Date Published: February 5, 2019
Publisher: Public Library of Science
Author(s): Xiaolin Wei, Zhitong Zhang, Joseph P. Hicks, John D. Walley, Rebecca King, James N. Newell, Jia Yin, Jun Zeng, Yan Guo, Mei Lin, Ross E. G. Upshur, Qiang Sun, Zirui Song
Abstract: BackgroundInappropriate antibiotic prescribing causes widespread serious health problems. To reduce prescribing of antibiotics in Chinese primary care to children with upper respiratory tract infections (URTIs), we developed an intervention comprising clinical guidelines, monthly prescribing review meetings, doctor–patient communication skills training, and education materials for caregivers. We previously evaluated our intervention using an unblinded cluster-randomised controlled trial (cRCT) in 25 primary care facilities across two rural counties. When our trial ended at the 6-month follow-up period, we found that the intervention had reduced antibiotic prescribing for childhood URTIs by 29 percentage points (pp) (95% CI −42 to −16).Methods and findingsIn this long-term follow-up study, we collected our trial outcomes from the one county (14 facilities and 1:1 cluster randomisation ratio) that had electronic records available 12 months after the trial ended, at the 18-month follow-up period. Our primary outcome was the antibiotic prescription rate (APR)—the percentage of outpatient prescriptions containing any antibiotic(s) for children aged 2 to 14 years who had a primary diagnosis of a URTI and had no other illness requiring antibiotics. We also conducted 15 in-depth interviews to understand how interventions were sustained.In intervention facilities, the APR was 84% (1,171 out of 1,400) at baseline, 37% (515 out of 1,380) at 6 months, and 54% (2,748 out of 5,084) at 18 months, and in control facilities, it was 76% (1,063 out of 1,400), 77% (1,084 out of 1,400), and 75% (2,772 out of 3,685), respectively. After adjusting for patient and prescribing doctor covariates, compared to the baseline intervention-control difference, the difference at 6 months represented a 6-month intervention-arm reduction in the APR of −49 pp (95% CI −63 to −35; P < 0.0001), and compared to the baseline difference, the difference at 18 months represented an 18-month intervention-arm reduction in the APR of −36 pp (95% CI −55 to −17; P < 0.0001). Compared to the 6-month intervention-control difference, the difference at 18 months represented no change in the APR: 13 pp (95% CI −7 to 33; P = 0.21). Factors reported to sustain reductions in antibiotic prescribing included doctors’ improved knowledge and communication skills and focused prescription review meetings, whereas lack of supervision and monitoring may be associated with relapse. Key limitations were not including all clusters from the trial and not collecting returned visits or sepsis cases.ConclusionsOur intervention was associated with sustained and substantial reductions in antibiotic prescribing at the end of the intervention period and 12 months later. Our intervention may be adapted to similar resource-poor settings.Trial registrationISRCTN registry ISRCTN14340536.
Partial Text: Preventing the development of antimicrobial resistance is a global policy priority. Overuse of antibiotics directly promotes development of antimicrobial resistance . The largest cause of inappropriate antibiotic use comes from treating respiratory infections, which are also the most common reason for primary care consultations . This challenge is most pressing in low- and middle-income countries (LMICs), where commonly 80% of upper respiratory tract infections (UTRIs), which are mostly viral, are inappropriately treated with antibiotics  compared to around 20% of URTIs in high-income countries (HICs) . Interventions aimed at both clinicians and patients/caregivers have been shown to be more effective than those aimed at only one group . Only 16 randomised trials trying to reduce inappropriate antibiotic prescribing for URTIs have been conducted worldwide, and most in LMICs had limitations in trial design and assessment. The duration of two well-designed trials in LMICs were shorter (14 days  and 6 months ) than those in HICs (generally 12 months) [8–10]. The effect sizes achieved were around a 25 percentage point (pp) reduction in antibiotic prescribing in LMICs [6,7] compared to around 10 pp in HICs [8–10], mainly because the baseline level of antibiotic prescribing was much higher in LMICs. Studies examining the sustained effects of trial interventions are rare: only two were conducted in HICs and reported sustained trial intervention effects [11,12]. In LMICs, primary care doctors are poorly trained, receive much lower pay, and see substantially more patients per day compared with their peers in HICs , while antimicrobial stewardship is weak . Sustained evidence on interventions that work for a long term in these settings is urgently needed.
