Keywords

Antibiotic, Antimicrobial, Containment of resistance, AMR, Appropriate use.

Abbrevations

PHE: Pharmaceutical Expenditure, THE: Total Health Expenditure, CPI: Consumer Price Index.

Introduction

The interventions on use of antimicrobials have remained limited to executive orders and one-time inspections within a clinical and educational framework in China. In addition, most interventions were made with fragmented and vertical approaches rather than integrated strategies with health system perspective. The most fundamental problem is the perverse incentive (in which health care providers rely on the sale of antibiotics to provide care) which distorts the behaviors of health professionals and patients, leading to inappropriate use. There is an urgent need to explore the relationships between necessary incentives (including financial and non-financial approaches) for both providers and patients.

The way antibiotics are used and the control of AMR is a great challenge for China, although our study shows that our project hospitals all had a reduction of antibiotics use and healthcare associated infection rate during 2013-2014. The ongoing national health system reforms create opportunities for China to address this challenge with more comprehensive and integrated strategies to fundamentally change the incentives for appropriate use of antibiotics. The containment of resistance may be achieved through the following four paths: strengthening surveillance at both national, regional and hospital levels; removal of perverse incentives in the health systems; prescription behavior changes with a wider health systems approach to achieve long term, equitable and sustainable results and coordination of stakeholders actions with transparent information sharing.

Bacterial infections are still one of the major diseases in China, and the antimicrobial agent plays a critical role in the health systems. However, antimicrobial resistance has been continuously increased, and has established serious threats to infection control [1].

Anti-Microbial Resistance In China

During 1999 and 2001, the mean prevalence of resistance among hospital-acquired infections was as high as 41% (with a range from 23% to 77%) and that among community- acquired infections was 26% (with a range from 15% to 39%) [2]. The high prevalence of Methicillin Resistant Staphylococcus Aureus (MRSA) has been a major problem in China. The isolate rate of MRSA in clinical settings was between 55%-63% during 2006-2010. The antimicrobial resistance spectrum of MRSA in China is broad, with higher resistance rates to macrolides, clindamycin, aminoglycosides and quinolones [3]. There are significant differences in the prevalence of MRSA among different regions of China. East China has the highest prevalence of 76.9%. The prevalence in large cities like Beijing, Shanghai and Guangzhou is higher than other cities [4-6]. 32.7% of S. aureus isolated from pediatric patients was MRSA, which was about half that seen in adult patients [7].

Among gram-negative bacterials, the resistant rates of non-fermentative bacteria including pseudomonas, acinetobacter and stenotrophornonas to cefoperazone/sulbactam was the lowest, which was 28.86%, 18.53% and 20.85% respectively, the resistant rate of pseudomonas and acinetobacter to imipenem was 33.81% and 22.86% respectively [8]. Since firstly reported in the 1990s, ESBL-producing enterobacteriaceae have spread rapidly in China, particularly after 2000. The prevalence of ESBLproducing E. coli strains varies across different regions of China. Carbapenems are regarded as the last resort against serious Gram-negative bacterial infections. Now carbapenem-resistant bacteria have emerged and spread rapidly.

Drug-resistant rate in nosocomial infection is high, and most are multiple drug-resistance. Antimicrobial agents with enzymeinhibitors are more sensitive than non-enzyme-inhibitors; the resistance has tendency of increasing, especially Acinetobacter baumannii and the third generation cephalosporins.

Anti-Microbial Use In China

The increasing prevalence of antimicrobial-resistance was closely related to the overuse of antimicrobial agents. As Figure 1 and Table 1 [9,10]. Shows, since the early 2000’s, the national pharmaceutical expenditure has always been between 40% and 50% of the national total health expenditure (THE). Even though the consumer price index kept stable, the pharmaceutical expenditure continuously surged during 2000-2013. It was 43.5% in 2006, much higher than that of the median of the lowincome countries defined by the World Bank in the same year (29.5%) and twice the level of the global median (23.1%) [11]. Thirty to fifty percent of the medicines consumed in hospitals are antimicrobials, around 70% of inpatients are treated with antimicrobials. The consumption of antimicrobials and infusions per capita is far higher that of high income countries (HICs) and the severity of inappropriate use of medicines is even more critical in China than in some low income countries [12]. The consumption of antimicrobials in the primary care is even higher. In 2008, 57% of prescriptions in primary care facilities contained antimicrobials, 39% contained infusions, and the average number of medicines per prescription was 3.1. [13]. The levels of these indicators are poorer in China than the global medians obtained by the World Health Organization from a survey conducted in primary care facilities during 1990-2009. These surveys showed a median proportion of prescriptions with antimicrobials of 38.2%, 42.8% and 48.7% in high and upper middle, lower middle, and low income countries, 11%, 15% and 23.2% for infusions, and 2.3, 2.6 and 2.5 for the average number of medicines per prescription [14]. By contrast, when comparing the THE per capita in China with most of the other countries, Chinese patients proportionally spend too much on medicines. In 2011, the THE per capita in China represents US$ 265 at purchasing power parity, less than the global median (US$ 442) and the global average (US$ 899). It is only one-third of the average in upper middle income countries (US$ 830), and 6% of the average in HICs (US$ 4,246) [15]. In 2006, China produced about 210,000 tons of antibiotics, among which 30,000 were exported, 180,000 were consumed domestically. The annual antibiotic consumption per person was about 138g, which is 10 times of that in US [16].

