducted by hospital type, geographical area, and study period. Studies were divided into 3 geographical regions: western, central, and eastern China. Chinese hospitals are divided into 3 levels, level 1 (1–100 beds), level 2 (101–500 beds), and level 3 (>500 beds), according to size, technology, equipment, and management level. Level 3 hospitals are the highest level with the best medical technology and equipment, while level 1 hospitals include community health service centers and township hospitals. All these hospitals have outpatient departments in addition to hospital wards.

Statistical analyses were conducted using R-3.1.3 statistical software package. Meta-analyses were conducted using Logit transformed proportions and the pooled estimates were back-transformed to ordinary proportions.21 Heterogeneity across the studies was evaluated by using the Q statistic and I2 statistic.22 For publication bias, we used Egger's weighted regression methods to assess. Pooled rates were calculated with 95% confidence interval (CI) using random-effects model.

Ethical Review

We have submitted the study design to “the Research Ethics Committee in Huazhong University of Science and Technology, Wuhan, China”. As the data this study needed have been published and can be freely accessed, the Research Ethics Committee considered that our study does not need Ethics Committee review.


Figure 1 shows the process of study selection and inclusion. In the end, 45 articles met the inclusion criteria, and all were published in Chinese. The main characteristics of the included studies are shown in Supplemental Digital Content-Table 2, and Supplemental Digital Content-Table 3, Of these studies, 18 were scored as high-quality studies, 24 moderate-quality studies, and 3 low-quality studies. Both of the overall and subgroup analyses were all observed significant heterogeneity (P < 0.001). The Egger's test result showed that there may be a publication bias (P < 0.001).

Flow diagram of study identification.

Figure 2 reports the percentages of URTI cases prescribed antibiotics from the studies included. Table 1 shows the pooled percentage of the URTI outpatient who were prescribed antibiotics. The overall average was 83.7% (95% CI: 80.6%–86.4%). Table 1 further shows that the percentages of antibiotics prescription for URTI vary substantially by level of hospital, geographic area, and study period. The proportion of URTI cases prescribed antibiotics was on average 76.7% in level 3 hospitals, 84.8% in level 2 hospitals, and 91.1% in level 1 hospitals. The reported antibiotic prescriptions of lower-level hospitals were much higher than higher-level hospitals, and the differences between hospital levels were statistically significant (P = 0.0009). Antibiotic prescription for URTI outpatients in western region (83.9%) and central region (86.6%) was higher than that in the eastern China (82.3%), but no statistically significant differences were found among geographical regions. The percentages of antibiotic prescription for URTI outpatients showed a downward trend, with the percentage of antibiotics before 2008 being statistically significantly higher than that in the subsequent years (P < 0.001).

Forest plot of reported percentage use of antibiotics with URTI in China. One included study (a034-Wenji Luo) was divided into 2 different subgroups in groupwise analysis, and the other one (a083-Manqing Gui) was divided into 3 different subgroups in groupwise analysis.
Percentage of URTI Outpatients Prescribed Antibiotics

Table 2 shows that of the URTI outpatients prescribed antibiotics in China, 79.7% were prescribed 1 antibiotic, 18.4% prescribed 2 antibiotics, and 1.1% prescribed 3 or more antibiotics. The proportion of URTI outpatients with 1 antibiotic prescribed in central (87.3%) and eastern (78.5%) China was higher than that in western (69.6%) China, the proportion of URTI outpatients with 2 antibiotics prescribed in central (11.7%) and eastern (19.4%) China was apparently lower than that in western (28.1%) China, while the proportion of URTI outpatients with 3 and more antibiotics prescribed was 1.3% in the eastern region, 0.5% in the central region, and 1.4% in the western region, though no statistically significant differences between the regions were detected. Level 3 and level 2 hospitals had significantly higher proportions of URTI outpatients with 1 antibiotic prescribed (P < 0.001), a lower proportion of URTI outpatients with 2 antibiotics prescribed (P < 0.001) and with 3 or more antibiotics (P = 0.012) than level 1 hospitals.