Our study is reported here as per the CONSORT extension (S1 CONSORT Checklist) for cluster trial guidelines , with the abstract reported as per the CONSORT guidelines for reporting randomised trials in journal and conference abstracts . We obtained ethical approval from the University of Leeds School of Medicine Research Ethics Committee (MREC15-016), the Guangxi Institute Review Boards at the Guangxi Autonomous Region Centre for Disease Control and Prevention (CDC) (GXIRB2014-0036), and Shandong University (20151102) for the trial and follow-up study.
We followed up all 14 facilities (seven intervention and seven control) in Rong county at 6 and 18 months after the intervention was implemented. At baseline, out of 88,845 prescriptions issued in the intervention arm, 6,112 (6.8%) were eligible for inclusion in the study, and in the control arm, 3,523 out of 60,885 (5.4%) prescriptions were eligible. At 6 months in the intervention arm, 5,094 out of 93,380 (5.5%) prescriptions were eligible, and in the control arm, 3,982 out of 65,233 (6.1%) prescriptions were eligible. At 18 months in the intervention arm, 5,084 out of 91,215 (5.6%) prescriptions were eligible, and in the control arm, 3,685 out of 69,939 (5.3%) prescriptions were eligible (Fig 1). We found that patient and doctor characters were well balanced across the three periods with a modest (>10%) imbalance in payment methods, doctor’s years of work, and diagnosis (acute pharyngitis and laryngitis) (Table 1). Our primary outcome sensitivity analysis that included diagnosis as a covariate indicated no substantive differences from the adjusted analysis excluding diagnosis (S4 Table), and so we did not include diagnosis in any other analyses and only discuss the primary outcome results from the main adjusted analysis. Additionally, for some covariate-adjusted analyses of prescribing outcomes, the preferred GEEs failed to converge, and we had to use less preferred forms of the GEEs (Table 2). However, for all crude analyses, the preferred GEEs converged, and as the results differed little between the covariate-adjusted and crude analyses (S2 Table), the covariate-adjusted results from the less preferred forms of the GEEs appear robust.
To our knowledge, our study is the first to investigate the post-trial sustainability of an antimicrobial stewardship programme in a resource-poor setting. Our main finding is that our comprehensive intervention, which targeted doctors and caregivers, was associated with a substantial reduction in antibiotic prescribing 18 months after implementation, or 12 months after all trial-directed intervention activities stopped. At both 6 months (the trial endline) and 18 months (12 months after the trial-directed intervention period) compared to baseline, our intervention achieved a clear reduction in antibiotic prescribing (in the one county for which we had data) that was much higher than what has been reported in previous similar trials (albeit in HIC settings) [8,10]. However, although there was no statistically significant change in antibiotic prescribing between 6 months and 18 months, we would not expect the improvements to be fully sustained over this and longer time periods in the absence of any further intervention-related inputs.
We found that, in one county of the trial sites, the benefits of our antimicrobial stewardship programme on antibiotic prescribing were well maintained 18 months after implementation, or 12 months after trial-led activities finished. This indicates that effects may be sustained for interventions including evidence-based guidelines, peer-review meetings, improved doctor–patient communications, and the provision of concise education to caregivers during consultations, in similar settings. However, although there was no statistically significant change in the APR after trial activities ceased, it is of course expected that, without further intervention-related inputs, the improvements in antibiotic prescribing would decline. This study implies that this type of intervention may be successful in other LMICs with similar challenges.