Figure 1: PHE, PHE/THE, CPI in China 2000-2013.

Table 1: National resistant rate of common bacterial pathogens.

Many studies indicated that China had a high prescribing rate of antibiotics, and the most commonly used antibiotics for inpatient care in China were broad-spectrum antibiotics [5,17-20]. Antibiotics have been less frequently prescribed in the Chinese hospitals since 2008 due to continued government efforts in strengthening the regulation during 2002-2011, especially the 2011 nationwide initiative to promote the quality of antibiotic use. The level of total consumption of inpatient dropped to 473 DDD/1000 patient days in 2012 from a high level of 910 DDD/1,000 patient days in 2008. However, in 2012, in Chinese hospitals, there were still 50% of hospitalized patients received antibiotics, the consumption of broad spectrum antibiotics still dominates, the proportion of penicillin’s (J01C) of the total antibiotic use in China was only 11%, and had a continuous decreasing trend since 2008 [21].

Inappropriate use of medicines therefore wastes limited health resources. This brings a huge financial burden to the government, the society, and the individuals, and also carries an implication of certain health risks. In 2005, a study of Public Security Concerns of Irrational Use of Antibiotics estimated that, the additional hospital medicines costs due to inappropriate use of antimicrobial is CNY 21.8 billion (US$ 2.7 billion, exchange rate=8.1), the additional hospitalization costs is CNY 42.0 billion (US$ 5.2 billion), the additional medicines costs and hospitalization costs brought by the resistance due to inappropriate use of antimicrobials is CNY 3.7 billion (US $ 0.5 billion) and 1.3 billion (US $ 0.2 billion) respectively. Conducting a multi factor adjustment, the hospitalization costs of the resistance group is 1.5 times of the sensitive group (non-resistance). Based on the actual mortality rate of the patients with resistant bacterial infections (11.7%) and the average mortality rate of general infections (5.4%), the additional deaths brought by the resistance due to inappropriate use of antimicrobials may be around CNY 489,000 per year for the country as a whole. The productivity loss can be estimated at CNY 4.7 billion (US$ 0.6 billion), and the annual medical costs brought by adverse drug reactions due to inappropriate use of antimicrobials can be estimated at CNY 1.9-9.1 billion (US$ 0.2-1.1 billion) [16].

Comment on the Current Policies in Improving Antibiotic Prescribing and Reducing Resistance

There are two major government agencies regulating the use of antibiotics. The China Food and Drug Administration (CFDA) is responsible for the registration, production and distribution. The National Health and Family Planning Commission (NHFPC) is responsible for the clinical use, pharmacy and infection control in health facilities. To promote the appropriate use of medicines, the Chinese government introduced and implemented a series of regulations and strategies, including requests to retail pharmacies to sell antimicrobials only with prescriptions in 2003 [22] and developing clinical pathways, standard treatment guidelines and clinical use guideline of antibiotics and other medicines in 2004 [23]. The national antimicrobials clinical use and resistance monitoring network was created in 2005 to collect, analyze and report routine data from tertiary hospitals [24]. Prescriptions was formally regulated in 2007 [25]. and pharmacy administration in health facilities was further strengthened in 2011 [26]. A national medicines use monitoring network was set up in 2009 to collect medicines use data from the secondary health facilities, and to recommend interventions for improving medicines use [27]. Antimicrobials to be stocked and used in different levels of health facilities were clearly defined and the national targets of antimicrobial clinical use were set in 2012 [28].