Percentage of URTI Outpatients With Antibiotic Prescription Prescribed 1, 2, or More Antibiotics


Based on data from 45 studies that included a total of 52,072 URTI outpatients, this systematic review found that the proportion of URTI cases prescribed antibiotics in China was 83.7%. Although no international standard has been established for the antibiotic prescription for URTI outpatients, the European Surveillance of Antimicrobial Consumption (ESAC) recommended that the proportion of antibiotic use with URTI should be 0%–20% in 2011.23 Studies elsewhere reported that the percentage of URTI cases prescribed antibiotics was 24.2% in the United States,24 40% in East Asia,10 and 45% in India.25 The percentage of URTI cases prescribed antibiotics in China is much higher than the recommended level and those in other countries. Our meta-analysis presents unequivocal evidence that there is substantial over-prescription of antibiotics for URTI patients in China.

Our meta-analysis also revealed that over-prescription of antibiotics is a more serious problem in China's primary care institutions (level 1 hospitals). Clinicians in level 3 hospitals usually have a higher educational levels and better training than those in lower-level hospitals,14 and recognize better the importance of rational use of antibiotics.26,27 In addition, economic incentives may induce clinicians to prescribe antibiotics excessively, and the incentives are expectantly stronger among primary care clinicians since drug prescriptions filled is a major sources of income for them.28 The higher rate of antibiotic prescription for URTI outpatients by primary care clinicians may be explained by a combination of lack of sufficient training and stronger economic incentives. As the primary healthcare centers in China cover a large number of patients, and URTIs are one of the most common health conditions encountered by primary care workers, the excessive use of antibiotics in primary healthcare causes a waste of health resources and the development of antibiotic resistance. Therefore, it is necessary to take measures to control the overuse of antibiotics for URTI cases in primary healthcare facilities in China.

It is worth noting that the percentages of URTI outpatients prescribed antibiotics in China showed a downward trend, which might be associated with the Chinese health authority's recent effort to curb the excessive use of antibiotics. In 2010, the Ministry of Health of China released a ruling, Prescription Management and Evaluation Standards in Clinical Practice. In April 2012, a regulation on the Management Method for Clinical Use of Antimicrobials was issued by the Ministry of Health of China, which established a hierarchical management system for antimicrobials use in clinical practice. The regulation clearly stated the rules for selection, procurement, clinical use, surveillance and early-warning, and intervention and withdrawal of antimicrobial use in healthcare facilities, which was implemented since August 1st, 2012.29 The regulation imposes restrictions on physicians’ antibiotics prescribing behaviors and asks them to prescribe antimicrobials judiciously based on the comprehensive assessment for the symptoms and blood and urine test results of patients.30 These guidelines may have reduced the overall antibiotic usage and usage for URTI in China. However, the percentage of URTI cases prescribed antibiotics in China is still at a very high level. It is imperative that greater efforts are needed to further promote rational use of antibiotics. In addition, although the difference of the percentage of URTI outpatients prescribed antibiotics between the regions was not significant, the combined prescription rate of antibiotics in the western region is high. This should attract the attention of the health administrative department.

This study conducted a comprehensive analysis of antibiotic prescription associated with URTI in China by the method of meta-analysis. However, certain limitations of this study should be noted. Firstly, the heterogeneity across studies was significant and the observed heterogeneity could not be explained by the available data. Secondly, the Egger's test result indicated that the publication bias could not be ruled out. In spite of these limitations, we think that the present study is important to reveal the prevalence of antibiotic utilization for URTI in China. Additionally, all the articles included in this review were retrospective studies. More prospective studies measuring the prescribing indicators are warranted to more accurately investigate the antibiotics utilization for URTI in China.


The percentage of URTI patients who were prescribed antibiotics in China is extremely high and the overuse is especially problematic in lower-level hospitals. Although our analysis shows a downward trend, likely attributable to China's recent efforts in curbing excessive antibiotic use, more measures are needed to promote the rational use of antibiotics, especially among primary health-care institutions.