Although there have been numerous policies issued for improving medicines use during the past ten years, and national medicines use monitoring networks and a national expert committee for quality use of medicines have been in place for some time, the problem of inappropriate use of medicines is yet unresolved. In 2010, among the top 20 adverse drug reaction reports of allopathic western medicines, 15 are from anti-infectious medicines; the top-three are levofloxacin, azithromycin, and ceftriaxone; 73.6% of the adverse drug event reports are infusions [29] indicating the severity of inappropriate use of infusions (often with antibiotics). The proportion of national pharmaceutical expenditure to the total national health expenditure was still 40.3%, [30]. with the average proportion of outpatient and inpatient medicines cost still at 50.7% and 43.4% of expenditure of public hospitals [31]. This is an unacceptably high level.

The main reason for the lack of success in improving appropriate prescribing is that intervention strategies have remained limited to executive orders and one-time inspections within the scope of clinical educational interventions. The pharmaceutical sector is a complex sector, with many stakeholders and different interests involved. Policy interventions on medicines use by any one actor will impact the behavior of others. Because of the special nature of the sector, a case-by-case solution targeting an individual problem often fails to achieve the expected result, as the goals of individual policies may be somewhat inconsistent or even mutually conflicting. Moreover, the interests of different entities often interfere with each other. Fragmented and vertical approaches rather than integrated strategies with health system perspectives, a lack of association between clinical and social sciences, or neglecting the behavior characteristics of prescriber and patients, will never solve the problem of inappropriate medicine use effectively and sustainably. The perverse incentives in Chinese health system distort the behaviors of health professionals and intensify inappropriate use of antimicrobials. A wider health systems approach is needed to achieve long term, equitable and sustainable results. It is urgent to explore the relationships between necessary incentives (including financial and non-financial approaches) for both providers and patients in changing their behaviors of using medicines.

Challenges to Reduce Resistance

According to the study of global antibiotic consumption [32] the worldwide antibiotic use rose a staggering 36 percent (from 54,083,964,813 standard units to 73,620,748,816 standard units) between 2000 and 2010. The BRICS countries — Brazil, Russia, India, China and South Africa, with 41% of the world population in 2010 [33] are responsible for more than three-quarters of that surge. Followed by India, China was the second largest consumer of antibiotics in the world in 2010. 57% of the increase in the hospital sector of BRICS countries was attributable to China.

The rapid growth of the economy enabled China to achieve universal health coverage in 2012 [34] which greatly secured the access to medicines including antibiotics of the Chinese people. However, this also brought the problem that many broad spectrum antibiotics are sold over the counter without presence of a documented clinical need, although there is a regulation officially issued, but unfortunately not implemented rigorously. Moreover, the official guideline for clinical use of antimicrobials was just developed, and evidence-based use is yet widely accepted by health professionals, reversely, following the opinions of the senior colleagues is the common practice [35]. Comparing with hospital care in urban areas, primary care and rural areas face even more challenges because of lack of qualified health professionals and poor access to information as well as less development of economy. Irrational use problems at primary care and rural areas may result increasing number of resistance problem in higher care. In addition, accompanied with the rapid economic development, the increasing travel and migration also contributes to the growth of that nation's resistance problem.

Most importantly, the Chinese health system has been suffering from perverse financial incentives, which intensifies inappropriate use of antimicrobials. These perverse incentives include inappropriate government subsidy approaches (limited resources focus on tertiary hospitals and infrastructure constructions, most other public health facilities depend on medicines sales to generate funding), distorted pricing policies (the level of medical service price is controlled far below the real cost by the government, while the levels of large scale medical equipment diagnosis, medical supplies and brand medicines are set by the government with much higher price than the real cost, which induced health providers to over prescribe expensive medicines and diagnostic tests rather than to provide quality and cost-effective care [36]. Other major problems include the conflict between insufficient public resources and the resource exhausted fee-for-service provider payment mechanism, [37] the unsound medicines procurement mechanisms without appropriate incentives for facilities to procure low-priced medicines, and a “reversed-proof” responsibility for medical disputes which encourages a defensive, high-prescription attitude of doctors [38].

Path to Reduce Resistance in the Future Four Pillars

Strengthening surveillance at different levels

National level: In responding to the World Health Assembly (WHA) resolutions which urged member states to formulate measures to promote appropriate and cost-effective use of antibiotics [39]. the Ministry of Health of P.R. China (MoH, now named as National Health and Family Planning Commission, NHFPC) committed to strengthen the surveillance of antimicrobial clinical use and resistance. In 2005, two national monitoring networks were established by MoH for the above purposes respectively. 35 tertiary hospitals joint the networks at the beginning, and expanded to 1,427 hospitals (including both tertiary and secondary hospitals) by the end of 2014. These two monitoring networks regularly collect, consolidate, summarize, analyze the antimicrobial clinical use and resistance data, established national databases for routine monitoring and evaluation, provide feedback to member hospitals, and report to the MoH periodically. A set of standardized indicators and methods for data collection were developed by the national monitoring network. An electronic data reporting system was developed by the national monitoring network as well, which enables online reporting of data by hospitals, and dissemination of standardized methods for data collection and reporting to local levels, and plays as a platform for information sharing across all levels of monitoring and evaluation.

Regional level: Until the end of 2014, each province has established its provincial monitoring network for monitoring the antimicrobial clinical use and resistance. For some areas, there are also some regions established cross city sub-provincial monitoring networks, which have been greatly strengthening the monitoring and evaluation, and contributing to the policy informing at local levels

Hospital level: According to the national campaign on improving use of antibiotics [40] all tertiary and secondary hospitals are required to conduct self-monitoring and evaluation of antimicrobial clinical use and resistance. A set of national targets were also set by the NHFPC, and disseminated to all tertiary and secondary hospitals. Specific targets include: the proportions of OP prescriptions and IP medical records with antibiotics<20% and <60% respectively; all antibiotic prophylaxis should be given before incision (except cesarean); the proportions of antibiotic prophylaxis during generally<24 hours (except specific conditions); and the total IP consumption of antibiotics for systemic use (J01)<400 DDD/1,000 inpatient days. Trainings were organized in each tertiary and secondary hospital to help clearly understand the specific requirements, targets, and strategies to achieve the targets.

Removal of perverse incentives in the health systems

The ongoing national health system reform has been creating an opportunity to address the perverse incentives in the Chinese health systems. The top decision makers are clearly committed to remove medicines revenue as a major source of financing for health facilities. The financing model of public hospitals has been shifting from generating revenue through selling medicines to providing quality services through market competition. The distort pricing system of medical service and medicinal products has been changing towards a value-based pricing and a price negotiation mechanism to replace the former cost-plus price setting methods. Health insurance programs are required to develop innovative strategies to create incentives for the appropriate use of medicines. These measures include: expanding coverage to both inpatient and outpatient services; increased diagnosis, treatment and dispensing fees to make up for the loss of medicine sales revenue; changing payment methods from retrospective fee-for-service to prospective capitation-based and case based mixed payments; and supporting polices to secure the quality of care, including the appropriate use of medicines.

Prescription behavior changes

Prescription behavior is determined by a variety of internal and external, social, economic and cultural factors. The effectiveness of interventions on prescribing depends to a large degree on the content, delivery mechanisms, intensity, and context and implementation environment. Interventions on medicines use can be put into several categories, including clinical educational, managerial, financial and regulatory measures [41,42]. Effective interventions are always broad-based with multiple dimensions, adapted to a particular situation, and addressing local barriers to change. No single intervention can be recommended for all behaviors in any setting [43-46]. Simple restriction of use did not lead to scientifically sound and cost-effective use of antibiotics. The general dislike of basic and cheaper antibiotics like penicillins and other narrow scope antibiotics seems deeply rooted. Clinical educational interventions, even linked to managerial measures, were obviously not enough to counteract the deep-rooted perverse incentives. Rather than simple restriction of use, more sophisticated and comprehensive policies are needed when hospital financing is heavily dependent on medicines sales, and prescribers themselves also gain additional income from dispensing or selling medicines.

In many resource-poor Low and Middle Income Countries where health systems are not appropriately funded and regulated, economic factors can be important barriers to compliance with guidelines [47]. How health care is financed and how health care providers are paid substantially affects treatment decisions, because the financing mechanisms create different incentives for health care providers [48]. New and more sophisticated financing mechanisms have needed with units of payment becoming broader, and prices for bundles of services set on a prospective basis [49,50].

Coordination of stakeholders and information sharing

Coordination and information sharing could provide an up-to-date overview of the present situation of ABR. Increased collaboration between networks will make it increasingly important to share experiences; shared experience will form the basis of coordinated collaborations to change antibiotic prescription behaviors. In addition, surveillance systems need to be flexible and adaptable to emerging resistance, so that they are not restricted to monitoring what is already known. Surveillance systems should also be able to deliver information promptly to avoid any delay in public health actions at both local and national levels.

Final brief conclusion

Use and resistance of antibiotics in Chinese public hospitals is a great challenge for China. The ongoing national health system reforms create opportunities for China to address this challenge with more comprehensive and integrated strategies to fundamentally change the incentives for appropriate use of antibiotics and containment of resistance. Use of data; proposal for china top level “one health principle”.

Funding Source

This work was supported by the Strategic Prosperity Fund of the British Foreign Commonwealth Office [14SS1].

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