1. WHO. Antimicrobial Resistance: A Global Threat. 2000; Accessed April 25, 2016.
2. Levy SB, Marshall B. Antibacterial resistance worldwide: causes, challenges and responses. Nat Med 2004; 10:S122–S129.
3. Malhotra-Kumar S, Lammens C, Coenen S, et al. Effect of azithromycin and clarithromycin therapy on pharyngeal carriage of macrolide-resistant streptococci in healthy volunteers: a randomised, double-blind, placebo-controlled study. Lancet 2007; 369:482–490.
4. Costelloe C, Metcalfe C, Lovering A, et al. Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis. BMJ 2010; 340:c2096.
5. Gwaltney JM. Mandell GL B, Bennett JE, Dolin REBT Principles and Practice of Infectious Disease. The common cold. 4th ed.New York: Churchill Livingstone; 1995. 561–566.
6. WHO. Using Indicators to Measure Country Pharmaceutical Situations. 2006; Accessed April 25, 2016.
7. WHO. The World Medicines Situation 2004. 2004; Accessed April 25, 2016.
8. WHO. The World Medicines Situation 2011. 2011; Accessed April 25, 2016.
9. WHO. The World Drug Situation 1988. 1988; Accessed April 25, 2016.
10. WHO. Medicines Use in Primary Care in Developing and Transitional Countries. 2009; Accessed April 25, 2016.
11. Arroll B. Antibiotics for upper respiratory tract infections: an overview of Cochrane reviews. Respir Med 2005; 99:255–261.
12. Li Y. China's misuse of antibiotics should be curbed. BMJ 2014; 348:g1083.
13. Kunin CM. Use of antimicrobial drugs in developing countries. Int J Antimicrob Agents 1995; 5:107–113.
14. Yin X, Song F, Gong Y, et al. A systematic review of antibiotic utilization in China. J Antimicrob Chemother 2013; 68:2445–2452.
15. Dong L, Yan H, Wang D. Drug prescribing indicators in village health clinics across 10 provinces of Western China. Fam Pract 2011; 28:63–67.
16. Jiang Q, Yu BN, Ying G, et al. Outpatient prescription practices in rural township health centers in Sichuan Province, China. BMC Health Serv Res 2012; 12:324.
17. Li Y, Xu J, Wang F, et al. Overprescribing in China, driven by financial incentives, results in very high use of antibiotics, injections, and corticosteroids. Health Aff (Millwood) 2012; 31:1075–1082.
18. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283:2008–2012.
19. WHO. How to investigate Drug Use in Health Facilities: Selected Drug Use Indicators - EDM Research Series No. 007. 1993: Accessed April 25, 2016.
20. NSAID. How to Investigate Antimicrobial Drug Use in Hospitals_ Selected Indicators. 2008; Accessed April 25, 2016.
21. Williams JG, Higgins JP, Brayne CE. Systematic review of prevalence studies of autism spectrum disorders. Arch Dis Child 2006; 91:8–15.
22. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ 2003; 327:557–560.
23. Adriaenssens N, Coenen S, Tonkin-Crine S, et al. European Surveillance of Antimicrobial Consumption (ESAC): disease-specific quality indicators for outpatient antibiotic prescribing. BMJ Qual Saf 2011; 20:764–772.
24. Stone S, Gonzales R, Maselli J, et al. Antibiotic prescribing for patients with colds, upper respiratory tract infections, and bronchitis: a national study of hospital-based emergency departments. Ann Emerg Med 2000; 36:320–327.
25. Kotwani A, Holloway K. Antibiotic prescribing practice for acute, uncomplicated respiratory tract infections in primary care settings in New Delhi, India. Trop Med Int Health 2014; 19:761–768.
26. Sun X, Jackson S, Carmichael GA, et al. Prescribing behaviour of village doctors under China's New Cooperative Medical Scheme. Soc Sci Med 2009; 68:1775–1779.
27. Currie J, Lin W, Zhang W. Patient knowledge and antibiotic abuse: evidence from an audit study in China. J Health Econ 2011; 30:933–949.
28. Reynolds L, McKee M. Factors influencing antibiotic prescribing in China: an exploratory analysis. Health Policy 2009; 90:32–36.
29. Chen Z. Ministry of Health of China. Report on the Management of Clinical Use of Antimicrobials in China. 2012; Accessed April 25, 2016.
30. China Imposes Regulation to Fight Antibiotics Abuses. 2012.–08/01/content_26086915.htm. Accessed April 25, 2016.

Supplemental Digital Content

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